Clinical trial NCT04784897
Conditions: COVID-19
Keywords: SARS-CoV-2 coronavirus Brilacidin COVID-19
Sponsor: Innovation Pharmaceuticals, Inc.
Start date: 2021-02-22; Completion date: 2021-07-30
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Brilacidin IV infusion, 3 days and up to 5 days, in addition to Standard of Care arm 2: Placebo IV infusion, 3 days and up to 5 days, in addition to Standard of Care
Interventions: intervention 1: Brilacidin intervention 2: Placebo intervention 3: Standard of Care (SoC)
Intervention descriptions: intervention 1: Brilacidin IV infusion intervention 2: Placebo IV infusion intervention 3: SoC therapies for COVID-19

Protocol documents:
Prot_000.pdf: 
CLINICAL PROTOCOL 
IPI-BRIc-201 
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 
Document type: 
Clinical Protocol - Amended 
Version number: 
1.2 
Version date: 
24-Dec-2020
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential.             
This information may not be used, published or disclosed without prior written approval from 
Innovation Pharmaceuticals Inc. 
NCT04784897


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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................... 2 
AMENDMENT RATIONALE AND REVISIONS ............................................................... 6 
PROTOCOL SYNOPSIS ........................................................................................................ 8 
LIST OF ABBREVIATIONS ............................................................................................... 19 
1. INTRODUCTION AND BACKGROUND ...................................................................... 21 
1.1. Disease Overview .......................................................................................................... 21 
1.2. Background of Brilacidin............................................................................................... 22 
1.2.1. Proposed Therapeutic Properties in COVID-19 ...................................................... 22 
1.3. Nonclinical and Clinical Studies with Brilacidin .......................................................... 24 
1.3.1. Nonclinical Studies .................................................................................................. 24 
1.3.2. Clinical Studies ........................................................................................................ 31 
1.4. Dose Rationale ............................................................................................................... 37 
1.4.1. Safety Profile for Selected Doses ............................................................................ 38 
1.4.2. Vital Signs Measurements during Study Treatment ................................................ 41 
1.4.3. PK/PD Modeling of Antiviral Efficacy Parameters for Selected Doses ................. 42 
2. STUDY OBJECTIVES AND ENDPOINTS .................................................................... 45 
3. STUDY OVERVIEW ........................................................................................................ 47 
4. STUDY POPULATION .................................................................................................... 50 
4.1. Inclusion Criteria ........................................................................................................... 50 
4.2. Exclusion Criteria .......................................................................................................... 50 
5. STUDY TREATMENT ..................................................................................................... 53 
5.1. Treatment Allocation ..................................................................................................... 53 
5.2. Subject Numbering ........................................................................................................ 53 
5.3. Treatment Blinding ........................................................................................................ 54 
5.4. Emergency Unblinding of Treatment ............................................................................ 54 
5.5. Investigational Product Supplies ................................................................................... 54 
5.5.1. Description .............................................................................................................. 54 
5.5.2. Storage Conditions .................................................................................................. 55 
5.5.3. Packaging and Labeling .......................................................................................... 55 
5.5.4. Dose Preparation ..................................................................................................... 55 
5.5.5. Administration of Prepared Dose ............................................................................ 56 
5.6. Investigational Product Handling and Accountability ................................................... 56 
5.7. Return of Clinical Supplies ............................................................................................ 57 
6. THERAPIES AND MEDICATIONS ............................................................................... 58 
6.1. Concomitant Medications and Concurrent Procedures ................................................. 58 
6.1.1. Concomitant Medications to be used with caution ................................................. 58 
7. STUDY PROCEDURES .................................................................................................... 60 


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7.1. Subject Demographics/Other Baseline Characteristics ................................................. 60 
7.1.1. Informed Consent .................................................................................................... 60 
7.1.2. Demographics .......................................................................................................... 60 
7.1.3. Medical History ....................................................................................................... 60 
7.2. Study Treatment ............................................................................................................. 60 
7.3. Efficacy Assessments .................................................................................................... 61 
7.3.1. Clinical Status .......................................................................................................... 61 
7.3.2. National Early Warning Score 2 (NEWS2) ............................................................ 61 
7.3.3. In-Hospital Outcomes .............................................................................................. 63 
7.4. Other Assessments ......................................................................................................... 63 
7.4.1. SARS-CoV-2 virus testing ...................................................................................... 63 
7.4.2. Biomarkers .............................................................................................................. 64 
7.4.3. Drug Concentration Measurements (Pharmacokinetic Assessments) ..................... 65 
7.4.4. Recording Concomitant Medications and Concurrent Procedures ......................... 65 
7.5. Safety Assessments ........................................................................................................ 66 
7.5.1. Physical Exam, Height and Weight ......................................................................... 66 
7.5.2. Vital Signs and Respiratory Status .......................................................................... 66 
7.5.3. Laboratory Evaluations ........................................................................................... 67 
7.5.4. Electrocardiogram (ECG) ........................................................................................ 68 
7.5.5. Recording Adverse Events (AEs) ............................................................................ 69 
7.6. Individual Subject Discontinuation ............................................................................... 69 
7.6.1. Study treatment discontinuation and study discontinuation .................................... 69 
7.6.2. Withdrawal of informed consent ............................................................................. 70 
7.6.3. Lost to follow-up ..................................................................................................... 71 
7.7. Study Stopping Rules .................................................................................................... 71 
7.8. Early Study Termination by the Sponsor ....................................................................... 71 
8. SAFETY MONITORING ................................................................................................. 72 
8.1. Adverse Events .............................................................................................................. 72 
8.1.1. Definitions ............................................................................................................... 72 
8.1.2. Severity of Adverse Events ..................................................................................... 73 
8.1.3. Causality of Adverse Events ................................................................................... 74 
8.1.4. Immediate Reporting of Serious Adverse Events (SAEs) ....................................... 74 
8.1.5. Adverse Events of Special Interest/ Blood Pressure category reporting ................. 75 
8.1.6. Data Monitoring Committee ................................................................................... 77 
8.2. Reporting Pregnancy/Study Drug Exposure During Pregnancy.................................... 77 
9. STATISTICAL METHODS ............................................................................................. 79 
9.1. Sample Size Considerations .......................................................................................... 79 
9.2. Interim Analyses/ Data Monitoring Committee Reviews.............................................. 80 
9.3. Definitions of Study Populations for Analysis .............................................................. 81 
9.4. Handling of Missing Data .............................................................................................. 81 
9.5. Baseline Characteristics and Demographic Variables ................................................... 81 
9.6. Efficacy Analysis ........................................................................................................... 81 
9.6.1. Primary Endpoint Analyses ..................................................................................... 81 
9.6.2. Secondary and Exploratory/ Other Endpoint Analyses ........................................... 82 


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9.6.3. Sensitivity Analyses ................................................................................................ 82 
9.7. Safety Analysis .............................................................................................................. 82 
10. SITE MONITORING AND QUALITY ASSURANCE ............................................... 84 
10.1. Site Monitoring ............................................................................................................ 84 
10.2. Quality Assurance ........................................................................................................ 84 
11. RECORDS MANAGEMENT ......................................................................................... 85 
11.1. Data Collection ............................................................................................................ 85 
11.2. Records Retention ........................................................................................................ 85 
12. ETHICS ............................................................................................................................. 86 
12.1. Regulatory and Ethical conduct ................................................................................... 86 
12.2. Responsibilities of the Investigator and IRB/IEC........................................................ 86 
12.3. Informed Consent Procedures ...................................................................................... 86 
12.4. Publication of Study Protocol and Results .................................................................. 87 
13. PROTOCOL ADHERENCE AND AMENDMENT .................................................... 87 
13.1. Protocol Adherence...................................................................................................... 87 
13.2. Protocol Amendment Policy ........................................................................................ 88 
14. REFERENCES ................................................................................................................. 89 
 
List of Tables 
Table 1: 
Schedule of Activities ........................................................................................... 17 
Table 2: 
Serious Adverse Events reported in Clinical Trials with Brilacidin by intravenous 
administration ........................................................................................................ 33 
Table 3: 
Median (mix, max) Brilacidin Plasma Pharmacokinetic Parameters derived in 
Study PMX63-203 (IV dosing) ............................................................................. 34 
Table 4: 
Median (mix, max) Brilacidin Plasma Pharmacokinetic Parameters derived in 
Study CTIX-BRI-204 (IV dosing) ........................................................................ 35 
Table 5: 
Adverse Events summary for Study CTIX-BRI-204 (Safety Population) ............ 38 
Table 6: 
Treatment-Related Adverse Events in Study PMX63-203 (Safety Population) ... 39 
Table 7: 
Mean Systolic Blood Pressure Effects in Study PMX63-203 (Safety Population)40 
Table 8: 
Number of Patients meeting Blood Pressure Criteria in the ABSSSI Program, by 
Study (Safety Population) ..................................................................................... 41 
Table 9: 
Objectives and Related Endpoints ........................................................................ 45 
Table 10:  List of Clinical Substrates for CYP2C8, CYP2C9 and CYP3A P450-mediated 
metabolism ............................................................................................................ 59 
Table 11: Clinical Status 8-point Ordinal Scale .................................................................... 61 
Table 12: National Early Warning Score 2 (NEWS2) .......................................................... 62 
Table 13:  Clinical Laboratory Testing (local) ....................................................................... 68 
Table 14:  CTCAE Details for Adverse Events of Special Interest ....................................... 76 


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List of Figures 
Figure 1:  Brilacidin, a 3-in-1 Combination of Therapeutic Properties ................................. 24 
Figure 2:  Pre-Treatment Efficacy of Brilacidin against SARS-CoV-2 ................................ 27 
Figure 3:  Inhibitory Dose-Response assessment of Brilacidin on SARS-CoV-2 virus 
multiplication in Calu-3 cells ................................................................................ 28 
Figure 4:  Assay Method Variation and Efficacy of Brilacidin Against SARS-CoV-2 in Vero 
cells ....................................................................................................................... 29 
Figure 5:  Efficacy of Brilacidin in combination with Remdesivir against SARS-CoV-2 .... 29 
Figure 6:  PK/PD model simulation: Brilacidin 3 days multiple dose, 0.6 mg/kg (D1), 0.3 
mg/kg (D2 and D3) ............................................................................................... 43 
Figure 7:  PK/PD model simulation: Brilacidin 5 days multiple dose, 0.6 mg/kg (D1), 0.3 
mg/kg (D2 to D5) .................................................................................................. 44 
Figure 8:  Study Design Schematic ....................................................................................... 47 
 
 
 


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AMENDMENT RATIONALE AND REVISIONS 
AMENDMENT 2, 24 December 2020 
Amendment Rationale 
The purpose of this amendment is to address feedback from FDA received with IND approval 
for this study to proceed, and to fix minor protocol discrepancies that have been identified. 
The study has not yet started. This amendment does not alter the patient population eligibility 
criteria. 
Changes to the Protocol 
Changes made to the protocol, are summarized as follows: 
• Addition of hematology, blood chemistry and coagulation safety laboratory tests on 
Study Day 2. 
• Added dose regimen as covariate (if expanded after DMC recommendation) to the 
analysis of the primary efficacy endpoint time to sustained recovery through Day 29. 
• Text added to emphasize respiratory swab sample collection is to be pre-dose on 
dosing days; efforts are to be made to allow for swabs to be collected at approximately 
the same time each collection day throughout the study. 
• Dose calculation for a subject’s study treatment infusions will be based on actual body 
weight measured at Screening. 
• Text added to clarify that blood samples for PK assessments are to be drawn from an 
alternate site other than the arm used for the study treatment infusion. 
Changes to specific sections of the protocol are shown in the Tracked Changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
AMENDMENT 1, 04 November 2020 
Amendment Rationale 
The purpose of this amendment was to address feedback from FDA received on the draft 
protocol during the pre-IND process, and to fix minor protocol discrepancies that had been 
identified. 
Changes to the Protocol 
Changes made to the protocol, are summarized as follows: 


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• Inclusion criterion update: edit made to moderate COVID-19 respiratory rate ≥ 20 to 
< 30 breaths per minute. 
• Exclusion criteria updates: addition of extracorporeal membrane oxygenation (ECMO) 
at the time of randomization to exclusion criterion #2; addition of moderate hepatic 
impairment to exclusion criterion #8; specifying male condom use throughout the 
study and for up to 30 days after stopping treatment. 
• Primary endpoint: altered to time to sustained recovery through Day 29; censoring of 
subjects who die or who are lost to follow-up after/before achieving recovering prior 
to Day 29 updated. 
• Replacement of Study Management Committee by an independent Data Monitoring 
Committee (DMC). The DMC will review safety data summaries and listings. 
• Adverse Events of Special Interest (AESIs): edited to include paresthesias / 
dysesthesias. 
• Individual subject discontinuation details altered, identifying that should study 
treatment discontinuation occur that scheduled efficacy and safety assessments should 
continue, unless a subject withdraws consent or is lost to follow-up. 
• Study stopping criteria added. 
• Additional follow-up visit, by telephone contact, included at Day 60. 
• Additional assessment included: an ECG post-infusion on Day 1. 
 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Innovation Pharmaceuticals Inc. 
Name of Finished Product: Brilacidin  
Name of Active Ingredient: Brilacidin tetrahydrochloride 
Study Number: IPI-BRIc-201 
Title of Study:   
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 
Study Centers: Approximately 15 
Number of Subjects Planned: 
Approximately 120 hospitalized participants with COVID-19 
Study Duration per subject:  
Each subject will complete the study in about 60 days, from screening at Day -1 or 1 to 
follow-up on Day 60 ±10 days 
Phase of Development: Phase 2 
Purpose and rationale:  
The purpose of this study is to evaluate the efficacy and safety of Brilacidin intravenous (IV) 
treatment in addition to current standard of care (SoC) compared with SoC alone in 
participants with moderate to severe COVID-19 
Primary Objective(s): 
• 
To evaluate the clinical efficacy of Brilacidin IV treatment in addition to SoC, 
compared with SoC alone, in subjects with COVID-19 
Secondary Objective(s): 
• 
To assess multiple clinical measures of disease severity and disease burden 
• 
To assess the safety and tolerability of Brilacidin IV treatment in subjects with COVID-
19 
Exploratory/ Other Objective(s): 
• 
In-hospital outcomes 
• 
To measure biological and immunological markers of illness/inflammation 
• 
To explore the change in the SARS-CoV-2 viral load 
• 
To estimate plasma pharmacokinetics of Brilacidin 
Design and Methodology: 
This Phase 2 study is a randomized, blinded, placebo-controlled, parallel group design. 
The target population to be treated are patients with moderate to severe COVID-19, SARS-
CoV-2 infection confirmed by positive standard polymerase chain reaction (PCR) test (or 


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equivalent/ other approved diagnostic test) within 4 days prior to starting study treatment, 
and hospitalized with respiratory distress but not yet requiring high-level respiratory support 
(as defined in exclusion criterion #2).  
The study is comprised of three parts: 
Screening/ Baseline visit (Day -1 to 1): Lasts up to 24-48 hours and comprises screening/ 
baseline assessments. This visit will confirm that study inclusion and exclusion criteria are 
met by participants prior to randomization. 
Treatment period (Day 1-3 with potential to expand to Day 4-5): Randomized subjects will 
receive blinded study treatment once daily for 3 days by IV infusion, in addition to SoC.  
Follow-up period (Day 4-6 through Day 60): Subjects will be assessed daily while 
hospitalized. Discharged patients will be asked to attend study visits at Days 15 and 29. All 
subjects will undergo a series of efficacy and safety assessments, including laboratory 
assays. Blood samples and nasopharyngeal (NP) swabs will be obtained on Days 1, 3, 5, 8, 
11 (while hospitalized) and/or on day of discharge; and Days 15 and 29 (by returning to the 
clinic/ remote visit or if still hospitalized). Note: NP swabs are to be collected.  
If subjects are discharged from hospital prior to Day 15, or Day 29, and a hospital visit is not 
possible, then visiting nursing services and mobile phlebotomy may support that visit 
remotely where these are available in accordance with local guidelines and should include 
all possible assessments (e.g., oxygen saturation with portable monitors). Every effort 
should be made to ensure discharged patient follow-up at Days 15 and 29, via a healthcare 
interaction (minimally by telephone call). A follow-up visit at Day 60(±10), by telephone 
call, is also included to confirm patient status. 
Study Treatments 
All subjects receive local SoC, plus allocated study treatment in addition. Two IV study 
treatment arms are planned: 
• 
SoC + Brilacidin IV 0.6 mg/kg (D1), 0.3 mg/kg (D2 and D3) with potential to expand 
dosinga of 0.3 mg/kg on D4 and D5 
• 
SoC + Saline IV infusion (D1, D2, and D3) with potential to expand dosinga on D4 and 
D5 
a Note: Dependent on safety review and recommendation by the Data Monitoring Committee (DMC). 
D1, D2, and D3 (above) refer to Day 1, Day 2 and Day 3 of study treatment. Similarly, D4 and D5 are Day 4 
and Day 5. 
Treatment randomization is 1:1 (n=60 per arm). Randomization will also be stratified by 
(1) Age (≤65 years, >65 years), (2) Severity of disease (moderate, severe), and (3) Country. 
Interim Analyses and Data Monitoring Committee Oversight 
An independent Data Monitoring Committee (DMC) will be established to conduct periodic 
safety reviews. An initial safety review is planned to occur after approximately 20 randomized 
subjects have completed up to Day 15, and a further safety review by the DMC is planned to 
occur after approximately 50% of subjects have completed up to Day 29. The DMC may 


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recommend expanding dosing to Days 4 and 5 (at the same doses as on Days 2 and 3), 
continuation of the Days 1-3 study dosing unchanged, or that the trial be interrupted or 
stopped for safety reasons. Details of the DMC will be prepared separately from this protocol 
in a DMC Charter; the charter may supersede the summary details presented here in the 
protocol. 
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. 


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• 
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 as defined 
below, throughout the study and for up to 30 days after stopping treatment. 
Effective contraception methods include: 
• Total abstinence (if this is the preferred and usual lifestyle of the subject).       
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before start of 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
• Male partner sterilization (at least 6 months prior to screening). The vasectomized 
male partner should be the sole partner for that female subject. 
• Double barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/vaginal suppository. 
• Use of oral*, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception.              
(*In the case of oral contraception, subjects should have been using the same pill on 
a stable dose for a minimum of 3 months before start of study treatment). 
• Intrauterine device (IUD) or intrauterine system (IUS)  
Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks before start of study treatment. In the case of oophorectomy alone, only 


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when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of childbearing potential. 
In addition, female subjects must also refrain from egg donation and in vitro 
fertilization during study treatment and for 7 days after stopping study 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. 
In addition, male participants must not donate sperm during study treatment and for 7 
days after stopping study treatment. 
Test Product, Dose, and Mode of Administration: 
Brilacidin for Injection is provided as a sterile frozen solution containing 50 mg/mL of 
Brilacidin free base and 20% w/v hydroxypropyl-beta-cyclodextrin (Kleptose HPB) in water 
for injection. Brilacidin sterile concentrated solution is a clear, colorless to yellow to brown 
solution supplied in 2 mL glass vials with a fill volume ~1.2 mL to ensure 1.0 mL 
extractable volume per vial. The sterile solution formulation provided requires further 
dilution with normal saline for subsequent intravenous infusion. 
The 2 mL glass vials are labelled as containing “Brilacidin for Injection, 50 mg/mL (free 
base) for 1.0 mL extractable volume”. 
For intravenous infusion administration, Brilacidin for Injection is diluted in sterile 0.9% 
w/v sodium chloride (normal saline) to provide the desired final dose within 8 hours of 
administration. Diluted Brilacidin drug product is stored at room temperature not above 
25°C, 77°F, prior to use and is filtered through a 0.2 μm membrane when administered 
intravenously over 60 minutes. Placebo IV infusion will be sterile saline. 
Brilacidin IV infusion requires unblinded pharmacist (or appropriate designee) preparation 
at the study site; allows for blinded treatment administration by use of local blinded 
labelling. A separate pharmacy manual will be provided. Dose calculation for a subject’s 
study treatment infusions will be based on actual body weight measured at Screening. 
On Day 1, randomized subjects will be allocated to one of the following two IV study 
treatment arms in a ratio of 1:1 
• 
SoC + Brilacidin IV 0.6 mg/kg (D1), 0.3 mg/kg (D2 and D3) with potential to expand 
dosinga of 0.3 mg/kg on D4 and D5 
• 
SoC + Saline IV infusion (D1, D2, and D3) with potential to expand dosinga on D4 and 
D5 
a Note: Dependent on safety review and recommendation by the DMC. 
D1, D2, and D3 (above) refer to Day 1, Day 2 and Day 3 of study treatment. Similarly, D4 and D5 are Day 4 
and Day 5. 
The rationale for looking to expand treatment duration to five days, from the initial dose 
regimen of three days, is to be able to provide a longer duration of systemic Brilacidin 
exposure at a level that can strongly suppress SARS-CoV-2 virus activity, and any 
associated symptoms, and thus provide a more optimal therapy to hospitalized patients with 
moderate or severe COVID-19. The longer treatment duration is expected to allow for 


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greater impact of Brilacidin treatment and provide enhanced benefit to the patient, with the 
5-day regimen incorporated only following recommendation by the DMC subsequent to 
DMC review of all available safety data following safety review interim analysis(es). 
Endpoint(s): 
Efficacy Endpoints 
Primary Efficacy endpoint based on the clinical status ordinal scale: 
• 
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 ordinal scale with response sustained through Day 29: 
- 
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. 
Secondary Efficacy: 
• 
Composite endpoints, from the ordinal scale:  
- 
Achieving recovery status scores (see definition in primary endpoint above) at Day 
29 
- 
Composite endpoint by Day 29, defined as: Death OR Respiratory failure (requires  
invasive mechanical ventilation) 
• 
Clinical status measures, from the ordinal scale: 
- 
Achieving at least one-point/ two-point improvement in clinical status at Days 8, 15 
and 29 
- 
Time to at least one-point/ two-point improvement in clinical status 
- 
Clinical status over time 
• 
National Early Warning Score (NEWS2) 
- 
Time to a NEWS2 of ≤2 and maintained for 24 hours 
- 
Change from baseline to Days 3, 5, 8, 11, 15, and 29 in NEWS2 
Exploratory Efficacy: 
• 
In-hospital outcomes 
- 
Duration of hospitalization 
- 
Time to discharge 
- 
Duration of invasive mechanical ventilation 
- 
Duration of supplemental oxygen support 
- 
Duration of ECMO 
- 
No oxygen therapy (and/or peripheral oxygen saturation SpO2 > 93% on room air) at 
Days 8, 15 and 29 
• 
All-cause mortality 
- 
28-day mortality (to Study Day 29) 
 


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Safety Endpoints 
• 
Incidence and severity of treatment-emergent Adverse Events (AEs), including Serious 
Adverse Events (SAEs) 
• 
Clinically significant changes in laboratory measures and vital signs 
Other Endpoints 
• 
SARS-CoV-2 viral load 
- 
Change from baseline in SARS-CoV-2 viral load from NP or OP samples at Days 3, 
5, 8, 11 (while hospitalized) and/or on day of discharge; and Days 15 and 29 (by 
returning to the clinic/ by remote visit or if still hospitalized) 
• 
Biological and immunological markers of illness/inflammation 
- 
Changes from baseline in biomarkers from blood samples may include, but are not 
limited to: CRP, ferritin, LDH, D-dimer, troponin T hs, absolute neutrophil count 
and IL-1β, IL-6, IL-10, total IL-18, TNF-α [at Days 2(local lab tests only), 3, 5, 8, 11 
(while hospitalized) and/or on day of discharge; and Days 15 [and 29(local lab tests 
only)] (by returning to the clinic/ by remote visit or if still hospitalized)] 
• 
Plasma pharmacokinetics of Brilacidin 
- 
Plasma concentrations of Brilacidin measured from blood samples collected on Days 
1 to 4 
Statistical Methods: 
Full details of the statistical methodology for summary and analyses of the data collected in 
this study will be prepared separately from the protocol in a Statistical Analysis Plan (SAP). 
This Phase 2 Proof of Concept (PoC) study is exploratory in nature and will be initiated with 
a dose regimen of Brilacidin in addition to SoC, compared to placebo with SoC. Proof of 
concept will be established by a significant treatment effect on the primary endpoint or a 
positive direction of effect amongst multiple efficacy endpoints. Comparisons will be 
performed against placebo plus SoC at a one-sided type I error rate of 0.05 which will not be 
adjusted for multiple testing. 
The selected primary efficacy endpoint is time to sustained recovery, where recovery is 
defined as the participant being well enough for hospital discharge, meaning the participant 
either no longer requires supplemental oxygen or ongoing medical care in the hospital, or is 
no longer hospitalized (with or without some limitation on activities). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, 
pharmacokinetic, and safety parameters. For categorical variables, summary tables with 
number and percentage of subjects within each category will be presented. For continuous 
variables, descriptive statistics including the number of subjects, mean, median, standard 
deviation, minimum, and maximum values will be presented. Kaplan-Meier methods will be 
used to summarize time to event endpoints, including the 25th, 50th (median), and 75th 
percentiles with associated 90% confidence intervals, as well as percentage of events and 
censored observations. 


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Sample Size 
This study is exploratory in nature and the sample size (up to 60 per treatment arm) was 
selected to provide sufficient power under a range of alternative hypotheses to support PoC 
of Brilacidin versus SoC. The type I error will not be adjusted to account for multiple 
comparisons. 
For the primary efficacy endpoint of time to recovery, assuming a total of 100 subjects (50 
per treatment arm included in analysis), if a total of 75 recovery events are observed, the 
comparison between treatment groups would provide at least 90% power with a one-sided 
type I error rate of 0.05 and a hazard ratio of 2.0 [equivalent to median time to recovery of 5 
days on Brilacidin versus 10 days on SoC].  If instead the hazard ratio is 1.67 (time to 
recovery on Brilacidin of 6 days versus 10 days on SoC) and 75 recovery events occur, the 
difference could be detected with at least 70% power. The assumptions for sample 
estimation are adapted from the median time to recovery data reported for the remdesivir 
(11 days) treatment group in Beigel et al 2020; remdesivir has Emergency Use 
Authorization (EUA) in multiple countries and has become SoC where available. 
Interim Analyses/ Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established to conduct periodic 
safety reviews. Details of the DMC will be prepared separately from this protocol in a DMC 
Charter. The charter may supersede the summary details presented here in the protocol. 
Safety data summaries and listings will be produced for DMC safety monitoring when 
needed. 
An initial safety review is planned to occur after approximately 20 randomized subjects have 
completed up to Day 15. This initial interim analysis will focus on review of cardiovascular 
safety, vital signs and adverse events that have occurred in the approximately 20 subjects to 
receive Days 1-3 of study treatment. A further safety review by the DMC is planned to occur 
after approximately 50% of subjects have completed up to Day 29, to allow for unblinded 
monitoring of safety data around the study mid-point. The DMC may recommend expanding 
dosing to Days 4 and 5 (at the same doses as on Days 2 and 3), continuation of the Days 1-3 
study dosing unchanged, or that the trial be interrupted or stopped for safety reasons. The 
DMC will be guided by the degree and incidence of hypertensive values/events observed in 
the ongoing study which should not exceed the number and/or severity of those observed in 
previous studies with Brilacidin IV treatment for expansion of dosing to occur as planned. 
The primary efficacy analysis will occur once all subjects complete the Day 29 visit (or 
discontinue from study, if before Day 29). Final database lock and updated safety reporting 
will follow the completion of Day 60 follow-up telephone visits. 
Analysis Population 
Efficacy analyses performed on the Intent-to-Treat (ITT) population will be considered 
primary, with the ITT population including all subjects who are randomized and receive at 


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least one dose of study drug. Subjects in this population will be analyzed according to the 
treatment group to which they were randomized. 
The Safety population includes all subjects in the ITT population. Subjects in this population 
will be analyzed according to treatment received. All safety analyses will be based on this 
population. 
The Per Protocol (PP) population is a subset of the ITT population and includes subjects 
who meet particular study completion criteria with no major protocol deviations; these 
criteria will be described in the SAP and will be approved prior to database lock and study 
unblinding. Efficacy analyses performed using the PP population will be considered 
supportive. 
All subjects in the ITT population who provide at least one PK sample and have at least one 
valid concentration measurement will be included in the PK population. 
Statistical Analysis 
The primary efficacy endpoint is time to sustained recovery which will be analyzed with the 
log-rank test for treatment difference, stratified by age group, disease severity and country, 
with dose regimen as covariate (if expanded after DMC recommendation), and summarized 
using Kaplan-Meier methodology. Secondary and exploratory/ other endpoints will be 
presented with summary statistics. Between treatment group comparisons for secondary and 
exploratory/ other endpoints will be performed via logistic regression, including proportional 
odds logistic regression for changes in the ordinal scale, and analysis of covariance models, 
stratified by age group, disease severity and country, for categorical and continuous 
endpoints, respectively. Sensitivity analyses may include longitudinal models and models 
adjusted for additional covariates. 
All safety data, demographic and baseline characteristics will be summarized descriptively 
through appropriate data tabulations, descriptive statistics, and categorical summaries on the 
Safety Population. 
 


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Table 1: 
Schedule of Activities 
 
Screening 
Treatment Period2 
Follow-up period 
Baseline 
 
Daily or twice daily assessments are until hospital discharge3 
 
EOS 
Study Day +/- window 
-1 to 1 
1 
2 
3 
4 
5 
6 
7 
8 
9, 10 
11 
12, 13, 14 
154   
+/-2 
16 to 28 Successful 
Discharge3 
294   
+/-3 
60    
+/-10 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ Current Medical Conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight5 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Height5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination6 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
12-lead ECG (local) 
X 
X16 
(post-dose) 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Vital signs (twice daily)3,7 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Respiratory status (twice daily)3,7 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Positive SARS-CoV-2 virus by PCR (local lab)8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swabs for SARS-CoV-2 quantitation 
(central lab)8 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Clinical Status Evaluation with 8-category ordinal scale3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NEWS2 (twice daily unless in ICU)7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test (urine/serum), if WOCBP (local lab)9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (local lab) 
X 
X2 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Blood chemistry (includes CRP, ferritin, LDH, D-dimer, 
troponin T hs) and Coagulation (local lab) 
X 
X2 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Blood sample collection for additional biomarkers, may 
include but not limited to IL-1β, IL-6, IL-10, total IL-18, 
TNF-α (central lab) 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Blood sample collection for Brilacidin plasma 
concentrations (central lab)10 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (IRT)11 
X 
X 
 pre-dose 
confirmation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug IV Infusion12 
 
X 
X 
X 
(X)13 (X)13 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure and pulse rate (around study IV 
infusion; pre-dose, 1h and 3h post start of infusion)14 
 
X 
X 
X 
(X)13 (X)13 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Assessment15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Prior and Concomitant Medications & 
Therapies/Procedures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1 
Informed consent must be signed prior to any study-related procedure.  
2 
Study treatment may start once screening/baseline measurements are completed and eligibility confirmed.  
Eligibility assessments for vital signs, respiratory status, and local laboratory tests do not need to be performed separately for screening and baseline if participants 
are randomized and treated on the same day/within 24 hours of commencing screening/signature of informed consent. 
EOS = End of Study 


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During the treatment period, all assessments should be performed in the morning pre-dose. 
3 
Any subject successfully discharged before Day 29 is to complete all assessments listed on the day of discharge. 
 
Daily or twice daily assessments are until hospital discharge, with the exception of Clinical Status Evaluation, which should be sought by telephone (between 7AM 
and 12 PM local time) up to Day 15 if a subject is successfully discharged before Day 15. 
4 
For Day 15/29 assessments: if subject is discharged prior to Day 15/29, visiting nursing services and mobile phlebotomy may support that visit remotely where these 
are available in accordance with local guidelines and should include all possible assessments. Every effort should be made to ensure discharged patient follow-up via 
a healthcare interaction. Visit windows for Day 15/29 visits only apply should a patient have been discharged. 
5 
Height and weight measured without shoes. If not possible to measure, height can be reported by the subject. 
6 
Complete physical examination to be performed at Screening/Baseline, including review of the following body systems: skin, neck (including thyroid), HEENT 
(head, eyes, ears, nose and throat), heart, lungs, abdomen, lymph nodes, extremities, vascular and neurologic function. Subsequent examinations may be abbreviated 
including, at a minimum: HEENT, heart, lungs, abdomen, extremities and examination of any body system where there are symptoms reported by the subject. 
7 
Vital signs include heart rate, systolic and diastolic blood pressures and body temperature. Respiratory status (respiratory rate, oxygenation and any oxygen 
supplementation) should be measured at the same time as the vital sign measurements, if possible. 
 
All parameters of the NEWS2 – including the vital sign parameters and oxygen saturation – should be recorded together in the morning, and then between noon and 
midnight, for the duration of hospitalization if outside of the ICU. Following hospital discharge these parameters should be recorded once at each return visit to the 
clinic (Days 15 and 29). 
8 
Results confirming positive SARS-CoV-2 virus by PCR or equivalent/ other approved diagnostic testing within 4 days prior to randomization may be used for 
eligibility. Nasopharyngeal swabs used from pre-dose assessment for quantitative PCR analysis at central laboratory. 
9 
Pregnancy test applicable only for females of childbearing potential, serum pregnancy test (serum hCG) will be performed by local laboratory. For enrollment a 
negative urine test is sufficient. 
10 Blood samples (for Brilacidin plasma concentration analysis) will be collected at the following timepoints: 
• 
Day 1: pre-dose, within 30 mins after the end of infusion, and between 8-12 hours from start of the Day 1 infusion. 
• 
Day 2: pre-dose (approximately 24 hours from start of the Day 1 infusion) 
• 
Day 3: pre-dose (approximately 24 hours from the start of the Day 2 infusion) 
• 
Day 4: at approximately 24 hours from the start of the Day 3 infusion. 
11 Brilacidin IV infusion requires unblinded pharmacist preparation at the study site. Brilacidin for Injection concentrated solution is diluted in sterile 0.9% w/v sodium 
chloride (normal saline) to provide the desired final dose within 8 hours of administration; diluted Brilacidin drug product is then stored at room temperature not 
above 25°C, 77°F, prior to use. Placebo IV infusion will be sterile saline. 
 
Since pharmacist preparation ahead of dosing is required, randomization using IRT may be performed prior of full confirmation of subject eligibility. Full 
confirmation of eligibility must then be confirmed pre-dose on Day 1. 
12 Brilacidin IV infusion is filtered through a 0.2 μm membrane when administered intravenously over 60 minutes. On study treatment days, assessments should be 
performed pre-dose unless otherwise specified. 
13 Brilacidin treatment may be expanding to Day 4 and Day 5 following an initial interim safety analysis; additional assessments then needed on Day 4 and Day 5. 
14 Blood pressure and pulse rate measured at additional timepoints during study treatment, around the timing of the study IV infusion; pre-dose, within no more than 30 
mins after the end of infusion, and 3 hours (±30 mins) post-start of infusion (i.e., ~2 hours post-end of infusion). Additional assessments to be made as appropriate 
based on the systolic and diastolic blood pressure values recorded. 
15 Adverse events (AEs) with onset after a subject has provided informed consent are to be recorded. At follow-up through Day 29, ongoing AEs assessed as related 
and all ongoing Serious AEs are to be further followed up to appropriate resolution. 
16 Post-dose ECG on Day 1 performed within 2 hours after the end of infusion. 


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LIST OF ABBREVIATIONS 
ABSSSI 
acute bacterial skin and skin structures infections 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BUN 
blood urea nitrogen 
cm 
centimeter  
COVID-19 
Coronavirus disease 2019 
CRO 
clinical research organization 
CRP 
C-reactive protein 
CS 
clinically significant 
CT 
computerized axial tomography 
D 
Day 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eGFR 
estimated glomerular filtration rate 
(e)CRF(s) 
(electronic) case report form(s) 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
GCP 
Good Clinical Practice 
HDPs 
host defense proteins 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
IL 
interleukin 
IN 
Investigator Notification 
IPI 
Innovation Pharmaceuticals Inc. 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV  
intravenous(ly) 
ITT 
Intent-to-Treat 
kg 
kilogram 
LDH 
lactate dehydrogenase  
mg 
milligram 
mL 
milliliter 


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MedDRA 
Medical Dictionary for Regulatory Activities 
mins 
minutes 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NCS 
not clinically significant 
OM 
oral mucositis 
PaO2 
arterial oxygen partial pressure 
PCR 
polymerase chain reaction 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
PoC 
Proof of Concept 
PP 
Per-Protocol 
PT 
preferred term 
RBC 
red blood cell 
RRT 
renal replacement therapy 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SD 
standard deviation 
SDV 
source document verification 
SoC 
standard of care 
SOC 
system organ class 
SOM 
severe oral mucositis 
SpO2 
peripheral oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE(s) 
treatment-emergent adverse event(s) 
TID 
three times per day 
TNF-α 
Tumor necrosis factor alpha 
ULN 
upper limit of normal 
WBC 
white blood cell 
WFI 
Water for Injection 
WHO 
World Health Organization 
WHO-DDE 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 


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1. INTRODUCTION AND BACKGROUND 
1.1.  
Disease Overview 
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified as the 
cause of an outbreak of respiratory illness due to coronavirus disease 2019 (COVID-19) that 
was first detected in Wuhan, China, in December 2019. The virus causes respiratory illness in 
people and can spread from person to person. Common signs of infection include fever, 
cough, shortness of breath, breathing difficulties, and other respiratory symptoms. 
Gastrointestinal symptoms (nausea, vomiting, diarrhea) also appear to be common clinical 
manifestations of COVID-19. In severe cases, SARS-CoV-2 can cause pneumonia, severe 
acute respiratory syndrome, kidney failure, and death (WHO 2020a). On 30 January 2020, the 
International Health Regulations Emergency Committee of the WHO declared the COVID-19 
outbreak a Public Health Emergency of International Concern (WHO 2020b). Further to the 
WHO declaration, on 31 January 2020, Health and Human Services declared a public health 
emergency in the United States (US) (DHHS 2020). 
As of November 3, 2020, over 47.2 million COVID-19 cases have been diagnosed in at least 
190 countries, resulting in over 1.2 million reported deaths, including over 9.3 million cases 
and almost 233,000 fatalities in the United States (Johns Hopkins Coronavirus Resource 
Center 2020). While COVID-19 mortality rates can vary greatly by geographic region, with 
differences in how rates are calculated, it is generally accepted that, for COVID-19, the 
overall mortality rate is many times higher than that seen with seasonal influenza; moreover, 
it has been observed that up to 15% of COVID-19 patients develop lung injury, including 
respiratory distress progressing to acute respiratory distress syndrome (ARDS) requiring 
prolonged ventilator support over weeks (Zhou et al 2020). This can result in intensive care 
units, hospitals and health care systems becoming overwhelmed. Presently, there are no 
approved vaccines and few minimally effective therapies to treat COVID-19. According to a 
May 1, 2020, Congressional Research Service report, worldwide economic growth could be 
reduced by 2 percent per month if current pandemic conditions persist, with global trade 
falling by 13 percent to 32 percent, with the economic downturn attributable to the COVID-19 
crisis could vastly exceed that of the Great Recession (2007-2009) (Congressional Research 
Service 2020). The Congressional Budget Office estimates the novel coronavirus pandemic 
will cost the U.S. economy $8 trillion through 2030 (Stein 2020). 
ARDS is characterized by pro-inflammatory cytokine release, inflammatory cellular 
infiltration and cell death, resulting in severe pulmonary damage and the development of 
respiratory failure that requires mechanical ventilation with high positive end-expiratory 
pressures (PEEP) to maintain life. In patients with a prior history of hypertension, diabetes 
and cardiovascular disease (common comorbid conditions), poor health outcomes have been 
reported that may be a result of poor underlying cardiac reserve—meaning that patients 
develop cardiac failure in response to ventilation, with pulmonary edema further exacerbating 
respiratory failure (Zhou et al 2020). 
ARDS is an important contributor to the morbidity and mortality associated with COVID-19. 
ARDS manifestation is connected to heightened inflammatory responses resulting from 


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SARS-CoV-2 infection, adversely impacting normal lung function. A therapeutic intervention 
that exhibits immunomodulatory properties might help control this inflammatory response as 
characterized by ARDS. An intervention that also exerts antiviral activity would provide an 
even more complete solution to the SARS-CoV-2 infection associated ARDS challenge. 
1.2.  
Background of Brilacidin 
Brilacidin is a fully synthetic, non-peptidic, host defense protein mimetic. Brilacidin is a small 
molecule, new chemical entity, created so as to mimic the amphiphilic structure of host 
defense proteins (HDPs), having one surface with positively charged groups (cationic) and the 
opposite surface consisting of hydrophobic groups. With this general synthetic form, there is 
no need for an agent to be of the size or composition of naturally-occurring proteins to 
effectively function as a HDP, as the ability to act as a HDP is retained by the much smaller 
synthetic amphiphilic molecule.  
Brilacidin has anti-inflammatory activity – the mechanism of which is proposed to be based 
largely on inhibition of phosphodiesterases (PDE4 and PDE3) and subsequent down-
regulation of pro-inflammatory cytokines (such as TNF-α, IL-1β, IL-6, IL-8). Like natural 
HDPs, Brilacidin has antibacterial activity (with a predominantly gram-positive spectrum). 
New in vitro research has demonstrated robust and consistent antiviral activity of Brilacidin 
against SARS-CoV-2, as summarized below. 
1.2.1.  
Proposed Therapeutic Properties in COVID-19 
Brilacidin has three complementary anti-COVID-19 therapeutic properties combined in a 
single drug: antiviral; immunomodulatory/anti-inflammatory; and antimicrobial (Figure 1). 
Brilacidin has demonstrated antiviral activity against SARs-CoV-2 in cell-based assays (see 
Section 1.3.1.3), and the mechanisms for this activity are postulated as being: 
1) Membrane Disruption: disrupting the viral envelope (virucidal) 
2) Entry Inhibition: by competing with the virus for the ACE2 receptor, preventing 
ACE2 receptor binding and viral entry 
3) Intracellular Targets: inhibiting viral replication intracellularly, by binding to SARS-
CoV-2 main protease (Mpro) 
4) Anti-inflammatory: suppressing IL-6 and other pro-inflammatory mediators 
implicated in the “cytokine storm”, through inhibition of phosphodiesterase 
The main proposed mechanism of action of Brilacidin involves the disruption of viral 
membrane integrity. Other direct antiviral mechanisms of action of Brilacidin may include 
blocking viral entry and interrupting viral replication intracellularly. An in silico quantum 
mechanical molecular screening study of 11,522 compounds (both FDA-approved and those 
in testing) identified Brilacidin as one of the most promising potential inhibitors of the novel 
coronavirus based on the potential of its physico-chemical properties to interfere with the 


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intracellular replication of SARS-CoV-2’s main protease (Mpro) (Cavasotto and Filippo 2020). 
An article detailing in vitro results and proposed mechanisms of action is being submitted for 
peer review publication, with a pre-print (Bakovic et al 2020) made available. 
Additional nonclinical (see Section 1.3.1.3) and clinical data support Brilacidin’s potential to 
function through the cAMP/cGMP pathway, by inhibition of phosphodiesterase. 
Phosphodiesterase type 4 (PDE4) is the predominant phosphodiesterase expressed in 
neutrophils, T cells and macrophages. PDE inhibitors show broad spectrum of anti-
inflammatory effects in almost all inflammatory cells. PDE4 inhibitors block the degradative 
action of PDE4 on cAMP, thereby increasing intracellular levels of cAMP levels which 
mediate phosphorylation of protein kinases. PDE4 inhibitors reduce neutrophil chemotaxis, 
recruitment and activation; inhibit the activation of CD4+ and CD8+ T cells; and inhibit 
monocytes chemotaxis (Tamimi et al 2012). Therefore, inhibition of PDEs is expected to have 
a therapeutic effect on the inflammatory state.  
Inhibition of PDE4 and PDE3 has been demonstrated for Brilacidin in vitro (see Section 
1.3.1.3). PDE4 and PDE3 inhibition results in subsequent down-regulation of pro-
inflammatory cytokines and chemokines (such as TNF-α, IL-6, IL-1β, MMP-9, MCP-1, IL-8, 
CINC-3), which have been identified as central drivers in the worsening prognoses of 
hospitalized COVID-19 patients. Experiments have been conducted to confirm such down-
regulation by Brilacidin in ex vivo cell-based assays (see Section 1.3.1.3), and also from 
clinical biomarker data (Phase 2 retention enema study, Section 1.3.2.3). 
Brilacidin’s antimicrobial properties, as demonstrated in a Phase 2b clinical trial of 
intravenous Brilacidin in the treatment of Acute Bacterial Skin and Skin Structure Infections 
(ABSSSI), may also help to fight or prevent secondary bacterial infections, which can co-
present in up to 20 percent of COVID-19 cases (Cox et al 2020; Kim et al 2020; Mirzaei et al 
2020). 
Collectively, these data support Brilacidin as a highly unique 3-in-1 combination—antiviral, 
anti-inflammatory, antimicrobial—novel COVID-19 therapeutic candidate (Figure 1). 
 
 


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Figure 1:  Brilacidin, a 3-in-1 Combination of Therapeutic Properties 
 
1.3.  
Nonclinical and Clinical Studies with Brilacidin 
Please refer to the Investigator’s Brochure for full background information.  
1.3.1.  
Nonclinical Studies 
1.3.1.1.  
Nonclinical Toxicology and Safety Pharmacology 
Toxicology 
Single and repeat dose toxicity studies have been conducted with intravenous (IV) and oral 
gavage administration of Brilacidin.  
For Brilacidin administered IV for up to 28 days, dose-limiting pharmacological effects have 
been relatively consistent in both rats and dogs. Salivation, retching, weight loss, and 
diminished feces relate to the gastrointestinal system; tremors and diminished activity to the 
neurological system; and labored respirations and changes in pulmonary tidal volumes to the 
respiratory system. Effects on peripheral nerves were observed as well as increases in blood 
pressure and heart rate. Brilacidin-related microscopic findings in repeat dose IV toxicity 
studies in rat and dog included microvacuolation of the axon hillock of neurons from the 
dorsal root ganglia, and microscopic changes in the kidney (tubular basophilia). There were 
no associated degenerative changes in the neuronal bodies or nerves/nervous tracts. The 
toxicological investigations indicate that the dog is the more sensitive of the species tested by 
IV administration, with a NOAEL dose of 0.25 mg/kg/day and associated mean Day 28 


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AUC(0-t) of 10902 ng•h/mL (males) or 10187 ng•h/mL (females). The nonclinical findings of 
a mild peripheral sensory axonopathy in rats and dogs administered Brilacidin are consistent 
with the clinical findings of mild transient paresthesia observed clinically. The onset of 
functional neurological changes has been reported to precede microscopic changes allowing 
for clinical monitoring, through adverse event reporting, and adjustment of dose and duration 
of administration if needed (Petterson et al 2008). 
Brilacidin demonstrated no genotoxic potential in vitro or in vivo.  
In a fertility and early embryonic development study in male and female rats, no effects on 
fertility parameters were observed at doses up to 1.5 mg/kg IV; the NOAEL was considered 
0.75 mg/kg based on clinical signs and decreased organ weights (prostate, seminal vesicle) 
considered adverse in males. 
Safety pharmacology 
In vivo, cardiovascular effects of increased blood pressure and heart rate at the highest dose 
tested (4 mg/kg IV) were observed without effect on cardiac rhythm or ECG. Decreased 
respiratory rate and minute volume and increased tidal volume at the highest dose (25 mg/kg 
IV) were observed in the respiratory system study. Nervous system effects observed were 
salivation and labored respiration in the highest dose group (25 mg/kg IV). In a nerve 
conduction study (non-GLP), the highest dose group (10 mg/kg IV) demonstrated slowing 
down of caudal nerve conduction velocity after 5 days administration and histopathological 
changes (intracytoplasmic granules) in dorsal root ganglion at the end of the recovery phase. 
Sensory and coordination studies (non-GLP) demonstrated marginal effects up to 10 mg/kg 
IV. 
In vitro, Brilacidin at the highest feasible test concentration (0.3 μM) did not result in hERG 
inhibition. Results from studies (non-GLP) using patch clamp assays support disturbances in 
channel function as a potential cause for observed paresthesias associated with high dose 
Brilacidin treatment when administered IV in the clinic. However, Brilacidin shows little if 
any accumulation in the CNS so any ion channel interactions would be expected to be 
localized in the periphery. In evaluating the significance of these interactions on the safety of 
Brilacidin IV, it can be recognized that several widely used drugs and drug classes target ion 
channels for therapeutic effects, e.g., repaglinide, nateglinide, disopyramide, and phenytoin 
and other widely used drugs display off-target activities at ion channels, e.g., haloperidol, 
fluoxetine, and verapamil. These marketed drugs are used chronically and support the 
rationale that ion channel effects should be adequately tolerated. 
1.3.1.2.  
Nonclinical Pharmacokinetics and metabolism 
After IV single dose administration, the half-life (t½) was approximately 8 hours in rats. 
(Human pharmacokinetics have been conducted and t½ ~20 hours after IV administration of 
Brilacidin to healthy subjects [Study PMX63-102, Study PMX63-103]). 


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Plasma protein binding of Brilacidin in vitro for mouse, rat, rabbit, monkey, and human 
plasma proteins was comparable, ranging from 94.4% to 98.5%. The plasma/blood 
partitioning studies indicated no preferential accumulation of [14C]-Brilacidin to human 
blood cells. 
Tissue distribution after IV administration of [14C]-Brilacidin (2 mg/kg) showed that in the 
lung, concentrations were high at the 1 hour and 3 hours post-dose timepoints, with lower 
concentrations from 24 hours post-dose onwards. The higher concentrations were mainly 
observed in the liver, lung, kidney, adrenal glands and cartilage at 1-hour post-dose; at 1 and 3 
hours post-dose, the small intestine mucosa contained the highest concentration of 
radioactivity, in both male and female rats. Highest concentrations of radioactivity were 
subsequently observed in small intestine mucosa at all time points (24, 168 and 504 hours 
post-dose), which would indicate biliary excretion as a possible route of elimination for 
Brilacidin. Tissues with the lowest concentrations of radioactivity were bone, brain, eye, 
white fat, seminal vesicles (male rats only), spinal cord, and urinary bladder (male rats only) 
at all time points. 
Rat, rabbit, dog, monkey, and human hepatocytes in vitro did not metabolize Brilacidin. In the 
rat following a single IV dose, in all three matrices (kidney, liver and feces) the major 
component detected was Brilacidin. Two additional components/potential metabolites were 
observed, although it is also possible that both are artifacts formed during the extraction 
process. 
Using the January 2020 FDA Guidance for in vitro DDI studies, available data indicates there 
is a potential for Brilacidin to reversibly inhibit CYP2C8, CYP2C9, and CYP3A4 with a 
possible although probably not likely time-dependent inhibition of CYP2B6. To further 
investigate any potential for drug-drug interactions with substrates metabolized by CYP2C8, 
CYP2C9, and CYP3A4 enzymes, an in vitro study (to accurately determine Ki’s) is planned 
to be performed in parallel with the conduct of this study. Please refer to Section 6.1.1 for 
details on cautionary monitoring for adverse effects of those drugs which are sensitive 
substrates of CYP2C8, CYP2C9, and CYP3A4 enzymes or are substrates with a narrow 
therapeutic range during study treatment. The likelihood for drug-drug interactions is low and 
will be further confirmed through additional study(ies). Of note, the safety profile of 
Brilacidin has already been established from intravenous dosing of over 400 subjects in the 
Brilacidin program, and no notable alerts regarding any drug-drug interactions have occurred 
to date. 
In the rat, following a single IV dose in a mass balance study, any radioactivity excreted was 
largely via the fecal route and indicates that possible excretion in the bile (and/or via the gut 
mucosa) is an important route of elimination of Brilacidin.  
These ADME data, demonstrating pulmonary exposure to Brilacidin from IV administration, 
are reassuring for the indication of COVID-19. As Brilacidin is excreted unchanged in the 
feces, there is also potential for treatment to address gastrointestinal symptoms (e.g., nausea, 
vomiting, diarrhea) that also appear to be common clinical manifestations of COVID-19. 


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1.3.1.3.  
Nonclinical Efficacy 
Pharmacodynamics: Anti-viral activity 
Using a pre-treatment assay, performed in monkey kidney Vero cells and also in human lung 
epithelial Calu-3 cells, researchers observed robust inhibition of SARS-CoV-2 virus 
multiplication. At 24 hours post-infection in the Vero cell assays, Brilacidin 
tetrahydrochloride at a concentration of 10 μM showed ~72% inhibition (p<0.01) (Figure 2, 
left panel), and in the Calu-3 cell assays, a concentration of 10 μM gave 95% inhibition 
(p<0.0001) and at 20 μM 97% inhibition (p<0.0001) (Figure 2, right panel). 
In the pre-treatment assay method, live virus was pre-treated with Brilacidin (before virus 
presentation to cells), with cells additionally pre-treated with drug and Brilacidin also present 
in the viral inoculum during the process of infection, and present post-infection. Virus was 
incubated with the respective concentrations of Brilacidin tetrahydrochloride tested for one 
hour, and virus treated with vehicle alone (DMSO) maintained alongside as control. The 
pretreatment virus-Brilacidin mix was then added to cells (which had been pre-treated with 
Brilacidin for two hours), with Brilacidin maintained in the medium concentration, and cells 
were infected with SARS-CoV-2 at a MOI: 0.1. The infection was allowed to proceed for 1 
hour at 37°C, after which the viral mix overlay was removed and Brilacidin-containing 
medium was added back to the cells. Cells were maintained at 37°C for 24 hours, at which 
time the supernatants were collected to assay for infectious virus. Supernatants were queried 
for infectious virus load by plaque assay. 
Without direct pre-treatment of virus, the inhibition achieved in the assay for a concentration 
of Brilacidin was reduced. For example, without pre-treatment of virus, the inhibition 
achieved in the Calu-3 cell assays was 39% inhibition with 10 μM and 61% inhibition with 20 
μM Brilacidin tetrahydrochloride, compared to 95% and 97% inhibition, respectively, with 
pre-treatment of virus. The pre-treatment assays, both in Vero and Calu-3 cells, support 
Brilacidin’s ability to prevent viral entry by, it is proposed, disrupting the viral envelope 
and/or preventing viral attachment to host cells. A majority of antiviral agents targeting 
SARS-CoV-2 attempt to inhibit viral replication, post-infection, rather than eliminating or 
blocking the virus prior to infection.  
Figure 2:  Pre-Treatment Efficacy of Brilacidin against SARS-CoV-2 
 
 
 
 
 
Statistical Significance 
** p < 0.0021 
**** p < 0.0001 


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Additional testing, using the same pre-treatment assay across a range of Brilacidin 
concentrations, showed Brilacidin tetrahydrochloride achieved ~90% inhibition against 
SARS-CoV-2 (IC90) at a concentration of 2.63 μM and an IC50 value of 0.565 μM 
(Figure 3), both of which are below clinically-achievable concentrations based on 
pharmacokinetics observed in a Phase 2b clinical trial of Brilacidin in treatment of ABSSSI: 
median Cmax in plasma was 7.67 μM Brilacidin (free-base) from a single IV dose of 0.6 
mg/kg. 
Figure 3:  Inhibitory Dose-Response assessment of Brilacidin on SARS-CoV-2 virus 
multiplication in Calu-3 cells 
Sigmoidal Hill-type function showing the relationship between the percent virus titer relative to DMSO and 
Brilacidin tetrahydrochloride concentration, with dashed lines showing the derived IC50 and IC90 values 
 
In a slightly different assay, cells were not exposed pre- or post-infection to Brilacidin and 
only the viral inoculum was pre-treated (with 10 μM Brilacidin tetrahydrochloride), and the 
treated inoculum used to infect Vero cells. At 24 hours post-infection, the infectious virus titer 
in the supernatant was quantified by plaque assay, which revealed a dramatic 90% reduction 
of virus titer (Figure 4, indicated as [entry]). This inhibition was approximately 25% higher 
than that observed when, in comparison, cells were exposed pre- and post-infection to 
Brilacidin and with no pre-treatment of virus nor drug present during infection. These data 
support the concept that Brilacidin has a direct inhibitory effect on the virus in a manner 
similar to the neutralization of antibodies, potentially by disrupting viral integrity and thus 
impairing the virion’s ability to complete the viral entry process. 


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Figure 4:  Assay Method Variation and Efficacy of Brilacidin Against SARS-CoV-2 in 
Vero cells 
 
Brilacidin has also undergone in vitro testing (in Calu-3 cells) in combination with other 
antiviral agents. Preliminary data of Brilacidin in combination with remdesivir (one of only 
two current COVID-19 treatments that has received Emergency Use Authorization, as well as 
a frontline treatment worldwide), demonstrates a statistically significant synergistic effect 
(Figure 5), with a combined overall inhibition against SARS-CoV-2 of ≥99%, reducing 
overall viral load to near undetectable levels. 
Brilacidin appears to have primarily an extracellular mechanism of action, by disrupting viral 
integrity and blocking viral entry. In contrast, remdesivir has an intracellular mechanism of 
action, affecting viral replication post-infection. Exhibiting different but synergistic antiviral 
properties, these two drugs may be an especially potent drug combination in treating COVID-
19. 
Figure 5:  Efficacy of Brilacidin in combination with Remdesivir against SARS-CoV-2 
 
 
 
 
 
 
 
 
 
Statistical Significance 
**** p < 0.0001 


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Combination in vitro testing is ongoing, and future investigations of efficacy against other 
coronaviruses (e.g., SARS-CoV-1, MERS-CoV, H-COVs) are planned. An article detailing in 
vitro results against SARS-CoV-2 and proposed mechanisms of action is being submitted for 
peer review publication, with a pre-print (Bakovic et al 2020) made available. Future in vivo 
studies are planned. 
Pharmacodynamics: Anti-inflammatory activity 
As demonstrated in vitro and ex vivo cell-based assays, the anti-inflammatory effect of 
Brilacidin is proposed to be based largely on inhibition of PDE4 and PDE3 with subsequent 
down-regulation of pro-inflammatory cytokines/chemokines (such as TNF-α, IL-1β, IL-6, IL-
8) and its regulators. Assays conducted include LPS-induced cytokine release ELISA (rat 
macrophages and human monocytic leukemia (THP-1) cells) and PDE-Glo™ PDE assay. 
Animal anti-inflammatory pharmacology data are available from two animal models. 
In both acute and fractionated radiation hamster models of oral mucositis, Brilacidin 
administered topically TID (to irradiated left buccal cheek pouch) over 28- or 35-day 
treatment periods, respectively, significantly reduced the number of days animals exhibited 
ulceration and the daily mean mucositis grades. Experiments in the fractionated radiation-
induced OM model clearly identified that a continuous Brilacidin 3 mg/mL TID regimen was 
most effective and all but eliminated ulcerative OM in experiments conducted, with 
reductions in the number of animal days with ulcerative OM over 90% relative to the control 
group responses (46.7% to 56.0% for control groups, and <4% for Brilacidin 3 mg/mL 
group). 
In a murine DSS-induced colitis model, despite the presence of severe colitis, after dosing 
with Brilacidin 400 mg/kg solution per rectum compared to DSS-treated controls rectal 
bleeding was significantly decreased and stools were significantly more firm. In addition, IL-
6 and IL-1β levels in colon tissue decreased with Brilacidin treatment and were lower than 
that of DSS-treated controls. Efficacy results similar to those for the Brilacidin treatment 
group were obtained with the positive control 5-ASA treated group. 
Pharmacodynamics: Anti-bacterial activity 
Brilacidin has demonstrated potent activity against Gram-positive bacteria, including 
staphylococci, beta-hemolytic streptococci and E. faecium, and several Gram-negative 
bacteria. Minimal propensity for the development of resistance has been demonstrated and 
broad-spectrum activity against multi-drug resistant strains of S. aureus, S. epidermidis and S. 
hemolyticus, including organisms resistant to two or more of the antibiotics methicillin, 
daptomycin, linezolid and vancomycin. Brilacidin has shown rapid bactericidal activity versus 
S. aureus and E. coli, plus significant antimicrobial activity against MSSA and MRSA at sub-
MIC levels for up to 7 hours post-exposure. Also, potent and rapid bactericidal activity with 
Brilacidin has been demonstrated against stationary cultures of MSSA and MRSA. 


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Importantly for the treatment of acute bacterial skin and skin structure infections (ABSSSI), 
Brilacidin was potent against multi-drug resistant staphylococci. 
1.3.2.  
Clinical Studies 
The clinical development program for Brilacidin includes healthy volunteers and patients with 
acute bacterial skin and skin structure infections (ABSSI), head and neck cancer (HNC), and 
ulcerative proctitis (UP)/ ulcerative proctosigmoiditis (UPS). 
As of December 2020, eight clinical trials have been completed;  
• 5 clinical trials with Brilacidin administered intravenously (3 in healthy volunteers and 
2 in patients with ABSSSI; total n treated with Brilacidin = 412); and 
• 2 clinical trials with Brilacidin administered topically (1 in HNC patients, by oral 
rinse, in attenuating oral mucositis [n treated with Brilacidin = 29]; and 1 in patients, 
by rectal retention enema, for mild to moderate UP or UPS [n treated with Brilacidin = 
17]); and 
• 1 with Brilacidin administered orally (1 in healthy volunteers, by delayed release oral 
tablet [n treated with Brilacidin = 6]). 
Please refer to the Investigator’s Brochure for details on the studies conducted with 
administration other than intravenous; a summary of intravenous experience is presented here. 
1.3.2.1.  
Clinical Safety 
The safety profile of Brilacidin has already been established from intravenous dosing of over 
400 subjects in the Brilacidin program. Intravenous administration of Brilacidin has identified 
transient, dose-limiting (non-serious) side effects of paresthesias and hypoesthesias, and 
elevation of blood pressure and heart rate at higher doses that normalized with treatment or 
discontinuation of study treatment. 
The most prominent neurological symptoms related to Brilacidin dosed intravenously 
included tingling and or numbness of the following body regions: lips/mouth/throat (lips), 
face/head/neck (face), fingers/hands (fingers), toes/feet (toes), and torso or perineal sites. 
These symptoms and signs were transient in nature and resolved after drug discontinuation. 
There did not appear to be any gender differences. In the opinion of an independent 
neurologist expert, the neurological adverse events related to Brilacidin likely represent a 
pharmacologic effect and are unlikely explained by neurotoxicity. 
Transient increases in blood pressure and heart rate have been noted in all IV-dosed clinical 
trials. While tachycardia is of concern, such adverse events are uncommon (i.e., 0, 1 or 2 non-
serious AEs per Brilacidin treatment group in Phase 2 studies; total patients treated = 319). 
Resolution of the observed blood pressure increases is accompanied by normalization of heart 
rate. Therefore, blood pressure increase has been the focus of safety management for IV 
dosing with Brilacidin. Data across clinical trials indicate that blood pressure increases are 


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unlikely to be >180/110 mmHg or be associated with progressive target organ involvement 
resulting in neurological, cardiac or renal complications. However, there were three patients 
treated with Brilacidin in Study PMX63-203 (5-day treatment regimen) who developed 
hypertension near 220/120 mmHg. When study drug was discontinued and patients were 
treated with anti-hypertensive medications, their blood pressure decreased; in all cases, blood 
pressure increases were observed as gradual over hours or days allowing for prompt medical 
intervention. For the Phase 2b study CTIX-BRI-204, which included the initial 3-day 
treatment regimen to be tested in this Phase 2 study for COVID-19, none of the reported 
blood pressure events were considered serious or severe in any treatment arm. 
In the IV program, 13 treatment-emergent serious adverse events (SAEs) have been observed 
(Table 2). Of these SAEs, none led to death, and 3/13 are considered treatment-related (10/13 
are considered not treatment-related). 
The three SAEs considered treatment-related occurred in the Phase 2a study (PMX63-203), 
on the treatment arm indicated;  
• Thrombocytosis (0.4 mg/kg Day 1, followed by 0.3 mg/kg on Days 2 to 5) 
• Hypertensive crisis (0.75 mg/kg Day 1, followed by 0.35 mg/kg on Days 2 to 5) 
• Hypertensive crisis (1.0 mg/kg Day 1, followed by 0.3 mg/kg on Days 2 to 5) 
All SAEs were followed to resolution. 
 


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Table 2: 
Serious Adverse Events reported in Clinical Trials with Brilacidin by 
intravenous administration 
Study 
Number 
Type of 
subjects 
exposed 
Details of Serious Adverse Event 
SOC 
SAE (preferred term) 
No. of 
eventsa 
Related to 
Brilacidin? 
PMX63-103 
Healthy 
volunteers 
Cardiac disorders 
Atrial fibrillation 
1 
No 
PMX63-203 
Patients with 
ABSSSI 
Blood and lymphatic 
system disorders 
Thrombocytosis 
1 
Yes 
Infections and 
infestations 
Staphylococcal 
infection 
1 
No 
Vascular Disorders 
Deep Vein Thrombosis 
1 
No 
Hypertensive crisis 
2 
Yes 
CTIX-BRI-204 
Patients with 
ABSSSI 
General disorders 
and administration 
site conditions 
Chest pain 
1 
No 
Infections and 
infestations 
Cellulitis 
3 
No 
Skin infection 
1 
No 
Tooth abscess 
1 
No 
Injury, poisoning and 
procedural 
complications 
Multiple injuries 
1 
No 
SOC = System Organ Class; SAE = Serious Adverse Event 
a Counts reflect number of subjects reporting one or more adverse events that map to the MedDRA dictionary term. 
At level of summarization (Preferred Term) subjects are counted once. 
1.3.2.2.  
Clinical Pharmacokinetics 
In Phase 1 studies, plasma concentrations of Brilacidin from intravenous administration 
showed linear pharmacokinetics that were dose-dependent for all dosing regimens and tested 
dose-levels. Gender was not a significant factor on drug disposition. Renal excretion does not 
appear to be a significant elimination pathway given the little (<1%) unchanged drug 
recovered in urine (Study PMX63-103). 
Given the relatively sparse PK sampling scheme employed in the Phase 2 studies, a 
population PK model was used to describe the time-course of Brilacidin using data pooled 
from the three studies conducted in healthy subjects and two Phase 2 studies conducted in 
patients with ABSSSI. The resultant predicted concentration-time profiles were used to 
estimate exposure to Brilacidin in the Phase 2 patients. Summary statistics for the resultant 
PK parameters and PK exposure estimates are provided in Table 3 for Study PMX63-203 and 
Table 4 for Study CTIX-BRI-204. 
The three-compartment population PK model results in different estimates of half-life from 
the Phase 1 studies as the estimates from those studies are derived using non-compartmental 


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methods. Despite the differences in methodology, the median values for half-life of the 
distribution phase t1/2,β (~10 h) and the terminal elimination phase t1/2,γ (~60-70 h) are in 
the expected range given the half-life estimates from the non-compartmental analyses of 
Phase 1 studies, with mean values ranged from 16.9 to 23.0 h (multiple dose study PMX63-
102). 
Table 3: 
Median (mix, max) Brilacidin Plasma Pharmacokinetic Parameters derived 
in Study PMX63-203 (IV dosing) 
Cohort 
N 
Cmax 
(ng/mL) 
Tmax 
(h) 
Cmin 
(ng/mL) 
AUC0-24h 
(μg•h/mL) 
AUC0-72h 
(μg•h/mL) 
AUC0-168h 
(μg•h/mL) 
t1/2(β) 
(h) 
t1/2(γ) 
(h) 
Cl 
(mL/h/kg) 
Vss 
(mL/kg) 
Low-dose 
(D1 0.4 mg/kg;  
D2-5 0.3 mg/kg/day) 
Day 1 
50 
5190 
(3150, 
33300) 
1.00 
(0.500, 
1.17) 
1040 
(603, 
3850) 
50.0 
(31.9, 
198) 
163 
(98.8, 
635) 
333  
(182, 
1480) 
10.0 
(5.77, 
13.3) 
71.4  
(26.8, 
897) 
4.01 
(0.766, 
7.54) 
249 
(74.5, 
1550) 
Day 2 
50 
5010 
(3000, 
28700) 
1.00 
(0.500, 
1.00) 
1260 
(619, 
5660) 
54.3 
(32.7, 
200) 
 
 
 
 
 
 
Day 3 
49 
5310 
(3060, 
30500) 
1.00 
(0.500, 
1.08) 
1360 
(623, 
7150) 
59.4 
(31.7, 
237) 
 
 
 
 
 
 
Day 4  
49 
5520 
(3040, 
32000) 
1.00 
(0.500, 
1.08) 
1630 
(677, 
8350) 
62.2 
(32.9, 
268) 
 
 
 
 
 
 
Day 5 
47 
5610 
(3060, 
33200) 
1.00 
(0.500, 
1.08) 
NA 
64.4 
(27.4, 
239) 
 
 
 
 
 
 
Medium-dose  
(D1 0.75 mg/kg;  
D2-5 0.35 mg/kg/day) 
Day 1 
54 10300 
(3910, 
53600) 
1.00 
(0.920, 
1.25) 
1920 
(717, 
3300) 
91.8 
(47.8, 
204) 
243  
(109, 
434) 
444  
(173, 
808) 
9.93 
(3.91, 
13.8) 
63.0 
(20.5, 
2000) 
4.11 
(0.316, 
11.0) 
265 
(120, 
1760) 
Day 2 
53 
6640 
(2770, 
27700) 
1.00 
(0.830, 
1.12) 
1750 
(516, 
3500) 
75.9 
(32.7, 
121) 
 
 
 
 
 
 
Day 3 
52 
6630 
(2490, 
27000) 
1.00 
(0.830, 
1.17) 
1830 
(518, 
3820) 
73.9 
(28.5, 
130) 
 
 
 
 
 
 
Day 4  
52 
6710 
(2390, 
27200) 
1.00 
(0.920, 
1.00) 
1920 
(544, 
4100) 
76.0 
(29.0, 
137) 
 
 
 
 
 
 
Day 5 
52 
6810 
(2420, 
27500) 
1.00 
(0.920, 
1.58) 
NA 
70.1 
(23.7, 
143) 
 
 
 
 
 
 
High-dose  
(D1 1.0 mg/kg;  
D2-5 0.3 mg/kg/day) 
Day 1 
53 14300 
(7860, 
29300) 
1.00 
(0.650, 
1.08) 
2630 
(1610, 
5380) 
126  
(83.7, 
228) 
289  
(165, 
572) 
501  
(208, 
1140) 
9.34 
(6.43, 
14.6) 
57.5 
(31.1, 
184) 
3.98 
(1.70, 
6.88) 
221 
(122, 
670) 


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Cohort 
N 
Cmax 
(ng/mL) 
Tmax 
(h) 
Cmin 
(ng/mL) 
AUC0-24h 
(μg•h/mL) 
AUC0-72h 
(μg•h/mL) 
AUC0-168h 
(μg•h/mL) 
t1/2(β) 
(h) 
t1/2(γ) 
(h) 
Cl 
(mL/h/kg) 
Vss 
(mL/kg) 
Day 2 
49 
7840 
(4660, 
15600) 
1.00 
(0.520, 
1.00) 
2040 
(815, 
5040) 
86.2 
(48.4, 
168) 
 
 
 
 
 
 
Day 3 
48 
7420 
(4130, 
15200) 
1.00 
(0.500, 
1.00) 
2090 
(839, 
5310) 
81.1 
(43.8, 
177) 
 
 
 
 
 
 
Day 4  
46 
7380 
(4340, 
15500) 
1.00 
(0.520, 
1.02) 
2120 
(816, 
5630) 
81.3 
(44.5, 
190) 
 
 
 
 
 
 
Day 5 
46 
7300 
(4410, 
15900) 
1.00 
(0.830, 
1.00) 
NA 
74.0 
(35.0, 
182) 
 
 
 
 
 
 
 
Table 4: 
Median (mix, max) Brilacidin Plasma Pharmacokinetic Parameters derived 
in Study CTIX-BRI-204 (IV dosing) 
Cohort 
N 
Cmax 
(ng/mL) 
Tmax 
(h) 
Cmin 
(ng/mL) 
AUC0-24h 
(μg•h/mL) 
AUC0-72h 
(μg•h/mL) 
AUC0-168h 
(μg•h/mL) 
t1/2(β) 
(h) 
t1/2(γ) 
(h) 
Cl 
(mL/h/kg) 
Vss 
(mL/kg) 
Single 
Low-dose 
D1 0.6 
mg/kg 
54 
7190 
(3650, 
13600) 
1.02 
(0.750, 
1.47) 
NA 
68.2 
(38.1, 
120) 
103 
(53.9, 
207) 
126 
(63.1, 
285) 
10.6 
(4.00, 
13.9) 
66.0 
(30.9, 
371) 
4.16 
(1.89, 
8.82) 
275 
(108, 
1310) 
Single 
High-dose  
D1 0.8 
mg/kg 
53 
8690 
(4330, 
17600) 
1.00 
(0.933, 
1.83) 
NA 
86.9 
(51.0, 
145) 
136 
(69.0, 
286) 
167 
(78.8, 
383) 
10.8 
(5.08, 
13.9) 
57.3 
(26.4, 
553) 
4.27 
(1.95, 
8.75) 
251 
(116, 
1310) 
Multiple-dose 
D1 0.6 mg/kg;          
D2-3 0.3 mg/kg/day 
 
 
 
 
 
 
 
 
 
Day 1 
52 
6570 
(3740, 
15100) 
1.00 
(0.850, 
1.70) 
1680 
(402, 
4250) 
73.9 
(39.2, 
161) 
180  
(103, 
463) 
244  
(132, 
720) 
10.5 
(6.43, 
15.3) 
70.3 
(32.0, 
323) 
4.33 
(1.46, 
8.41) 
271 
(100, 
700) 
Day 2 
52 
4850 
(2610, 
10800) 
1.02 
(1.00, 
1.08) 
1460 
(680, 
4950) 
57.4 
(24.5, 
161) 
 
 
 
 
 
 
Day 3 
50 
4630 
(2570, 
11500) 
1.02 
(1.00, 
1.22) 
NA 
47.4 
(26.3, 
140) 
 
 
 
 
 
 
1.3.2.3.  
Clinical Efficacy 
Brilacidin by intravenous administration 
Brilacidin demonstrated marked clinical efficacy in treatment of ABSSSI in two Phase 2 
clinical trials. In a Phase 2a clinical study involving 215 patients with ABSSSI, clinical 
success in treating the infections was found in approximately 90% of patients in each of three 
Brilacidin treatment groups, varying slightly by timepoint and analysis population, compared 
with daptomycin as active control (SLD = single loading dose; dose in mg/kg): (1) 1.0 SLD + 
0.35 qd x 4 days, (2) 0.75 SLD + 0.35 qd x 4 days, (3) 0.40 SLD + 0.30 qd x 4 days, and (4) 
daptomycin 4 qd x 7 days. In all efficacy analyses, across all treatment arms, the 95% 


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confidence intervals around the point estimates for clinical success overlapped, indicating a 
consistent and high clinical success rate, similar to the active comparator (daptomycin). 
The clinical response results observed in Phase 2a Study PMX63-203 were confirmed in a 
Phase 2b clinical study (CTIX-BRI-204) which treated 209 patients with ABSSSI. Clinical 
success in treating the infections found was achieved across the three Brilacidin treatment 
groups and daptomycin active control group between 83.3% to 100%, and all 95% confidence 
intervals overlapped. The 4 treatment groups were (SLD = single loading dose; dose in 
mg/kg): (1) 0.6 SLD, (2) 0.8 SLD, (3) 0.60 SLD + 0.30 qd x 2 days, and (4) daptomycin 4 qd 
x 7 days. Patients given Brilacidin on active treatment days were also given placebo on other 
days to maintain the double-blind design. 
After an extensive PK/PD analysis and discussion with experts (including a meeting with 
FDA), it was deemed that cardiovascular and neurosensory effects were dose-related, and 
when given systemically in lower doses, as in the Phase 2b ABSSSI trial, these effects are 
likely to reduce in both frequency and severity.  
The lowest dose tested (0.6 SLD) in the Phase 2b Study CTIX-BRI-204 was efficacious 
(comparable to the daptomycin arm) and generally well-tolerated, and is the IV dose proposed 
for progression to Phase 3 testing in the ABSSSI indication. 
Brilacidin by other routes of administration 
Brilacidin administered as an oral rinse has demonstrated anti-inflammatory efficacy in a 
Phase 2 clinical trial for attenuation of oral mucositis in adult patients with HNC receiving 
chemoradiation therapy. Brilacidin oral rinse markedly reduced the incidence of severe oral 
mucositis through completion of radiation, relative to placebo. Safety findings observed were 
typical for patients with head and neck cancer being treated with chemoradiation therapy, 
with a safety profile for Brilacidin comparable to placebo. 
Brilacidin administered per rectum as a daily (at night) retention enema has demonstrated 
anti-inflammatory efficacy in a Phase 2 clinical trial for induction of remission of active mild 
to moderate ulcerative proctitis (UP) or ulcerative proctosigmoiditis (UPS). Brilacidin rectal 
enema resulted in clinical remission after 6 weeks of treatment in a majority of subjects for 
the doses tested. Endoscopic improvement was demonstrated. Certain markers indicative of 
inflammation – including fecal calprotectin, and IL-1β and IL-6 measured in colon tissue 
biopsies (from rectum and sigmoid) at Week 6 – reduced with study treatment, supporting the 
treatment group clinical responses. 


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1.4.  
Dose Rationale 
In this study, all subjects are to receive local SoC plus allocated study treatment in addition. 
Two IV study treatment arms are planned: 
• 
SoC + Brilacidin IV 0.6 mg/kg (D1), 0.3 mg/kg (D2 and D3) with potential to expand 
dosinga of 0.3 mg/kg on D4 and D5 
• 
SoC + Saline IV infusion (D1, D2, and D3) with potential to expand dosinga on D4 and 
D5 
a Note: Dependent on safety review and recommendation by the Data Monitoring Committee (DMC). 
D1, D2, and D3 (above) refer to Day 1, Day 2 and Day 3 of study treatment. Similarly, D4 and D5 are Day 4 and 
Day 5. 
The doses of Brilacidin are selected from the dose range previously tested in the IV program.  
From the Phase 2 program conducted with Brilacidin administered IV for the indication of 
ABSSSI, a multiple dose regimen (0.6 mg/kg on Day 1, followed by 0.3 mg/kg on Days 2 and 
3) from the Phase 2b study (CTIX-BRI-204) is initially selected for testing in this trial.  
An independent Data Monitoring Committee (DMC) will be established to conduct periodic 
safety reviews (Section 8.1.6). An initial safety review is planned to occur after approximately 
20 randomized subjects have completed up to Day 15. This initial interim analysis will focus 
on review of cardiovascular safety, vital signs and adverse events. At the time of the initial 
interim safety review (or any subsequent safety review), the DMC may recommend 
expanding dosing to Days 4 and 5 at the same doses as on Days 2 and 3. Brilacidin was also 
administered IV for 5 days of treatment in the ABSSSI program, in the Phase 2a study 
(PMX63-203), albeit with slightly different 5-day dosing regimens. 
The rationale for looking to expand treatment duration to five days, from the initial dose 
regimen of three days, is to be able to provide a longer duration of systemic Brilacidin 
exposure at a level that can strongly suppress SARS-CoV-2 virus activity, and any associated 
symptoms, and thus provide a more optimal therapy to hospitalized patients with moderate or 
severe COVID-19. The longer treatment duration is expected to allow for greater impact of 
Brilacidin treatment and provide enhanced benefit to the patient, with the 5-day regimen 
incorporated only following recommendation by the DMC subsequent to DMC review of all 
available safety data following safety review interim analysis(es). 
The safety profile of the proposed 3-day, and potential 5-day, regimens are covered by the 
dose range previously investigated, and the safety findings are regarded as manageable for 
hospitalized COVID-19 patients meeting the protocol entry requirements. The potential for 
the selected dose regimens to achieve efficacy in human has been modeled, using plasma 
concentration data from the prior ABSSSI development program and comparing to derived in 
vitro antiviral efficacy parameters (IC50 and IC90) from experiments with human lung 
epithelial cells. 


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1.4.1.  
Safety Profile for Selected Doses 
Safety Profile: Up to three (3) days multiple dose regimen 
The adverse events summary from Phase 2b Study CTIX-BRI-204 is presented in Table 5. 
Numbness/Tingling (N/T), defined as paraesthesia/paraesthesia oral or hypoaesthesia/ 
hypoaesthesia oral, was the most frequently reported AE, reported for 58.5% to 73.6% of 
subjects in the Brilacidin groups, and 8.0% for the daptomycin group, respectively. All 
numbness/tingling events tended to be transient, mild in intensity, and were reported by the 
investigator as related to study treatment.  
Adverse events were reported for 46% of subjects in the daptomycin group and for 79.2-
92.5% of subjects across the Brilacidin groups. Excluding N/T events, all-causality AE rates 
across all treatment groups were 52.8%, 56.6%, 69.8%, and 46.0%, and drug-related AE rates 
were 7.5%, 7.5%, 15.1%, and 26.0%, in the Brilacidin 0.6 mg/kg, 0.8 mg/kg, 0.6/0.3 mg/kg 
and daptomycin groups, respectively. Nausea was reported in 13.8% of the combined 
Brilacidin groups, and in 8.0% of the daptomycin group. 
Infrequent, transient episodes of “hypertension” or “blood pressure increased” events (i.e., 
SBP >160 mmHg) were reported in 2 (3.8%), 9 (17.0%), 14 (26.4%), and 5 (10.0%) subjects, 
respectively, for the Brilacidin 0.6 mg/kg, 0.8 mg/kg, 0.6/0.3 mg/kg and daptomycin groups. 
Of note, the incidence of blood-pressure related AEs in the daptomycin group was higher than 
in the single dose 0.6 mg/kg arm, and daptomycin is not known to affect blood pressure. 
Hence, sensitivity of data collection and reporting would appear to indicate that, for the 
reporting in this study, the background rate for such blood pressure related AEs is up to 
~10%, and that for the single dose 0.6 mg/kg arm, the incidence indicates no distinct drug-
related adverse effects. None of the reported blood pressure events were considered serious or 
severe; in any treatment arm, and the majority were reported as related to study drug. 
Table 5: 
Adverse Events summary for Study CTIX-BRI-204 (Safety Population) 
Type of Adverse Event 
Brilacidin 
D1 0.6 mg/kg 
Brilacidin 
D1 0.8 mg/kg 
Brilacidin 
D1 0.6 mg/kg; 
D2-3 0.3 mg/kg/day 
Daptomycin 
D1-7 4 mg/kg/day 
 
N=53 
N=53 
N=53 
N=50 
None 
20.8% (11) 
18.9% (10) 
7.5% (4) 
54.0% (27) 
At least 1 treatment-
emergent 
79.2% (42) 
81.1% (43) 
92.5% (49) 
46.0% (23) 
Leading to study drug 
withdrawal 
5.7% (3) 
1.9% (1) 
3.8% (2) 
2.0% (1) 
At least 1 related 
66.0% (35) 
69.8% (37) 
88.7% (47) 
34.0% (17) 
At least 1 SAE 
5.7% (3) 
1.9% (1) 
3.8% (2) 
0 
At least 1 ‘tingling’ 
and/or ‘numbness’ 
58.5% (31) 
62.3% (33) 
73.6% (39) 
8.0% (4) 


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Type of Adverse Event 
Brilacidin 
D1 0.6 mg/kg 
Brilacidin 
D1 0.8 mg/kg 
Brilacidin 
D1 0.6 mg/kg; 
D2-3 0.3 mg/kg/day 
Daptomycin 
D1-7 4 mg/kg/day 
At least 1 ‘hypertension’ 
and/or ‘blood pressure 
increased’ 
3.8% (2) 
17.0% (9) 
26.4% (14) 
10.0% (5) 
There were no deaths in the study, and a total of 7 SAEs were reported for 6 subjects, all in 
the Brilacidin treatment groups: three in the 0.6 mg/kg group, one in the 0.8 mg/kg group, and 
two in the 0.6/0.3 mg/kg group.  None were considered treatment-related by the investigator, 
and none were blood pressure-related or related to peripheral neurologic events. 
Of the 7 withdrawals from the study due to adverse events, 6 were Brilacidin-treated subjects 
and 1 was a daptomycin-treated subject. Four (4) of these withdrawals were for serious 
adverse events. Of the other three withdrawals, two were classified as moderate severity 
hypoaesthesia related to study drug (one in the 0.8 mg/kg group and one in the 0.6/0.3 mg/kg 
group), occurring on Day 1 after completing the first Brilacidin dose. The remaining study 
withdrawal occurred after an allergic reaction to daptomycin. 
Safety Profile: Five (5) days multiple dose regimen 
The adverse events summary from Phase 2a Study PMX63-203 is presented in Table 6. Safety 
analysis showed 87% of patients in the highest dose group experienced at least one peripheral 
sensory effect, primarily tingling (paresthesia) and numbness (hypoesthesia). The lowest dose 
produced sensory effects in 65% of patients. Excluding numbness/tingling, the treatment-
related adverse event rates were similar across treatment groups. 
Table 6: 
Treatment-Related Adverse Events in Study PMX63-203 (Safety Population) 
Treatment-Related 
Adverse Events 
(TRAEs) 
Low-dose 
(D1 0.4 mg/kg; 
D2-5 0.3 mg/kg/day) 
Medium-dose  
(D1 0.75 mg/kg; 
D2-5 0.35 mg/kg/day) 
High-dose 
(D1 1.0 mg/kg; 
D2-5 0.3 mg/kg/day) 
Daptomycin 
(D1-7 4 mg/kg/day) 
 
N=52 
N=54 
N=54 
N=55 
At least one TRAE 
75% (39) 
70.4% (38) 
94.4% (51) 
12.7% (7) 
Excluding numbness 
& tingling 
9.6% (5) 
5.6% (3) 
7.4% (4) 
10.9% (6) 
Numbness & 
tinglinga 
65.4% (34) 
64.8% (35) 
87.0% (47) 
1.8% (1) 
Discontinued due to 
TRAEb 
1.9% (1) 
3.7% (2) 
9.2% (5) 
0 
a Including burning sensation 
b TRAE discontinuations were due to hypertension, nausea/vomiting, vertigo, and injection site pain 
Approximately 80% of the sensory effects caused by Brilacidin were mild and the remainder 
were moderate in intensity. Only one patient who was in the highest dose group experienced a 
severe sensory effect. The effects were noted earlier (Day 1) for the higher two Brilacidin 


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dose groups compared with the lowest dose group (Day 3). These events were transient and 
did not require medical intervention. All (100%) of patients having a sensory AE had 
resolution of these effects by the conclusion of the trial. There were no discontinuations due 
to sensory AEs (numbness/tingling). 
There were no deaths in the study, and 5 patients experienced a serious adverse event (SAE) 
of which 3 SAEs were regarded as treatment-related. These treatment-related SAEs were 
hypertensive crisis (n=1 in medium-dose group; n=1 in high-dose group; both discontinued 
study), and thrombocytosis (n=1 in low-dose group). 
Blood pressure was measured pre-dose, during infusion, and 3 hours post-infusion each day 
of the 7-day treatment period. Given that antibiotics are dosed acutely – and not over a 
period of months or years – the systolic blood pressure measurement was deemed more 
relevant than the diastolic blood pressure measurement by consulted cardiology experts. 
Although transient elevations in SBP were observed across the treatment groups, there was 
no evidence of end-organ involvement, nor of sustained hypertension by the end of the 
treatment period (Table 7). 
Table 7: 
Mean Systolic Blood Pressure Effects in Study PMX63-203 (Safety 
Population) 
Systolic Blood 
Pressure 
Low-dose 
(D1 0.4 mg/kg; 
D2-5 0.3 mg/kg/day) 
Medium-dose  
(D1 0.75 mg/kg; 
D2-5 0.35 mg/kg/day) 
High-dose 
(D1 1.0 mg/kg; 
D2-5 0.3 mg/kg/day) 
Daptomycin 
(D1-7 4 mg/kg/day) 
 
N=52 
N=54 
N=54 
N=55 
Screening 
Mean SBP (mmHg) 
129.1 
125.1 
128.1 
127.8 
Day 5, 3 hr post-dose 
Mean SBP (mmHg) 
129.9 
127.3 
128.8 
125.3 
Mean Change 
(mmHg) 
+3.0 
+3.8 
+0.8 
-2.3 
Moreover, across the three Brilacidin treatment groups, the outlier analysis revealed a low 
rate (6/160; 3.8%) of hypertension events, defined as SBP ≥180 mmHg in at least one 
measurement during the treatment period. Consulted cardiology experts felt that this cut-off 
was the most clinically relevant for an acutely dosed drug. These six events appeared to be 
dose-related (low-dose, 1 event; medium-dose, 2 events; high-dose, 3 events); however, 
geographic clustering is a potential confounder, as these cases occurred at just 3 of the 21 
enrolling sites. Only one of these patients (high-dose group) had elevated SBP ≥180 mmHg 
for two consecutive measurements (next day). 
There were three patients (from the medium and high dose groups) who developed 
hypertension near 220/120 mmHg. When study drug was discontinued and patients were 
treated with anti-hypertensive medications, their blood pressure decreased. In all cases, blood 


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pressure increases were observed as gradual over hours or days allowing for prompt medical 
intervention. 
Given the overall risk:benefit assessment for use of Brilacidin in treatment of COVID-19, the 
proposed protocol doses of Brilacidin are supported by the available safety data in the 
previous Phase 2, and additional Phase 1, clinical studies with Brilacidin administered 
intravenously. Blood pressure monitoring during study treatment to monitor for safety alerts is 
described in Section 1.4.2. 
1.4.2.  
Vital Signs Measurements during Study Treatment 
The blood pressure data from the prior Phase 2 ABSSSI program was examined for the 
following criteria: 
• 
Systolic blood pressure increased: ≥180 and increase from baseline ≥20 
• 
Diastolic blood pressure increased: ≥110 and increase from baseline ≥15 
Table 8: 
Number of Patients meeting Blood Pressure Criteria in the ABSSSI 
Program, by Study (Safety Population) 
Study PMX63-203 
BP Criteria 
Low-dose 
(D1 0.4 mg/kg; 
D2-5 0.3 mg/kg/day) 
Medium-dose  
(D1 0.75 mg/kg; 
D2-5 0.35 mg/kg/day) 
High-dose 
(D1 1.0 mg/kg; 
D2-5 0.3 mg/kg/day) 
Daptomycin 
(D1-7 4 mg/kg/day) 
N=52 
N=54 
N=54 
N=55 
Single 
Confirmed 
Single 
Confirmed 
Single 
Confirmed 
Single 
Confirmed 
SBP ≥180 and increase 
from baseline ≥20 
1 
1 
2 
2 
3 
1 
0 
0 
DBP ≥110 and increase 
from baseline ≥15 
1 
0 
4 
4 
5 
2 
0 
0 
Study CTIX-BRI-204 
BP Criteria 
Brilacidin 
D1 0.6 mg/kg 
Brilacidin 
D1 0.8 mg/kg 
Brilacidin 
D1 0.6 mg/kg; 
D2-3 0.3 mg/kg/day 
Daptomycin 
D1-7 4 mg/kg/day 
N=53 
N=53 
N=53 
N=50 
Single 
Confirmed 
Single 
Confirmed 
Single 
Confirmed 
Single 
Confirmed 
SBP ≥180 and increase 
from baseline ≥20 
0 
0 
3 
1 
5 
2 
2 
0 
DBP ≥110 and increase 
from baseline ≥15 
0 
0 
7 
4 
2 
0  
1 
0 
In Study PMX63-203, single BP values were measured; in Study CTIX-BRI-204, single BP values was reported as the average of triplicate 
measurements. A confirmed value is a value either repeated at timepoint, or by measurement meeting that criteria at a different timepoint. 
In Study PMX63-203, patients that met the BP noted were typically treated for increased 
blood pressure, with IV and/or oral anti-hypertensive treatments; in Study CTIX-BRI-204, 
such concomitant treatment was not initiated. 


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Vital signs were measured more intensely in Study CTIX-BRI-204 than in Study PMX63-
203. 
In this study, blood pressure and pulse rate measurements will be measured more intensely 
during the treatment period with study drug, during hospitalization. On Days 1-3 (and 
potentially Day 4-5 also, after initial interim safety readout), measurements will be made pre-
dose, within no more than 30 mins after the end of infusion, and 3 hours (±30 mins) post-start 
of infusion (i.e., ~2 hours post-end of infusion). 
If systolic blood pressure ≥ 180 mmHg and increase from baseline ≥ 20 mmHg, the 
measurement is to be repeated within 15-30 minutes. If the repeat measurement is confirmed, 
the attending physician is to review the patient profile and determine if treatment for 
hypertension is needed. After a confirmed systolic blood pressure elevation, blood pressure 
measurements are to be performed approximately every 4 hours or as frequently as necessary 
in accordance with local standard of care. 
Similarly, if diastolic blood pressure ≥ 110 mmHg and increase from baseline ≥ 15 mmHg, 
the measurement is to be repeated within 15-30 minutes. If the repeat measurement is 
confirmed, the attending physician is to review the patient profile and determine if treatment 
for hypertension is needed. After a confirmed diastolic blood pressure elevation, blood 
pressure measurements are to be performed approximately every 4 hours or as frequently as 
necessary in accordance with local standard of care. 
See Section 8.1.5 (Adverse Events of Special Interest/ Blood Pressure category reporting) and 
Section 9.2 (Interim Analyses/ Data Monitoring Committee Reviews). 
1.4.3.  
PK/PD Modeling of Antiviral Efficacy Parameters for Selected Doses 
The potential for the selected dose regimens to achieve efficacy in human has been modeled, 
using plasma concentration data from the prior Phase 2b study (for the ABSSSI development 
program) and comparing to derived in vitro antiviral efficacy parameters (IC50 and IC90) 
from experiments with human lung epithelial cells. (The CC10 was also included in the 
preliminary modeling readouts, but is removed from final assessment readouts as that 
parameter – as an indicator of a safety margin – is not relevant since it is far above achievable 
Cmax concentrations following selected regimen dosing.) 
Using a previously-developed population PK model describing the disposition of Brilacidin 
(developed for the ABSSSI program - Van Wart et al 2015; Van Wart et al [ICPD] 2016), 
calculated PK/PD targets generated from the in vitro antiviral analyses (i.e., the IC50 and 
IC90, see Section 1.3.1.3), and demographic characteristics from clinical studies conducted 
with Brilacidin in patients with ABSSSI, an R Shiny simulation application was created to 
evaluate various Brilacidin dosing regimens for the treatment of patients with COVID-19. 
Protein binding is not adjusted for in the model, as the protein load in the in vitro assays has 
not been calculated - 10% fetal bovine serum is present in the Calu-3 cell culture. The total 
plasma Brilacidin concentrations is presented in the modeling, and the total concentration of 
Brilacidin present in vitro used. 


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Final modeling readouts for the selected dose regimens are shown in Figure 6 and Figure 7. 
The concentration-time profiles are presented on linear (A, left panel) and semi-log (B, right 
panel) Y axes.  
Plots of the median and 90% prediction interval (PI) for total plasma Brilacidin concentrations 
are shown, simulated for the selected dosing regimens. The IC90 and IC50 parameters from in 
vitro, as Brilacidin free-base values, are shown as dotted red-lines and are labelled 
accordingly. 
The figures demonstrate that the in vitro viral inhibition parameters of IC50 and IC90 are 
clinically-achievable concentrations for a sustained duration of time with the selected 
regimens:  
• For the 3 days multiple dose regimen [of 0.6 mg/kg (D1), 0.3 mg/kg (D2 and D3)], 
over the 7 days (168 hours) after start of treatment the simulated population median is 
above the IC50 threshold for 103 hours, with the IC90 threshold exceeded for 40.7 
hours. 
• For the 5 days multiple dose regimen [of 0.6 mg/kg (D1), 0.3 mg/kg (D2 to D5)], 
over the 7 days (168 hours) after start of treatment the simulated population median is 
above the IC50 threshold for 152 hours, with the IC90 threshold exceeded for 63.7 
hours. 
Figure 6:  PK/PD model simulation: Brilacidin 3 days multiple dose, 0.6 mg/kg (D1), 
0.3 mg/kg (D2 and D3) 
    
 
A  
B  


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Figure 7:  PK/PD model simulation: Brilacidin 5 days multiple dose, 0.6 mg/kg (D1), 
0.3 mg/kg (D2 to D5) 
 
The modeling is only taking one therapeutic property of Brilacidin into consideration - i.e., 
it’s applying in vitro antiviral parameter targets to simulated in vivo human plasma 
concentrations, without taking into consideration the anti-inflammatory potential of Brilacidin 
in vivo, which should also be able to impact the course of COVID-19 disease.  
Given the limitations of modeling, particularly application between in vitro and in vivo 
systems, the proposed doses selected appear appropriate for testing in this Phase 2 Proof-of 
Concept study. Selecting doses within the range previously tested in the Phase 2 program for 
the indication of ABSSSI also allows for an expected safety profile and known expectation of 
associated safety signals with those Brilacidin dose regimens. 
 
A 
B 


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2.  
STUDY OBJECTIVES AND ENDPOINTS 
Table 9: 
Objectives and Related Endpoints 
Objective(s) 
Endpoint(s) 
PRIMARY 
 
• 
To evaluate the clinical efficacy of 
Brilacidin IV treatment in addition to 
SoC, compared with SoC alone, in 
subjects with COVID-19 
Primary Endpoint based on the clinical status ordinal 
scale: 
• 
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 ordinal scale with response 
sustained through Day 29: 
- 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. 
SECONDARY 
 
• 
To assess multiple clinical measures of 
disease severity and disease burden 
- 
Composite endpoints, from the 
ordinal scale 
 
 
• 
Achieving recovery status scores (see definition in 
primary endpoint above) at Day 29 
• 
Composite endpoint by Day 29, defined as: 
- Death OR 
- Respiratory failure (requires invasive  
mechanical ventilation) 
- 
Clinical status measures, from the 
ordinal scale 
Endpoints based on the 8-point ordinal scale: 
• 
Achieving at least one-point/ two-point 
improvement in clinical status at Days 8, 15 and 
29 
• 
Time to at least one-point/ two-point improvement 
in clinical status 
• 
Clinical status over time 
- 
Change in the National Early 
Warning Score (NEWS2) 
• 
Time to a NEWS2 of ≤2 and maintained for 24 
hours 
• 
Change from baseline to Days 3, 5, 8, 11, 15, and 
29 in NEWS2 
• 
To assess the safety and tolerability of 
Brilacidin IV treatment in subjects with 
COVID-19 
• 
Incidence and severity of treatment-emergent 
Adverse Events (AEs), including Serious Adverse 
Events (SAEs) 


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• 
Clinically significant changes in laboratory 
measures and vital signs 
EXPLORATORY/ OTHER 
 
• 
In-hospital outcomes 
• 
Duration of hospitalization 
• 
Time to discharge 
• 
Duration of invasive mechanical ventilation 
• 
Duration of supplemental oxygen support 
• 
Duration of ECMO 
• 
No oxygen therapy (and/or peripheral oxygen 
saturation SpO2 > 93% on room air) at Days 8, 15 
and 29 
• 
All-cause mortality 
• 
28-day mortality (to Study Day 29) 
• 
To measure biological and 
immunological markers of 
illness/inflammation 
• 
Changes from baseline in biomarkers from blood 
samples may include, but are not limited to:  
CRP, ferritin, LDH, D-dimer, troponin T hs, 
absolute neutrophil count [at Days 2, 3, 5, 8, 11 
(while hospitalized) and/or on day of discharge; 
and Days 15 and 29 (by returning to the clinic/ by 
remote visit or if still hospitalized)]; 
and IL-1β, IL-6, IL-10, total IL-18, TNF-α [at 
Days 3, 5, 8, 11 (while hospitalized) and/or on day 
of discharge; and Day 15 (by returning to the 
clinic/ by remote visit or if still hospitalized)]; 
• 
To explore the change in the SARS-
CoV-2 viral load 
• 
Change from baseline in SARS-CoV-2 viral load 
from NP or OP samples at Days 3, 5, 8, 11 (while 
hospitalized) and/or on day of discharge; and Days 
15 and 29 (by returning to the clinic/ by remote 
visit or if still hospitalized) 
• 
To estimate the plasma 
pharmacokinetics of Brilacidin 
• 
Plasma concentrations of Brilacidin measured 
from blood samples collected on Days 1 to 4 


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3.  
STUDY OVERVIEW 
This Phase 2 study is a randomized, blinded, placebo-controlled, parallel group design. 
The target population to be treated are patients with moderate to severe COVID-19, 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 
hospitalized with respiratory distress but not yet requiring high-level respiratory support (as 
defined in exclusion criterion #2). 
The study is comprised of three parts (Figure 8): 
Figure 8:  Study Design Schematic 
 
Note: Study treatment is in addition to standard of care (SoC) 
BRI = Brilacidin; D = Day; EOS = End of Study; PBO = placebo; R = randomization 
Screening/ Baseline visit (Day -1 to 1): Lasts up to 24-48 hours and comprises screening/ 
baseline assessments. This visit will confirm that study inclusion and exclusion criteria are 
met by participants prior to randomization. 
Treatment period (Day 1-3 with potential to expand to Day 4-5): Randomized subjects will 
receive blinded study treatment once daily by IV infusion, in addition to SoC.  
Follow-up period (Day 4-6 through Day 60): Subjects will be assessed daily while 
hospitalized. Discharged patients will be asked to attend study visits at Days 15 and 29. (Of 
note: the median hospital stay for COVID-19 has been reported to be 12 days with an 
interquartile range of 1 to 14 days [Cao et al 2020]). All subjects will undergo a series of 
efficacy and safety assessments, including laboratory assays. Blood samples and 
nasopharyngeal (NP) swabs will be obtained on Days 1, 3, 5, 8, 11 (while hospitalized) and/or 


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on day of discharge; and Days 15 and 29 (by returning to the clinic/ remote visit or if still 
hospitalized). Note: NP swabs are to be collected. 
If subjects are discharged from hospital prior to Day 15, or Day 29, and a hospital visit is not 
possible, then visiting nursing services and mobile phlebotomy may support that visit 
remotely where these are available in accordance with local guidelines and should include all 
possible assessments (e.g., oxygen saturation with portable monitors). Every effort should be 
made to ensure discharged patient follow-up at Days 15 and 29, via a healthcare interaction 
(minimally by telephone call). A follow-up visit at Day 60(±10), by telephone call, is also 
included to confirm patient status. 
All subjects receive local SoC, plus allocated study treatment in addition. Two IV study 
treatment arms are planned: 
• SoC + Brilacidin IV 0.6 mg/kg (D1), 0.3 mg/kg (D2 and D3) with potential to expand 
dosinga of 0.3 mg/kg on D4 and D5 
• SoC + Saline IV infusion (D1, D2, and D3) with potential to expand dosinga on D4 
and D5 
a Note: Dependent on safety review and recommendation by the DMC. 
D1, D2, and D3 (above) refer to Day 1, Day 2 and Day 3 of study treatment. Similarly, D4 and D5 are Day 4 and 
Day 5. 
Treatment randomization is 1:1 (n=60 per arm). Randomization will also be stratified by 
(1) Age (≤65 years, >65 years), (2) Severity of disease (moderate, severe), and (3) Country. 
An independent Data Monitoring Committee (DMC) will be established to conduct periodic 
safety reviews (Section 8.1.6). An initial safety review is planned to occur after approximately 
20 randomized subjects have completed up to Day 15. This initial interim analysis will focus 
on review of cardiovascular safety, vital signs and adverse events that have occurred in the 
approximately 20 subjects to receive Days 1-3 of study treatment. A further safety review by 
the DMC is planned to occur after approximately 50% of subjects have completed up to Day 
29, to allow for unblinded monitoring of safety data around the study mid-point. The DMC 
may recommend expanding dosing to Days 4 and 5 (at the same doses as on Days 2 and 3), 
continuation of the Days 1-3 study dosing unchanged, or that the trial be interrupted or 
stopped for safety reasons. The DMC will be guided by the degree and incidence of 
hypertensive values/events observed in the ongoing study which should not exceed the 
number and/or severity of those observed in previous studies with Brilacidin IV treatment for 
expansion of dosing to occur as planned. 
The rationale for looking to expand treatment duration to five days, from the initial dose 
regimen of three days, is to be able to provide a longer duration of systemic Brilacidin 
exposure at a level that can strongly suppress SARS-CoV-2 virus activity, and any associated 
symptoms, and thus provide a more optimal therapy to hospitalized patients with moderate or 
severe COVID-19. The longer treatment duration is expected to allow for greater impact of 
Brilacidin treatment and provide enhanced benefit to the patient, with the 5-day regimen 


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incorporated only following recommendation by the DMC subsequent to DMC review of all 
available safety data following safety review interim analysis(es). 
Study stopping rules are presented in Section 7.7. Recommendation guidelines and details of 
the DMC will be prepared separately from this protocol in a DMC Charter. The charter may 
supersede the summary details presented here in the protocol. 


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4.  
STUDY POPULATION 
4.1.  
Inclusion Criteria 
Participants eligible for enrollment and inclusion in this study must meet all of the following 
criteria: 
1. 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. 
2. Male or non-pregnant female adults between 18 and 80 years of age, inclusive, at time of 
informed consent. 
3. SARS-CoV-2 infection confirmed by positive standard polymerase chain reaction (PCR) 
test (or equivalent/ other approved diagnostic test) ≤ 4 days before randomization. 
4. Currently hospitalized and requiring medical care for COVID. 
5. Moderate OR severe COVID-19, defined by respiratory function at screening, as below: 
Moderate, meet at least one of the following criteria: 
• Peripheral oxygen saturation SpO2 > 93% on room air; 
• Respiratory rate ≥ 20 to < 30 breaths per minute. 
Severe, meet 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. 
6. Body mass index (BMI) of ≥18 to <40kg/m2 at screening. 
7. Agrees to the collection of nasopharyngeal (NP) swabs and venous blood per protocol. 
8. 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. 
4.2.  
Exclusion Criteria 
Participants meeting ANY of the following criteria are not eligible for this study and are to be 
excluded: 
1. Participation in any other clinical trial of an investigational treatment. 


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2. Requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation 
(ECMO) at the time of randomization. 
3. Has explicitly expressed the wish not to receive intensive care support (Do not resuscitate 
or Do not intubate order) should this become necessary. 
4. 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. 
5. Requiring systemic anti-infective therapy for suspected or confirmed active 
bacterial/fungal/viral systemic infection other than COVID-19. 
6. 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. 
7. If has a history of hypertension in the last 3 months, must have been receiving appropriate 
anti-hypertensive therapy in accordance with local guidelines. 
8. Evidence of moderate or severe hepatic impairment (Child-Pugh Class B or C). 
9. Estimated GFR (eGFR) <30 mL/min/1.73m2 (based on CKD-EPI formula). 
10. Prior to a participant’s study entry, known allergies or intolerance to Brilacidin or 
formulation excipients. 
11. 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. 
12. Pregnancy or breast-feeding, or positive urine or serum pregnancy test in a pre-dose 
assessment. 
13. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception as defined 
below, throughout the study and for up to 30 days after stopping treatment. 
Effective contraception methods include: 
• Total abstinence (if this is the preferred and usual lifestyle of the subject).        
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before start of 


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study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
• Male partner sterilization (at least 6 months prior to screening). The vasectomized 
male partner should be the sole partner for that female subject. 
• Double barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/vaginal suppository. 
• Use of oral*, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception.                       
(*In the case of oral contraception, subjects should have been using the same pill on a 
stable dose for a minimum of 3 months before start of study treatment). 
• Intrauterine device (IUD) or intrauterine system (IUS)  
Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks before start of study treatment. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of childbearing potential. 
In addition, female subjects must also refrain from egg donation and in vitro fertilization 
during study treatment and for 7 days after stopping study treatment. 
14. 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. 
In addition, male participants must not donate sperm during study treatment and for 7 
days after stopping study treatment. 


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5.  
STUDY TREATMENT 
A separate pharmacy manual will be provided. 
5.1.  
Treatment Allocation 
Subject registration and random assignment to treatment will be accomplished using an 
Interactive Response Technology (IRT) to one of the treatment groups. 
Approximately 120 study participants will be randomized to receive either Brilacidin or 
placebo in addition to available SoC. Subjects that are eligible will be randomized to one of 
the following two IV study treatment arms in a ratio of 1:1 (n=60 per arm) 
• SoC + Brilacidin IV 0.6 mg/kg (D1), 0.3 mg/kg (D2 and D3) with potential to expand 
dosinga of 0.3 mg/kg on D4 and D5 
• SoC + Saline IV infusion (D1, D2, and D3) with potential to expand dosinga on D4 
and D5 
a Note: Dependent on safety review and recommendation by the DMC. 
D1, D2, and D3 (above) refer to Day 1, Day 2 and Day 3 of study treatment. Similarly, D4 and D5 are Day 4 and 
Day 5. 
Randomization of subjects to treatment will also be stratified by (1) Age (≤65 years, 
>65 years), (2) Severity of disease (moderate, severe), and (3) Country. 
Brilacidin for Injection concentrated solution, for dilution with normal saline for subsequent 
IV infusion, will be provided by the Sponsor. SoC administered alongside the study treatment 
will be supplied by the investigational site. 
5.2.  
Subject Numbering 
Each subject screened is assigned a unique subject number, which is a combination of the site 
number (three-digit) that is provided by the Sponsor, and a three-digit sequential number 
assigned at the site. Once assigned to a subject, the subject number will not be reused.  
At each study site, the first subject is assigned subject number -001, and subsequent subjects 
are assigned consecutive numbers (e.g., the second subject is assigned subject number -002, 
the third subject is assigned subject number -003). The Investigator or site staff will contact 
the IRT system and provide the requested identifying information for the subject to register 
them. 
If the subjects fails to be randomized for any reason, the IRT system must be notified of the 
decision being taken that the subject was not treated. The reason for not being treated will be 
entered into the eCRF/IRT system. 


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5.3.  
Treatment Blinding 
This is a double-blind study, and the identity of the investigational product and placebo 
control will be concealed by use of study treatments that are identical in presentation to the 
administering medical staff.  
The subject’s randomization number generated by the IRT system for a subject will be shared 
with the site’s unblinded pharmacist, and they will consult the open randomization code 
previously provided to them for this study.  
The unblinded pharmacist will keep the randomization code confidential throughout the 
conduct of the study, except in the event of subject medical emergencies for which individual 
subject unblinded may be initiated.  
5.4.  
Emergency Unblinding of Treatment 
In the event of a medical emergency, the subject-specific treatment may be identified; 
however, every effort should be made to maintain the blind. Unblinding at the study site for 
any other reason will be considered a protocol violation.  
Where possible, the Investigator (or designated physician) shall contact the Medical Monitor 
before breaking the blind for any subject.  
The subject-specific treatment code can be obtained from the site’s unblinded pharmacist, or 
from contacting the appropriate emergency phone number for the IRT System. Instructions on 
how to perform an unblinding will be provided separately. 
Any intentional or unintentional breaking of the blind is to be reported immediately to the 
Sponsor. When the blinding code for a subject has been broken, the reason must be fully 
documented.  
5.5.  
Investigational Product Supplies 
5.5.1.  
Description 
The investigational drug product supplied is Brilacidin for Injection, 50 mg/mL (free base), 
provided in 2 mL glass vials with 1 mL extractable volume, to be stored frozen at -20±5°C. 
The provided solution formulation contains 50 mg/mL of Brilacidin free base and 20% w/v 
hydroxypropyl-beta-cyclodextrin (Kleptose HPB) in water for injection. Brilacidin sterile 
concentrated solution is a clear, colorless to yellow to brown solution supplied in 2 mL clear 
glass vials with 13 mm Omniflex Plus serum stoppers and sealed with flip off seals. Each vial 
has a fill volume ~1.2 mL to ensure 1.0 mL extractable volume per vial. The sterile solution 
formulation provided requires further dilution with normal saline for subsequent intravenous 
infusion. 


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The 2 mL glass vials are labelled as containing “Brilacidin for Injection, 50 mg/mL (free 
base) for 1.0 mL extractable volume”. 
Brilacidin IV infusion requires unblinded pharmacist preparation at the study site; allows for 
blinded treatment administration by use of local blinded labelling. 
5.5.2.  
Storage Conditions 
Brilacidin vials must be stored according to the labeled storage conditions, which is to be 
stored frozen at -20±5°C. The Investigator, or an approved representative (e.g., pharmacist, 
designated study site staff member), will ensure that all investigational product is stored in a 
secured and locked area with restricted access. 
If any investigational product is deemed to have been exposed to temperatures outside the 
range noted above, the supplies should not be administered to any participant until the 
Sponsor provides further direction. 
5.5.3.  
Packaging and Labeling 
Vials will be packaged in cartons of at least 10 vials. 
Vial and carton labels will be in the local language (or in English in case allowed according to 
local regulation) and comply with the legal requirements of each country, as applicable. 
Labeling will include storage conditions for the study treatment and clearly identify for 
investigational use only. 
5.5.4.  
Dose Preparation 
For intravenous infusion administration, Brilacidin for Injection is diluted in sterile 0.9% w/v 
sodium chloride (normal saline) to provide the desired final dose within 8 hours of 
administration. Placebo IV infusion will be sterile 0.9% w/v sodium chloride (normal saline). 
Intravenous infusion requires unblinded pharmacist (or appropriate designee) preparation, 
with appropriate mg/kg per study participant prepared. The Brilacidin dose will be prepared 
according to the protocol-specified treatment regimen (see Section 5.1). Dose calculation for a 
subject’s study treatment infusions will be based on actual body weight measured at 
Screening. 
Dose preparation is to be conducted by an identified unblinded study pharmacist (or 
appropriate designee), the “dose preparer”. Prior to dilution, the appropriate number of 
Brilacidin vial(s) will be removed from freezer storage and thawed at room temperature for 
approximately 1 hour. The thawed vial(s) should be mixed by gentle inversion. The dose 
preparer will document on the appropriate vial labels the subject randomization number and 
date the vial was opened/used. 


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Using aseptic technique, the appropriate volume of Brilacidin 50 mg/mL (free base) required 
for subject dosing is to be added to a plastic infusion bag containing sterile 0.9 % saline, to 
achieve a final volume of 100 mL.  
An IV infusion set equipped with an in-line 0.2 μm membrane filter will be attached to the 
infusion bag. A label containing the subject's study number, randomization number, dose date, 
and protocol study number will be attached onto the infusion bag containing the prepared 
dose; the label will be blinded to the study treatment to be administered.  
The desired final dose in the infusion bag can be prepared within eight (8) hours of 
administration. The prepared, diluted drug product in the infusion bag is to be stored at room 
temperature not above 25°C, 77°F, in-between preparation and administration. 
Any unused Brilacidin 50 mg/mL (free base) solution remaining in an opened vial should be 
retained for performing drug accountability. Any next dose(s) for a subject is/(are) to be 
prepared from unopened frozen vials. 
5.5.5.  
Administration of Prepared Dose 
Diluted Brilacidin solution is stored at room temperature not above 25°C, 77°F, prior to use 
and is filtered through a 0.2 μm membrane when administered intravenously over 60 minutes. 
The placebo control arm will use 100 mL normal saline solution administered in the same 
way to maintain blinding. 
The identity of the prepared dose will be concealed by use of study treatments that are 
identical in presentation to the administering medical staff. 
The prepared study dose in the infusion bag provided to the medical staff will be administered 
intravenously by an infusion pump over a 60±5 minute interval into the peripheral vein; the 
IV infusion set must include an in-line 0.2 μm membrane filter. 
The IV line for study treatment should be dedicated. IV lines should not be flushed with 
dextrose 5% in water (D5W). Approximately two (or more) mL of 0.9 % saline may be used 
to flush the line before and after administration. Heparin (in 0.9% saline) may also be used 
following study treatment administration to keep the catheter patent. 
5.6.  
Investigational Product Handling and Accountability 
Investigational product must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site staff have access. Upon receipt, all study treatment must be stored according 
to the instructions specified on the label. 
It is the responsibility of the Investigator to ensure that the current disposition of the study 
treatments is maintained at his/her study site where investigational product is inventoried and 
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Investigational product is to be dispensed only in accordance with the protocol. 
A Drug Accountability Log must be maintained and contain an accurate record of the 
shipment and dispensing of investigational product. Monitoring of drug accountability will be 
performed by a study monitor during site visits or remotely, and at the completion of the trial. 
The original Drug Accountability Log should remain at the study site and a copy will be 
provided for the Trial Master File at the conclusion of the study. 
5.7.  
Return of Clinical Supplies 
All used and unused investigational product/packaging must be retained at the site until the 
conclusion of the study or until permission for disposition is granted. The study monitor will 
complete the final drug accountability and assist the site with return and/or destruction of 
investigational product/packaging at the end of the study. Used IV related supplies will be 
destroyed after use in compliance with local hospital or institutional policies. 


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6.  
THERAPIES AND MEDICATIONS 
6.1.  
Concomitant Medications and Concurrent Procedures 
All medications, procedures, non-drug therapies (including physical therapy and blood 
transfusions) administered after the participant was enrolled into the study will be captured in 
the eCRF.  
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Study Medical Monitor before 
randomizing a participant or allowing a new medication to be started. If the subject is already 
enrolled, contact the Study Medical Monitor to determine if the participant should continue 
participation in the study. 
For subjects discharged from hospital prior to Day 29, they must be told to notify the treating 
physician about any new medications he/ she takes through end of the study. 
During the course of the study, subjects may receive antiviral treatment, intravenous, oral or 
inhaled corticosteroids, antibiotics and other agents where these forms part of SoC for the 
treatment of COVID-19 at their participating site. 
6.1.1.  
Concomitant Medications to be used with caution 
Using the January 2020 FDA Guidance for in vitro DDI studies, available data indicates there 
is a potential for Brilacidin to reversibly inhibit CYP2C8, CYP2C9, and CYP3A4 with a 
possible although probably not likely time-dependent inhibition of CYP2B6. (Please refer to 
the Investigator’s Brochure for additional information). 
Investigators may, at their discretion, co-administer known inhibitors of CYP2C8, CYP2C9, 
and CYP3A4 during study treatment, but their duration should be kept as short as possible, 
and patients are to be closely monitored. Particularly, caution is advised when study treatment 
is co-administered with drugs that are sensitive substrates of CYP2C8, CYP2C9, and 
CYP3A4 and/or have a narrow therapeutic index. Table 10 presents a list of some clinical 
substrates for CYP2C8, CYP2C9 and CYP3A P450-mediated metabolism 
The patient and the treating physician should be aware of potential signs of adverse effects/ 
overdose of concomitant medication(s) and in the event of suspected study drug related 
toxicity; administration of study drug should be held according to the treating physician’s 
judgement. 
 
 


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Table 10:  List of Clinical Substrates for CYP2C8, CYP2C9 and CYP3A P450-
mediated metabolism 
 
Sensitive substrates 
Moderate sensitive 
substrates 
CYP2C8 
repaglinide(b) 
montelukast, pioglitazone, 
rosiglitazone 
CYP2C9 
celecoxib(c) 
glimepiride, phenytoin, 
tolbutamide, warfarin 
CYP3A 
alfentanil, avanafil, buspirone, conivaptan, darifenacin, 
darunavir(f), ebastine, everolimus, ibrutinib, lomitapide, 
lovastatin(g), midazolam, naloxegol, nisoldipine, 
saquinavir(f), simvastatin(g), sirolimus, tacrolimus, 
tipranavir(f), triazolam, vardenafil 
alprazolam, aprepitant, 
atorvastatin(c), colchicine, 
eliglustat(e), pimozide, 
rilpivirine, rivaroxaban, 
tadalafil 
budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavir(f), lurasidone, 
maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan 
 
Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index 
inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are 
drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given 
metabolic pathway in clinical DDI studies. Sensitive substrates of CYP3A with ≥10-fold increase in 
AUC by co-administration of strong index inhibitors are shown above the dashed line. Other 
elimination pathways may also contribute to the elimination of the substrates listed in the table above 
and should be considered when assessing the drug interaction potential. 
The list of clinical substrates was compiled from the FDA Guidance for in vitro DDI studies [link to 
“Table 3-1: Examples of clinical substrates for P450-mediated metabolism (for concomitant use 
clinical DDI studies and/or drug labeling) (12/03/2019)]”; from the Indiana University School of 
Medicine’s “Clinically Relevant” Table; and from the University of Washington’s Drug Interaction 
Database. Note that this may not be an exhaustive list. For a complete and most updated drug list, 
please check the website: https://.crediblemeds.org/healthcareproviders/drug-list. 
(a) Listed based on an in vivo induction study and the observed effect might be partly attributable to 
induction of other pathway(s). 
(b) OATP1B1 substrate. 
(c) Listed based on pharmacogenetic studies. 
(d) S-lansoprazole is a sensitive substrate in CYP2C19 EM subjects. 
(e) Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A. 
(f) Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. 
(g) Acid form is an OATP1B1 substrate 
Abbreviations: 
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; 
EM: extensive metabolizer; OATP1B1: organic anion transporting polypeptide 1B1. 


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7.  
STUDY PROCEDURES 
Refer to Table 1 for the schedule of assessments, with specific timepoints for study 
procedures. 
7.1.  
Subject Demographics/Other Baseline Characteristics 
7.1.1.  
Informed Consent 
Eligible participants may only be included in the study after providing IRB/EC-approved 
written informed consent prior to initiating screening for the study. Participants will be given 
the approved Informed Consent Form (ICF) describing the study and any risks associated with 
participation. The subject will be allowed as much time as needed to read and understand the 
information presented in the ICF. Appropriate study personnel will be available to answer any 
questions the subject might have regarding the study or study-related procedures. If the 
subject chooses to participate in the study, he or she will be asked to sign and date the consent 
form and will be provided with a copy for his or her records. 
If applicable, in cases where the participant’s legal/authorized representative gives consent (if 
allowed according to local requirements), the participant must be informed about the study to 
the extent possible. If the participant is capable of doing so, he/she must indicate agreement 
by personally signing and dating the written informed consent document. 
7.1.2.  
Demographics 
Subject demographic data collected includes year of birth or age, gender, ethnicity, race, and 
child-bearing potential (for females only). 
7.1.3.  
Medical History 
Any relevant medical history – including date of onset of COVID-19 disease symptoms, date 
of diagnosis of COVID-19, and COVID-19 disease protocol solicited medical history 
(including any paresthesia / dysesthesias at screening/baseline) – and current medical 
conditions will be captured.  
Diagnoses and not symptoms will be recorded whenever possible. 
7.2.  
Study Treatment 
After confirmation of eligibility for study entry, blinded study drug treatment can commence. 
Details of IV infusion start and stop times will be recorded in the eCRF, and any interruption 
requirements captured. 


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7.3.  
Efficacy Assessments 
7.3.1.  
Clinical Status  
Assessment of clinical status will be made using an 8-point ordinal scale, adapted from scales 
published (WHO 2020a; WHO 2020c), and following the National Institute of Allergy and 
Infectious Diseases (NIAID) ordinal scale framework (as used in ACTT trials). 
Each day the worse score for the previous day will be recorded, i.e., on Day 3, Day 2 score is 
obtained and recorded as Day 2. For hospitalized patients, assessment is made for baseline 
(Day 1), Day 2, and every day until Day 29 (end of study). If a subject is discharged from the 
hospital, assessment is to be sought by telephone (between 7AM and 12 PM local time) up to 
Day 15 if a subject is successfully discharged before Day 15, and also on Day 29. 
Table 11: Clinical Status 8-point Ordinal Scale 
Score 
Description 
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 
7.3.2. National Early Warning Score 2 (NEWS2) 
The National Early Warning Score 2 (NEWS2) has demonstrated an ability to discriminate 
subjects at risk of poor outcomes (Williams et al 2012). This score is based on seven (7) 
clinical parameters. NEWS2 values reported for the study will be calculated electronically 
based on vital sign parameters and NEWS2 related assessments recorded by the investigator 
in the appropriate eCRFs. 


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In addition to the vital signs – whereby, in addition to systolic blood pressure, the associated 
diastolic blood pressure must also be entered into the appropriate additional eCRF field – the 
patient’s level of consciousness and the presence/absence of respiratory support must be 
recorded. The NEWS2 parameter for respiratory support is the selection of either air or 
“oxygen” can include other forms of ventilation to maintain oxygen saturation. These should 
be recorded at the same time points as the vital sign measurements (see Section 7.5.2). 
Table 12: National Early Warning Score 2 (NEWS2) 
 
SpO2 = oxygen saturation 
The oxygen saturation should be scored according to either the SpO2 Scale 1 or 2 presented in 
Table 12. The SpO2 Scale 2 is for patients with a target oxygen saturation requirement of 
88%-92% (e.g., in patients with hypercapnic respiratory failure related to advanced lung 
diseases, such as chronic obstructive pulmonary disease [COPD]). This should only be used in 
patients confirmed to have hypercapnic respiratory failure by blood gas analysis on either a 
prior or their current hospital admission. 
The decision to use the SpO2 Scale 2 should be made by the treating physician and should be 
recorded in the eCRF. In all other circumstances, the SpO2 Scale 1 should be used. 
For physiological parameter “Air or Oxygen?”: Any patients requiring the use of oxygen or 
other forms of ventilation to maintain oxygen saturations and support respiration should be 
assigned a score of 2. 


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The consciousness level should be recorded according to the best clinical condition of the 
patient during the assessment. Patients who are assessed as “Alert” (A) should be assigned a 
score of 0. Patients assessed as “New Confusion” (C), “Responsive to Voice” (V), 
“Responsive to Pain” (P), or “Unconscious” should be assigned a score of 3. 
Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and temperature 
according to Table 12. 
For the duration of hospitalization while the subject is outside of the ICU, the measurements 
of the NEWS2 are to be performed twice daily. All parameters – including the vital sign 
parameters and oxygen saturation – should be recorded together in the morning, and then 
between noon and midnight, for the duration of hospitalization if outside of the ICU. 
Following hospital discharge these parameters should be recorded once at each return visit to 
the clinic (Days 15 and 29). 
Repeat measurements may be taken, as clinically appropriate. 
7.3.3.  
In-Hospital Outcomes 
The following in-hospital outcomes will be captured on eCRFs or derived from other data 
collected on the eCRF: 
• Duration of hospitalization* 
• Time to discharge 
• Duration of invasive mechanical ventilation 
• Duration of supplemental oxygen support 
• Duration of ECMO 
• No oxygen therapy (and/or peripheral oxygen saturation SpO2 > 93% on room air) at 
Days 8, 15 and 29 
*If a subject is unable to be discharged due to administrative reasons, then the date that the 
subject, in the opinion of the investigator, is ready to be discharged to be reported in the 
hospitalization status as date of discharge. 
7.4. Other Assessments 
7.4.1.  
SARS-CoV-2 virus testing 
SARS-CoV-2 virus is to be measured using PCR or equivalent/ other approved diagnostic 
testing at Screening, except for those subjects who have had another validated test done 
within 4 days of randomization. A positive PCR SARS-CoV-2 test result is needed prior to 
randomization. 


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Nasopharyngeal (NP) swab samples are to be collected from the pre-dose assessment through 
Day 11 (while hospitalized) and/or on day of discharge; and Days 15 and 29 (by returning to 
the clinic/ remote visit or if still hospitalized).  
Swab collection is to be pre-dose on dosing days; efforts are to be made to allow for swabs to 
be collected at approximately the same time each collection day throughout the study. 
Note: NP swabs are to be collected. In exceptional circumstances only, such as NP swabs 
cannot be used due to participant nasal physiology, the collection method for all samples from 
such a subject may be altered to Oropharyngeal (OP) swabs, if provided for by the central lab.  
Collected swabs are to be stored in the refrigerator/ or a -20°C or -70°C freezer, with the 
temperature of storage likely dependent on the time between collection and shipment. 
Subsequently, samples are expected to be batch shipped on dry ice to a central laboratory for 
testing. Follow instructions provided in a separate laboratory manual. 
Swab samples will be assayed using quantitative reverse transcriptase PCR to quantify SARS-
CoV-2 viral load. Pretreatment and posttreatment samples with detectable SARS-CoV-2 may 
be sequenced for resistance monitoring of the viral polymerase gene. 
Sample analysis may be performed ongoing or in batches. Analytical data will be shared with 
care while the study is ongoing, to ensure that for study personnel the subject treatment 
blinding is maintained. 
7.4.2.  
Biomarkers 
Blood samples will be collected for measurement of biological and immunological markers of 
illness/inflammation. These will include: 
Local laboratory testing: CRP, ferritin, LDH, D-dimer, troponin T hs, absolute neutrophil 
count [at Screening, Days 1, 2, 3, 5, 8, 11 (while hospitalized) and/or on day of discharge; and 
Days 15 and 29 (by returning to the clinic or if still hospitalized)] – see Section 7.5.3. 
Central laboratory testing: IL-1β, IL-6, IL-10, total IL-18, TNF-α [at Days 1, 3, 5, 8, 11 
(while hospitalized) and/or on day of discharge; and Day 15 (by returning to the clinic or if 
still hospitalized)]. 
For central laboratory testing samples, follow instructions outlined in the laboratory manual 
regarding sample collection, numbering, processing, storage and shipment. 
Sample analysis may be performed ongoing or in batches. Analytical data will be shared with 
care while the study is ongoing, to ensure that for study personnel the subject treatment 
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7.4.3.  
Drug Concentration Measurements (Pharmacokinetic Assessments) 
Blood samples will be collected for measurement of Brilacidin concentration in plasma. 
Sparse sampling will be performed on Days 1 to 4.  
All blood samples for PK assessments will be drawn from the opposite arm than that used to 
administer study treatment, or from an alternate site other than the arm used for the study 
treatment infusion. 
Samples will be collected as follows: 
• Day 1: pre-dose, within 30 mins after the end of infusion, and between 8-12 hours 
from start of the Day 1 infusion. 
• Day 2: pre-dose (approximately 24 hours from start of the Day 1 infusion) 
• Day 3: pre-dose (approximately 24 hours from the start of the Day 2 infusion) 
• Day 4: at approximately 24 hours from the start of the Day 3 infusion. 
The exact time of the sample collection and the exact time of study drug dosing preceding the 
sample are recorded in the eCRF. 
Blood samples (approximately 3 mL) to provide approximately 1 mL of plasma for PK 
analysis will be collected in appropriately labeled tubes containing potassium EDTA at the 
times specified. Samples are to be centrifuged at approximately 2000 g for about 10 minutes 
at 4°C within a target of 30 minutes after collection; separated plasma is to be transferred into 
the appropriately labeled screw-capped polypropylene tubes and stored at -20°C ± 5°C until 
shipped.  
Additional instructions are outlined in the laboratory manual regarding sample collection, 
numbering, processing, storage and shipment. 
Samples will be analyzed using a validated liquid chromatographic method with tandem mass 
spectrometry detection (LC-MS/MS) assay method. Sample analysis may be performed 
ongoing or in batches. Analytical data will be shared (with Sponsor study team 
members/designees) with care while the study is ongoing, to ensure that for study personnel 
the subject treatment blinding is maintained. 
7.4.4.  
Recording Concomitant Medications and Concurrent Procedures 
Relevant prior, and any concomitant medications or concurrent procedures used from the time 
the subject signs the ICF through the end of study, must be recorded in the eCRF on an 
ongoing basis. Details recorded may include the medication name/ dose/ route of 
administration or procedure name, start and stop dates, and indication for use. 


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7.5.  
Safety Assessments 
7.5.1.  
Physical Exam, Height and Weight 
Physical examinations will be performed by an Investigator, Sub-Investigator or appropriately 
qualified designee (e.g., Physician’s Assistant, Advanced Practice Registered Nurse 
Practitioner, or Registered Nurse as per local regulations). At the Screening visit a complete 
physical examination is to be conducted, including skin, neck (including thyroid), HEENT 
(head, eyes, ears, nose and throat), heart, lungs, abdomen, lymph nodes, extremities, vascular 
and neurologic systems. Clinically relevant findings that are present prior to signing informed 
consent are to be recorded on the appropriate eCRF that captures medical history. Height will 
be measured at Screening also. Subsequent visit assessments can be an abbreviated physical 
examination (including at a minimum: HEENT, heart, lungs, abdomen, extremities and 
examination of any body system where there are symptoms reported by the subject). 
Height and body weight are to be measured with the subject in indoor clothing and shoes 
removed. Height is to be recorded to the nearest 1 cm, and body weight to the nearest 0.1 kg. 
If not possible to measure, height can be reported by the subject. 
If an on-study assessment is determined by the Investigator to be a clinically significant 
change from baseline for that subject, the finding may be considered an AE. Refer to Section 
8.1. 
7.5.2.  
Vital Signs and Respiratory Status 
Vital signs include heart rate, systolic and diastolic blood pressures and body temperature 
(recorded in °C) as per local practice.  
Respiratory status should be measured at the same time as the vital sign measurements, if 
possible. Documentation of respiratory status includes respiratory rate, and details of 
oxygenation and any oxygen supplementation (as below): 
• Oxygenation: SpO2 or PaO2  
• Oxygen supplementation: room air, low flow O2 (L/min and %), high flow O2 (L/min 
and %), CPAP/BIPAP (FiO2 or %), mechanical ventilation (FiO2 or %), ECMO. 
Measurements are to be performed twice daily. (The measurements will assist in completing 
the NEWS2 score twice daily, while the subject is outside of the ICU). The vital sign 
parameters and oxygen saturation should be recorded together in the morning, and then 
between noon and midnight, for the duration of hospitalization. Following hospital discharge 
these parameters should be recorded once at each return visit to the clinic (Days 15 and 29). 
Repeat measurements may be taken, as clinically appropriate. 


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If an on-study assessment is determined by the Investigator to be a clinically significant 
change from baseline for that subject, the finding may be considered an AE. Refer to 
Section 8.1. 
During Study Treatment 
Blood pressure and pulse rate measurements will be measured more intensely during the 
treatment period with study drug, during hospitalization. On Days 1-3 (and potentially Day 4-
5 also, after initial interim safety readout), measurements will be made pre-dose, within no 
more than 30 mins after the end of infusion, and 3 hours (±30 mins) post-start of infusion (i.e., 
~2 hours post-end of infusion). 
If systolic blood pressure ≥ 180 mmHg and increase from baseline ≥ 20 mmHg, the 
measurement is to be repeated within 15-30 minutes. If the repeat measurement is confirmed, 
the attending physician is to review the patient profile and determine if treatment for 
hypertension is needed. After a confirmed systolic blood pressure elevation, blood pressure 
measurements are to be performed approximately every 4 hours or as frequently as necessary 
in accordance with local standard of care. 
Similarly, if diastolic blood pressure ≥ 110 mmHg and increase from baseline ≥ 15 mmHg, 
the measurement is to be repeated within 15-30 minutes. If the repeat measurement is 
confirmed, the attending physician is to review the patient profile and determine if treatment 
for hypertension is needed. After a confirmed diastolic blood pressure elevation, blood 
pressure measurements are to be performed approximately every 4 hours or as frequently as 
necessary in accordance with local standard of care. 
See Section 8.1.5 (Adverse Events of Special Interest/ Blood Pressure category reporting) and 
Section 9.2 (Interim Analyses/ Data Monitoring Committee Reviews). 
7.5.3.  
Laboratory Evaluations 
A certified local laboratory will perform the clinical laboratory tests for this study, as outlined 
in Table 13. The laboratory will be local to the study site.  
Reports of laboratory results must be reviewed by the Investigator or qualified designee.  
For each laboratory test result outside the reference range, the Investigator must ascertain if 
the abnormal lab result is a clinically significant result for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed; the Investigator may repeat the laboratory test or request additional tests to 
verify the results of the original laboratory test.  
The Investigator must review the results of all laboratory tests as they become available. For 
each test result outside the reference range, on the printed document (or alternate source 
record) the Investigator must note Not Clinically Significant (NCS) or Clinically Significant 
(CS) for each out of range laboratory value, and is to initial to confirm their review.  


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All abnormal laboratory events of clinical significance should be followed until the laboratory 
values have returned to normal or baseline levels or are deemed clinically stable. If a subject 
has any clinically significant, study-related abnormalities at the end of the study, the Medical 
Monitor should be notified and every effort made to arrange follow-up evaluations at 
appropriate intervals to document the course of the abnormalities.  
Blood and urine samples will be collected at the timepoints identified in the Schedule of 
Assessments. Unscheduled clinical laboratory testing may be obtained at any time during the 
study to assess any perceived safety concerns. 
If an on-study laboratory value is determined by the Investigator to be a clinically significant 
change from baseline for that subject, this may be considered an AE. Refer to Section 8.1. If 
the laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., 
anemia), not the laboratory result (i.e., hemoglobin decreased). 
Table 13:  Clinical Laboratory Testing (local) 
Laboratory Testing 
Variables 
Hematology 
hemoglobin; hematocrit; red blood cell (RBC) count; platelet 
counts; white blood cell (WBC) count with differential 
[neutrophils (%, abs), lymphocytes (%, abs), monocytes (%, 
abs), eosinophils (%, abs), basophils (%, abs)] 
Serum Chemistry 
urea (BUN), uric acid, creatinine, glucose (random),bicarbonate, 
calcium, sodium, potassium, total bilirubin, alanine 
aminotransferase (ALT), gamma-glutamyl-transferase (GGT), 
aspartate aminotransferase (AST), alkaline phosphatase, total 
bilirubin, albumin, lactate dehydrogenase (LDH), CRP, ferritin, 
D-dimer, troponin T hs 
Coagulation 
Prothrombin time (PT), International normalized ratio (INR), 
Partial thromboplastin time (PTT), Activated partial 
thromboplastin time (APTT) 
WOCBP only: 
Pregnancy Testing  
Urine/serum (ß-hCG) pregnancy testing required only for 
women of childbearing potential.  
7.5.4.  
Electrocardiogram (ECG) 
A single standard supine 12-lead ECG will be obtained after a subject has rested quietly for at 
least 10 minutes. The ECG may be repeated if the result is abnormal, as clinically appropriate. 
ECG data will be reviewed by the Investigator or appropriate local designee. The Investigator 
must review and initial the tracing (or alternate source record) and the assessment of any 
reviewer (if not themselves). 


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7.5.5.  
Recording Adverse Events (AEs) 
Adverse events should be sought by non-directive questioning of the subject and are to be 
recorded, graded, and assessed as defined in Section 8.1 of this protocol. 
All AEs, whether observed by an Investigator or Study Coordinator or reported by the subject, 
whether related to study drug or not related to study drug, shall be documented in the eCRF 
and subject records, together with details of the onset, duration, the relationship to the study 
drug and/or related to background standard-of-care and degree of severity, the action taken 
regarding study treatment, if other medication or therapies have been taken (concomitant 
medication/non-drug therapy), and the outcome. 
If an AE constitutes a serious adverse event (SAE), the procedure outlined in Section 8.1.4 is 
to be followed. 
7.6.  
Individual Subject Discontinuation 
7.6.1.  
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the subject or the 
investigator. 
Study treatment must be discontinued under the following circumstances: 
• Subject decision, for any reason 
• Investigator believes that continuation would negatively impact the subject's overall 
status or the risk/benefit of study treatment 
• Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, 
fever, chills, urticaria, dyspnea, headache, myalgia, and hypotension. Immediate 
discontinuation of study treatment and initiation of appropriate medical treatment is 
required in such cases. 
• Any protocol deviation or situation that results in a significant risk to the subject’s 
safety. 
Transient hypertensive episodes may be addressed by initiation of treatment for hypertension. 
If adverse events emerge, as assessed by the investigator following local guidelines, that meet 
criteria for hypertensive urgency (e.g., SBP >220 mmHg or DBP >120 mmHg) or 
hypertensive emergency, the investigator is to consider temporarily stopping study treatment 
and potentially discontinuation of study treatment. 
If discontinuation of study treatment occurs for a subject, the investigator must determine the 
primary reason for the discontinuation of study treatment and record this information. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 


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study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.6.2). Where possible, subjects are to continue with (if 
hospitalized) or return for the assessments indicated in the Schedule of Activities (Table 1). If 
they fail to return for these assessments for unknown reasons, every effort (e.g., telephone, 
e-mail, and letter) should be made to contact the subject/pre-designated person contact as 
specified in the lost to follow-up section (Section 7.6.3). This contact should preferably be 
done according to the study visit schedule and documented in the site study file. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject This 
telephone contact should preferably be done according to the study visit schedule.  
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
Subjects who discontinue from the study will not be replaced. 
7.6.2.  
Withdrawal of informed consent 
A subject may voluntarily withdraw consent to participate in the study for any reason at any 
time at their own request. 
Withdrawal of consent occurs only when a subject requests the following: 
• Does not want to participate in the study any more; 
and 
• Does not want any further visits or assessments; 
and 
• Does not want any further study-related contacts. 
In this situation, the investigator should make reasonable efforts (e.g., telephone, e-mail, 
letter) to understand the primary reason for the subject’s decision to withdraw his/her consent 
and record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. All efforts should 
be made to complete the assessments prior to study discontinuation. A final evaluation at the 
time of the subject’s study discontinuation should be made as detailed in the assessment table. 
The Sponsor will continue to retain and use all research results (data) for the subject that have 
already been collected as part of study evaluations. 


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7.6.3.  
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g., dates of 
telephone calls, registered letters, etc. A subject should not be considered as lost to follow-up 
until due diligence has been completed or until the completion of the study. 
7.7.  
Study Stopping Rules 
An independent Data Monitoring Committee (DMC) will review safety at intervals during the 
study, including mortality and SAEs. Enrollment in the study will be placed on hold if any of 
the following occurs: 
• There is a doubling of the mortality rate on Brilacidin treatment compared to placebo, 
with data stratified by age/ severity/ country (assessed after approximately 50% of 
subjects have enrolled/completed) 
• The number and/or severity of AEs, including Adverse Events of Special Interest 
(AESIs) (Section 8.1.5), abnormal safety monitoring assessments, or abnormal 
laboratory findings justify putting the study on hold (assessed after approximately 20 
subjects, and after 50% of subjects, have enrolled/completed). 
The study may resume following the safety review, if the DMC and Sponsor agree it is safe to 
proceed. Alternatively, the study may be stopped. 
Recommendation guidelines and further details of the DMC will be prepared separately from 
this protocol in a DMC Charter. The charter may supersede the summary details presented 
here in the protocol. See Section 8.1.6. 
7.8.  
Early Study Termination by the Sponsor 
This study can be terminated at any time for any reason by the Sponsor. Should this be 
necessary, the Sponsor and the investigators will ensure that proper study discontinuation 
procedures are completed, and that adequate consideration is given to the protection of the 
subject’s interests. 
 


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8.  
SAFETY MONITORING 
8.1.  
Adverse Events 
8.1.1.  
Definitions 
An Adverse Event (AE) is defined as any untoward medical occurrence (e.g., sign, symptom, 
disease, syndrome, intercurrent illness, clinically significant abnormal laboratory finding, 
injury, or accident) in a clinical-trial subject that emerges or worsens after providing written 
informed consent for participation in the study. The untoward medical occurrence may not 
necessarily have a causal relationship with the use of medicinal [investigational] product. An 
AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal [investigational] product, whether or not considered 
related to the medicinal [investigational] product. 
Pre-existing medical conditions/diseases (i.e., medical history(ies)) are considered AEs if they 
worsen after administration of a medicinal [investigational] product. Abnormal laboratory 
values or test results constitute AEs only if they induce clinical signs or symptoms, or are 
considered clinically significant, or require therapy. 
Serious Adverse Event (SAE) is defined as an adverse event that meets one or more of the 
following criteria: 
• Results in death 
• Is immediately life-threatening (i.e., the subject was at immediate risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe.) 
• Requires in-patient hospitalization or prolongs an existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Is a congenital anomaly/birth defect 
• Is another significant medical event as defined below: 
Significant medical events are those that may not result in death, be life-threatening, or 
require hospitalization, but are, in the opinion of the investigator, and based upon 
appropriate medical judgment, an event that might jeopardize the subject and/or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Any of the above must be reported immediately to the Sponsor or designee as indicated in the 
Immediately Reportable Serious Adverse Event section of this protocol. 
Pre-Planned Hospitalization: A hospitalization planned prior to signing the ICF is not 
considered an SAE, but rather a therapeutic intervention.  However, if during the pre-planned 
hospitalization an event occurs which prolongs the hospitalization or meets any other SAE 
criteria, the event will be considered an SAE.  Surgeries or interventions that were under 


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consideration but not performed prior to enrollment in the study will not be considered serious 
if they are performed after enrollment in the study for a condition that has not changed from 
its baseline level.  Hospitalizations for social reasons or due to long travel distances are also 
not SAEs. 
Note: The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition. 
8.1.2.  
Severity of Adverse Events 
The Investigator is responsible for evaluating all AEs and determining the severity of the 
event. Severity is graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 when applicable. For an AE not found on the CTCAE listing, 
they will be allocated a grade according to the following guidelines. 
Grade 1   Mild Adverse Event (any of the following): 
• Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated, or non-prescription intervention indicated; asymptomatic 
laboratory finding only; marginal clinical relevance. 
Grade 2   Moderate Adverse Event (any of the following): 
• Moderate; minimal, local, or noninvasive intervention indicated; limiting (age-
appropriate) instrumental Activities of Daily Living [ADL] (e.g., preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, laundry). 
Grade 3   Severe Adverse Event (any of the following): 
• Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL (e.g., 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
getting in and out of bed). 
Grade 4   Life-threatening Adverse Event (any of the following): 
• Life-threatening consequences; urgent intervention indicated; individual at risk of 
death at the time of the event if immediate intervention is not undertaken. 
Grade 5   Fatal Adverse Event: 
• Death related to AE. 


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8.1.3.  
Causality of Adverse Events 
The relationship is characterized as:  
• Not Related/ Unlikely Related: There is not a temporal or causal relationship between 
the use of the study drug and the onset of the AE; no association of the event to use of 
study drug.  
• Possible: There may or may not be a reasonable temporal relationship between the use 
of the study drug and the onset of the AE; the association of the event with the study 
drug is unknown, however, a relationship between drug and event cannot be ruled out.  
• Probable: There is a reasonable temporal relationship between the use of the study 
drug and the onset of the AE; the association of the event with the study drug seems 
likely and the AE is unlikely to be caused by the concurrent/underlying illness, other 
drugs or procedures. 
• Definite: There is a reasonable temporal relationship between the use of the study drug 
and the onset of the AE, and it cannot be reasonably explained by any known 
characteristics of the subject’s clinical state, environment or other drugs or procedures. 
It disappears or decreases upon discontinuation of the study drug and reappears with 
re-administration of the study drug.  
For the purpose of regulatory safety reporting, AEs that are assessed as not related/unlikely 
related to the study drug, as per the protocol definition, will not qualify as adverse reactions 
(see Section 8.1.4). 
Information about common side effects already known about the study medication can be 
found in the Investigator’s Brochure. A summary of this information will be included in the 
informed consent and should be discussed with the subject during the study as needed. 
8.1.4.  
Immediate Reporting of Serious Adverse Events (SAEs) 
Any SAE during the Screening, Treatment, and Follow-up (through Day 29) periods, whether 
deemed related to study treatment or not, must be reported by the Investigator to Sponsor or 
the authorized representative within 24 hours of their awareness of the event. Any new 
SAE(s) reported by the subject to the Investigator that occur after the end of the Follow-up 
period (through Day 29) that are suspected by the Investigator to have a causal relationship 
with the study treatment should be reported to Sponsor or the authorized representative within 
24 hours of their awareness of the event. Information about all SAEs (either initial or follow-
up information) is collected and recorded on the Serious Adverse Event Form.  
Summary of actions to be taken by the Investigator: 
• Investigator to complete and forward an SAE Form (within 24 hours) with all 
information known to date, including Investigator’s assessment of causality. 
• If the event is fatal or life-threatening, the Investigator is to telephone the Sponsor or 
the authorized representative immediately on awareness of event. 


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• Obtain and maintain all pertinent medical records (discharge summary, autopsy report, 
etc.) relating to the subject’s treatment and follow-up. 
• Provide follow-up and/or updated information to Sponsor or the authorized 
representative, as it becomes available. 
If the SAE is not previously documented in the Investigator’s Brochure and is thought to be 
related to the investigational study drug, the Sponsor or the authorized representative may 
urgently require further information from the Investigator for Health Authority reporting. 
Sponsor or the authorized representative may need to issue an Investigator Notification (IN) 
to inform all Investigators involved in any study with the same drug that this SAE has been 
reported. Suspected unexpected serious adverse reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
national regulatory requirements (in participating countries) and any local requirements. 
The Investigator will collect information on SAEs until a subject’s health has returned to the 
baseline state of health, or the Investigator does not expect any further improvement or 
worsening of the subject’s condition. The Investigator must report follow-up information as 
and when it becomes known to the Investigator.  
Any new SAEs reported by the subject to the Investigator that occur after the last scheduled 
study contact and are determined by the Investigator to be reasonably associated with the 
administration of study drug should be reported to Sponsor or the authorized representative, 
and the IRB/IEC, as required.  
8.1.5.  
Adverse Events of Special Interest/ Blood Pressure category reporting 
Adverse events of special interest (AESIs) are (i) hypertension Grade 3 or greater, and (ii) 
paresthesias / dysesthesias Grade 2 or greater.  
The CTCAE (version 5.0) details, including definitions, for AESIs are provided in Table 14. 
Hypertension is under the Vascular disorders System Organ Class (SOC); paresthesia and 
dysesthesia are under the Nervous System disorders SOC; and oral dysesthesia is under the 
Gastrointestinal disorders SOC. 


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Table 14:  CTCAE Details for Adverse Events of Special Interest 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hypertension 
Systolic BP 120 - 
139 mm Hg or 
diastolic BP 80 - 
89 mm Hg 
Systolic BP 140 - 
159 mm Hg or 
diastolic BP 90 - 99 
mm Hg if 
previously WNL; 
change in baseline 
medical intervention 
indicated; recurrent 
or persistent (>=24 
hrs); symptomatic 
increase by >20 mm 
Hg (diastolic) or to 
>140/90 mm Hg; 
monotherapy 
indicated initiated 
Systolic BP >=160 
mm Hg or diastolic 
BP >=100 mm Hg; 
medical intervention 
indicated; more than 
one drug or more 
intensive therapy 
than previously used 
indicated 
Life-threatening 
consequences 
(e.g., malignant 
hypertension, 
transient or 
permanent 
neurologic 
deficit, 
hypertensive 
crisis); urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a pathological increase in blood pressure. 
Paresthesia 
Mild symptoms Moderate 
symptoms; limiting 
instrumental ADL 
Severe symptoms; 
limiting self care 
ADL 
- 
- 
Definition: A disorder characterized by functional disturbances of sensory neurons resulting in abnormal 
cutaneous sensations of tingling, numbness, pressure, cold, and/or warmth. 
Dysesthesia 
Mild sensory 
alteration 
Moderate sensory 
alteration; limiting 
instrumental ADL 
Severe sensory 
alteration; limiting 
self care ADL 
- 
- 
Definition: A disorder characterized by distortion of sensory perception, resulting in an abnormal and 
unpleasant sensation. 
Oral dysesthesia 
Mild discomfort; 
not interfering 
with oral intake 
Moderate pain; 
interfering with oral 
intake 
Disabling pain; tube 
feeding or TPN 
indicated 
- 
- 
Definition: A disorder characterized by a burning or tingling sensation on the lips, tongue or entire mouth. 
ADL = Activities of Daily Living; TPN = Total Parenteral Nutrition; WNL = Within Normal Limits 
Blood pressure measurements will also be summarized for the following criteria: 
• 
Systolic blood pressure increased: ≥180 and increase from baseline ≥20 
• 
Diastolic blood pressure increased: ≥110 and increase from baseline ≥15 
During study treatment, if a blood pressure values meets one of the above safety alert 
categories, the measurement is to be repeated within 15-30 minutes; if the repeat 
measurement is confirmed, the attending physician is to review the patient profile and 
determine if treatment for hypertension is needed (see Section 7.5.2). The Investigator or 
attending physician shall contact the Medical Monitor to review the patient profile as 
appropriate. 


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Ongoing during the study, the Sponsor will closely monitor the incidence and duration of 
related Grade 3 hypertension or greater (in accordance with CTCAE criteria), and monitor for 
incidence of confirmed hypertensive values. The Medical Monitor will review such data on a 
frequent basis; such safety data will also be a key component of the periodic safety review by 
the DMC (see Section 9.2). 
The incidence and duration of all paresthesias / dysesthesias Grade 2 or greater (in accordance 
with CTCAE criteria) will also be closely reviewed ongoing during the study, by the Sponsor 
and Medical Monitor, and by the DMC. As numbness/paresthesia has been reported as an 
uncommon manifestation of COVID-19, events regarded both as related and unrelated to 
study treatment will be closely monitored, and will be reviewed in relation to frequency of 
other peripheral nervous system AEs. 
8.1.6.  
Data Monitoring Committee 
This study will include an independent Data Monitoring Committee (DMC) which will be 
composed of at least three external medical experts familiar with the conduct of and/or data 
review of clinical studies. The DMC will conduct periodic safety reviews, and will 
recommend to the Sponsor whether to continue, modify, or terminate a clinical trial. 
Specific details regarding committee composition, responsibilities, data monitoring, 
recommendation guidelines, and meeting frequency/administration will be described in a 
separate DMC Charter, to be established between the Sponsor and the DMC. 
See Section 7.7 (Study Stopping Rules) and Section 9.2 (Interim Analyses/ Data Monitoring 
Committee Reviews). 
8.2.  
Reporting Pregnancy/Study Drug Exposure During Pregnancy 
Although pregnancy itself is not regarded as an AE, the outcome of any pregnancy that occurs 
during the study must be documented.  
Prior to study enrollment, study participants must agree in the ICF to take appropriate 
measures to avoid pregnancy at all times during the study, commencing from the time of 
consent, throughout the study and for 30 days after stopping treatment (i.e., approximately 4 
weeks after the last dose of study drug). If pregnancy occurs, they must agree to report the 
pregnancy and cooperate with the Investigator as set forth below. 
Should a pregnancy occur, the study participant must immediately inform the Investigator.  
Any female study participant receiving study drug who becomes pregnant must immediately 
discontinue study drug.  The Investigator should counsel the study participant, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus.  The study participant 
must agree to follow up by the Investigator regarding the outcome of any pregnancy that 
occurs during the study.  Outcome is defined as elective termination of the pregnancy, 
miscarriage, or delivery of the fetus.  For pregnancies with an outcome of live birth, the 
newborn infant will be followed by the Investigator for a minimum of eight weeks.  Any 


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congenital anomaly/birth defect noted in the infant must be reported as an SAE [within 
24 hours of awareness].  The Investigator will notify Sponsor or its authorized representative 
of a pregnancy occurring in a study participant within 14 days of first becoming aware of such 
pregnancy.  All follow-up information gathered by the Investigator shall be reported to the 
Sponsor within 14 days of Investigator’s first knowledge of such information. 


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9.  
STATISTICAL METHODS 
Full details of the statistical methodology for summary and analyses of the data collected in 
this study will be prepared separately from this protocol in a Statistical Analysis Plan (SAP). 
This Phase 2 Proof of Concept (PoC) study is exploratory in nature and will be initiated with a 
dose regimen of Brilacidin in addition to SoC, compared to placebo with SoC. Proof of 
concept will be established by a significant treatment effect on the primary endpoint or a 
positive direction of effect amongst multiple efficacy endpoints. Comparisons will be 
performed against placebo plus SoC at a one-sided type I error rate of 0.05 which will not be 
adjusted for multiple testing. 
The selected primary efficacy endpoint is time to sustained recovery, where recovery is 
defined as the participant being well enough for hospital discharge, meaning the participant 
either no longer requires supplemental oxygen or ongoing medical care in the hospital, or is 
no longer hospitalized (with or without some limitation on activities). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, 
pharmacokinetic, and safety parameters. For categorical variables, summary tables with 
number and percentage of subjects within each category will be presented. For continuous 
variables, descriptive statistics including the number of subjects, mean, median, standard 
deviation, minimum, and maximum values will be presented. Kaplan-Meier methods will be 
used to summarize time to event endpoints, including the 25th, 50th (median), and 75th 
percentiles with associated 90% confidence intervals, as well as percentage of events and 
censored observations. 
9.1.  
Sample Size Considerations 
This study is exploratory in nature and the sample size (up to 60 per treatment arm) was 
selected to provide sufficient power under a range of alternative hypotheses to support initial 
PoC of Brilacidin versus SoC. The type I error will not be adjusted to account for multiple 
comparisons. 
For the primary efficacy endpoint of time to recovery, assuming a total of 100 subjects (50 per 
treatment arm included in analysis), if a total of 75 recovery events are observed, the 
comparison between treatment groups would provide at least 90% power with a one-sided 
type I error rate of 0.05 and a hazard ratio of 2.0 [equivalent to median time to recovery of 5 
days on Brilacidin versus 10 days on SoC]. If instead the hazard ratio is 1.67 (time to recovery 
on Brilacidin of 6 days versus 10 days on SoC) and 75 recovery events occur, the difference 
could be detected with at least 70% power. The assumptions for sample estimation are 
adapted from the median time to recovery data reported for the remdesivir (11 days) treatment 
group in Beigel et al 2020; remdesivir has Emergency Use Authorization (EUA) in multiple 
countries and has become SoC where available. 
A total of 100 subjects with 50 per treatment group will also support secondary endpoints. For 
example, for the secondary endpoint of clinical improvement (2-point increase in ordinal 


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scale) at Day 15, applying an unadjusted one-sided type I error rate of 0.05, 50 subjects per 
arm would provide 80% power to detect a treatment effect of 0.2079 increase in proportion of 
clinical improvement within the Brilacidin treatment group over a proportion of 0.6500 in the 
SoC group. There would be at least 70% power to detect a treatment effect of 0.1854 under 
the same sample size. (The assumptions for sample estimation are based on clinical 
improvement data reported for SoC and remdesivir treatment groups in Spinner et al 2020). 
9.2.  
Interim Analyses/ Data Monitoring Committee Reviews 
An independent Data Monitoring Committee (DMC) will be established to conduct periodic 
safety reviews (Section 8.1.6). 
Safety data summaries and listings will be produced for DMC safety monitoring when 
needed. 
An initial safety review is planned to occur after approximately 20 randomized subjects have 
completed up to Day 15. This initial interim analysis will focus on review of cardiovascular 
safety, vital signs and adverse events that have occurred in the approximately 20 subjects to 
receive Days 1-3 of study treatment. A further safety review by the DMC is planned to occur 
after approximately 50% of subjects have completed up to Day 29, to allow for unblinded 
monitoring of safety data around the study mid-point. The DMC may recommend expanding 
dosing to Days 4 and 5 (at the same doses as on Days 2 and 3), continuation of the Days 1-3 
study dosing unchanged, or that the trial be interrupted or stopped for safety reasons. The 
DMC will be guided by the degree and incidence of hypertensive values/events observed in 
the ongoing study which should not exceed the number and/or severity of those observed in 
previous studies with Brilacidin IV treatment for expansion of dosing to occur as planned. 
The rationale for looking to expand treatment duration to five days, from the initial dose 
regimen of three days, is to be able to provide a longer duration of systemic Brilacidin 
exposure at a level that can strongly suppress SARS-CoV-2 virus activity, and any associated 
symptoms, and thus provide a more optimal therapy to hospitalized patients with moderate or 
severe COVID-19. The longer treatment duration is expected to allow for greater impact of 
Brilacidin treatment and provide enhanced benefit to the patient, with the 5-day regimen 
incorporated only following recommendation by the DMC subsequent to DMC review of all 
available safety data following safety review interim analysis(es). 
Study stopping rules are presented in Section 7.7. Recommendation guidelines and further 
details of the DMC will be prepared separately from this protocol in a DMC Charter. The 
charter may supersede the summary details presented here in the protocol. 
Other interim analyses may be conducted to support decision making concerning the current 
clinical study or in case of any safety concerns. 
The primary efficacy analysis will occur once all subjects complete the Day 29 visit (or 
discontinue from study, if before Day 29). Final database lock and updated safety reporting 
will follow the completion of Day 60 follow-up telephone visits. 


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9.3.  
Definitions of Study Populations for Analysis 
Efficacy analyses performed on the Intent-to-Treat (ITT) population will be considered 
primary, with the ITT population including all subjects who are randomized and receive at 
least one dose of study drug. Subjects in this population will be analyzed according to the 
treatment group to which they were randomized. 
The Safety population includes all subjects in the ITT population. Subjects in this population 
will be analyzed according to treatment received. All safety analyses will be based on this 
population. 
The Per Protocol (PP) population is a subset of the ITT population and includes subjects who 
meet particular study completion criteria with no major protocol deviations; these criteria will 
be described in the SAP and will be approved prior to database lock and study unblinding. 
Efficacy analyses performed using the PP population will be considered supportive. 
All subjects in the ITT population who provide at least one PK sample and have at least one 
valid concentration measurement will be included in the PK population. 
9.4.  
Handling of Missing Data 
When analyzing time to sustained recovery, if subjects are lost to follow-up prior to achieving 
recovery or die prior to Day 29, their time to recovery will be censored at Day 29. Subjects 
who are lost to follow-up after achieving recovery but prior to Day 29 will be censored at the 
day of achieving recovery. Missing data rules for all endpoints will be described in the study 
SAP. 
9.5.  
Baseline Characteristics and Demographic Variables 
Summary statistics will be provided by treatment group for baseline characteristics and 
demographic variables. Relevant medical histories and current medical conditions at baseline 
will be summarized by system organ class and preferred term, by treatment group. Summaries 
will be provided on the ITT population. 
9.6.  
Efficacy Analysis 
Summaries of efficacy parameters will be performed on the ITT population. Additional 
sensitivity analyses may be performed on the Per Protocol population or on subgroups. 
Additional detail will be provided in the SAP. 
9.6.1.  
Primary Endpoint Analyses 
The primary endpoint is time to sustained recovery through Day 29, where day of recovery is 
defined as the first day on which the subject satisfies one of the following three categories 
from the ordinal scale (Table 11) with response sustained through Day 29: 


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• Score of 6: Hospitalized, not requiring supplemental oxygen - no longer requires 
ongoing medical care (other than for per protocol dosing or assessments, as 
appropriate); 
• Score of 7: Not hospitalized, limitation on activities and/or requiring home oxygen;  
• Score of 8: Not hospitalized, no limitations on activities. 
The primary endpoint of time to sustained recovery will be analyzed with the log-rank test for 
treatment difference, stratified by age group, disease severity and country, with dose regimen 
as covariate (if expanded after DMC recommendation), and summarized using the Kaplan-
Meier methodology. Subjects who are lost to follow-up prior to achieving recovery or who 
have died prior to Day 29 will be censored at Day 29. Subjects who are lost to follow-up after 
achieving recovery but prior to Day 29 will be censored at the day of achieving recovery. 
All safety data, demographic and baseline characteristics will be summarized descriptively 
through appropriate data tabulations, descriptive statistics, and categorical summaries on the 
Safety Population. 
9.6.2.  
Secondary and Exploratory/ Other Endpoint Analyses 
Categorical endpoints will be summarized with frequencies and percentages. Comparisons 
between treatment arms will be performed using logistic regressions adjusted for 
randomization strata at specified timepoints. Longitudinal analyses using generalized 
estimating equations may be performed. Continuous measures will be summarized with 
descriptive statistics. Comparisons between treatment groups will be performed using analysis 
of covariance models adjusted for randomization strata at specified timepoints. Mixed models 
with repeated measures will be applied for longitudinal modeling of continuous measures. 
The clinical status 8-point ordinal scale will be analyzed using ordinal categorical data 
methods, including a proportional odds logistic regression. Longitudinal analysis of the 8-
point scale over time will be performed to investigate temporal patterns of improvement. 
9.6.3.  
Sensitivity Analyses 
Sensitivity analyses of efficacy parameters controlling for baseline covariates (such as 
presence of certain comorbidities) or on subgroups (such as those subjects treated with an 
antiviral therapy as SoC) may be performed. Full details of sensitivity analyses will be 
presented in the SAP. 
9.7.  
Safety Analysis 
All safety data, demographic and baseline characteristics will be summarized descriptively 
through appropriate data tabulations, descriptive statistics, and categorical summaries on the 
Safety Population.  


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The duration of exposure (in days) to Brilacidin and standard of care therapies will be 
summarized by descriptive statistics by treatment group.  Changes from baseline in clinical 
laboratory parameters, vital signs (blood pressure and heart rate), and ECG parameters will be 
summarized. Treatment-emergent changes from values within normal range to abnormal 
values in clinical laboratory parameters will be characterized by summary of actual values and 
changes from baseline and shift tables.  
Adverse event (AE) data will be listed individually and treatment-emergent adverse events 
(TEAEs) will be summarized by MedDRA system organ class (SOC) and preferred term 
(PT). SAEs, AEs leading to discontinuation and/or deaths will likewise be listed and 
summarized separately. AEs will be further summarized by grade and relatedness as judged 
by the Investigator. Each subject will be counted only once within a SOC or a PT using the 
event with the highest severity and strongest relationship, respectively, within each category. 
Prior and concomitant medications and concurrent procedures will be classified on the basis 
of World Health Organization Drug Dictionary (WHO-DDE) terminology. Concomitant 
medications and significant non-drug therapies prior to and after the start of the study 
treatment will be listed and summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system, by treatment group. 


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10.  
SITE MONITORING AND QUALITY ASSURANCE 
10.1.  
Site Monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Sponsor/designee representative will review the protocol and study Case Report Forms 
(CRFs) with the investigator(s) and their staff. During the study, a study monitor will visit the 
site regularly (as possible, due to COVID-19 restrictions) to check the completeness of 
subject records, the accuracy of entries on the CRFs, the adherence to the protocol and to 
GCP, the progress of enrollment, and to ensure that consent is being sought and obtained in 
compliance with applicable regulations, and that the investigational drug is being stored, 
dispensed and accounted for according to specifications. The Investigator and key trial 
personnel must be available to assist the monitor during these visits. 
The investigator has ultimate responsibility for maintaining source documents for each subject 
in the study, consisting of case and visit notes (hospital or clinic medical records) containing 
demographic and medical information, laboratory data, electrocardiograms, and the results of 
any other tests or assessments. All information on CRFs must be traceable to these source 
documents in the subject's file. 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. No information in these records about the identity of 
the subjects will leave the study center; on CRFs, subjects will only be identified by initials 
and unique subject numbers. Monitoring standards require full verification for the presence of 
informed consent, adherence to the inclusion/ exclusion criteria, documentation of SAEs, and 
the recording of primary efficacy and safety variables. Additional checks of the consistency of 
the source data with the CRFs will be performed according to the study-specific monitoring 
plan. 
If planned on-site monitoring visits are not possible due to COVID-19 restrictions, use of 
central and remote monitoring programs will be considered to maintain oversight of clinical 
sites. In addition, remote review of medical records may be explored with trial sites to support 
and allow for source document review. 
10.2.  
Quality Assurance 
During study conduct, the Sponsor or its designee will conduct periodic monitoring visits to 
ensure that the protocol and GCPs are being followed. Study monitors will review source 
documents to confirm accuracy of data recorded on CRFs. The investigator and institution 
will allow monitors for the Sponsor or its designee, and appropriate regulatory authorities (as 
applicable), direct access to source documents to perform this verification. 
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by the Sponsor or 
designee, and/or to inspection by appropriate regulatory authorities. 


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The investigator and their relevant personnel are to be available during the monitoring visits, 
and possible audits or inspections, and must allow for sufficient time in their schedule for 
such process. 
11.  
RECORDS MANAGEMENT 
11.1.  
Data Collection 
A validated clinical data management system will be used for capturing and managing data 
from the study. Designated investigator site staff will enter the data required by the protocol 
into the electronic eCRFs following the CRF Completion Guidelines.  
The Investigator should ensure the accuracy, completeness, and timeliness of the data 
recorded on the eCRFs. Data recorded on the eCRF will be consistent with source documents. 
Any discrepancies must be explained or resolved. 
Completed eCRFs will be reviewed by the Sponsor’s monitoring staff or the Sponsor’s 
designee. An eCRF will be completed for each consented subject. 
The monitor and Sponsor/designee staff review the data entered into the CRFs by site staff for 
completeness and accuracy, and request clarifications and data queries. Queries will be sent to 
the site using an electronic data query. Designated site staff are required to respond to each 
query and confirm or correct the data, or make any required additions to the CRF entries. If 
the electronic query system is not used, a paper Data Query Form will be faxed to the site. 
Site personnel will complete and sign the faxed copy and fax it back to the Sponsor/designee 
staff that will make the correction to the database. The signed copy of the Data Query Form is 
kept at the investigator site. 
The investigator must certify that the data entered into the electronic Case Report Forms are 
complete and accurate. After database lock, the investigator will receive copies of the subject 
data for archiving at the site. 
11.2.  
Records Retention 
The investigator agrees to keep study records, including the identity of all participating 
subjects (sufficient information to link records, e.g., CRFs and hospital records), all original 
signed informed consent forms, copies of all CRFs, serious adverse event forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (e.g., letters, meeting minutes, telephone calls reports).  The records 
should be retained by the investigator according to ICH, local regulations, or by an agreement 
with the Sponsor (if needed), whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period, the Sponsor should be prospectively notified. The study records must be 
transferred to a designee acceptable to the Sponsor such as another investigator, another 


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institution, or to an independent third party. Notice of such transfer will be provided to the 
Sponsor in writing. 
When retention requirements have been met, the investigator must obtain written permission 
from the Sponsor before disposing of any records. 
12.  
ETHICS  
12.1.  
Regulatory and Ethical conduct 
This study will be conducted in accordance with the ethical principles that have their origin in 
the current Declaration of Helsinki, and will be conducted in compliance with the protocol, 
the International Conference on Harmonisation guideline on Good Clinical Practice, and 
applicable regulatory requirements. 
12.2.  
Responsibilities of the Investigator and IRB/IEC 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
any protocol amendments, informed consent forms and subject information, and other 
relevant documents, e.g., recruitment advertisements, if applicable, from the IRB/IEC. A 
signed and dated statement that the protocol and informed consent/subject information have 
been approved by the IRB/IEC must be given to the Sponsor/designee before study initiation. 
A copy of all reports relating to this study submitted to the IRB must be sent to the 
Sponsor/designee.  
If an inspection of the clinical site is requested by a regulatory authority, the investigator must 
information the Sponsor/designee immediately that this request has been made 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate an apparent immediate hazard to trial subjects. In 
that event, the investigator must notify the IRB/IEC and Sponsor/designee in writing 
immediately after the implementation. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with this protocol and key 
responsibilities of study oversight, delegation, and information access. With any protocol 
amendment, the protocol signature page is to be resigned to confirm understanding and 
agreement with any protocol changes. 
12.3.  
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant’s legal/authorized representative gives consent (if 
allowed according to local requirements), the participant must be informed about the study to 


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the extent possible. If the participant is capable of doing so, he/she must indicate agreement 
by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures, and the 
process of obtaining informed consent should be documented in the subject source 
documents. The investigator will retain the original of each subject’s signed consent form. A 
copy of the signed consent form will be given to the subject. 
The Sponsor/designee will provide to investigators in a separate document a proposed 
Informed Consent Form (ICF) that complies with the ICH guideline and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed 
consent form suggested by the investigator must be agreed to by the Sponsor/designee before 
submission to the IRB/IEC, and a copy of the approved version must be provided to the 
Sponsor/designee after IRB/IEC approval. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the ICF and should be discussed with the 
subject during the study as needed. Any new information regarding the safety profile of the 
investigational drug that is identified between IB updates will be communicated as 
appropriate, for example, via an investigator notification or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the subject. 
12.4.  
Publication of Study Protocol and Results 
The Sponsor will post the key design elements of this protocol in a publicly accessible 
database such as clinicaltrials.gov. The results of this trial will be either submitted for 
publication and/or posted in a publicly accessible database of clinical trial results. 
13.  
PROTOCOL ADHERENCE AND AMENDMENT 
13.1.  
Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations, and no 
requests to approve deviations will be granted by the Sponsor/designee. 
This protocol defines the study objectives, procedures and data to be collected on study 
participants. No additional procedures or data for any research related purpose may be 
performed or collected. 
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by the 
Sponsor and approved by the IRB/IEC it cannot be implemented.  
All significant protocol deviations will be recorded and reported in the Clinical Study Report. 


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13.2.  
Protocol Amendment Policy 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the Sponsor, government regulatory authorities (where required), 
and the IRB/IEC. Only the Sponsor may formally amend the protocol text. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate an apparent immediate hazard(s) to trial subjects. 
In that event, the investigator must notify the IRB/IEC and Sponsor/designee in writing 
immediately after the implementation. 
 


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14.  
REFERENCES 
Available upon request 
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Exhibits Potent In Vitro Antiviral Activity Against SARS-CoV-2. Published online 30 
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Beigel JH, Tomashek KM, Dodd LE, et al., on behalf of the ACTT-1 Study Group Members 
(2020). Remdesivir for the Treatment of Covid-19 — Preliminary Report. N Engl J Med; May 
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Cao B, Wang Y, Wen D, et al (2020). A Trial of Lopinavir-Ritonavir in Adults Hospitalized 
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SARS-CoV-2 proteins through docking and quantum mechanical scoring. ChemRxiv. 
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[U.S.] Department of Health & Human Services (DHHS) (2020). Determination that a Public 
Health Emergency Exists Nationwide as the Result of the 2019 Novel Coronavirus. 31 
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nCoV.aspx  
Johns Hopkins Coronavirus Resource Center. World Map: 
https://coronavirus.jhu.edu/map.html 
Kim D, Quinn J, Pinsky B (2020). Rates of co-infection between SARS-CoV-2 and other 
respiratory pathogens. Research Letter. JAMA; 323(20):2085-86. 
Mirzaei R, Goodarzi P, Asadi M, et al (2020). Bacterial co‐infections with SARS‐CoV‐2. 
IUBMB Life: Early View. Published online 08 August 2020. 
Petterson JC, Chouinard L, Kerlin RL, et al (2008). Neurotoxic effects of zoniporide: a 
selective inhibitor of the Na+/H+ exchanger isoform 1. Toxicol Pathol 36:608-19. 
Sorbera LA, Graul AI, Dulsat C. Taking Aim at Fast-Moving Target: Targets to Watch for 
SARS-CoV-2 and COVID-19. Drugs of the Future, 45(4):1-6 (Advanced Publication). 
Clarivate Analytics. 
Spinner CD, Gottlieb RL, Criner GJ, et al (2020). Effect of Remdesivir vs Standard Care on 
Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical 
Trial. JAMA; 324(11):1048-57. 
Stein J (2020). Coronavirus fallout will haunt U.S. economy for years, costing it $8 trillion 
through 2030, CBO says. Washington Post (June 1, 2020). 
Tamimi A, Serdarevic D, Hanania NA (2012). The effects of cigarette smoke on airway 
inflammation in asthma and COPD: Therapeutic implications. Resp Med; 106(3):319-28. 


Innovation Pharmaceuticals Inc. 
Confidential 
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Clinical Protocol, Version 1.2 
 
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Van Wart SA, Bhavnani SM, Forrest A, Jorgensen DM, Tack KJ, et al (2015). Population 
Pharmacokinetics (PPK) of Brilacidin in Healthy Subjects and Patients with Acute Bacterial 
Skin and Skin Structure Infection (ABSSSI). Joint 55th Interscience Conference on 
Antimicrobial Agents & Chemotherapy and 28th International Congress of Chemotherapy 
(ICAAC) (September 18, 2015) (San Diego, CA). 
Van Wart SA, Bhavnani SM, Rubino CM, Ambrose PG, for the Institute for Clinical 
Pharmacodynamics (ICPD) Report (2016). Population Pharmacokinetic Analysis of Brilacidin 
Using Data from Healthy Subjects and Patients with Acute Bacterial Skin and Skin Structure 
Infections. Final Report ICPD 00401-1, March 31, 2016. Report on file. 
Williams B, Alberti G, Ball C, et al (2012). Royal College of Physicians, National Early 
Warning Score (NEWS2), Standardising the assessment of acute-illness severity in the NHS, 
London. 
WHO (2020a). COVID-19 Therapeutic Trial Synopsis. Geneva, Switzerland: WHO R&D 
Blueprint, Feb 18 2020. 
WHO (2020b). Statement on the second meeting of the International Health Regulations 
(2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV). 
Geneva, Switzerland, 30 January 2020. 
WHO (2020c). A Multi-centre, Adaptive, Randomized, Double-Blind, Placebo-Controlled 
Clinical Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of 
COVID-19 in Hospitalized Patients. WHO R&D Blueprint, version number 2.0, 24 February 
2020. 
Zhou F, Yu T, Du R, et al (2020). Clinical course and risk factors for mortality of adult 
inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet; 
395(10229):1054-62. 

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Statement: 
By signing this document, I acknowledge that I have read the Statistical Analysis Plan and approve of 
the planned statistical analysis described herein.  
I agree that the planned statistical analyses are appropriate for the objective of the study and are 
consistent with the methodology described in the protocol, clinical development plan, and all regulatory 
guidelines. 
I also understand that any subsequent changes to the statistical analyses, as described herein, may have 
a regulatory impact and/or result in timeline adjustments. All changes to the planned analyses will be 
described in the clinical study report. 


 
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STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
CHANGES COMPARED TO PREVIOUS STATISTICAL ANALYSIS PLAN (SAP) VERSIONS 
 
 
Previous SAP 
section 
Change 
SAP v1 
 Not approved version, v1 was considered a working draft version 
SAP v2.0 – 
Several sections 
Addition of a sentence with the consideration that a stratification factor will not be included in a 
model if it does not have enough sample size to be considered. 
 
 
 


 
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Table of contents 
1. 
List of Abbreviations ..................................................................................................... 7 
1.1 
Abbreviations ............................................................................................................................ 7 
2. 
Introduction .................................................................................................................... 9 
2.1 
Background & Rationale ........................................................................................................... 9 
2.2 
Study Objectives ..................................................................................................................... 12 
2.2.1 Primary Objective ........................................................................................................................................ 12 
2.2.2 Secondary Objectives .................................................................................................................................. 12 
2.2.3 Exploratory Objectives ................................................................................................................................. 12 
2.3 
Study Design ........................................................................................................................... 13 
2.3.1 Eligibility and Randomization ....................................................................................................................... 15 
2.3.2 Eligibility Criteria .......................................................................................................................................... 15 
2.3.2.1 Inclusion Criteria 
15 
2.3.2.2 Exclusion Criteria 
16 
2.3.3 Withdrawals ................................................................................................................................................. 17 
2.3.4 Study treatment ........................................................................................................................................... 17 
2.3.4.1 Study treatment discontinuation and study discontinuation 
18 
2.3.5 Replacement of Patients.............................................................................................................................. 18 
2.3.6 Study termination ......................................................................................................................................... 18 
3. 
Analysis Populations................................................................................................... 19 
3.1 
Intention-to-Treat Population ................................................................................................. 19 
3.2 
Safety Population .................................................................................................................... 19 
3.3 
Per Protocol Population ......................................................................................................... 19 
3.4 
PK Population .......................................................................................................................... 19 
3.5 
Screening Failures .................................................................................................................. 19 
4. 
Study Endpoints and Derived Variables .................................................................... 20 
4.1 
Baseline and Demographics Characteristics ........................................................................ 22 
4.2 
Efficacy Endpoints .................................................................................................................. 22 
4.2.1 Rules Applicable to Ordinal Scale (Primary and Secondary Endpoints) ..................................................... 22 
4.2.2 Primary Efficacy Endpoint............................................................................................................................ 25 
4.2.3 Secondary Efficacy Endpoints ..................................................................................................................... 26 
4.2.4 Exploratory and Other Endpoints ................................................................................................................ 28 
4.3 
Safety Endpoints ..................................................................................................................... 30 
4.4 
Pharmacokinetic Endpoints ................................................................................................... 32 
4.5 
Other Derived Variables .......................................................................................................... 32 
5. 
General Statistical Methods ........................................................................................ 33 


 
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5.1 
Sample Size ............................................................................................................................. 33 
5.2 
Subject´s Disposition .............................................................................................................. 34 
5.2.1 Subject´s Disposition and Withdrawals ....................................................................................................... 34 
5.2.2 Protocol Deviations ...................................................................................................................................... 35 
5.3 
Summary of Statistical Methods ............................................................................................ 35 
5.3.1 Demographics, Other Baseline Characteristics and Medication ................................................................. 38 
5.3.1.1 Demographic Characteristics 
38 
5.3.1.2 Focused COVID-19 Medical History 
38 
5.3.1.3 Medical History 39 
5.3.1.4 Physical examination 
39 
5.3.1.5 Electrocardiogram (ECG) 
39 
5.3.1.6 Vital signs and Oxygenation/Respiratory parameters 
39 
5.3.1.7 National Early Warning Score (NEWS2) 40 
5.3.1.8 Clinical Status 40 
5.3.1.9 Laboratory Evaluations 40 
5.3.1.10 Prior and Concomitant Medications 
41 
5.3.2 Efficacy Analyses ......................................................................................................................................... 42 
5.3.2.1 Primary endpoint 
42 
5.3.2.2 Secondary endpoints 
43 
5.3.2.2.1 Proportion of subjects achieving recovery status scores (categories 6, 7 or 8) in the 8-point 
ordinal scale at Day 29 of follow-up ......................................................................................................... 43 
5.3.2.2.2 Proportion of subjects that die or develop respiratory failure by Day 29 ................................ 44 
5.3.2.2.3 Proportion of subjects achieving at least one or two points of improvement in clinical status 
scale at Days 8, 15 and 29 ...................................................................................................................... 44 
5.3.2.2.4 Time to at least one or two points of improvement in the ordinal scale of clinical status. ...... 45 
5.3.2.2.5 Subject clinical status and the mean change using ordinal scale at baseline, days 3, 5, 8, 11, 
15 and 29/60. ........................................................................................................................................... 46 
5.3.2.2.6 Time to a NEWS2 score of < 2 and maintained for 24 hours. ................................................ 47 
5.3.2.2.7 Change from baseline to Days 3, 5, 8, 11, 15 and 29 in NEWS2 score. ................................ 48 
5.3.3 Safety Analyses ........................................................................................................................................... 48 
5.3.3.1 Treatment Exposure 
49 
5.3.3.2 Adverse Events 49 


 
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5.3.3.3 Serious Adverse Events 51 
5.3.3.4 Physical Examination 
52 
5.3.3.5 Electrocardiogram (ECG) 
52 
5.3.3.6 Vital Signs and Oxygenation/ Respiratory parameters 
53 
5.3.3.7 Laboratory Evaluation 55 
5.3.4 Exploratory and Other Analyses .................................................................................................................. 57 
5.3.4.1 Duration of hospitalization 
57 
5.3.4.2 Time to discharge 
58 
5.3.4.3 Duration of supplemental oxygen support 
58 
5.3.4.4 Duration of invasive mechanical ventilation 
59 
5.3.4.5 Duration of ECMO 
59 
5.3.4.6 Proportion of subjects achieving No oxygen therapy (and/or peripheral oxygen saturation SpO2 > 
93% on room air) at Days 8, 15 and 29 
59 
5.3.4.7 28-day Mortality 60 
5.3.4.8 Change from baseline in biomarkers. 
60 
5.3.4.9 Change from baseline in SARS-CoV-2 viral load. 61 
5.3.4.10 Plasma pharmacokinetics of Brilacidin 
62 
5.3.5 Interim Analyses .......................................................................................................................................... 63 
5.3.6 Sensitivity Analyses ..................................................................................................................................... 63 
5.3.7 Study Estimand and Handling of Missing Data ........................................................................................... 64 
5.3.8 Subgroup Analyses ...................................................................................................................................... 68 
5.3.9 Reporting Conventions ................................................................................................................................ 68 
5.3.10 
Study Timelines ....................................................................................................................................... 68 
5.3.11 
Technical Details ..................................................................................................................................... 68 
5.3.12 
Software ................................................................................................................................................... 68 
6. 
References ................................................................................................................... 68 
 
 


 
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1. 
LIST OF ABBREVIATIONS 
1.1 
Abbreviations 
ACE 
Angiotensin-converting enzyme 
ACTT 
Adaptive COVID-19 Treatment Trial 
AE(s) 
Adverse event(s) 
AESI 
Adverse Events of Special Interest 
ANCOVA 
Analyses of Covariance 
ARDS 
Acute respiratory distress syndrome 
ATC 
Anatomic and therapeutic category 
BMI 
Body mass index 
BRI 
Brilacidin 
CHMP 
Committee on Human Medicinal Products 
CI 
Confidence Interval 
CIF 
Cumulative incidence function 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CS 
Clinical Status 
CSR 
Clinical Study Report 
D 
Day 
DBP 
Diastolic Blood Pressure 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
EMA 
European Medicine Agency 
EOS 
End of Study 
EWP 
Efficacy Working Party 
FiO2 
Fraction of inspired oxygen 
HDP 
Host defense proteins 
HLGT 
High level group term 
HLT 
High level term 
HR 
Hazard ratios 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
IP 
Investigational Product 
IPI 
Innovation Pharmaceuticals Inc. 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
LDH 
Lactate dehydrogenase 
LLT 
Lower level term 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NEWS2 
National Early Warning Score 2 
NP 
Nasopharyngeal 
OP 
Oropharyngeal 
OS 
Overall Survival 
PaO2 
Arterial oxygen partial pressure 
PBO 
Placebo 
PCR 
Polymerase Chain Reaction 
PDE 
Phosphodiesterases 


 
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PEP 
Primary Endpoint 
PK 
Pharmacokinetics 
PoC 
Proof of Concept 
PP 
Per Protocol 
PT 
Preferred term 
Q1 
First quartile 
Q3 
Third quartile 
R 
Randomization 
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical Analyses Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic Blood Pressure 
SE 
Standard Error 
SoC 
Standard of Care 
SOC 
System organ class 
SpO2 
Peripheral oxygen saturation 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
TNF-α 
Tumor necrosis factor alpha 
ULN 
Upper Limit of Normal Range 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


 
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2. 
INTRODUCTION 
This study is being conducted under the sponsorship of Innovation Pharmaceuticals Inc., in both the US 
and Russia. 
 
 
 
 
  
Statistical analyses are being performed 
. 
The statistical analysis plan (SAP) was written based on protocol version 1.2 (24 December 2020). This 
SAP provides a detailed description of the strategy and statistical techniques to be used to perform the 
analyses of data collected. 
This document does not address the specific analysis of pharmacokinetic (PK) data collected in this study. 
These analyses will be discussed in a separate analysis plan to support the population PK report. 
This SAP supersedes any statistical considerations that were identified in the study protocols approved 
prior to the date of this SAP. Substantial changes from the protocol version 1.2 are summarized in this 
plan. 
This SAP may be revised prior to database lock and unblinding of the treatment codes to reflect any 
changes or additional details based on external information, regulatory feedback, or issues identified 
during the blinded data review. Any additional analyses or major changes performed after the last version 
of the SAP is finalized will be identified in the appropriate section of the clinical study report (CSR). 
SAS code presented in this document is example code and may differ slightly from final analysis code. 
2.1 
Background & Rationale 
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified as the cause of an 
outbreak of respiratory illness due to coronavirus disease 2019 (COVID-19) that was first detected in 
Wuhan, China, in December 2019. The virus causes respiratory illness in people and can spread from 
person to person. Common signs of infection include fever, cough, shortness of breath, breathing 
difficulties, and other respiratory symptoms. Gastrointestinal symptoms (nausea, vomiting, diarrhea) also 
appear to be common clinical manifestations of COVID-19. In severe cases, SARS-CoV-2 can cause 
pneumonia, severe acute respiratory syndrome, kidney failure, and death (WHO 2020a). On 30 January 
2020, the International Health Regulations Emergency Committee of the WHO declared the COVID-19 
outbreak a Public Health Emergency of International Concern (WHO 2020b). Further to the WHO 
declaration, on 31 January 2020, Health and Human Services declared a public health emergency in the 
United States (US) (DHHS 2020). 


 
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As of November 3, 2020, over 47.2 million COVID-19 cases have been diagnosed in at least 190 
countries, resulting in over 1.2 million reported deaths, including over 9.3 million cases and almost 
233,000 fatalities in the United States (Johns Hopkins Coronavirus Resource Center 2020). While 
COVID-19 mortality rates can vary greatly by geographic region, with differences in how rates are 
calculated, it is generally accepted that, for COVID-19, the overall mortality rate is many times higher than 
that seen with seasonal influenza; moreover, it has been observed that up to 15% of COVID-19 patients 
develop lung injury, including respiratory distress progressing to acute respiratory distress syndrome 
(ARDS) requiring prolonged ventilator support over weeks (Zhou et al 2020). This can result in intensive 
care units, hospitals and health care systems becoming overwhelmed. Presently, there are no approved 
vaccines and few minimally effective therapies to treat COVID-19. According to a May 1, 2020, 
Congressional Research Service report, worldwide economic growth could be reduced by 2 percent per 
month if current pandemic conditions persist, with global trade falling by 13 percent to 32 percent, with 
the economic downturn attributable to the COVID-19 crisis could vastly exceed that of the Great 
Recession (2007-2009) (Congressional Research Service 2020). The Congressional Budget Office 
estimates the novel coronavirus pandemic will cost the U.S. economy $8 trillion through 2030 (Stein 
2020). 
ARDS is characterized by pro-inflammatory cytokine release, inflammatory cellular infiltration and cell 
death, resulting in severe pulmonary damage and the development of respiratory failure that requires 
mechanical ventilation with high positive end-expiratory pressures to maintain life. In patients with a prior 
history of hypertension, diabetes and cardiovascular disease (common comorbid conditions), poor health 
outcomes have been reported that may be a result of poor underlying cardiac reserve - meaning that 
patients develop cardiac failure in response to ventilation, with pulmonary edema further exacerbating 
respiratory failure (Zhou et al 2020). 
ARDS is an important contributor to the morbidity and mortality associated with COVID-19. ARDS 
manifestation is connected to heightened inflammatory responses adversely impacting normal lung 
function. A therapeutic intervention that exhibits immunomodulatory properties might help control this 
inflammatory response as characterized by ARDS. An intervention that also exerts antiviral activity would 
provide an even more complete solution to the SARS-CoV-2 infection associated ARDS challenge. 
Brilacidin is a fully synthetic, non-peptidic, host defense protein mimetic. Brilacidin is a small molecule, 
new chemical entity, created so as to mimic the amphiphilic structure of host defense proteins (HDPs), 
having one surface with positively charged groups (cationic) and the opposite surface consisting of 
hydrophobic groups. With this general synthetic form, there is no need for an agent to be of the size or 
composition of naturally-occurring proteins to effectively function as a HDP, as the ability to act as a HDP 
is retained by the much smaller synthetic amphiphilic molecule. 


 
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Brilacidin has anti-inflammatory activity – the mechanism of which is proposed to be based largely on 
inhibition of phosphodiesterases (PDE4 and PDE3) and subsequent downregulation of pro-inflammatory 
cytokines (such as TNF-α, IL-1β, IL-6, IL-8). Like natural HDPs, Brilacidin has antibacterial activity (with 
a predominantly gram-positive spectrum). 
New in vitro research has demonstrated robust and consistent antiviral activity of Brilacidin against SARS-
CoV-2, as summarized below. 
Brilacidin has three complementary anti-COVID-19 therapeutic properties combined in a single drug: 
antiviral; immunomodulatory/anti-inflammatory; and antimicrobial. Brilacidin has demonstrated antiviral 
activity against SARS-CoV-2 in cell-based assays (see Section 1.3.1.3 of the protocol), and the 
mechanisms for this activity are postulated as being: 
1) Membrane Disruption: disrupting the viral envelope (virucidal) 
2) Entry Inhibition: by competing with the virus for the ACE2 receptor, preventing ACE2 receptor binding 
and viral entry 
3) Intracellular Targets: inhibiting viral replication intracellularly, by binding to SARSCoV-2 main protease 
(Mpro) 
4) Anti-inflammatory: suppressing IL-6 and other pro-inflammatory mediators implicated in the “cytokine 
storm”, through inhibition of phosphodiesterase 
The main proposed mechanism of action of Brilacidin involves the disruption of viral membrane integrity. 
Other direct antiviral mechanisms of action of Brilacidin may include blocking viral entry and interrupting 
viral replication intracellularly. An in silico quantum mechanical molecular screening study of 11,522 
compounds (both FDA-approved and those in testing) identified Brilacidin as one of the most promising 
potential inhibitors of the novel coronavirus based on the potential of its physico-chemical properties to 
interfere with the intracellular replication of SARS-CoV-2’s main protease (Mpro) (Cavasotto and Filippo 
2020). A peer-reviewed article detailing in vitro results and proposed mechanisms of action is published 
(Bakovic et al 2021), with a pre-print (Bakovic et al 2020) made available. 
Additional nonclinical and clinical data support Brilacidin’s potential to function through the cAMP/cGMP 
pathway, by inhibition of phosphodiesterase. PDE4 is the predominant phosphodiesterase expressed in 
neutrophils, T cells and macrophages. PDE inhibitors show broad spectrum of anti-inflammatory effects 
in almost all inflammatory cells. PDE4 inhibitors block the degradative action of PDE4 on cAMP, thereby 
increasing intracellular levels of cAMP levels which mediate phosphorylation of protein kinases. PDE4 
inhibitors reduce neutrophil chemotaxis, recruitment and activation; inhibit the activation of CD4+ and 
CD8+ T cells; and inhibit monocytes chemotaxis (Tamimi et al 2012). Therefore, inhibition of PDEs is 
expected to have a therapeutic effect on the inflammatory state. 


 
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Inhibition of PDE4 and PDE3 has been demonstrated for Brilacidin in vitro. PDE4 and PDE3 inhibition 
results in subsequent down-regulation of proinflammatory cytokines and chemokines (such as TNF-α, IL-
6, IL-1β, MMP-9, MCP-1, IL-8, CINC-3), which have been identified as central drivers in the worsening 
prognoses of hospitalized COVID-19 patients. Experiments have been conducted to confirm such 
downregulation by Brilacidin in ex vivo cell-based assays (see protocol Section 1.3.1.3), and also from 
clinical biomarker data (Phase 2 retention enema study (see protocol Section 1.3.2.3). 
Brilacidin’s antimicrobial properties, as demonstrated in a Phase 2b clinical trial of intravenous Brilacidin 
in the treatment of Acute Bacterial Skin and Skin Structure Infections, may also help to fight or prevent 
secondary bacterial infections, which can co-present in up to 20 percent of COVID-19 cases (Cox et al 
2020; Kim et al 2020; Mirzaei et al 2020). 
Collectively, these data support Brilacidin as a highly unique 3-in-1 combination—antiviral, anti-
inflammatory, antimicrobial—novel COVID-19 therapeutic candidate. 
2.2 
Study Objectives  
Primary, secondary and exploratory objectives are specified in sections below 2.2.1, 2.2.2 and 2.2.3, 
respectively. 
2.2.1 Primary Objective 
To evaluate the clinical efficacy of Brilacidin IV treatment in addition to SoC, compared with SoC alone, 
in subjects with COVID-19. 
2.2.2 Secondary Objectives 
To assess multiple clinical measures of disease severity and disease burden. 
To assess the safety and tolerability of Brilacidin IV treatment in subjects with COVID-19. 
2.2.3 Exploratory Objectives  
To evaluate the following In-hospital outcomes: 
• 
Duration of hospitalization 
• 
Time to discharge 
• 
Duration of invasive mechanical ventilation 
• 
Duration of supplemental oxygen support 
• 
Duration of ECMO (Extracorporeal Membrane Oxygenation) 
• 
No oxygen therapy (and/or peripheral oxygen saturation SpO2 > 93% on room air) at Days 8, 15 
and 29 
 
To evaluate All-cause 28-day mortality. 
To measure biological and immunological markers of illness/inflammation. 
To explore the change in the SARS-CoV-2 viral load. 


 
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To estimate the plasma pharmacokinetics of Brilacidin. 
 
2.3 
Study Design  
This study is a Phase 2, randomized, double-blind, placebo-controlled, multicenter clinical trial with 
parallel group design to evaluate the efficacy and safety of Brilacidin in hospitalized participants with 
COVID-19. 
Approximately 120 adult hospitalized subjects with COVID-19 will be randomized. 
The key eligibility criteria includes adult subjects, aged between 18 and 80 years, with moderate to severe 
COVID-19, 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 
hospitalized with respiratory distress but not yet requiring high-level respiratory support (as defined in 
exclusion criterion #2). 
Subjects that are eligible will be randomized to receive either Brilacidin or placebo in addition to available 
SoC, by randomization to one of the following two IV study treatment arms in a ratio of 1:1 (n=60 per 
arm): 
• 
SoC + Brilacidin IV 0.6 mg/kg (D1), 0.3 mg/kg (D2 and D3) with potential to expand dosinga of 
0.3 mg/kg on D4 and D5 
• 
SoC + Saline IV infusion (D1, D2, and D3) with potential to expand dosinga on D4 and D5 
a Note: Dependent on safety review and recommendation by the Data Monitoring Committee (DMC). 
D1, D2, and D3 (above) refer to Day 1, Day 2 and Day 3 of study treatment. Similarly, D4 and 
D5 are Day 4 and Day 5. 
Randomization of subjects to treatment will also be stratified by (1) Age (≤65years, >65years), (2) 
Severity of disease (moderate, severe), and (3) Country. The generated randomization list will be 
uploaded into the IBM Clinical Development system (IRT system) which will manage the assignment. 
 
The study is comprised of three parts, which are also shown in Figure 1: 
• 
Screening/ Baseline visit (Day -1 to 1) 
• 
Study treatment period (Day 1-3 with potential to expand to Day 4-5) 
• 
Follow-up period (Day 4-6 through Day 60) 
 
 
The schedule of visits and assessments can be found in the protocol Table 1 Schedule of Activities. 
 
 


 
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Figure 1: Study Flow Chart 
Note: Study treatment is in addition to standard of care (SoC) 
BRI = Brilacidin; D = Day; EOS = End of Study; PBO = placebo; R = randomization 
 
 
Subjects will be screened (Day -1 to 1) and baseline assessments will be performed within a maximum 
of 48 hours. This visit will confirm that study inclusion and exclusion criteria are met by participants prior 
to randomization. Results confirming positive SARS-CoV-2 virus by PCR or equivalent/ other approved 
diagnostic testing should take place within 4 days prior to randomization and may be used for eligibility. 
During the treatment period, on Study Days 1 to 3 (with potential to expand to Day 4-5, after initial interim 
safety readout), randomized subjects will receive blinded study treatment once daily for 3 days by IV 
infusion, in addition to SoC. 
Subjects who successfully complete the treatment period, will enter a follow-up period, Day 4 or 6 through 
Day 60. Subjects will be assessed daily while hospitalized. Discharged patients will be asked to attend 
study visits at Days 15 and 29. All subjects will undergo a series of efficacy and safety assessments, 
including laboratory assays. Blood samples and nasopharyngeal (NP) swabs will be obtained on Days 1, 
3, 5, 8, 11 (while hospitalized) and/or on day of discharge; and Days 15 and 29 (by returning to the clinic/ 
remote visit or if still hospitalized). If subjects are discharged from hospital prior to Day 15, or Day 29, and 
a hospital visit is not possible, then visiting nursing services and mobile phlebotomy may support that visit 
remotely where these are available in accordance with local guidelines and should include all possible 
assessments (e.g., oxygen saturation with portable monitors). Every effort should be made to ensure 
discharged patient follow-up at Days 15 and 29, via a healthcare interaction (minimally by telephone call). 
A follow-up visit at Day 60(±10), by telephone call, is also included to confirm patient status.  


 
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An independent Data Monitoring Committee (DMC) will be established to conduct periodic safety reviews. 
An initial safety review is planned to occur after approximately 20 randomized subjects have completed 
up to Day 15, and a further safety review by the DMC is planned to occur after approximately 50% of 
subjects have completed up to Day 29. The DMC may recommend expanding dosing to Days 4 and 5 (at 
the same doses as on Days 2 and 3), continuation of the Days 1-3 study dosing unchanged, or that the 
trial be interrupted or stopped for safety reasons. Details of the DMC will be prepared separately from this 
protocol in a DMC Charter; the charter may supersede the summary details presented here. 
2.3.1 Eligibility and Randomization 
After confirming eligibility, subjects will be randomized in blocks using a centralized randomization method 
with an allocation ratio of 1:1 for Brilacidin and Placebo, respectively. Once assigned to a patient, the 
randomization number will neither be replaced nor used a second time. A patient is considered enrolled 
when he or she is randomized into the trial, even if he or she does not receive study medication. The 
stratification factors are: country, categorized age group (< 65 years / > 65 years) and COVID-19 severity 
(moderate/ severe). The use of three stratification factors create 8 strata, and the block size used was 2. 
A separate Randomization documents the tools and methods used to generate the randomization list. 
The randomization list has been generated using SAS 9.4 with a seed to ensure its reproducibility. The 
generated list is uploaded into the IBM Clinical Development system (IRT system) which will manage the 
random assignment to treatment. The unblinded randomization list will be provided from the Unblinded 
Statistician to the Unblinded Programmer who will upload it into the IBM Clinical Development system. 
2.3.2 Eligibility Criteria 
2.3.2.1 
Inclusion Criteria 
Participants eligible for enrollment and inclusion in this study must meet all of the following criteria: 
1. 
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. 
2. 
Male or non-pregnant female adults between 18 and 80 years of age, inclusive, at time of informed 
consent. 
3. 
SARS-CoV-2 infection confirmed by positive standard polymerase chain reaction (PCR) test (or 
equivalent/ other approved diagnostic test) ≤ 4 days before randomization. 
4. 
Currently hospitalized and requiring medical care for COVID. 
5. 
Moderate OR severe COVID-19, defined by respiratory function at screening, as below:  
Moderate, meet at least one of the following criteria: 
• 
Peripheral oxygen saturation SpO2 > 93% on room air; 
• 
Respiratory rate ≥ 20 to < 30 breaths per minute. 
Severe, meet at least one of the following criteria: 


 
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• 
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. 
6. 
Body mass index (BMI) of ≥18 to <40kg/m2 at screening. 
7. 
Agrees to the collection of nasopharyngeal (NP) swabs and venous blood per protocol. 
8. 
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. 
2.3.2.2 
Exclusion Criteria 
Participants meeting ANY of the following criteria are not eligible for this study and are to be excluded: 
1. 
Participation in any other clinical trial of an investigational treatment. 
2. 
Requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) at 
the time of randomization. 
3. 
Has explicitly expressed the wish not to receive intensive care support (Do not resuscitate or Do not 
intubate order) should this become necessary. 
4. 
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. 
5. 
Requiring systemic anti-infective therapy for suspected or confirmed active bacterial/fungal/viral 
systemic infection other than COVID-19. 
6. 
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. 
7. 
If has a history of hypertension in the last 3 months, must have been receiving appropriate anti-
hypertensive therapy in accordance with local guidelines. 
8. 
Evidence of moderate or severe hepatic impairment (Child-Pugh Class B or C). 
9. 
Estimated GFR (eGFR) <30 mL/min/1.73m2 (based on CKD-EPI formula). 
10. Prior to a participant’s study entry, known allergies or intolerance to Brilacidin or formulation 
excipients. 
11. 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. 
12. Pregnancy or breast-feeding, or positive urine or serum pregnancy test in a pre-dose assessment. 
13. Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using effective methods of contraception as defined below, throughout the 
study and for up to 30 days after stopping treatment. 
 
Effective contraception methods include: 
• 
Total abstinence (if this is the preferred and usual lifestyle of the subject). 
 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), 
total hysterectomy or tubal ligation at least six weeks before start of study treatment. In case of 


 
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oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment. 
• 
Male partner sterilization (at least 6 months prior to screening). The vasectomized male partner 
should be the sole partner for that female subject. 
• 
Double barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository. 
• 
Use of oral*, injected or implanted hormonal methods of contraception or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal 
ring or transdermal hormone contraception. 
(*In the case of oral contraception, subjects should have been using the same pill on a stable 
dose for a minimum of 3 months before start of study treatment). 
• 
Intrauterine device (IUD) or intrauterine system (IUS) 
Women are considered post-menopausal and not of childbearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy), total hysterectomy or tubal ligation at least six weeks before start of study 
treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment is she considered not of childbearing 
potential.  
In addition, female subjects must also refrain from egg donation and in vitro fertilization during study 
treatment and for 7 days after stopping study treatment. 
14. 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.  
In addition, male participants must not donate sperm during study treatment and for 7 days after 
stopping study treatment. 
2.3.3 Withdrawals  
Refer to sections 2.3.4.1 below and 7.6 of the protocol. 
2.3.4 Study treatment 
The investigational drug product (IP) supplied is Brilacidin for Injection, 50 mg/mlL(free base).  
For intravenous infusion administration, Brilacidin for Injection is diluted in sterile 0.9% w/v sodium 
chloride (normal saline) to provide the desired final dose within 8 hours of administration. Dose calculation 
for a subject’s study treatment infusions will be based on actual body weight measured at Screening. 
On Day 1, randomized subjects will be allocated to one of the following two IV study treatment arms: 
• 
SoC + Brilacidin IV 0.6 mg/kg (D1), 0.3 mg/kg (D2 and D3) with potential to expand dosing 
(dependent on safety review and recommendation by the DMC) of 0.3 mg/kg on D4 and D5 
• 
SoC + Saline IV infusion (D1, D2, and D3) with potential to expand dosing (dependent on 
safety review and recommendation by the DMC) on D4 and D5 
 


 
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At the initial safety review by the DMC, the recommendation was to expand study drug dosing to Days 4 
and 5 (at the same doses as on Days 2 and 3). This change was made by the Sponsor and sites were 
informed to move from the 3-dose regimen to the 5-dose regimen. 
2.3.4.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier than the 
protocol planned duration and can be initiated by either the subject or the investigator. 
If discontinuation of study treatment occurs for a subject, the investigator must determine the primary 
reason for the discontinuation of study treatment and record this information. Subjects who discontinue 
study treatment or who decide they do not wish to participate in the study further should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent (see Protocol Section 7.6.2). 
Where possible, subjects are to continue with (if hospitalized) or return for the assessments indicated in 
the Schedule of Activities (Protocol Table 1). If they fail to return for these assessments for unknown 
reasons, every effort (e.g., telephone, e mail, and letter) should be made to contact the subject/pre-
designated person contact as specified in the lost to follow-up section (Protocol Section 7.6.3). This 
contact should preferably be done according to the study visit schedule and documented in the site study 
file. 
Subjects who discontinue from study treatment or from the study will not be replaced. 
All available data measured prior to withdrawal or discontinuation from the study will be used in analysis. 
The reason for early treatment discontinuation and/or study withdrawal should be recorded in the case 
report form and will be reported in the overall disposition summaries. 
2.3.5 Replacement of Patients 
No replacement of patients will be considered in this trial since will be carried out according to intent to 
treat principles. 
2.3.6 Study termination 
This study can be terminated at any time for any reason by the Sponsor. Should this be necessary, the 
Sponsor and the investigators will ensure that proper study discontinuation procedures are completed, 
and that adequate consideration is given to the protection of the subject’s interests.


 
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3. 
ANALYSIS POPULATIONS 
3.1 
Intention-to-Treat Population 
The Intent-to-Treat (ITT) population will include those randomized subjects who received at least one 
dose of study drug. Subjects in this population will be analyzed according to the treatment arm to which 
they were randomized.  
The ITT will be the main population for demographic, baseline characteristics, efficacy, and exploratory 
analyses. Efficacy analyses performed on the ITT population will be considered primary. 
3.2 
Safety Population 
The Safety population will include all subjects in the ITT population. Subjects in this population will be 
analyzed according to treatment they actually received. All safety analyses will be based on this 
population. 
3.3 
Per Protocol Population 
The Per Protocol population (PP) will consist of ITT subjects who meet all of the following criteria: 
1. Complete study treatment (allocated regimen, either 3-dose or 5-dose) 
2. No major protocol deviations that will potentially impact the primary study objective. 
The following criteria have been identified a priori as major deviations that will potentially impact the 
primary study objective. Additional major deviations may be identified during the study. These will be 
reviewed and approved by the sponsor prior to database lock and unblinding of treatment assignment. 
1. Deviation from key inclusion/exclusion criteria. 
2. Receipt of treatment different from the randomized treatment assignment. 
3. Receipt of prohibited medication per protocol in the treatment period. 
The reason for excluding subjects from the per-protocol population will be summarized by randomized 
treatment arm and presented in a data listing. 
The Per Protocol population will be used for sensitivity analysis of the efficacy endpoints. Efficacy 
analyses performed using the PP population will be considered supportive. 
3.4 
PK Population 
The PK population will be defined in a separate PK analysis plan. 
3.5 
Screening Failures  
Screen failure patients will be defined and a listing, including the number of patients, demography and 
why considered a screening failure, will be created.


 
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4. 
STUDY ENDPOINTS AND DERIVED VARIABLES 
This section is intended to outline the way to build the variables needed to assess all study endpoints and 
state definitions properly. For the statistical methods that will be used, refer to section 0. 
The following table summarizes the endpoints corresponding to the objectives of the study: 
Objective(s) 
Endpoint(s) 
PRIMARY 
• 
To evaluate the clinical efficacy of 
Brilacidin IV treatment in addition 
to SoC, compared with SoC 
alone, in subjects with COVID-19 
Primary Endpoint based on the clinical status ordinal scale: 
• 
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 ordinal scale: 
- 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; 
and does not descend in the scale (being re-hospitalized 
with or without requiring supplemental oxygen or dies) in the 
remaining period of follow-up through Day 29 
SECONDARY 
• 
To 
assess 
multiple 
clinical 
measures of disease severity and 
disease burden 
- 
Composite endpoints, from 
the ordinal scale 
• 
Achieving recovery status scores (see definition in 
primary endpoint above) at Day 29 
• 
Composite endpoint by Day 29, defined as: 
- Death OR 
- Respiratory 
failure 
(requires 
invasive 
mechanical ventilation) 
- 
Clinical status measures, from 
the ordinal scale 
Endpoints based on the 8-point ordinal scale: 
• 
Achieving at least one-point/ two-point improvement in 
clinical status at Days 8, 15 and 29 
• 
Time to at least one-point/ two-point improvement in 
clinical status 
• 
Clinical status over time 
- 
Change in the National 
Early 
Warning 
Score 
(NEWS2) 
• 
Time to a NEWS2 of ≤2 and maintained for 24 hours 
• 
Change from baseline to Days 3, 5, 8, 11, 15, and 29 in 
NEWS2 
• 
To assess the safety and tolerability 
of Brilacidin IV treatment in subjects 
with COVID-19 
• 
Incidence and severity of treatment-emergent Adverse 
Events (AEs), including Serious Adverse Events (SAEs) 
 
• 
Clinically significant changes in laboratory 
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EXPLORATORY/ OTHER 
 
• 
In-hospital outcomes 
• 
Duration of hospitalization 
• 
Time to discharge 
• 
Duration of invasive mechanical ventilation 
• 
Duration of supplemental oxygen support 
• 
Duration of ECMO 
• 
No oxygen therapy (and/or peripheral oxygen 
saturation SpO2 > 93% on room air) at Days 8, 15 and 
29 
• 
All-cause mortality 
• 
28-day mortality (to Study Day 29) 
• 
To 
measure 
biological 
and 
immunological 
markers 
of 
illness/inflammation 
• 
Changes from baseline in biomarkers from blood 
samples may include, but are not limited to: 
CRP, ferritin, LDH, D-dimer, troponin hs (troponin T, 
troponin I), absolute neutrophil count [at Days 2, 3, 5, 8, 
11 (while hospitalized)  and/or on day of discharge; and 
Days 15 and 29 (by returning to the clinic/ by remote 
visit or if still hospitalized)]; 
and IL-1β, IL-6, IL-10, total IL-18, TNF-α [at Days 3, 5, 
8, 11 (while hospitalized) and/or on day of discharge; 
and Day 15 (by returning to the clinic/ by remote visit or 
if still hospitalized)]; 
• 
To explore the change in the 
SARS-CoV-2 viral load 
• 
Change from baseline in SARS-CoV-2 viral load from 
NP or OP samples at Days 3, 5, 8, 11 (while 
hospitalized) and/or on day of discharge; and Days 15 
and 29 (by returning to the clinic/ by remote visit or if 
still hospitalized) 
• 
To 
estimate 
the 
plasma 
pharmacokinetics of Brilacidin 
• 
Plasma concentrations of Brilacidin measured 
from blood samples collected on Days 1 to 4 
 
 
 


 
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4.1 
Baseline and Demographics Characteristics  
The baseline value is defined as the last available measurement prior to the first dose of study drug 
accounting for date, and time (where available), unless otherwise specified. 
Specific disease history (COVID-19 related) variables include: 
 
- Time from onset of first COVID-19 symptoms until randomization is defined as the time 
elapsed (in days) from the date of onset of first COVID-19 symptoms until the randomization date 
- Time from onset of first COVID-19 symptoms until hospitalization is defined as the time 
elapsed (in days) from the date of onset of first COVID-19 symptoms until the hospitalization date 
- Time from diagnosis of COVID-19 until randomization is defined as the time elapsed (in days) 
from the date of diagnosis of COVID-19 until the randomization date 
- Time from diagnosis of COVID-19 until hospitalization is defined as the time elapsed (in days) 
from the date of diagnosis of COVID-19 until the hospitalization date 
- Time from hospitalization until randomisation is defined as the time elapsed (in days) from 
the hospitalization date until the randomization date 
 
4.2 
Efficacy Endpoints 
4.2.1 Rules Applicable to Ordinal Scale (Primary and Secondary Endpoints) 
The primary and multiple secondary efficacy endpoints use data collected by an ordinal scale, developed 
specifically for efficacy assessment of COVID-19. 
A special WHO committee arrived at an ordinal scale (WHO 2020a; WHO 2020c) that graduates the 
severity of the Clinical Status (CS) of a subject on an 8-point score. Following this scale along with the 
National Institute of Allergy and Infectious Diseases ordinal scale framework (as used in Adaptive COVID-
19 Treatment Trial (ACTT) trials), an adapted scale has been used as follows: 
Score 
Description 
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) 






 
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4.2.2 Primary Efficacy Endpoint 
The primary endpoint based on the ordinal scale is “Time to sustained recovery through Day 29", which 
is defined as time (in days) from randomization until the first day on which the subject satisfies one of the 
categories 6, 7 or 8 (meaning the subject either no longer requires supplemental oxygen or ongoing 
medical care in the hospital, or is no longer hospitalized [with or without some limitation on activities]) on 
the 8-point ordinal scale and does not descend in the scale (being re-hospitalized with or without requiring 
supplemental oxygen or dies) in the remaining period of follow-up through Day 29. i.e., relapse by Day 29 
after initial recovery negates that recovery. 
If response after initial recovery is not sustained, and the subject experiences relapse, the initial recovery 
is not counted as such. Any subsequent recovery, sustained through Day 29, will be recognized and 
counted. 
 
 


 
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4.2.3 Secondary Efficacy Endpoints 
The secondary endpoints for this trial are divided in two main groups: 
 
1) 
Multiple clinical measures of disease severity and disease burden, as follows: 
• 
Composite endpoints, from the ordinal scale defined in section 4.2.1: 
 
- 
Achievement of recovery status scores (score 6, 7 or 8 in the ordinal scale) at Day 29: 
 
The proportion of subjects achieving recovery status scores (6, 7, 8) in the 8-point ordinal 
scale at Day 29 will be derived as a binomial outcome from the ordinal status scale of 8 points 
as the proportion of subjects with a score of 6, 7, or 8 at Day 29. Any other case will be considered 
as not recovery status. Please refer to section 5.3.2 for details on the handling of intercurrent 
events and missing data. 
 
- 
Composite endpoint by Day 29, defined as: Death OR Respiratory failure (requires invasive 
mechanical ventilation): 
 
The proportion of subjects that meet the composite event of death or respiratory failure 
(considered when a subject requires invasive mechanical ventilation) by Day 29 will be 
derived as the proportion of subjects achieving one of the two events that compose the endpoint: 
death by Day 29 (score 1 in the clinical status scale) or respiratory failure (requiring invasive 
mechanical ventilation, score 2 the clinical status scale) by Day 29. Any other case will be 
considered as not achieving the composite event. Please refer to section 5.3.2 for details on the 
handling of intercurrent events and missing data. 
 
• 
Clinical status measures, from the ordinal scale defined in section 4.2.1: 
 
- 
Achievement of at least one-point/ two-point improvement in clinical status at Days 8, 15 and 29: 
 
The proportion of subjects achieving at least one category improvement in clinical status 
at Day 8, 15 and 29 will be derived as the proportion of subjects with at least one point of 
improvement from baseline clinical status score at Days 8, 15 and 29 respectively. The change in 
the ordinal scale will be estimated as the difference “assessment score (Day 8, 15 or 29) – baseline 
score” and the improvement of at least one point will be when the result of the difference is >=1. 
Only subjects with available information at baseline and time-point of assessment will be 
considered in the analyses. 
 
The proportion of subjects achieving at least two category improvement in clinical status at 
Day 8, 15 and 29 will be derived as the proportion of subjects with at least two points of 
improvement from baseline clinical status score at Days 8, 15 and 29 respectively. The change in 
the ordinal scale will be estimated as the difference “assessment score (Day 8, 15 or 29) – baseline 
score” and the improvement of at least two points will be when the result of the difference is >=2. 


 
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Only subjects with available information at baseline and time-point of assessment will be 
considered in the analyses. 
 
- 
Time to at least one-point/ two-point improvement in clinical status scale 
 
Time to at least one category improvement in clinical status is defined as time (in days) from 
randomization until get an elevation of at least one point in the 8-point ordinal scale. The subjects 
will be considered as having achieved the event the first day in which they have an elevation of at 
least one point in the scale from baseline. 
 
Time to at least two category improvement in clinical status is defined as time (in days) from 
randomization until get an elevation of at least two points in the 8-point ordinal scale. The subjects 
will be considered as having achieved the event the first day in which they have an elevation of at 
least two points in the scale from baseline. 
 
- 
Clinical status over time 
Clinical status over time is considered as the score of the 8-point ordinal scale at all time-points 
of assessment.  
 
 
• 
National Early Warning Score (NEWS2) 
 
- 
Time to a NEWS2 of ≤2 and maintained for 24 hours 
 
Time to a NEWS2 of <2 and maintained for 24 hours is defined as time (in days) from 
randomization until get a NEWS2 score lower or equal to 2 being maintained for at least 24 hours 
(for example, if a subject achieves a NEWS2 <2 at Day 2, the NEWS2 should also be <2 at Day 
3 to reach the event). Please refer to section 5.3.2 for details on the handling of intercurrent events 
and missing data. 
 
 
- 
Change from baseline to Days 3, 5, 8, 11, 15, and 29 in NEWS2: 
 
Change from baseline in NEWS2 at Days 3, 5, 8, 11, 15, and 29 will be derived taking the 
baseline score as reference, meaning that it will be the difference between the assessment score 
and the baseline score at each time-point of assessment. If NEWS2 score is not available at any 
of Days 3, 5, 8, 11 or 15, no change from baseline will be calculated for that assessment. 
 
2) 
Endpoints to assess the safety and tolerability of Brilacidin IV treatment in subjects with COVID-19 
infection: 
See section 4.3 for definition of safety and tolerability endpoints. 


 
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4.2.4 Exploratory and Other Endpoints 
The following outcomes will be derived from data collected on the eCRF: 
 
• 
Duration of hospitalization: 
Duration of hospitalization from randomization to discharge is defined as the time elapsed 
(in days) from randomization until hospital discharge.  
 
Please refer to section 5.3.4 for details on the handling of intercurrent events and missing data. 
 
• 
Time to discharge: 
Time to discharge from randomization is defined as the time elapsed (in days) from 
randomization until hospital discharge.  
 
Please refer to section 5.3.4 for details on the handling of intercurrent events and missing data. 
 
• 
Duration of invasive mechanical ventilation 
Duration of invasive mechanical ventilation is defined as the cumulative time (for all episodes 
of use of mechanical ventilation during the observation period [day 1 to 29]), in days, from the 
mechanical ventilation necessity until it is retired due to an improvement. 
 
• 
Duration of supplemental oxygen support 
Duration of supplemental oxygen support is defined as the cumulative time (for all episodes 
of use of supplemental oxygen support (low flow O2, high flow O2, CPAP/BIPAP, mechanical 
ventilation, ECMO) during the observation period [day 1 to 29]), in days, from the supplemental 
oxygen necessity until it is retired due to an improvement. 
 
• 
Duration of ECMO: 
Duration of ECMO is defined as the cumulative time (for all episodes of use of ECMO during 
the observation period [day 1 to 29]), in days, from the ECMO necessity until it is retired due to 
an improvement. 
 
• 
No oxygen therapy (and/or peripheral oxygen saturation SpO2 > 93% on room air) at Days 8, 
15 and 29 
The proportion of subjects with no oxygen therapy (and/or peripheral oxygen saturation 
SpO2 > 93% on room air) will be derived as the proportion of subjects without any oxygen 
therapy and/or peripheral oxygen saturation SpO2 > 93% on room air at the corresponding time-
point of assessment. 


 
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• 
All cause-mortality 
Overall survival (OS) is defined as the time (in days) from randomization to death. 
 
28-day mortality is the proportion of subjects that are dead by Day 29. The proportion will be 
estimated from the OS survival analysis. 
 
• 
Biological and immunological markers of illness/inflammation  
 
Biomarker values and changes from baseline include, but are not limited to: CRP, ferritin, LDH, 
D-dimer, troponin hs (troponin T, troponin I), absolute neutrophil count [at Days 2, 3, 5, 8, 11 
(while hospitalized) and/or on day of discharge; and Days 15 and 29 (by returning to the clinic/ 
by remote visit or if still hospitalized)]; 
and IL-1β, IL-6, IL-10, total IL-18, TNF-α [at Days 3, 5, 8, 11 (while hospitalized) and/or on day 
of discharge; and Days 15 (by returning to the clinic/ by remote visit or if still hospitalized)]. 
 
• SARS-CoV-2 viral load 
 
Viral load and change from baseline in SARS-CoV-2 viral load from NP or OP samples at 
Days 3, 5, 8, 11 (while hospitalized) and/or on day of discharge; and Days 15 and 29 (by 
returning to the clinic/ by remote visit or if still hospitalized). 
Number and percent of subjects with a positive or negative SARS-CoV-2 PCR test on Days 
3, 5, 8, 11 (while hospitalized) and/or on day of discharge; and Days 15 and 29 (by returning to 
the clinic/ by remote visit or if still hospitalized). 
Time to viral clearance 
Time to viral clearance is defined as the time elapsed (in days) from randomization until 
negative viral load. 
 
 
 
 
 
 
 
 
 


 
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4.3 
Safety Endpoints 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
 
Treatment Emergent Adverse Events (TEAEs): 
TEAEs are AEs with an onset after the initiation of study drug or randomization date (whichever is earlier) 
until end of the follow-up period (Day 60±10). This will also include any AE with onset prior to initiation of 
study drug that increased in severity during the treatment period. 
All AEs (including serious adverse events [SAEs]) will be coded to a lower level term (LLT), preferred term 
(PT), high level term (HLT), high level group term (HLGT), and associated primary system organ class 
(SOC) will be coded according to the Medical Dictionary for Regulatory Affairs (MedDRA) version 23.1 or 
later. 
 
SAEs: 
An SAE is defined as any AE that fulfills any of the following criteria: 
• 
Results in death. 
• 
Is life-threatening. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is another significant medical event (Significant medical events are those that may not result 
in death, be life-threatening, or require hospitalization, but are, in the opinion of the investigator, 
and based upon appropriate medical judgment, an event that might jeopardize the subject 
and/or may require medical or surgical intervention to prevent one of the outcomes listed 
above). 
 
AEs by Relationship to Study Drug 
 
The causality/relationship assessment of an AE to the IP will be rated as follows by the investigator: 
 
 
• 
Not Related/ Unlikely Related: There is not a temporal or causal relationship between the use of 
the study drug and the onset of the AE; no association of the event to use of study drug.  


 
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• 
Possible: There may or may not be a reasonable temporal relationship between the use of the 
study drug and the onset of the AE; the association of the event with the study drug is unknown, 
however, a relationship between drug and event cannot be ruled out.  
• 
Probable: There is a reasonable temporal relationship between the use of the study drug and the 
onset of the AE; the association of the event with the study drug seems likely and the AE is unlikely 
to be caused by the concurrent/underlying illness, other drugs or procedures.  
• 
Definite: There is a reasonable temporal relationship between the use of the study drug and the 
onset of the AE, and it cannot be reasonably explained by any known characteristics of the 
subject’s clinical state, environment or other drugs or procedures. It disappears or decreases upon 
discontinuation of the study drug and reappears with re-administration of the study drug.  
 
All AEs should be assigned with a relationship as above and missing relationship will be queries for 
resolution.  
For analysis purposes, all AEs will be reclassified into 2 categories of related (include definitely, possibly 
related) and non-related (include not related and unlikely related) to IP. 
 
AEs by Severity: 
The investigator will also assess the severity (intensity) of each AE, grading according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 when applicable. For an AE not found on 
the CTCAE listing, they will be allocated a grade according to the following guidelines. 
Grade 1   Mild Adverse Event (any of the following): 
• 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated, or non-prescription intervention indicated; asymptomatic laboratory finding only; 
marginal clinical relevance. 
Grade 2   Moderate Adverse Event (any of the following): 
• 
Moderate; minimal, local, or noninvasive intervention indicated; limiting (age-appropriate) 
instrumental Activities of Daily Living [ADL] (e.g., preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, laundry). 
Grade 3   Severe Adverse Event (any of the following): 
• 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL (e.g., bathing, 
dressing and undressing, feeding self, using the toilet, taking medications, getting in and out 
of bed). 
Grade 4   Life-threatening Adverse Event (any of the following): 
• 
Life-threatening consequences; urgent intervention indicated; individual at risk of death at the 
time of the event if immediate intervention is not undertaken. 
Grade 5   Fatal Adverse Event: 
• 
Death related to AE. 


 
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All AEs should be assigned with severity as above and missing severity will be queried for resolution. 
Missing severity will not be imputed. 
For summaries by severity grade, the most severe grade will be used for those AEs that occurred more 
than once in an individual subject during the study. 
 
Other safety endpoints include: Treatment exposure, physical examination, ECG, vital signs and 
oxygenation/respiratory parameters and laboratory safety evaluation. More details in section 5. 
 
4.4 
Pharmacokinetic Endpoints 
Plasma concentrations of Brilacidin measured from blood samples collected on Days 1 to 4. More details 
will be given in a separate PK analysis plan. 
4.5 
Other Derived Variables 
In the case that more derived variables than the ones described in this document are required for the 
analysis, they will be defined and described in the statistical report. Once the variables are created, it will 
be checked that their values are correct and that they represent exactly what it is expected. 
 
 


 
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5. 
GENERAL STATISTICAL METHODS 
At the initial interim safety review by the DMC, the recommendation was to expand study drug dosing to 
Days 4 and 5 (at the same doses as on Days 2 and 3). This change was made by the Sponsor and sites 
were informed to move from the 3-dose regimen to the 5-dose regimen. 
Therefore, all applicable baseline and safety data will be summarized by study drug treatment arm 
(placebo or Brilacidin) and dose regimen (3-dose or 5-dose), to be termed “study arms” (and overall, when 
appropriate). For efficacy data summarization, there will be three study drug treatment groups, comprised 
from the two treatment arms and two dose regimens, where placebo 3-dose regimen and placebo 5-dose 
regimen are pooled, i.e., pooled placebo group (which assumes there is no difference between regimens 
from a clinical point of view), with two active treatment groups of Brilacidin 3-dose regimen and Brilacidin 
5-dose regimen. 
Statistical comparisons will be performed between Brilacidin 5-dose regimen and pooled placebo as the 
main comparison of interest, and between Brilacidin 3-dose regimen and pooled placebo as secondary. 
The assumption for considering both placebo dose regimens not clinically different and pooling in a 
combined group will be checked (for selected endpoints) as an appropriate action with specified sensitivity 
analyses (detailed in section 5.3.6). In addition, pooled Brilacidin is to be compared to pooled placebo (see 
section 5.3.6). 
 
5.1 
Sample Size  
Sample size is based on the primary efficacy endpoint of time to recovery by Day 29, being the day of 
recovery defined under an ordinal scale related to hospitalization, limitation of activities and oxygen 
requirement by the subject. 
Assuming that a median time to recovery of 5 days on Brilacidin versus 10 days on SoC (i.e., a hazard 
ratio of 2.0), and assuming that a total of 75 recovery events are observed if 100 subjects (50 per treatment 
arm) are included in analysis, the comparison between treatment arms would provide at least 90% power 
with a one-sided type I error rate of 0.05. If the assumption is that time to recovery for Brilacidin is of 6 
days versus 10 days on SoC, which is equivalent to a hazard ratio of 1.67, the comparison between 
treatment arms would provide at least 70% power with a one-sided type I error rate of 0.05. 
Assumptions for time to recovery for both arms of the study have been adapted from the median time to 
recovery data reported for the remdesivir (11 days) treatment group in Beigel et al 2020; remdesivir has 
Emergency Use Authorization in multiple countries and has become SoC where available. 


 
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A total of 100 subjects with 50 per treatment arm will also support secondary endpoints. For example, for 
the secondary endpoint of clinical improvement (2-point increase in ordinal scale) at Day 15, applying an 
unadjusted one-sided type I error rate of 0.05, 50 subjects per arm would provide 80% power to detect a 
treatment effect of 0.2079 increase in proportion of clinical improvement within the Brilacidin treatment arm 
over a proportion of 0.6500 in the SoC group. There would be at least 70% power to detect a treatment 
effect of 0.1854 under the same sample size. (The assumptions for sample estimation are based on clinical 
improvement data reported for SoC and remdesivir treatment groups in Spinner et al 2020). 
Due to the exploratory nature of this study, a sample size up to 60 subjects per treatment arm randomised 
with a 1:1 ratio is considered to provide sufficient power under the alternative hypotheses exposed above 
in order to support initial PoC of Brilacidin versus SoC. 
Interim analyses are planned for this study. Details can be found in section 5.3.5. 
5.2 
Subject´s Disposition  
5.2.1 Subject´s Disposition and Withdrawals 
This section describes subject disposition for both study status and the analysis populations. 
Screened 
subjects 
will 
include 
all 
subjects 
who 
signed 
the 
informed 
consent 
form 
and are entered into the clinical database. 
Randomized subjects will include all subjects who were provided a treatment assignment that was 
recorded in the interactive response technology database, regardless of whether the treatment kit was 
used. 
The safety experience of subjects who were treated, but not randomized will be reported separately, and 
these subjects will not be included in the safety population. Subjects treated without being randomized will 
not be considered as randomized and will not be included in any efficacy population. 
For subject study status, the total number and percentage of subjects in each of the following categories 
will be presented in the CSR using a flowchart diagram or summary table: 
• 
Screened subjects. 
• 
Screen failure subjects. 
• 
Enrolled subjects. 
• 
Nonrandomized but treated subjects (if applicable). 
• 
Randomized subjects. 
• 
Randomized but not treated subjects (if applicable). 
• 
Subjects in the ITT Population. 
• 
Subjects in the Safety Population. 
• 
Subjects in the PP Population. 
• 
Subjects discharged from the hospital. 
• 
Subjects who discontinued study treatment early, including primary reason for discontinuation. 


 
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• 
Subjects who discontinued study early, including primary reason for discontinuation. 
 
For all categories of subjects (except for the screened, enrolled and nonrandomized categories) the 
summaries will be provided by randomized treatment arms and dose regimen, and percentages will be 
calculated using the number of randomized subjects as the denominator. 
The number (%) of subjects in each population will also be summarized by the stratification factors 
(country, categorized age group (< 65 / > 65 years) and COVID-19 severity), and by treatment arms and 
dose regimen. The number of mis-stratified subjects, will also be presented for randomized subjects. They 
will also be listed. 
A listing of subjects with population assignment including individual reasons of exclusion from the 
respective analysis populations will be provided. Data listing for early termination reasons will be also 
provided. 
5.2.2 Protocol Deviations 
Protocol deviations, including violations of inclusion/exclusion criteria, will be collected and assessed as 
“minor” or “major” by the clinical team and the final version will be provided to the biostatistics contract 
research organization 
 prior to the database lock. Important deviations will be identified by the 
sponsor and project team prior to database lock. Important quantitative deviations will be verified 
programmatically from the database. 
All protocol deviations will be collected separately from the database and listed. The final listing of protocol 
deviations will be reviewed before database lock to assist in the Per Protocol population selection and 
definition of the final study populations as well as a preliminary assessment of the quality of the trial data. 
All important deviations will be summarized by deviation type and listed in the CSR. 
 
5.3 
Summary of Statistical Methods 
This study is designed as a phase 2 study, exploratory in nature, to evaluate the efficacy of Brilacidin. 
Comparisons will be performed between Brilacidin in addition to SoC against placebo plus SoC at a one-
sided type I error rate of 0.05 which will not be adjusted for multiple testing. The study will be considered 
to have achieved proof-of-concept when the 1-sided p-value is <0.05. Accordingly, the primary and key 
secondary efficacy endpoints will present 2-sided 90% Confidence Intervals (90%CIs) when applicable. 
Unless otherwise specified, efficacy analyses will be performed in the ITT population, where subjects will 
be in the treatment arm to which they were randomized. Moreover, supportive efficacy analyses will be 
performed in the PP population. Safety related analyses will use the safety population. Pharmacokinetic 
analyses will be carried out in the PK population (refer to separate analysis plan). 


 
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All relevant subject data will be included in listings. All subjects entered into the database will be included 
in subject data listings. The listings will be generally sorted by treatment arm and regimen and then Subject 
ID, unless specified otherwise. 
All applicable baseline and safety data will be summarized by treatment arm and dose regimen, termed 
“study arms” (and overall, when appropriate), unless specified otherwise. In addition, data will be 
summarized by time-point and/or follow-up date when appropriate. For efficacy data summarization, there 
will be three study drug treatment groups, comprised from the two treatment arms and two dose regimens, 
where placebo 3-dose regimen and placebo 5-dose regimen are pooled, i.e., pooled placebo group, with 
two active treatment groups of Brilacidin 3-dose regimen and Brilacidin 5-dose regimen.  
Continuous variables will be summarized using the number of observations (n), mean (95%CI, if 
appropriate), standard deviation (SD), Standard error (SE, if appropriate), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum along with the total number of subjects contributing values. 
Descriptive statistics for categorical/qualitative data will include frequency counts and percentages. The 
denominator for all percentages will be the number of subjects in the treatment arm and dose regimen (or 
treatment group, for efficacy endpoints) within the population of interest, unless stated otherwise in the 
table footnote. 
Statistical comparisons will be performed between Brilacidin 5-dose regimen and pooled placebo as the 
main comparison of interest, and between Brilacidin 3-dose regimen and pooled placebo as secondary. 
Kaplan-Meier model will be used to analyse time-to-event endpoints (such as time to recovery, time to at 
least one-point/ two-point improvement in clinical status, time to a NEWS2 of ≤2). For these analyses, in 
addition to the Kaplan-Meier curve, median,(corresponding 90%CI) and 25th percentile (Q1) and 75th 
percentile (Q3), and the number of events and censored cases distribution will be shown. Group 
comparisons will be done using the (stratified) log-rank test and the adjusted hazard ratios (HR) with 
90%CI obtained from a Cox proportional hazards model. 
Endpoints considering the proportion of subjects achieving an event (such as number of subjects achieving 
recovery status scores or the composite event death or respiratory failure requiring invasive mechanical 
ventilation at Day 29, or achieving at least one-point/two-point improvement in clinical status at Days 8, 15 
and 29), or achieving no oxygen therapy (and/or peripheral oxygen saturation SpO2 > 93% on room air) 
at Days 8, 15 and 29) will be analyzed using logistic regression models with treatment group and 
stratification factors as covariates (in the event that any of the stratification factors does not achieve 
enough size for obtaining reliable estimations, that stratification factor will be not considered as a covariate 
in the model). Odds ratios and the corresponding 2-sided 90%CIs will be calculated for comparisons 
between each respective Brilacidin dose regimen versus the pooled placebo arm. 


 
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The shift analysis of proposed ordinal scale endpoint will be analysed using the proportional odds model 
and the stratification variables. The common odds ratio can also be interpreted as the average shift over 
the total ordinal outcome scale caused by the treatment under study. The stratified non-parametric van 
Elteren test, using modified ridit scores which is a direct extension of the Wilcoxon's rank-sum test for 2-
samples, will be calculated as a sensitivity analysis to compare the scale as an ordinal rather than a binary 
outcome, without assuming proportional odds (see section 5.3.6). 
The median of absolute values with 90%CI will be calculated using the Hodges-Lehmann methods (i.e. 
median of all cross differences between treatments based on the Mann-Whitney distribution). 
Change from baseline for biomarkers, SARS-CoV-2 viral load and NEWS2 score will be analysed using 
Analyses of Covariance (ANCOVA) Models including baseline score as covariate and the stratification 
variables (country, categorized age group (< 65 / > 65 years) and COVID-19 severity as factors (in the 
event that any of the stratification variables does not achieve enough size for obtaining reliable estimations, 
that stratification variable will be not considered as a factor in the model). In addition, selected biomarkers 
will be analysed using a repeated measures mixed model.  
Handling of quantitation limits for laboratory, biomarkers and viral load data are discussed below. 
Data that are continuous in nature but are less than the lower limit of quantitation or above the upper 
limit of quantitation will be imputed as follows: 
- 
A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “< x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, etc. 
For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate 
summary statistics. 
- 
A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the datum 
is reported in the form of “> x” (where x is considered the LOQ). Values with decimal points will 
follow the same logic as above. 
- 
The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of “≤ 
x” or “≥ x” (where x is considered the LOQ). 
Analyses of PK data will be discussed in a separate analysis plan to support the population PK report. 
 
In general, values reported in Unscheduled or Successful Discharge visits are to be considered 
under the relevant Day for statistical analyses and summaries. 


 
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In addition to the study Protocol Deviation Logs, an Unresolved Data Issues Report has been created in 
order to reflect issues arisen during data collection which cannot be fitted appropriately in the eCRF. The 
unresolved data issues captured in the report will need to be taken into account by programming, for 
affected subject data entries, and will require confirmation with Data management on appropriate 
correction/ resolution prior to database lock. 
 
5.3.1 Demographics, Other Baseline Characteristics and Medication 
Summary statistics will be provided by treatment arm and dose regimen and overall for baseline 
characteristics and demographic variables; summaries will be provided on the ITT population. Prior and 
concomitant medications will be reported for the Safety population. 
The baseline value is defined as the last available measurement prior to the first dose of study drug 
accounting for date, and time (where available) which can be found in screening, baseline/Day 1 or 
unscheduled visits of the CRF, unless specified otherwise. 
 
5.3.1.1 
Demographic Characteristics 
Descriptive statistics by treatment arm and dose regimen and overall will be performed for the demographic 
characteristics and disease history. Listings will also be presented for the demographic characteristics and 
disease history, respectively. 
 
5.3.1.2 
Focused COVID-19 Medical History 
The following variables for disease history will be summarized by treatment arm and dose regimen and 
overall:  
- 
COVID Symptoms at study entry, including (categorized) body location of any tingling/numbness 
sensations 
- 
Time from onset of first COVID-19 symptoms until randomization 
- 
Time from onset of first COVID-19 symptoms until hospitalization 
- 
Time from diagnosis of COVID-19 until randomization 
- 
Time from diagnosis of COVID-19 until hospitalization 
- 
Time from hospitalization until randomization 
- 
Type of swab analyzed, type of test, and results of SARS-CoV-2 test (local) 
 
Listings will also be presented. 


 
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5.3.1.3 
Medical History 
Medical history abnormalities will be coded to Medical Dictionary for Regulatory Activities (MedDRA) 
terms. The version used will be specified in the data display footnote. Conditions will be summarized by 
system organ class and preferred term by treatment arm and dose regimen and overall. Listings will also 
be presented. 
 
 
5.3.1.4 
Physical examination 
Results of physical examination assessments (including skin, neck (including thyroid), HEENT (head, 
eyes, ears, nose and throat), heart, lungs, abdomen, lymph nodes, extremities, vascular and neurologic 
systems) will be summarized by treatment arm and dose regimen, according to: 
- 
Normal 
- 
Abnormal Not Clinically Significant 
- 
Abnormal Clinically Significant 
The result of the baseline physical exam and the significant findings will be presented by listing. 
5.3.1.5 
Electrocardiogram (ECG) 
A single standard supine 12-lead ECG will be obtained after a subject has rested quietly for at least 10 
minutes. The ECG may be repeated if the result is abnormal, as clinically appropriate. ECG data will be 
reviewed by the Investigator or appropriate local designee. The Investigator must review and initial the 
tracing (or alternate source record) and the assessment of any reviewer (if not themselves). 
Summary statistics (including number, mean, SD, median, Q1, Q3, minimum, and maximum) for all ECG 
variables at baseline will be calculated by treatment arm and dose regimen. Only evaluable data will be 
used, and missing data at baseline will not be imputed. 
Summaries of evaluation (normal; abnormal not clinically significant; abnormal clinically significant) will be 
provided by treatment arm and dose regimen. 
All ECG results will be listed on a by-subject basis. 
5.3.1.6 
Vital signs and Oxygenation/Respiratory parameters 
The vital signs at baseline will be described by treatment arm and dose regimen. The variables to be 
included are: 
- 
Blood Pressure: 


 
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o Systolic (SBP) 
o Diastolic (DBP) 
- 
Heart rate 
- 
Body temperature (also for overall) 
o Temperature location 
o Temperature by location 
- 
Height, weight and BMI (also for overall) 
Respiratory parameters will be described by treatment arm and dose regimen and overall. The variables 
to be included are: 
- 
Respiratory rate on (i) room air or (ii) oxygen supplementation 
- 
SpO2 on room air or PaO2/FiO2 ratio if on oxygen supplementation 
- 
Oxygen supplementation requirement (room air (none), low flow O2, high flow O2, CPAP/BIPAP, 
mechanical ventilation, or ECMO). 
Summary statistics (including number, mean, SD, SE (for SBP and DBP), median, Q1, Q3, minimum, and 
maximum) for all vital signs and appropriate respiratory parameters at baseline will be calculated by 
treatment arm and dose regimen and overall (if appropriate). The proportion of subjects in each oxygen 
supplementation requirement category will be summarized. Only evaluable data will be used, and missing 
data at baseline will not be imputed 
All vital signs and oxygenation/respiratory measurements will be listed. 
5.3.1.7 
National Early Warning Score (NEWS2)  
The National Early Warning Score (NEWS2) will be summarized by the mean, SD, SE, median, Q1, Q3 
quartiles and the minimum and maximum values by treatment arm and dose regimen. Listings will also be 
presented for the NEWS2 score and its sub-score components, respectively. In addition, if the subject has 
hypercapnic respiratory failure (yes/no) will be reported by treatment arm. Only evaluable data will be 
used, and missing data at baseline will not be imputed. Data will be listed by subject. 
5.3.1.8 
Clinical Status 
For the clinical status 8-point ordinal scale, the number and percentage of subjects for all categories in the 
8-point ordinal scale will be reported by treatment arm and dose regimen and overall. In addition, clinical 
status will be summarized by means of the median, Q1, Q3 quartiles and the minimum and maximum 
values by treatment arm and dose regimen. Listings will also be presented. 
5.3.1.9 
Laboratory Evaluations 
Laboratory assessments at baseline include haematology (including absolute neutrophil count), blood 
chemistry (including CRP, ferritin, LDH, D-dimer, troponin hs [troponin T, troponin I]), coagulation and 


 
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additional biomarker parameters (which include, but are not limited to: IL-1β, IL-6, IL-10, total IL-18, TNF-
α). 
The summary statistics (including number, mean, SD, median, Q1, Q3, minimum, and maximum) of all 
quantitative laboratory variables at baseline will be calculated by treatment arm and dose regimen. Only 
evaluable data will be used, and missing data at baseline will not be imputed. Data will be listed by subject. 
 
5.3.1.10 
Prior and Concomitant Medications 
Prior medications are those that the subject used prior to the randomization date. Concomitant medications 
are defined as medications that continued or started on or after the randomization date, collected up to 
60±10 days after randomization. 
Prior and concomitant medications will be summarized by treatment arm and dose regimen according to 
the World Health Organization Drug Dictionary (WHO-DD), using the version in effect at the time of 
database lock and considering the first digit of the anatomic and therapeutic category (ATC) class and the 
first 3 digits of the ATC class (therapeutic category). Subjects will be counted once in each ATC category 
(anatomic or therapeutic).  
Prior and concomitant medications will be summarized separately; in these summarizes, medications 
indicated for COVID-19 will be excluded and reported separately. For those medications indicated for 
COVID-19, prior together with concomitant will be summarized. 
Prior and concomitant medications and medications for COVID-19 will use the Safety population. 
Medications (indicating prior, concomitant or both) will be listed on a by-subject basis reporting to ATC 
level 5; this listing will exclude those indicated for COVID-19, and a separate listing will be provided for 
such medications. 
Administration of new or altered anti-hypertensive treatment post-randomization will be summarized by 
onset timing (overall, during study; onset during study treatment period, onset during follow-up period), 
and supported by a separate listing. 
A summary of non-drug therapies or procedures will also be presented (summarized by MedDRA coding), 
if appropriate, and a separate by-subject listing will be provided. 
 
 


 
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5.3.2 Efficacy Analyses 
Analyses of efficacy endpoints will be performed in the ITT population. In addition, sensitivity analyses will 
be performed in PP population and will be considered supportive. 
 
5.3.2.1 
Primary endpoint 
The primary endpoint “Time to sustained recovery through Day 29” will be considered as described in 
section 4.2.1 
Subjects who remained hospitalized (having a score less than 6 in the ordinal scale for all available 
measurements), and remain alive, will be censored at their last evaluation time-point.  
When analyzing time to sustained recovery, if subjects are lost to follow-up (for this endpoint) prior to 
achieving recovery (a score of 6, 7 or 8) or die prior to Day 29, their time to recovery will be censored at 
Day 29. Subjects who are lost to follow-up after achieving recovery but prior to Day 29 will be censored at 
the day of achieving recovery. 
Time to sustained recovery will be analyzed using Kaplan-Meier methods. The treatment difference for 
time to sustained recovery will be analyzed with the stratified log-rank test where each regimen, Brilacidin 
3-doses and Brilacidin 5-doses, will be compared separately to the pooled placebo group. 
The treatment effect will be evaluated by a Kaplan-Meier model. The Kaplan-Meier curve for time to 
recovery, the median (corresponding 90%CI) and Q1 and Q3 , as well as number/percentage of events 
and censored cases distribution will be presented. 
The model to be used will be processed by: 
proc 
lifetest data=<sas-data-set> 
method=km 
plots=(rmst 
rmtl) 
rmst 
rmtl(tau=90) maxtime=29; 
time <<time to recovery> * <event=recovery> (censor value=0)>; 
strata <<treatment group>>/test=(logrank); 
run; 
 
 
 
Additionally, treatment regimen comparisons to the pooled placebo group will be performed using the 
adjusted hazard ratios (HR) with 90%CI for the stratification factors (country, categorized age group (< 65 
/ > 65 years) and COVID-19 severity (moderate/ severe) from the Cox model. In the event that any of the 
stratification factors does not achieve enough size for obtaining reliable estimations, the model will not be 
adjusted by that stratification factor. 


 
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The model to be used will be processed by: 
 
proc phreg data=<sas-data-set>; 
Class <<treatment group> <age group> <disease severity> <country>>/param=ref 
ref=first; 
model <<time to recovery> * <event=recovery> (censor value=0)> = <treatment 
group> <country> <age group> <disease severity>> / eventcode=1 risklimits; 
hazardratio <treatment group> / alpha=0.05; run; 
 
Clinical status data will be listed by subject. In addition, listings will include primary endpoint derivation of 
time to sustained recovery. 
 
5.3.2.2 
Secondary endpoints 
The secondary efficacy endpoints related with the clinical severity and disease burden will be assessed 
as: 
- 
Composite endpoints, from the ordinal scale 
- 
Clinical status measures, from the ordinal scale 
- 
NEWS2 Score 
Clinical status evaluations are performed as described in section 4.2.1. All parameters related to NEWS2 
should be recorded together in the morning and then between noon and midnight, for the duration of 
hospitalization (if outside ICU). Following hospital discharge, these parameters should be recorded once 
at each return visit to the clinic (Days 15 and 29), with Clinical status captured at the Day 60 follow-up 
telephone contact. 
Analyses to be performed are described in the following subsections. 
 
5.3.2.2.1 
Proportion of subjects achieving recovery status scores (categories 6, 7 or 8) in 
the 8-point ordinal scale at Day 29 of follow-up 
The proportion of subjects achieving recovery status scores (6, 7, 8) in the 8-point ordinal scale at Day 29 
will be derived as a binomial outcome from the ordinal status scale of 8 points as the proportion of subjects 
with a score of 6, 7, or 8 at Day 29. Any other score of the ordinal scale will be considered as not recovery 
status. Analyses will be based on the Last Observation Carried Forward (LOCF) approach meaning that 
the score for subjects lost-to-follow or with score not assessed at Day 29 will be the score in their last 
observation available. Listings will include this endpoint and LOCF values will be identified on them. 


 
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The number and proportion of subjects achieving recovery status scores (categories 6, 7 or 8) in the 8-
point ordinal scale at Day 29 of study will be reported by treatment group. Additionally, the comparison of 
the proportion between treatment groups will be performed using a logistic regression model with treatment 
group and stratification factors (country, categorized age group (< 65 / > 65 years) and COVID-19 severity) 
as covariates (in the event that any of the stratification factors does not achieve enough size for obtaining 
reliable estimations, that stratification factor will be not considered as a covariate in the model). Odds ratios 
and the corresponding 2-sided 90%CIs will be calculated. 
 
5.3.2.2.2 
Proportion of subjects that die or develop respiratory failure by Day 29 
The proportion of subjects that meet the composite event of death or respiratory failure (considered when 
a subject requires invasive mechanical ventilation) by Day 29 will be derived as the proportion of subjects 
achieving one of the events that compose the endpoint: death by Day 29 (score 1 in the clinical status 
scale) or respiratory failure (requiring invasive mechanical ventilation, score 2 the clinical status scale) by 
Day 29. Analyses will be based on the LOCF approach meaning that subjects lost-to-follow up or with 
score not assessed before Day 29 not having achieved any of the 2 endpoints before being lost (or score 
not assessed) will be considered as not having achieved the composite event by Day 29. If death (score 
1) or invasive mechanical ventilation (score 2) by Day 29 are not achieved, the composite event will be 
considered as not being achieved. Listings will include this endpoint (differentiating death or respiratory 
failure development) and LOCF values will be identified on them. 
The number and proportion of subjects achieving composite event of death or respiratory failure (requiring 
mechanical ventilation) by Day 29 will be reported by treatment group. Additionally, the comparison of the 
proportion between treatment groups will be performed using a logistic regression model with treatment 
group and stratification factors (country, categorized age group (< 65 / > 65 years) and COVID-19 severity) 
as covariates (in the event that any of the stratification factors does not achieve enough size for obtaining 
reliable estimations, that stratification factor will be not considered as a covariate in the model). Odds ratios 
and the corresponding 2-sided 90%CIs will be calculated. 
 
5.3.2.2.3 
Proportion of subjects achieving at least one or two points of improvement in 
clinical status scale at Days 8, 15 and 29 
The proportion of subjects achieving at least one or two category improvement in the ordinal scale at Day 
8, 15 and 29 will be derived as the proportion of subjects with at least one or two points of improvement 
from baseline clinical status score at Days 8, 15 and 29 respectively. The change in the ordinal scale will 
be estimated as the difference “assessment score (Day 8, 15 or 29) – baseline score”. The improvement 


 
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of at least one or two points will be considered when the result of the difference is >=1 or >=2 respectively. 
Analyses will be based on the LOCF approach meaning that the score for subjects lost-to-follow or with 
score not assessed at Days 8, 15 and 29 will be the score in their last observation available. Only subjects 
with available information at baseline and an additional time-point of assessment will be considered in the 
analyses. Listings will include this endpoint and LOCF values will be identified on them. 
The number and proportion of subjects achieving at least one or two points of improvement in clinical 
status scale at days 8, 15 and 29 of study will be reported by treatment group. Additionally, the comparison 
of the proportion between treatment groups will be performed using a logistic regression model with 
treatment group and stratification factors (country, categorized age group (< 65 / > 65 years) and COVID-
19 severity) as covariates (in the event that any of the stratification factors does not achieve enough size 
for obtaining reliable estimations, that stratification factor will be not considered as a covariate in the 
model). Odds ratios and the corresponding 2-sided 90%CIs will be calculated. 
 
5.3.2.2.4 
Time to at least one or two points of improvement in the ordinal scale of clinical 
status. 
Time to at least one or two category improvement in clinical status is defined as time (in days) from 
randomization until get an elevation of at least one or two points in the 8-point ordinal scale. The subjects 
will be considered as having achieved the event the first day in which they have an elevation of at least 
one/two point/s in the scale from baseline. Those subjects without improvement by the Day 29 study follow-
up visit will be censored at last available assessment. Only subjects with available information at baseline 
will be considered in the analyses. These endpoints will be included in listings. 
A Kaplan-Meier analysis will be performed to assess the time to improvement. The median time to event 
as well as the estimated percent of subjects without event during the study period will be estimated based 
on Kaplan-Meier method for each treatment group.  
Stratified log-rank test for comparisons between groups will be calculated. Additionally, treatment 
comparisons will be performed using a Cox Proportional Hazards Model where the adjusted hazard ratios 
(HR) with 90%CI between treatment regimens versus pooled placebo is adjusted for the stratification 
factors (country, categorized age group (< 65 / > 65 years) and COVID-19 severity). In the event that any 
of the stratification factors does not achieve enough size for obtaining reliable estimations, the model will 
not be adjusted by that stratification factor. Only subjects with available information of the clinical status 
scale at baseline will be included in the analyses. 
NOTE: Subjects who need a re-hospitalization or with more than one improvement during the study period 
will only be counted once corresponding to the first improvement. 
 


 
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5.3.2.2.5 
Subject clinical status and the mean change using ordinal scale at baseline, days 
3, 5, 8, 11, 15 and 29/60. 
The number and percentage of subjects in each clinical status category for each day from baseline (Days 
3, 5, 8, 11, 15, 29 and 60), will be summarized by treatment group. In addition, stacked bar charts (%) by 
day will be produced. Shift tables will also be produced. These endpoints will be included in listings. 
As a supportive analysis, the evolution of the clinical status will also be summarized in a descriptive way 
by mean, SD, SE, median, Q1, Q3, minimum, and maximum. 
The shift analysis of proposed ordinal scale endpoint will be analysed using the proportional odds model. 
The odds of observing a better category (higher number) of clinical status will be analyzed at Days 3, 5, 8, 
11, 15 and 29 with a proportional odds model (POM). The odds ratio for treatment group estimated from 
the POM can be interpreted as a summary of the odds ratios obtained from separate binary logistic 
regressions using all possible cutoff points of the ordinal outcome (e.g. the cutoff of level 3 ‘Hospitalized, 
on non-invasive ventilation or high flow oxygen devices’ will combine levels 1 and 2 versus combined 
levels 3, 4, 5, 6, 7 and 8). The assumption of POM is that the effect of treatment is identical across all 
possible cutoff points of the ordinal outcome. The proportional odds assumption will be checked by a score 
test will include treatment group and the stratification variables (country, categorized age group (< 65 / > 
65 years) and COVID-19 severity) as covariates. In the event that any of the stratification variables does 
not achieve enough size for obtaining reliable estimations, that stratification variable will be not considered 
as a covariate in the model. The estimated odds ratios, p-values and 90% confidence intervals will be 
presented. 
The common odds ratio can also be interpreted as the average shift over the total ordinal outcome scale 
caused by the treatment under study. 
The example of model is shown below: 
proc glimmix data=<sas-data-set> empirical=mbn method=quad; 
class <<subject_id> <treatment group> <age group> <disease severity> 
<country>>; 
model <<scale_score>> = <<treatment group> | <country> <age group> <disease 
severity> > time/dist=mult link=clogit solution;  
random int / subject = <subject_id>; 
estimate 'treatment group vs placebo arm' trt 1 -1 / or; 
run; 
 
The stratified non-parametric van Elteren test, using modified ridit scores which is as a direct extension of 
the Wilcoxon's rank-sum test for 2-samples, will be calculated as a sensitivity analysis to compare the 
scale as an ordinal rather than a binary outcome, without assuming proportional odds. 


 
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The SAS proc freq with modified ridit scores will be used to obtain the Van Elteren test as follow: 
proc freq data=<sas-data-set>; 
ods select cmh; 
table <time>*<treatment group>*<change_againts_baseline>/cmh2 
scores=modridit; 
run; 
 
The median of the absolute values with 90% confidence interval (90%CI) will be calculated using the 
Hodges-Lehmann methods (i.e. median of all cross differences between treatments based on the Mann-
Whitney distribution). 
 
5.3.2.2.6 
Time to a NEWS2 score of < 2 and maintained for 24 hours. 
All NEWS2 measurements will be considered for this analysis, regardless of being measured just once or 
twice daily. Maintenance for 24 hours will be checked across all available measurements for each subject. 
Time to a NEWS2 of <2 and maintained for 24 hours is defined as time (in days) from randomization until 
get a NEWS2 score lower or equal to 2 being maintained for at least 24 hours (for example, if a subject 
achieves a NEWS2 <2 at Day 2, the NEWS2 should also be <2 at Day 3 to reach the event). This endpoint 
can only be calculated during hospitalization, since if a subject has been discharged measurements are 
recorded in intervals higher than 24 hours after discharge. Subjects who did not reach NEWS2 of < 2 by 
Day 29 study follow-up visit will be censored at last available assessment. Those subjects followed up will 
be censored at the last assessment available date. Subjects who have died will be censored on date of 
death. 
This endpoint and the sub-scores that compose the NEWS2 will be included in listings. 
A Kaplan-Meier analysis will be performed to assess the time to achieve a NEWS2 score of < 2. The 
median time to event as well as the estimated percent of subjects without event during the study period 
will be estimated based on Kaplan-Meier method for each treatment group. Treatment comparisons will 
be performed using the adjusted hazard ratios (HR) with 90%CI from a Cox Proportional Hazard Model, 
adjusted for the stratification factors (country, categorized age group (< 65 / > 65 years) and COVID-19 
severity). In the event that any of the stratification factors does not achieve enough size for obtaining 
reliable estimations, the model will not be adjusted by that stratification factor. 
Only subjects with available information for NEWS2 score at baseline will be included in the analyses. 
NOTE: Subjects who need a re-hospitalization or with more than one improvement during the study period 
will only be counted once corresponding to the first improvement. 


 
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5.3.2.2.7 
Change from baseline to Days 3, 5, 8, 11, 15 and 29 in NEWS2 score. 
The baseline value will be taken from the time-point (before noon or between noon and midnight) whose 
date and time in the CRF is the last available prior to the first dose of study drug (that can be available in 
Screening, Day 1 or Unscheduled visits). For days after baseline where the NEWS2 score has been 
measured twice, the highest NEWS2 score will be used for change from baseline.  
NEWS2 score used in this analysis will come from the derived value associated with the respiratory status 
eCRF.  
Change from baseline to Days 3, 5, 8, 11, 15, and 29 in NEWS2 score will be derived taking the baseline 
score as reference, meaning that it will be the difference between the assessment score and the baseline 
score at each time-point of assessment. Change from baseline will be reported by treatment group. If 
NEWS2 score is not available at any of Days 3, 5, 8, 11 or 15, no change from baseline will be calculated 
for that assessment. Only subjects with available information for NEWS2 score at baseline will be included 
in the analyses. These endpoints will be included in listings. 
Additionally, change from baseline of the NEWS2 score in the Brilacidin treatment groups will be compared 
to pooled placebo using an ANCOVA model, including the baseline score as covariate and the stratification 
variables (country, categorized age group (< 65 / > 65 years) and COVID-19 infection severity) as factors. 
In the event that any of the stratification variables does not achieve enough size for obtaining reliable 
estimations, that stratification variable will be not considered as a factor in the model). Least square mean 
difference between the treatment groups will be provided with 2-sided 90%CIs. 
In addition, a line plot of mean change from baseline (SE), will be displayed for NEWS2, by treatment 
group and visit. 
 
5.3.3 Safety Analyses 
The population used for safety analyses will be the Safety Population. Safety of treatment will be assessed 
on the basis to AEs during IV infusion, SAEs and AEs of special interest (AESIs). 
In general, change from baseline is calculated only for subjects with non-missing values for both the 
baseline and the time-point of interest and will be missing otherwise. Unless otherwise specified, 
denominators for all percentages will be the total number of subjects in the safety population with non-
missing values for the assessment of interest. 
Safety analyses will be carried out for subjects by actual treatment received, irrespective of the treatment 
to which the subject was randomized. 


 
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5.3.3.1 
Treatment Exposure 
Subjects are initially planned to receive IV administration of Brilacidin on Day 1 (0.6 mg/kg), Day 2 (0.3 
mg/kg) and Day 3 (0.3 mg/kg) or placebo Day 1, Day 2 and Day 3. Additionally, depending on safety review 
and recommendation by the DMC, they will receive doses on days D4 and D5 (Brilacidin 0.3 mg/kg or 
placebo). Exposure to the investigational product (Brilacidin IV or placebo) will be summarized by 
descriptive statistics by treatment arm and dose-regimen as follows: 
- 
Number of subjects under each regimen (3-day or 5-day) 
- 
Total number of doses administered and number of doses by dose level (0.6 mg/kg or 0.3 mg/kg) 
- 
Duration of exposure (in days) 
Treatment assignment as well as type of regimen (3-day or 5-day) will be listed by subject. A listing of 
investigational product infusion data by day of administration will be provided. 
Randomization number assignment, and strata assignment, will be listed; those subjects that were mis-
stratified (due to incorrect eCRF data entry at time of randomization relating to severity) will be identified. 
 
5.3.3.2 
Adverse Events 
 
Summary of AEs: 
The primary focus of AE reporting will be on TEAEs. All reported AEs (regardless of TEAE or not) will be 
included in a by-subject AE listing, identifying which is treatment-emergent and which it not. Subsets of 
AEs of special interest will also be listed.  
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as treatment-emergent or not. The algorithm for imputing date/time 
of onset will be conservative and will classify an AE as treatment-emergent unless there is definitive 
information to determine it is pre-treatment or post-treatment. Details on classification of AEs with missing 
or partial-onset dates are provided in Section 5.3.7. 
AE summaries will include number (n) and percentage (%) of subjects experiencing an AE within each 
treatment arm and dose regimen, and overall if appropriate. The denominator for computation of 
percentages is the number of subjects in the safety population within each treatment arm and dose 
regimen. The number of events will be included in some summaries as well whenever appropriate.  


 
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Unless otherwise specified, sorting order will be by decreasing number of events in PTs within SOCs 
based on total subjects. When more than one PT has same number of events, the order of presentation 
will be alphabetical in PTs. 
Multiple occurrences of the same event in the same subject will be counted only once in the tables within 
a treatment arm and dose regimen. 
Summary of All TEAEs: 
The following TEAE summaries will be generated for the safety population: 
• 
An overview of TEAEs. Number (%) of subjects will be provided by treatment arm and dose 
regimen, to include following: 
o TEAEs. 
o Grade 3 (Severe), Grade 4 (Life-threatening), and Grade 5 (Fatal) TEAEs. 
o Serious TEAEs. 
o Treatment-related AEs (defined as those events other than ‘not related’ and ‘unlikely 
related’ as assessed by the investigator). 
o TEAEs serious leading to death. 
o TEAEs leading to study drug permanently discontinuation. 
o TEAEs leading to dose adjusted/ dose temporarily discontinued. 
o TEAEs leading to discontinuation/withdrawal from the study. 
o TEAEs of special interest: (i) hypertension Grade 3 or greater, and (ii) paresthesias / 
dysesthesias Grade 2 or greater. 
• 
All TEAEs by primary SOC and PT. 
• 
All TEAEs presented by PT. 
• 
All treatment-related AEs presented by primary SOC and PT. 
• 
All treatment-related AEs Grade 3 or higher, presented by primary SOC and PT. 
• 
All TEAEs by maximal severity (ie, Grade 1, Grade 2, Grades 3 to 5), presented by primary 
SOC and PT. 
 
Summary of Potentially Clinically Important TEAEs 


 
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• 
Most common TEAEs by primary SOC and PT. The most common TEAEs are defined as those 
PTs with incidence of ≥5% in any of the treatment arms and dose regimen. This cutoff maybe 
adjusted based on clinical judgement. 
• 
TEAEs with potential difference between treatment arms and dose regimen, by primary SOC 
and PT. The events with potential difference are defined as those PTs with a difference in 
incidence rate of >10% between either Brilacidin treatment regimen and its matching placebo 
regimen. This cutoff maybe adjusted based on clinical judgement. 
• 
TEAEs of special interest (all grades and per protocol) by onset timing (overall, during study; 
onset during study treatment period, onset during follow-up period), presented by primary SOC 
and PT. 
• 
TEAEs of special interest (all grades and per protocol) by maximal severity, presented by 
primary SOC and PT. 
 
 
5.3.3.3 
Serious Adverse Events 
 
Summary of SAEs and TEAEs leading to treatment change: 
• 
All treatment-emergent SAEs by primary SOC and PT. 
• 
TEAEs leading to study drug permanently discontinued or dose adjusted/ dose temporarily 
discontinued, by primary SOC and PT, defined as those AEs with action taken of treatment ‘study 
drug permanently discontinued’ or ‘dose adjusted/ temporarily discontinued’.  
• 
TEAEs resulting in study discontinuation/ withdrawal from the study 
 
Summary of Deaths 
The following summaries of deaths will be generated for the safety population. 
• 
Number (%) of subjects who died by study period (on study, during treatment period, during 
follow-up period) and reason(s) for death. 
• 
TEAEs leading to death (death as an outcome in the AE eCRF as reported by the investigator) 
by primary SOC and PT.  
• 
Listing of deaths with details on demographics, treatment, and cause of death. 


 
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Data Listings will be provided for: 
• 
All AEs 
• 
SAEs 
• 
TEAEs of special interest (all grades and per protocol) 
• 
TEAEs leading to premature study drug discontinuation/interruption or study discontinuation 
• 
Study-Drug-Related TEAEs 
 
5.3.3.4 
Physical Examination 
Physical examination after baseline maybe abbreviated (including at a minimum: HEENT, heart, lungs, 
abdomen, extremities and examination of any body system where there are symptoms reported by the 
subject). 
Post-baseline physical exams will be presented by listing. 
 
5.3.3.5 
Electrocardiogram (ECG) 
A single standard supine 12-lead ECG will be obtained after a subject has rested quietly for at least 10 
minutes. The ECG may be repeated if the result is abnormal, as clinically appropriate. ECG data will be 
reviewed by the Investigator or appropriate local designee. The Investigator must review and initial the 
tracing (or alternate source record) and the assessment of any reviewer (if not themselves). 
Summary statistics (including number, mean, SD, median, Q1, Q3, minimum, and maximum) for all ECG 
variables (actual values and changes from baseline) will be calculated for each visit or study assessment 
(baseline, each postbaseline time-point) by treatment arm and dose regimen. Only evaluable data will be 
used, and missing data will not be imputed.  
The baseline value is defined as the last available measurement prior to the first dose of study drug 
accounting for date, and time (where available) which can be found in screening or unscheduled visits of 
the CRF. 
Summaries of evaluation (normal; abnormal not clinically significant; abnormal clinically significant) will be 
provided by visit and treatment arm and dose regimen. 
Categorical analysis of QT and QTcB/ QTcF interval data based on the number and percentage of subjects 
meeting or exceeding predefined limits in terms of absolute interval values or changes from baseline will 
be presented by treatment arm and dose regimen for baseline (as appropriate) and post-baseline values.  
 


 
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Parameter (Unit) 
Criteria 
QT (msec) 
>=500 
QTcB (msec) 
450 <480 
480 <500 
≥500 
Change from baseline >60 
Change from baseline >30 and <60 
QTcF (msec) 
450 <480 
480 <500 
≥500 
Change from baseline >60 
Change from baseline >30 and <60 
 
All ECG results will be listed on a by-subject basis. In addition, a listing of subjects meeting criteria above 
will be produced. 
There will be an analysis visit window for the Day 15 ECG, of -2 to +3 days (Study Day 13 to 18; to be 
confirmed prior to database lock). In case several values are found in the visit window, the record collected 
on the day closest to the nominal day will be selected. If there are 2 days equidistant from the nominal 
day, the later day will be selected. 
5.3.3.6 
Vital Signs and Oxygenation/ Respiratory parameters 
A summary of vital signs (including heart rate, systolic and diastolic blood pressure and body temperature 
(recorded in °C) including change from baseline (where appropriate), presented by descriptive statistics 
(including SE for SBP and DBP), will be displayed for each day from baseline through Day 15, and at Day 
29. Temperature summarization also includes measurement location. Only evaluable data will be used, 
and missing data will not be imputed. 
The baseline value for temperature and Oxygenation/Respiratory parameters is defined as the last 
available measurement prior to the first dose of study drug accounting for date, and time (where available) 
which can be found in screening, baseline/Day 1 or unscheduled visits of the CRF. For systolic and 
diastolic blood pressure and heart rate baseline is considered to be Day 1 pre-dose around infusion (Study 
drug administration form in eCRF). 
For dosing days, the scheduled time-points around dosing will be summarized. For dosing and non-dosing 
days with available twice daily assessments, the daily values for a subject used in group summaries are 
those reported from the assessment, either “before noon” or “between noon and midnight”, at which the 
SBP recorded is highest, i.e., worst value (see below). 
Additionally, change from pre-dose within each dosing day for post-dose values will be summarized by 
treatment arm and dose regimen. Pre-dose and post-dose vital signs (systolic and diastolic blood pressure 
and heart rate) on study drug treatment days are in the Study drug administration eCRF; the values will 


 
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be presented in a combined listing with all other Vital Signs eCRF data (including additional 
measurements). 
In addition, a line plot of mean (SE) and/or median, and change from baseline (SE), will be displayed for 
systolic and diastolic blood pressure (mmHg), by treatment arm and dose regimen and visit. Individual line 
plots by subject (including all measurements for all days) will also be plotted to assist with interpretation of 
any study drug elevations; will only be created for individual subjects with any instance of SBP ≥ 160 
mmgHg, and/or when DBP ≥ 100 mmHg . 
The percentage of subjects meeting the following blood pressure measurement criteria (and the individual 
components of) will be summarized by treatment arm and dose regimen, overall for study and by visit (in 
addition, by time-point on infusion days). For this analysis, as for change from baseline, for days with 
available twice daily assessments, the daily values for a subject used in group summaries are those 
reported from the assessment, either “before noon” or “between noon and midnight”, at which the SBP 
recorded is highest. 
• 
Systolic blood pressure increased: ≥180 mmHg and increase from baseline ≥20 mmHg 
• 
Diastolic blood pressure increased: ≥110 mmHg and increase from baseline ≥15 mmHg 
If any subject meets the DBP substantial increase which is not captured by the SBP highest time-point, 
he/she will be reported on a footnote. 
All vital signs measures and details of these substantial changes, and the individual components of, will 
be listed. 
For Respiratory parameters of SpO2 and PaO2, PaO2/FiO2, these will not be summarized due to 
collection under different oxygen support statuses.  
Respiratory rate will be summarized on each day from baseline (Day 1) through Day 15, and at Day 29, 
with summarization split by (i) on room air or (ii) on oxygen supplementation (excluding if on mechanical 
ventilation). For days with available twice daily assessments, the daily value for a subject used in group 
summaries is to be that reported from the assessment, either “before noon” or “between noon and 
midnight”, at which the respiratory rate recorded is (i) on oxygen supplementation (excluding if on 
mechanical ventilation) > on room air, or (ii) if both time-points have the same oxygen support, the highest 
respiratory rate value. 
The number and proportion of subjects in each oxygen supplementation category (room air (none), low 
flow O2, high flow O2, CPAP/BIPAP, mechanical ventilation, ECMO) for each day from baseline (Day 1) 
through Day 15, and at Day 29, will be summarized by treatment arm and dose regimen. In addition, 
stacked bar charts for oxygen supplementation (%) by day (baseline through Day 15, and at Day 29) will 
be produced.  


 
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For days with available twice daily assessments for oxygen supplementation, the daily value for a subject 
used in group summaries is to be that reported from the assessment, either “before noon” or “between 
noon and midnight”, for the most intensive support, where ECMO > mechanical ventilation > CPAP/BIPAP, 
high flow O2 > low flow O2 > room air (no oxygen support). 
Once discharged and no longer in hospital, oxygen therapy status is determined based on the clinical 
status ordinal scale captured by daily phone call. Note: the clinical status recordings and imputation rules 
apply to these data interpreted from the ordinal scale score as specified in Section 4.2.1. 
See 5.3.4.4 for duration of supplemental oxygen support. 
Oxygenation/Respiratory parameters will be listed. 
Analysis Visit Windows for Vital Signs and Oxygenation/ Respiratory parameters: 
For days 15 and 29, analysis visit windows will be as below (to be confirmed prior to database lock): 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Day 15 
15 
13 
18 
Day 29 
29 
25 
35 
 
In case several values are found in the visit window, the record collected on the day closest to the nominal 
day will be selected. If there are 2 days equidistant from the nominal day, the later day will be selected. 
 
5.3.3.7 
Laboratory Evaluation 
Local laboratory assessments include haematology, blood chemistry and coagulation parameters. 
The summary statistics (including number, mean, SD, median, Q1, Q3, minimum, and maximum) of all 
quantitative laboratory variables (laboratory values and changes from baseline) will be calculated for each 
visit or study assessment (baseline and each post-baseline time-point), by treatment arm and dose 
regimen. 
The baseline value is defined as the last available measurement prior to the first dose of study drug 
accounting for date, and time (where available) which can be found in screening, baseline/Day 1 or 
unscheduled visits of the CRF. 
The number (%) of subjects with abnormal results (out of normal range) for each of the laboratory variables 
will be summarized by treatment arm and dose regimen and visit. 
Shift tables for baseline versus Days 3, 8, 15, and 29 will be presented for the chemistry and hematology 
laboratory parameters tabulated below (where ULN = upper limit of normal range), based on four 
categories as specified. 


 
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Panel 
Lab Test Label 
Criteria 
Level 1 
Level 2 
Level 3 
Level 4 
Chemistry 
Alanine 
aminotransferase 
(ALT) increased  
>ULN - 3.0 x 
ULN 
 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Aspartate 
aminotransferase 
(AST) increased  
>ULN - 3.0 x 
ULN 
 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Gamma-
glutamyltransferase 
(GGT) increased 
>ULN - 2.5 x 
ULN 
 
>2.5 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Total bilirubin 
increased 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 10.0 x 
ULN 
>10.0 x ULN 
Creatinine 
increased 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 6.0 x 
ULN 
>6.0 x ULN 
Hematology 
Anemia/ 
Hemoglobin 
decreased 
<LLN - 100 g/L  <100 - 80 g/L 
<80 g/L 
- 
Platelet count 
decreased 
<LLN - 75.0 x 
10^9 /L 
<75.0 - 50.0 x 
10^9 /L 
<50.0 - 25.0 x 
10^9 /L 
<25.0 x 10^9 
/L 
White blood cells 
decreased 
<LLN - 3.0 x 
10^9 /L 
<3.0 - 2.0 x 
10^9 /L 
<2.0 - 1.0 x 
10^9 /L 
<1.0 x 10^9 /L 
 
Data will be listed by subject. A listing of subjects meeting Level 3 or Level 4 abnormality criteria above 
will also be produced. 
In addition, a box-plot will be presented for every quantitative laboratory parameter by treatment arm and 
dose regimen and visit. 
Evaluable data for each nominal visit will take into account analysis visit windows (shown below) and other 
than this, missing data will not be imputed. 
Note that as a general consideration, analysis visit windows will be included for laboratory safety 
parameters as presented below (to be confirmed prior to database lock): 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline/ Day 1 
1 
- 
1 (pre-dose) 
Day 2 
2 
2 
2 
Day 3 
3 
3 
3 
Day 5 
5 
4 
6 
Day 8 
8 
7 
9 
Day 11 
11 
10 
12 
Day 15 
15 
13 
18 
Day 29 
29 
25 
35 
 


 
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If multiple valid, non-missing measurements exist for post-baseline analysis windows spanning multiple 
days, the record collected on the day closest to the nominal day will be selected. If there are 2 days 
equidistant from the nominal day, the later day will be selected. 
 
5.3.4 Exploratory and Other Analyses 
The exploratory analyses comprise: 
 
- 
In-hospital outcomes: 
o Duration of hospitalization 
o Time to discharge 
o Duration of invasive mechanical ventilation 
o Duration of supplemental oxygen support 
o Duration of ECMO 
o No oxygen therapy (and/or peripheral oxygen saturation SpO2 > 93% on room air) at Days 
8, 15 and 29 
- 
28-day all cause-mortality 
Other analyses comprise: 
- 
SARS-CoV-2 viral load 
- 
Biological and immunological markers of illness/inflammation 
- 
Plasma pharmacokinetics of Brilacidin 
 
These exploratory and other analyses will be performed in the ITT population. 
5.3.4.1 
Duration of hospitalization 
Duration of hospitalization from randomization is defined as the time elapsed (in days) from randomization 
until hospital discharge, where hospital discharge will be considered as the first date of either hospital 
discharge or achieving a maintained (not descending) or improved (ascending) clinical status of 6 [which 
implies the subject is ready to be discharged; see section 4.2.1]. Duration of hospitalization will be 
calculated only for those subjects discharged from hospital alive on or prior to Day 29. If a subject is re-
hospitalized for COVID-19 after initial discharge, i.e., has more than one period of time in hospital for 
COVID-19, the initial and subsequent durations in hospital will be summated as long as the subject is 
discharged from the re-hospitalization alive on or prior to Day 29. For those subjects not being discharged 
during the study period through to Day 29, the duration of hospitalization will be set to 28 days (maximum 
observation time, between Day 1 and Day 29). 


 
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The duration of hospitalization will be summarized by means of descriptive statistics by treatment group. 
Additionally, comparisons for each Brilacidin group vs pooled placebo will be performed by means of the 
Wilcoxon rank sum test. 
A subject listing for duration of hospitalization and time to discharge will be included, along with details for 
dates of admission/ discharge/ and re-admission/ re-discharge, etc., as appropriate. If date/time of hospital 
discharge are imputed (see section 4.2.1), the listing will display original entry in the eCRF and the imputed 
data, identifying which is imputed for endpoint calculation. 
5.3.4.2 
Time to discharge 
Time to discharge from randomization is defined as the time elapsed (in days) until hospital discharge, 
where hospital discharge will be considered as the first date of either hospital discharge or achieving a 
maintained (not descending) or improved (ascending) clinical status of 6 [which implies the subject is ready 
to be discharged; see section 4.2.1]. Time to discharge will be calculated only for those subjects 
discharged from hospital alive on or prior to Day 29. If a subject has more than one period of time in 
hospital during the study, i.e., is re-hospitalized for COVID-19 after initial discharge, the time to the latest 
discharge time-point will be that used in summarization, as long as the subject is discharged from the re-
hospitalization alive on or prior to Day 29. Subjects not being discharged will be censored at Day 29 
(maximum observation time of 28 days). 
A Kaplan-Meier analysis will be performed to assess the time to discharge by treatment group. The median 
time to event as well as the estimated percent of subjects without event during the study period will be 
estimated based on Kaplan-Meier method for each treatment group. Group comparisons will be done using 
the (stratified) log-rank test. Curves will also be presented. 
 
A subject listing for duration of hospitalization and time to discharge will be included, along with details for 
dates of admission and discharge. If date/time of hospital discharge are imputed (see section 4.2.1), the 
listing will display original entry in the eCRF and the imputed data, identifying which is imputed for endpoint 
calculation. 
 
5.3.4.3 
Duration of supplemental oxygen support 
Duration of supplemental oxygen support will be considered as described in section 4.2.3 
The duration of supplemental oxygen support will be summarized by means of descriptive statistics and 
by treatment group. 
A subject listing stating duration of any oxygen supplementation by type will be included. 


 
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5.3.4.4 
Duration of invasive mechanical ventilation 
Duration of invasive mechanical ventilation will be considered as described in section 4.2.3 
The duration of mechanical ventilation will be summarized by means of descriptive statistics and by 
treatment group. 
A subject listing stating duration of invasive mechanical ventilation will be included. 
 
5.3.4.5 
Duration of ECMO 
Duration of ECMO will be considered as described in section 4.2.3 
The duration of ECMO will be summarized by means of descriptive statistics and by treatment group. 
A subject listing stating duration of ECMO will be included. 
 
 
 
 
5.3.4.6 
Proportion of subjects achieving No oxygen therapy (and/or peripheral oxygen 
saturation SpO2 > 93% on room air) at Days 8, 15 and 29 
The proportion of subjects without oxygen therapy (and/or peripheral oxygen saturation SpO2 > 93% on 
room air [when hospitalized]) will be considered as described in section 4.2.3. 
During hospitalization, oxygen therapy status is determined from oxygen supplementation data entry; “no 
oxygen therapy” in these instances is considered met when the subject is on room air and SpO2 > 93% 
(from Respiratory Status eCRF); if oxygen supplementation “room air” entry is missing, SpO2 value can 
be taken (and will be sufficient to achieve the endpoint), and if SpO2 value entry is missing, oxygen 
supplementation “room air” entry alone can be taken (and will be sufficient to achieve the endpoint). Once 
discharged and no longer in hospital, oxygen therapy status is determined based on the clinical status 
ordinal scale captured by daily phone call; “no oxygen therapy” is considered met for grade 8. 
If there are multiple values on the same day, if either value meets the SpO2 criteria (measured on room 
air), the subject will be counted as having achieved the endpoint. 
Analyses will be based on the LOCF approach meaning that the value for subjects lost-to-follow up or with 
score not assessed at Days 8, 15 and 29 will be the value in their last observation available. 


 
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This number and proportion of subjects will be reported by treatment group, for the study overall (through 
Day 29) and by time-point of assessment.  
A subject listing by specified time-point, containing Oxygen therapy (Yes/No) and SpO2 if measured on 
room air, will be included. 
 
5.3.4.7 
28-day Mortality 
28-day Mortality rate will be estimated by treatment group. 
A Kaplan-Meier analysis will be performed to evaluate overall survival as defined in section 4.2.3. Subjects 
alive at the Day 29 study follow-up visit will be censored at that assessment; time to death will be censored 
at the last known date of being alive (through Day 29). 
The median time to event as well as the estimated percent of subjects without event during study period 
will be estimated based on Kaplan-Meier method for each treatment group. Group comparisons will be 
done using the (stratified) log-rank test. Curves will also be presented. This endpoint will be listed. 
 
 
 
5.3.4.8 
Change from baseline in biomarkers. 
Change from baseline of the biomarkers will be considered as described in section 4.2.3 
The baseline value is defined as the last available measurement prior to the first dose of study drug 
accounting for date, and time (where available) which can be found in baseline/Day 1 or unscheduled visits 
of the CRF. 
A summary of biomarker data including change from baseline will be presented by descriptive statistics, 
displayed by visit and treatment group. 
Only subjects with available information for biomarkers at baseline will be included in the analyses. 
Change from baseline to Days 2, 3, 5, 8, 11, 15 and 29 of the biomarkers in the Brilacidin treatment groups 
will be compared to pooled placebo using ANCOVA, including the log2-transformed baseline value as 
covariate and the stratification variables (country, categorized age group (< 65 / > 65 years) and COVID-
19 infection severity) as factors. In the event that any of the stratification variables does not achieve enough 
size for obtaining reliable estimations, that stratification variable will be not considered as a factor in the 
model. Least square mean difference between each the treatment arm versus placebo will be provided 
with 2-sided 90%CIs. 


 
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In addition, a box-plot showing the underlying distribution of change from baseline will be presented for 
each parameter by treatment group and visit. 
Data will be listed by subject. 
Evaluable data for each nominal visit will take into account analysis visit windows (shown below) and other 
than this, missing data will not be imputed. 
Note that as a general consideration, analysis windows will be included for pro-inflammatory biomarkers 
(IL-1β, IL-6, IL-10, total IL-18, TNF-α) and SARS-CoV-2 viral load parameters as presented below (to be 
confirmed prior to database lock): 
Visit ID 
Nominal Day Lower Limit 
Upper Limit 
Baseline/ Day 1 
1 
- 
1 (pre-dose) 
Day 3 
3 
2 
3 
Day 5 
5 
4 
6 
Day 8 
8 
7 
9 
Day 11 
11 
10 
12 
Day 15 
15 
13 
18 
Day 29a 
29 
25 
35 
a Applicable to SARS-CoV-2 viral load parameters only 
 
If multiple valid, non-missing measurements exist for post-baseline analysis windows spanning multiple 
days, the record collected on the day closest to the nominal day will be selected. If there are 2 days 
equidistant from the nominal day, the later day will be selected. 
Serum CRP levels will also be analyzed on a log-scale fitting a repeated measures mixed model including 
treatment group, day (through Day 15), the three stratification factors and log2 transformed baseline CRP 
as a covariate. In the event that any of the stratification factors does not achieve enough size for obtaining 
reliable estimations, that stratification factor will be not considered in the model. Interactions between day 
and each of the terms in the model will also be included. The back-transformed ratios of Brilacidin in 
addition to SoC vs SoC alone will be reported with 90% CIs. In addition, IL-6 will be analyzed in the same 
manner. 
 
5.3.4.9 
Change from baseline in SARS-CoV-2 viral load. 
Quantitative data per sample are: threshold value (Ct), copy/mL and log10 copy/mL; qualitative data per 
sample are: positive/ negative (for SARS-CoV-2) 
Change from baseline of the SARS-CoV-2 viral load (copy/mL) will be considered as described in section 
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The baseline value is defined as the last available measurement prior to the first dose of study drug 
accounting for date, and time (where available) which can be found in baseline/Day 1 or unscheduled visits 
of the CRF. 
Summary statistics of quantitative data (values and changes from baseline) will be calculated for each 
visit, by treatment group.  
Change from baseline to Days 3, 5, 8, 11, 15 and 29 of the SARS-CoV-2 viral load in the Brilacidin 
treatment groups will be compared to pooled placebo using ANCOVA, including the baseline value (log10-
transformed) as covariate and the stratification variables (country, categorized age group (< 65 / > 65 
years) and COVID-19 infection severity) as factors. In the event that any of the stratification factors does 
not achieve enough size for obtaining reliable estimations, that stratification factor will be not considered 
in the model. Least square mean difference between each treatment group versus pooled placebo will be 
provided with 2-sided 90%CIs. 
Only subjects with available information for SARS-CoV-2 viral load at baseline will be included in the 
analyses. 
Data will be summarized by swab type: nasopharyngeal (requested by protocol) or oropharyngeal. 
Qualitative viral load data will also be summarized. Number and percent of subjects with a positive or 
negative SARS-CoV-2 PCR test on Days 3, 5, 8, 11, 15 and 29 will be tabulated. Time to viral clearance, 
i.e., time to negative SARS-CoV-2 PCR test, will be determined with Kaplan-Meier analysis where subjects 
will be considered to have achieved the event the first day for which the SARS-CoV-2 PCR test result is 
negative. If subjects are lost to follow-up (for this endpoint) prior to achieving negative SARS-CoV-2 or die 
prior to Day 29, their time to viral clearance will be censored at their last test measurement day. 
In addition, a box-plot showing the underlying distribution of change from baseline will be presented by 
treatment group and visit. 
Data will be listed by subject. 
Evaluable data for each nominal visit will take into account analysis visit windows (as shown in Section 
5.3.4.8) and other than this, missing data will not be imputed. 
 
5.3.4.10 
Plasma pharmacokinetics of Brilacidin 
This document does not address the specific analysis of PK data collected in this study. These analyses 
will be discussed in a separate analysis plan to support the population PK report. 
 


 
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5.3.5 Interim Analyses 
An initial safety review occurred after approximately 20 randomized subjects had completed up to Day 15. 
This initial interim analysis focused on review of cardiovascular safety, vital signs and adverse events that 
occurred in the approximately 20 subjects to receive Days 1-3 of study treatment. A further safety review 
by the DMC also occurred, as planned, after approximately 50% of subjects had completed up to Day 29. 
The DMC recommended expanding dosing to Days 4 and 5 (at the same doses as on Days 2 and 3), after 
the initial safety review. The DMC was guided by the degree and incidence of hypertensive values/events 
observed in the ongoing study which should not exceed the number and/or severity of those observed in 
previous studies with Brilacidin IV treatment for expansion of dosing to occur as planned. 
Study stopping rules for placing the enrollment on hold were defined in the protocol. In addition, 
recommendation guidelines and further details of the DMC were prepared separately from this plan in a 
DMC Charter. 
Other interim analyses were allowed for as potential to be conducted to support decision making 
concerning the current clinical study or in case of any safety concerns. 
The primary efficacy analysis will occur once all subjects complete the Day 29 visit (or discontinue from 
study, if before Day 29). Final database lock and updated safety reporting will follow the completion of Day 
60 follow-up telephone visits. 
 
 
 
5.3.6 Sensitivity Analyses 
Pre-specified sensitivity analyses are limited in this analysis plan. Current proposals for inclusion as 
sensitivity analyses are included below. These details will be reviewed and determined prior to database 
lock. 
An initial sensitivity analysis will be conducted with the specified study analyses, to evaluate the 
assumption that there is no difference between the placebo 5-dose regimen and the placebo 3-dose 
regimen. The primary efficacy endpoint and selected other endpoints (i.e., composite endpoint by Day 29, 
defined as Death OR Respiratory failure; achieving at least one-point/ two-point improvement in clinical 
status at Days 8, 15 and 29; duration of hospitalization; time to discharge; 28-day mortality; change from 
baseline in CRP; change from baseline in SARS-CoV-2 viral load) will be summarized for the two placebo 
regimens. 
Also, if Brilacidin 5-dose or 3-dose regimen suggests efficacy > pooled placebo, pooled Brilacidin will be 
compared to pooled placebo for the primary efficacy endpoint. Summaries will also be presented. 


 
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For the secondary endpoint measuring the evolution of the clinical status using ordinal scale on days 3, 5, 
8, 11, 15 and 29, the stratified non-parametric van Elteren test, using modified ridit scores which is as a 
direct extension of the Wilcoxon's rank-sum test for 2-samples, will be calculated as a sensitivity analysis 
to compare the scale as an ordinal rather than a binary outcome, without assuming proportional odds. 
The SAS proc freq with modified ridit scores will be used to obtain the Van Elteren test as follow: 
 
proc freq data=<sas-data-set>; 
ods select cmh; 
table <time>*<treatment group>*<change_againts_baseline>/cmh2 
scores=modridit; 
run; 
 
The analyses of efficacy endpoint(s) will also be performed using the PP population. These analyses will 
be considered as supportive as a kind of sensitivity analyses. Pre-specified analyses using the PP 
population includes the primary endpoint only. 
 
 
 
5.3.7 Study Estimand and Handling of Missing Data 
As per the ICH E9(R1) (Addendum on estimands and sensitivity analysis in clinical trials 
EMA/CHMP/ICH/436221/2017), the plan for the assessment of the Primary endpoint (PEP) is 
described here after using the 4 attributes of the estimand: 
1. Population: In essence, hospitalized adult (≥18 years old) patients with moderate or severe 
COVID-19, SARSCoV-2 infection confirmed by positive standard PCR test (or equivalent) 
within 4 days prior to starting study treatment, and hospitalized with respiratory distress but not 
yet requiring high-level respiratory support. A detailed description is given in section 2.3.2 of 
this SAP. 
Primary endpoint: The PEP is defined as time to sustained recovery (from COVID-19 infection) 
through Day 29, which is the time (in days) from randomization to the day of recovery without 
subsequent relapse. Day of recovery is defined as the first day on which the subject satisfies 
one of the categories 6, 7 or 8 on the following 8-point ordinal scale for clinical status with 
response sustained through Day 29: 


 
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(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 
If response after initial recovery is not sustained, and the subject experiences relapse, the initial 
recovery is not counted as such, Any subsequent recovery, sustained through Day 29, will be 
recognized and counted. See sections 4.2.1 and 0 for details. 
 
2. Intercurrent events: In principle, the rates of intercurrent events and missing data are 
estimated to be very low due to the type of endpoint, easily available with a fast-clinical 
assessment, and the early time-point of assessment. Thus, no impact is expected in the primary 
analysis. However, we describe hereafter the relevant intercurrent events expected to occur in 
this study and the methods for handling them: 
a. No treatment initiation with the IP: Not applicable since efficacy population requires 
treatment for analysing data. 
b. Treatment discontinuation: “Treatment Policy” strategy, i.e., the efficacy observed 
assessment will be used regardless of this intercurrent event. 
c. Death before the time of assessment: it will be handled as the “Composite” strategy, 
i.e., the PEP will be considered as censored at Day 29. 
d. Other reasons for not assessing the PEP: 
• 
Reasons likely related to the treatment (i.e. due to efficacy or safety issues) or to a 
bad clinical evolution: they will be handled as in 2.c. using the “Composite” strategy. 


 
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• 
Non treatment-related reasons. In principle no cases are expected, and the 
“Hypothetical” strategy will be used. 
e. Any additional medication or any other potential reason for study discontinuation: 
“Treatment Policy” strategy, i.e., the efficacy observed assessment will be used 
regardless of this intercurrent event. 
3. Population-level summary: Estimation of the p-value from the stratified log-rank test 
comparing groups (Brilacidin 5-dose regimen vs pooled placebo as main comparison and 
Brilacidin 3-dose regimen vs pooled placebo as secondary) and the hazard ratio (HR) for the 
PEP will be used as the population-level summary. The Cox model adjusted by the 
randomisation strata variables will be used for the inferential analysis (p-value, HR and 90% 
Confidence Intervals). 
The following sensitivity analyses are proposed: 
• 
For the PEP: Perform analyses using the PP population. 
• 
For the PEP: 
Summarize pooled placebo and pooled Brilacidin and compare pooled placebo vs pooled 
Brilacidin; if Brilacidin 5-dose or Brilacidin 3-dose suggests efficacy against pooled placebo. 
 
• 
For the PEP and selected endpoints: 
Summarize descriptively placebo 5-dose regimen and the placebo 3-dose regimen; to evaluate 
assumption of no differences between them; 
Composite endpoint by Day 29, defined as Death OR Respiratory failure; achieving at least one-
point/ two-point improvement in clinical status at Days 8, 15 and 29; duration of hospitalization; 
time to discharge; 28-day mortality; change from baseline in CRP; change from baseline in SARS-
CoV-2 viral load 
 
• 
For the evolution of the clinical status using ordinal scale, comparison as ordinal rather than 
binary by means of a stratified non-parametric test 
 
The handling of missing data will follow the principles specified in the ICH-E9 guideline. 
Missing data for efficacy and exploratory endpoints are described in section 5.3 for statistical analyses. 
In general, missing baseline data will not be imputed. The following approaches are default methods 
for missing data handling in summary tables. 


 
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- 
Categorical data at baseline will be summarized for each treatment group using counts (n) and 
percentages (%). The denominator will be the analysis population specified for the summary, 
unless otherwise specified. Missing data may be presented as a separate category. 
- 
Continuous data: The analyses and summaries for variables with continuous scales will be 
based on observed data only. 
Missing data commonly encountered during the study may comprise: 
- 
Missing/Partial Dates: For incomplete days or months, an imputation will be done by assigning the 
first day of month or the first month of year, respectively. For incomplete years in dates after 
randomization, the year of randomization will be assigned.  
- 
Categorical endpoints measured “at” or “by” pre-defined days: In general, analyses will be based 
on the LOCF approach. Details for each specific endpoint are described in their corresponding 
subsections of 5.3 section for statistical analyses. 
- 
Continuous variables: mixed models are robust to the presence of missing at random and 
conducts the analysis with all participants despite the presence of missingness. Of note, this 
method calculates the estimations based on the variance-covariance structure but without any 
formal imputations. 
 
Missing data commonly encountered for safety and baseline variables may comprise: 
- 
Missing/Partial Dates for AEs or Concomitant Medications: 
Missing or partial AE onset dates and times will be imputed so that if the partial AE onset 
date/time information does not indicate that the AE started prior to treatment or after the TEAE 
period, the AE will be classified as treatment-emergent. These data imputations are for 
categorization purpose only and will not be used in listings. No imputation is planned for 
date/time of AE resolution. 
No imputation for medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
- 
Handling of Missing Assessment of Relationship of AEs to IP 
If the assessment of the relationship to IP is missing, then the relationship to IP in the frequency 
tables is considered as possibly related, but no imputation should be done at the data level. 
- 
Handling of Missing Severity of AEs 


 
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If the severity is missing for 1 of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, a “missing” category will be added in the summary table. 
5.3.8 Subgroup Analyses 
Subgroup analyses will be performed to assess the impact on efficacy of certain factors. 
The primary efficacy endpoint will be evaluated with respect to the following subgroups: 
- 
COVID-19 infection severity at baseline, Moderate vs Severe 
- 
Age, ≤65years vs >65years 
5.3.9 Reporting Conventions 
The descriptive statistics will be reported to 2 decimal places, except for 1) those parameters with low 
measurements such as biomarkers or others, that will be reported to 3 or 4 decimal places, as appropriate; 
2) those parameters not requiring decimal places, that will be reported without any decimal place. 
Estimated parameters, such as regression coefficients will be reported to 3 decimal places. Percentages 
should be rounded to a single decimal place. P-values ≥0.0001 will be reported to 4 decimal places; p-
values less than 0.0001 will be reported as “<0.0001”. Vital Signs, oxygenation, laboratory and biomarker 
parameters will be reported in International Units. 
5.3.10 
Study Timelines 
Date first subject enrolled: 22-Feb-2021 
Date last subject enrolled: 02-Jun-2021 
The primary analysis of safety and efficacy is planned after all subjects complete the final study visit or 
terminate early from the study and database close. 
 
5.3.11 
Technical Details 
The most updated study protocol has been used as a reference for this document. SAS programs, SAS 
Logs and SAS outputs generated during the creation of the Statistical Report will be archived in the 
 File System. 
 
5.3.12 
Software 
The statistical analysis will be performed using the scientific software SAS® V9.4 or later releases and 
SAS® Enterprise Guide V7.15 or later releases. 
6. 
REFERENCES 


 
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[U.S.] Department of Health & Human Services (DHHS) (2020). Determination that a Public Health 
Emergency Exists Nationwide as the Result of the 2019 Novel Coronavirus. 31 January 2020. 
https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019- nCoV.aspx 
Bakovic A, Risner K, Bhalla N, et al (2020). Brilacidin, a COVID-19 Drug Candidate, Exhibits Potent In 
Vitro 
Antiviral 
Activity 
Against 
SARS-CoV-2. 
Published 
online 
30 
October 
2020. 
https://www.biorxiv.org/content/10.1101/2020.10.29.352450v1.full 
Bakovic A, Risner K, Bhalla N, et al (2021). Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell 
Culture. Viruses; 13(2):271; https://doi.org/10.3390/v13020271 
Cavasotto C and JD Filippo (2020). In silico drug repurposing for COVID-19: targeting SARS-CoV-2 
proteins through docking and quantum mechanical scoring. ChemRxiv. 
Cox MJ, Loman N, Bogaert D, et al (2020). Co-infections: potentially lethal and unexplored in COVID-19. 
Lancet. Correspondence. Vol 1;1:E11 (May 1, 2020). 
Johns Hopkins Coronavirus Resource Center. World Map: https://coronavirus.jhu.edu/map.html 
Kim D, Quinn J, Pinsky B (2020). Rates of co-infection between SARS-CoV-2 and other respiratory 
pathogens. Research Letter. JAMA; 323(20):2085-86. 
Mirzaei R, Goodarzi P, Asadi M, et al (2020). Bacterial co‐infections with SARS‐CoV‐2. IUBMB Life: Early 
View. Published online 08 August 2020. 
Spinner CD, Gottlieb RL, Criner GJ, et al (2020). Effect of Remdesivir vs Standard Care on Clinical Status 
at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA; 324(11):1048-57. 
Stein J (2020). Coronavirus fallout will haunt U.S. economy for years, costing it $8 trillion through 2030, 
CBO says. Washington Post (June 1, 2020). 
Tamimi A, Serdarevic D, Hanania NA (2012). The effects of cigarette smoke on airway inflammation in 
asthma and COPD: Therapeutic implications. Resp Med; 106(3):319-28. 
WHO (2020a). COVID-19 Therapeutic Trial Synopsis. Geneva, Switzerland: WHO R&D Blueprint, Feb 18 
2020. 
WHO (2020b). Statement on the second meeting of the International Health Regulations (2005) 
Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV). Geneva, Switzerland, 
30 January 2020. 
WHO (2020c). A Multi-centre, Adaptive, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of 
the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized 
Patients. WHO R&D Blueprint, version number 2.0, 24 February 2020. 
Zhou F, Yu T, Du R, et al (2020). Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet; 395(10229):1054-62.