Clinical trial NCT04402957
Conditions: COVID Severe Acute Respiratory Syndrome Sars-CoV2 Acute Kidney Injury Acute Respiratory Distress Syndrome
Sponsor: Arch Biopartners Inc.
Start date: 2020-10-14; Completion date: 2022-06-02
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the proportion of subjects alive and free of respiratory failure (e.g. need for non-invasive or invasive mechanical ventilation, high flow oxygen, or ECMO) and free of the need for continued renal replacement therapy (RRT) on Day 28. The need for continued RRT at Day 28 will be defined as either dialysis in the past 3 days (Day 26, 27, or 28) or an eGFR on Day 28 \<10 mL/min/1.73 m2.

Detailed description:
This study is a parallel group, randomized, third-party blinded, multicenter study to assess safety and efficacy of LSALT peptide versus placebo in hospitalized patients with confirmed infection or recent confirmed infection with complications associated with COVID-19. Following screening and after establishing baseline parameters such as lung and renal function, clinical chemistries, coagulation, hematology, and urinalysis, and satisfying all inclusion and exclusion criteria, patients will be randomized to one of two blinded treatment regimens:

1. 100 mL of 5 mg IV LSALT peptide infusion over 2 hours daily
2. 100 mL drug-free IV saline infusion over 2 hours daily.

Thirty (30) patients will be randomized to active drug (LSALT peptide) and 30 patients will be randomized to matching placebo. This study will be third-party blind with only the Pharmacist at the site unblinded for the purpose of preparing drug/placebo for injection.

Patients will be followed for safety and efficacy up to Day 28, with Day 1 being the day of randomization to assess safety. After assessing the risk of ARDS and satisfying all inclusion and exclusion criteria, the patient will be randomized to 5 mg LSALT peptide or blinded placebo to be given intravenously once daily for a maximum of 14 days. Physical and respiratory examinations, vital signs, and adverse events will be recorded throughout the study, including Day 28 (EOS). Blood chemistries, hematology, coagulation, urinalysis, ECG, SARS-CoV-2 tests, eGFR, and chest x-ray (CXR) will be assessed at Day 1 (Screening/Baseline) prior to initiation of study drug, and on Day 3, EOT, and at EOS, as well as when clinically indicated. The ECG at EOS will only be obtained if clinically indicated. An additional CXR will be obtained at time of clinical improvement. Cytokines/biomarkers and pharmacokinetics (PK) will be assessed at Day 1 (Screening/Baseline) prior to initiation of study drug, at 1 (mid-dose) and 2 hours (end of infusion) of drug therapy on Days 1, 3, EOT, and a single blood sample at EOS for cytokines/biomarkers only. Where applicable, a urinary pregnancy test will be obtained at Screening in women of childbearing potential. Questionnaires (APACHE II, SOFA) will be obtained at Baseline, Day 3, EOT, and EOS; venous blood gas (VBG) or HCO3 (bicarbonate) levels may be substituted for arterial blood gas (ABG) if it is considered standard-of-care (SOC) or in the patient's best interest, and results in comparable APACHE II and SOFA scores. Other questionnaires (Berlin Definition and modified Medical Research Council Dyspnea Scale) will be assessed at Baseline, Day 3, EOT, and EOS. IgG, IgA, and IgM antiviral antibodies will be collected at Baseline and EOS. Patients will be maintained on the SOC per institutional guidelines, including prophylaxis or treatment of VTE, throughout the study.

A Data and Safety Monitoring Board (DSMB) will evaluate patients on a continuing basis for primarily safety assessments. Per the DSMB Charter, the DSMB will meet at least monthly if not more frequently based upon enrollment throughout the study period.

Arms: arm 1: 100 mL drug-free IV saline infusion over 2 hours daily arm 2: 100 mL of 5 mg IV LSALT peptide infusion over 2 hours daily
Interventions: intervention 1: LSALT peptide intervention 2: Placebo
Intervention descriptions: intervention 1: LSALT, a peptide drug with the sequence NH3-LSALTPSPSWLKYKAL-COOH, binds to dipeptidase-1 (DPEP-1) but does not inhibit its biologic enzymatic activity. LSALT peptide inhibits leukocyte recruitment in multiple experimental disease models through the direct inhibition of leukocyte adhesion to DPEP-1 present in lungs, kidney, and liver. intervention 2: 0.9% saline solution

Protocol documents:
Prot_SAP_000.pdf: 
Protocol AB002 
 
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March 17, 2021 
 
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PROTOCOL AB002 
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof 
of Concept Study of LSALT Peptide as Prevention of Acute 
Respiratory Distress Syndrome (ARDS) and Acute Kidney Injury 
(AKI) in Patients Infected with SARS-CoV-2 (COVID-19) 
Investigational Product: 
LSALT peptide 
Indication: 
LSALT peptide is indicated for prevention of acute 
respiratory distress syndrome and acute kidney injury in 
patients infected with confirmed COVID-19. 
Phase: 
2 
Date: 
Amendments: 
June 9, 2020 
1 (July 15, 2020) 
2 (August 15, 2020) 
3 (February 15, 2021) 
4 (March 17, 2021)
Name and Affiliation of  
Principal Investigator (PI): 
A list of the Principal Investigators is maintained in the trial 
master file 
Name and Address of Sponsor: Arch Biopartners Inc. 
545 King Street West 
Toronto, Ontario 
M5V 1M1 Canada 
GCP Statement: 
This study will be performed in compliance with GCP, 
including the archiving of essential documents. 
 
Confidentiality Statement 
The information contained in this document is the property of Arch Biopartners Inc.  All content are regarded as 
confidential and, except to the extent necessary to obtain informed consent or as required by law, may not be used, 
reproduced, or disclosed to third parties in any form whatsoever without written permission from Arch Biopartners 
Inc.  Persons to whom the information is disclosed must be informed that the information is confidential and may 
not be further disclosed as above. 


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SYNOPSIS 
TITLE:  Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study 
of LSALT Peptide as Prevention of Acute Respiratory Distress Syndrome (ARDS) and Acute 
Kidney Injury (AKI) in Patients Infected with SARS-CoV-2 (COVID-19) 
INVESTIGATIONAL PRODUCT:  LSALT peptide 
INDICATION:  LSALT peptide is indicated for the prevention of ARDS and AKI in patients 
infected with confirmed COVID-19. 
PHASE OF DEVELOPMENT:  2  
INVESTIGATIONAL SITES/LOCATIONS:  Multicenter 
PRIMARY OBJECTIVE:  To evaluate the proportion of subjects alive and free of respiratory 
failure (e.g., need for non-invasive or invasive mechanical ventilation, high flow oxygen [≥ 6 
L/minute], or ECMO) and free of the need for continued renal replacement therapy (RRT) on 
Day 28. The need for continued RRT at Day 28 will be defined as either dialysis in the past 3 
days (Day 26, 27, or 28) or an eGFR on Day 28 <10 mL/min/1.73 m2. 
SECONDARY OBJECTIVES:  To evaluate the following: 
 Incidence and time to mild, moderate, and severe ARDS per patient between treatment 
groups 
 Ventilation-free days 
 Time on nasal canula or oxygen mask 
 28-day mortality– both all-cause and attributable 
 ICU length of stay (in days) 
 Hospitalization length of stay (in days) 
 Virologic clearance rate 
 Incidence of other organ disorders 
 Need and duration for extracorporeal membrane oxygenation (ECMO) 
 Vasopressor-free days 
 Clinical improvement in chest x-rays  
 Change in baseline modified Medical Research Council (mMRC) dyspnea scale  
 SOFA scores assessed periodically 
 Change from baseline in liver function tests (ALT, AST, and total bilirubin levels) 
 Change from baseline in SCr and eGFR  
 Change from baseline in highly-sensitive troponin (hs-troponin) 
 Change from baseline ACT, aPTT, and/or PT/INR levels 
 Change from baseline for antiviral (SARS-CoV-2) immunoglobulins; IgG, IgM, and IgA at 
EOS. 


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HEALTH OUTCOMES OBJECTIVE: 
 Total healthcare costs from admission to discharge. 
EXPLORATORY OBJECTIVES: To evaluate: 
 Change in serum cytokines including IL-1α, IL-1ß, and ferritin levels, as well as other 
exploratory biomarkers. 
 Change in baseline antiviral immunoglobulins (IgG, IgM, IgA) at EOS. 
 Pharmacokinetics of LSALT peptide over the study period. 
STUDY DESIGN AND METHODOLOGY:  This study is a parallel group, randomized, third-
party blinded, multicenter study to assess safety and efficacy of LSALT peptide versus placebo 
in hospitalized patients with confirmed infection or recent confirmed infection with complications 
associated with COVID-19.  
Patients will be followed for safety and efficacy up to Day 28, with Day 1 being the day of randomization 
to assess safety. 
After assessing the risk of ARDS and satisfying all inclusion and exclusion criteria, the patient 
will be randomized to 5 mg LSALT peptide or blinded placebo to be given intravenously once
daily for a maximum of 14 days. Physical and respiratory examinations, vital signs, and adverse 
events will be recorded throughout the study, including Day 28 (EOS). Blood chemistries, 
hematology, coagulation, urinalysis, ECG, SARS-CoV-2 tests, eGFR, and chest x-ray (CXR) will 
be assessed at Day 1 (Screening/Baseline) prior to initiation of study drug, and on Day 3, EOT, 
and at EOS, as well as when clinically indicated. The ECG at EOS will only be obtained if 
clinically indicated. An additional CXR will be obtained at time of clinical improvement.
Cytokines/biomarkers and pharmacokinetics (PK) will be assessed at Day 1 (Screening/Baseline) 
prior to initiation of study drug, at 1 (mid-dose) and 2 hours (end of infusion) of drug therapy on 
Days 1, 3, EOT, and a single blood sample at EOS for cytokines/biomarkers only. Where 
applicable, a urinary pregnancy test will be obtained at Screening in women of childbearing 
potential. Questionnaires (APACHE II, SOFA) will be obtained at Baseline, Day 3, EOT, and 
EOS; venous blood gas (VBG) or HCO3 (bicarbonate) levels may be substituted for arterial blood 
gas (ABG) if it is considered standard-of-care (SOC) or in the patient’s best interest, and results 
in comparable APACHE II and SOFA scores. Other questionnaires (Berlin Definition and 
modified Medical Research Council Dyspnea Scale) will be assessed at Baseline, Day 3, EOT,
and EOS. IgG, IgA, and IgM antiviral antibodies will be collected at Baseline and EOS. Patients 
will be maintained on the SOC per institutional guidelines, including prophylaxis or treatment of 
VTE, throughout the study.  
A Data and Safety Monitoring Board (DSMB) will evaluate patients on a continuing basis for 
primarily safety assessments. Per the DSMB Charter, the DSMB will meet at least monthly if not 
more frequently based upon enrollment throughout the study period. 
NUMBER OF PATIENTS (PLANNED):  Thirty (30) patients will be randomized to active 
drug (LSALT peptide) and 30 patients will be randomized to matching placebo. This study will 
be third-party blind with only the Pharmacist at the site unblinded for the purpose of preparing 
drug/placebo for injection.  


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DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: 
Key Inclusion Criteria: 
Eligible patients must fulfill the following inclusion criteria: 
1. Male and female hospitalized patients between 18 and 80 years of age at time of consent. 
2. Clinical and laboratory diagnosis of COVID-19 infection. Patients must be positive for the 
SARS-CoV-2 by Real-Time Reverse Transcriptase (RT)-PCR Diagnostic Panel or have an 
existing complication secondary to SARS-CoV-2 infection which was positive within 2 
weeks of entry into the study. Further, patients must have at least two of the following three 
symptoms: 
 Fever (oral temperature ≥ 100.4 °F [> 38 °C]) with or without chills 
 Dyspnea or difficulty breathing (≥ 2 on mMRC dyspnea scale) 
 Nonproductive cough; 
 Or other signs and symptoms of established complications to SARS-CoV-2 infection 
(e.g., coagulopathy, cardiomyopathy, acute kidney injury [AKI], and/or acute liver injury) 
within the limits of Exclusion Criteria #8.   
3. Patients must present with moderate to severe illness as defined below: 
 Moderate illness: Patients who have evidence of lower respiratory disease by clinical 
assessment or imaging and an oxygen saturation (SpO2) > 93% on room air at sea level 
 Severe illness: Patients who have a respiratory frequency > 30 breaths per minute (bpm), 
SpO2 ≤ 93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction 
of inspired oxygen (PaO2/FiO2) < 300, or lung infiltrates > 50% (COVID-19 Treatment 
Guidelines Panel, 2020).   
4. APACHE II score < 20 or establishment of survivability of the patient beyond 48 hours 
following randomization. 
5. Therapies which have been shown to be beneficial and are included in standard COVID-19 
treatment guidelines (e.g., those of WHO or NIH, or institutional guidelines) are permitted. 
6. 
Sexually active women of child-bearing potential (WCBP) must be using a medically 
acceptable method of birth control throughout the study and for at least 1 day following the end 
of study, and have a negative urine pregnancy test at the Screening visit. A WCBP is defined
as a female who is biologically capable of becoming pregnant. A medically acceptable
method of birth control includes intrauterine devices in place for at least 3 months, surgical
sterilization, or the implant. In patients who are not sexually active, abstinence is an acceptable
form of birth control and urine will be tested per protocol. Women who are of nonchild-
bearing potential, i.e., post-menopause, must have this condition captured in their medical 
history. Pregnant women and nursing mothers are excluded from this study. 
7. 
Patient or Legally Authorized Representative (LAR) is available and willing to give written 
informed consent, after being properly informed of the nature and risks of the study and prior 
to engaging in any study-related procedures. 
 


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Key Exclusion Criteria: 
The presence of any of the following excludes a patient from study enrollment: 
1. Known sensitivity, allergy, or previous exposure to LSALT peptide. 
2. Exposure to any investigational drug or device <90 days prior to entry into study.  
3. Treatment with immunomodulators or immunosuppressant drugs, including but not limited 
to IL-6 inhibitors, TNF inhibitors, anti-IL-1 immunomodulators, and JAK inhibitors within 
five half-lives or 30 days (whichever is longer) prior to randomization and throughout the 
study period. However, should any of these treatments become SOC and incorporated into 
clinical treatment guidelines (e.g., those of WHO or NIH, or institutional guidelines), the 
treatment is permitted. Further, low-dose oral prednisone (≤ 20 mg/day) and inhaled steroids 
(e.g., for treatment of asthma) are allowed in the study. 
4. Anticipated transfer to another hospital or medical center within 72 hours, which is not a 
study site. 
5. Uncontrolled or poorly-treated active hepatitis B (HBV), hepatitis C (HepC), or HIV 
infection. Those subjects who are positive for HBV, HepC, or HIV but are well-controlled 
with low viral loads are allowed to participate in the study: 
 HBV low viral load defined as <20,000 IU/mL 
 HepC low viral load defined as <800,000 IU/mL 
 HIV low viral load defined as <5000 copies/mL.   
6. Participation in another drug or device study at any time during this study, for example: 
 Ulinastatin 200,000 IU or greater 
 High dose intravenous Vitamin C 
 Budesonide and formoterol  
 Bevacizumab to prevent ARDS 
 Dornase alfa to reduce hypoxemia in ventilated trauma patients. 
7. As indicated in the inclusion criteria, pregnant female patients are excluded from study. 
Further, female patients who are nursing are excluded from study.   
8. Has any medical condition considered to be clinically significant and could potentially affect 
patient safety or study outcome, including but not limited to:  
 Acute or chronic kidney disease (stage-4 or -5 renal impairment; eGFR<30 mL/min/1.73 
m2 or hemodialysis) 
 End-stage malignancy undergoing treatment 
 Immunocompromised patients or those with medical/surgical conditions (e.g., solid organ 
transplantation) which require chronic immunosuppression 


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 Chronic hematologic disease which, in the opinion of the PI, prohibits the patient from 
entering into study 
 Acute liver injury with AST and/or ALT levels greater than 3x ULN, unless recent injury 
(within 2 weeks) likely due to COVID-19 infection 
 History of coagulopathy of unknown etiology, as defined by abnormal ACT (only if part 
of SOC), aPTT, and/or PT/INR values at least 2-fold outside normal limits, and currently 
present at screening, and/or 
 End-stage lung disease, acute lung injury, very severe chronic obstructive pulmonary 
disease (COPD) as assessed by the GOLD criteria (GOLD Stage IV), or mechanical 
ventilation. 
TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION:   
LSALT peptide or an equivalent volume of commercially-available 0.9% sodium chloride (saline) 
solution to a volume of 100 mL mini-IV bag by an unblinded Pharmacist or designate. The drug 
will be infused into the patient through a peripheral 18, 20, or 22 g intravenous catheter over 2 
hours and under the supervision of the Principal Investigator. Study drug may also be administered 
through a central line.  Study drug will be administered once daily at a consistent time throughout 
the study. 
DURATION OF TREATMENT:  Maximum of 14 days. 
DISCONTINUATION FROM TREATMENT: 
Reasons for permanent discontinuation of treatment include the following: 
 Patient experiences two or more Grade 2 toxicities or one or more Grade 3 or 4 toxicity 
considered by the PI to be associated with LSALT peptide treatment (CTCAE v5.0, 2017)
 Patient requests to discontinue treatment or patient withdrawal of consent 
 PI considers that it is not in the best interest of the patient to continue treatment due to an 
adverse event.  
 Protocol deviation requiring discontinuation of study treatment for safety reasons, and/or 
 Pregnancy. 
Patients who discontinue treatment for any reason (except withdrawal of consent from study 
participation) will not be discontinued from the study and will continue to be followed for all 
assessments until Day 28, or if not possible then for all assessments necessary to determine the 
value of the primary endpoint at Day 28.  
EFFICACY ENDPOINTS: 


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Primary efficacy endpoint: 
 To evaluate the proportion of subjects alive and free of respiratory failure (e.g., need for 
non-invasive or invasive mechanical ventilation, high flow oxygen [≥ 6 L/minute], or 
ECMO) and free of the need for continued renal replacement therapy (RRT) on Day 28. 
The need for continued RRT at Day 28 will be defined as either dialysis in the past 3 days 
(Day 26, 27, or 28) or an eGFR on Day 28 <10 mL/min/1.73 m2.     
Secondary efficacy endpoints include: 
 All-cause mortality 
 The presence and severity of ARDS as an ordinal outcome of the proportion of patients 
who have none, mild, moderate, or severe ARDS  
 Time to each of mild, moderate, and severe ARDS 
 The number of ventilation-free days and ECMO-free days 
 Time on nasal canula or oxygen mask 
 Length of stay in ICU and hospital (admission to discharge)  
 Virologic clearance rate  
 Worst PaO2/FiO2 ratio following enrollment  
 Change in PaO2/FiO2 ratio 
 Vasopressor-free days 
 Change from maximal radiographic damage to EOT 
 Change in baseline mMRC score 
 Change in APACHE II score 
 Proportion of patients with extrapulmonary organ dysfunction using the daily SOFA score
 Change in liver function tests (ALT, AST, total bilirubin) 
 Change in renal function tests (SCr, eGFR) 
 Change in hs-troponin levels  
 Change in ACT, aPTT, and/or PT/INR values 
 Change in antiviral IgG, IgA, and IgM levels. 
Health Outcomes endpoint: 
 Total healthcare costs from admission to discharge between treatment groups. 
Exploratory Endpoints: 
  Change in serum cytokines including IL-1α, IL-1ß, and ferritin levels, as well as other 
exploratory biomarkers drawn at the same time as LSALT peptide concentrations. 
 Change in baseline antiviral immunoglobulins (IgG, IgM, IgA) at EOS.  


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SAFETY ENDPOINTS: 
 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory tests 
 Physical examinations 
 Vital signs 
 12-lead electrocardiogram 
 Radiologic findings  
PHARMACOKINETICS (PK):  Blood samples will be obtained at Baseline prior to the start 
of drug infusion on Day 1, then midpoint (1 hour after start of infusion), and immediately 
following the daily 2-hour infusions on Days 1, 3, and at EOT regardless of active or placebo 
therapy. These blood samples will be analyzed for parent LSALT peptide and associated 
fragments (metabolites). Cytokines will be measured at the same times to assess relationship 
between drug concentrations and cytokine levels. 
STATISTICAL METHODS:   
Sample Size:  Sixty subjects are planned for enrollment (randomized and treated) in this study. 
Efficacy Analyses:  Continuous variables will be summarized with descriptive statistics (the 
number of non‑missing values [n], mean, median, standard deviation [SD], minimum, and 
maximum). All categorical variables will be summarized with frequency counts and percentages, 
as applicable. Time to event variables will be summarized using Kaplan-Meier survival curves 
and compared between treatment groups using either Log-rank tests or Cox’s Proportional 
Hazard model adjusting for baseline covariates, as necessary.  For continuous variables assessed 
at multiple time points, a Mixed Model Repeated Measures (MMRM) approach will be used or 
Analysis of Covariance (ANCOVA) if assessed at a single time point post-baseline. For 
categorical endpoints Cochran-Mantel-Haenszel (CMH) methods will be used, or a logistic 
regression approach, in the case of continuous covariates. The primary efficacy analysis 
population will be the Full Analysis Set (FAS), which will include all subjects randomized who 
receive any part of at least one infusion of randomized treatment, assigned to treatment group as 
randomized.   
Additional details regarding precise endpoint definitions (including transformations, as 
applicable), analysis model specifications and α-level control for primary and important 
secondary endpoints associated with multiplicity will be provided in a separate statistical analysis 
plan (SAP), to be finalized prior to unblinding the study.     
Although significant missing data with respect to the primary endpoint is not anticipated for a 
study of this duration (due to the nature of the endpoint), methods for handling missing data and 
intercurrent events, including for secondary endpoints will be specified in the SAP. These 
methods will be consistent with missing data due to death as having a worst possible outcome.   


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Safety Analysis: 
All patients randomized and who received any part of at least one infusion of randomized 
treatment will be evaluated for safety according to the treatment actually received. The safety 
analyses will include evaluation of the incidence of treatment-emergent AEs, SAEs, and AEs 
leading to discontinuation of study treatment tabulated by Overall, System Organ Class, and 
Preferred Term using the MedDRA coding system. Additional tables with AEs by severity and 
relationship to drug as assessed by the PI will be presented. Laboratory data, vital signs, radiologic 
evidence, drug and cytokine concentrations, and ECGs assessments will be evaluated over time 
on study using descriptive statistics, including changes from baseline. Shift analyses of relevant 
clinical laboratory parameters will be produced showing shifts across low, normal, and high 
categories. 
 
 


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DOCUMENT APPROVAL 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements. 
ARCH BIOPARTNERS REPRESENTATIVE 
 
___________________________________________ 
 
_______________________ 
Signature 
Daniel A. Muruve, MD 
 
 
 
 
 
Date 17-March-2021 
 
PRINCIPAL INVESTIGATOR 
 
___________________________________________ 
 
___18-March-2021_______ 
Signature 
 
 
 
 
 
 
 
Date 
Print Name:  __Alain Tremblay_______ 
 


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TABLE OF CONTENTS 
 
SYNOPSIS .......................................................................................................................................2 
1 
LIST OF ABBREVIATIONS.................................................................................................14 
2 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS ........17 
 Institutional Review Board (IRB) or Ethics Committee (EC) ................................................17 
 Ethical Conduct of the Study ..................................................................................................17 
 Patient Information and Consent ............................................................................................17 
3 
INTRODUCTION ..................................................................................................................18 
 COVID-19 Background ..........................................................................................................18 
 Acute Respiratory Distress Syndrome ....................................................................................19 
 Scoring systems ......................................................................................................24 
 LSALT peptide .......................................................................................................................25 
 Inflammation and Organ Injury ..............................................................................25 
 Pre-Clinical Data for Dipeptidase-I and LSALT Peptide in AKI ..........................27 
 Drug Metabolism and Pharmacokinetics ................................................................29 
 Toxicology and Safety ............................................................................................29 
 Preliminary Safety in Humans ................................................................................31 
 Pharmacokinetics ....................................................................................................32 
 Study Rationale .......................................................................................................................32 
 Dose Justification ....................................................................................................................33 
4 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................34 
 Study Objectives .....................................................................................................................34 
 Primary Objective ...................................................................................................34 
 Secondary Objectives .............................................................................................34 
 Health Outcomes Objective ....................................................................................35 
 Exploratory Objectives ...........................................................................................35 
 Study Endpoints ......................................................................................................................35 
 Primary Efficacy Endpoint .....................................................................................35 
 Secondary Efficacy Endpoints ................................................................................35 
 Health Outcomes endpoint: ....................................................................................36 
 Exploratory Endpoints: ...........................................................................................36 
 Safety Endpoints .....................................................................................................36 
5 
INVESTIGATIONAL PLAN .................................................................................................36 
 Overall Study Design and Plan – Description ........................................................................36 
 Number of Patients (Planned) .................................................................................................37 
 Discussion of Study Design ....................................................................................................38 
 Selection of Study Population ................................................................................................38 
 Inclusion Criteria ....................................................................................................38 
 Exclusion Criteria ...................................................................................................39 
 Removal of Patient from Therapy ..........................................................................40 
6 
STUDY PRODUCT ...............................................................................................................41 
 Study Medication Supply .......................................................................................................41 


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 Description and Formulation of Study Product ......................................................41 
 Study Drug Dosage and Preparation ......................................................................41 
 Pharmacy records ...................................................................................................41 
 Conditions for Storage and Use ..............................................................................41 
 Study Drug Administration.....................................................................................................42 
 Patient Numbering ..................................................................................................42 
 Method of Assigning Patients to Treatment Groups ..............................................42 
 Dispensing, Compliance and Accountability .........................................................42 
 Prior and Concomitant Therapy ..............................................................................................43 
7 
EFFICACY AND SAFETY ASSESSMENTS ......................................................................43 
 Efficacy Assessments .............................................................................................................43 
 Primary Efficacy Endpoint .....................................................................................43 
 Secondary Efficacy Endpoints ................................................................................43 
 Health Outcomes endpoint .....................................................................................44 
 Exploratory Endpoints ............................................................................................44 
 Pharmacokinetic Variables .....................................................................................................45 
 Safety Assessment ..................................................................................................................45 
 Adverse Events .......................................................................................................45 
 Other Assessments ..................................................................................................48 
8 
STUDY PROCEDURES AND FLOW CHART ...................................................................50 
 Study Flow Chart ....................................................................................................................50 
 Study Visits .............................................................................................................................51 
 Screening (Day 1a) .................................................................................................51 
 Baseline Visit (Day 1b) ..........................................................................................51 
 Treatment Period (Days 2 – 14 mornings) .............................................................51 
 End of Treatment (EOT) .........................................................................................53 
 End of Study (Day 28 EOS ± 3 days) .....................................................................53 
 Premature Withdrawal / Early Termination Visit ...................................................53 
 Unscheduled Visits .................................................................................................53 
 Appropriateness of Measurements .........................................................................54 
 Data Quality Assurance ..........................................................................................54 
9 
STATISTICAL METHODS PLANNED AND SAMPLE SIZE ...........................................54 
 Determination of Sample Size ................................................................................................54 
 Patient Populations .................................................................................................................54 
 Full Analysis Set (FAS) ..........................................................................................54 
 Per Protocol (PP) Population ..................................................................................54 
 Safety Population ....................................................................................................54 
 Statistical Methods ..................................................................................................................54 
 Demographic, Medical, and Disease History .........................................................55 
 Efficacy Analyses ...................................................................................................55 
 Pharmacokinetic Analysis ......................................................................................55 
 Safety Analysis .......................................................................................................55 
 Interim Analysis .....................................................................................................56 
 Study Stopping Rules .............................................................................................56 
 Missing Data ...........................................................................................................57 


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10 QUALITY CONTROL AND QUALITY ASSURANCE .....................................................57 
 Source Data and Records ........................................................................................................57 
 Reporting of Results ...............................................................................................................57 
 Confidentiality of Patient Data ...............................................................................................58 
11 REPORTING AND PUBLICATION .....................................................................................58 
 Confidentiality of Study Data .................................................................................................58 
12 REFERENCES .......................................................................................................................59 
13 APPENDICES ........................................................................................................................69 
 Appendix 1.  Bottle Label .......................................................................................................69 
 Appendix 2.  Clinical Laboratory Tests ..................................................................................71 
 Appendix 3.  Berlin Definition ...............................................................................................72 
 Appendix 4.  Sequential Organ Failure Assessment (SOFA) score .......................................73 
 Appendix 5.  Modified Medical Research Council (mMRC) Dyspnea Scale ........................74 
 Appendix 6.  Acute Physiology and Chronic Health Evaluation II score ..............................75 
 
TABLE OF FIGURES 
Figure 1.  Human neutrophils bound DPEP-1 COS1 monolayers with/without LSALT ..............21 
Figure 2.  LSALT peptide (green) binding to cells expressing DPEP1, DPEP2, DPEP3 .............21 
Figure 3.  Respiratory system compliance is associated with right to left shunt fraction..............23 
Figure 4.  Graphic Illustration of Neutrophils Binding to DPEP-1. ..............................................26 
Figure 5.  Intact LSALT peptide 5 mg single and multiple dose plasma concentrations ..............32 
Figure 6:  Vial Labels ....................................................................................................................69 
Figure 7:  Outside Carton Labels ...................................................................................................70 
 
LIST OF TABLES 
Table 1. The Berlin Definition of Acute Respiratory Distress Syndrome .....................................24 
Table 2. The SOFA Score* ............................................................................................................25 
 
 


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1 
LIST OF ABBREVIATIONS 
ABG
Arterial blood gas
ACT
Activated clotting (coagulation) time
AE
Adverse event
AECC
American–European Consensus Conference 
AKI
Acute kidney injury
ANCOVA
Analysis of covariance
APACHE II
Acute Physiology and Chronic Health Evaluation II
aPTT
Activated partial thromboplastin time
ARDS
Acute respiratory distress syndrome
AUC0-∞
Area under the concentration-time curve from 0 → ∞
BMI
Body mass index
CDC
Centers for Disease Control & Prevention
CHF
Congestive heart failure
Cmax
Maximal concentration
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstruction pulmonary disease
COS-1
CV-1 in origin and carrying SV40 genetic material
CRF
Case report form
CRO
Contract research organization
DM
Diabetes mellitus
DPEP-1
Dipeptidase-1
DSMB
Data and safety monitoring board
ECG
Electrocardiogram
ECMO
Extracorporeal membrane oxygenation
eCRF
Electronic Case Report Form
EC
Ethics Committee
eGFR
Estimated glomerular filtration rate
EOS
End of study
EOT
End of treatment
FAS
Full analysis set
FDA
Food and Drug Administration
FiO2
Fraction of inspired oxygen
GCP
Good Clinical Practice
HA
Hyaluronic acid
HBV
Hepatitis B virus
HED
Human equivalent dose
HepC
Hepatitis C virus
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
hs-troponin
Highly-sensitive troponin levels
ICF
Informed consent form
ICU
Intensive care unit


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IL-X
Interleukin X (e.g., IL-2 = interleukin 2)
IND
Investigational New Drug
IP-10
Interferon gamma-induced protein 10
IRB
Institutional Review Board
IRI
Ischemia/reperfusion injury
ITT
Intent-to-treat study population
IV 
Intravenous 
IWRS 
Interactive Web Response System (for randomization) 
LAR 
Legal authorized representative 
LIS 
Lung injury score 
LLN 
Lower limit of normal 
LPS 
Lipopolysaccharide 
MCP3 
Monocyte-chemotactic protein 3 
MedDRA 
Medical dictionary for regulatory activities 
MERS 
Middle East Respiratory Syndrome 
mITT 
Modified intent-to-treat study population 
mMRC 
Modified Medical Research Council 
MMRM 
Mixed Model Repeated Measures 
MOF 
Multiorgan failure 
MRTobs 
Mean residence time (observed) 
MTD 
Maximal tolerated dose 
PaO2 
Partial pressure of oxygen 
PECAM1 
Platelet and endothelial cell adhesion molecule 1 
PEEP 
Positive end-expiratory pressure 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PNGaseF 
Peptide:N-glycosidase F 
PO 
Oral (per os) 
PP 
Per protocol study population 
PT/INR 
Prothrombin time/International normalized ratio 
RRT 
Renal replacement therapy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SCr 
Serum creatinine 
SD 
Standard deviation 
SOC 
Standard-of-Care 
SOFA 
Sequential Organ Failure Assessment score 
SpO2 
Fraction of O2-saturated Hgb relative to total Hgb in blood 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
TEC 
Tubular epithelial cells 


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Tmax 
Time at Cmax (maximal concentration) 
TNFα 
Tumor necrosis factor – α  
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
VAS 
Visual analog scale 
VBG 
Venous blood gas 
VTE 
Venous thromboembolism 
WCBP 
Women of child-bearing potential 
WIS 
Working internal standard solution 
ZO-1 
Zonula occludens – 1  
 
 
 


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2 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS 
 
Institutional Review Board (IRB) or Ethics Committee (EC) 
An Institutional Review Board (IRB) or Ethics Committee (EC) will review the study protocol and 
any amendments. The IRB will also review the informed consent forms, their updates (if any), and 
any written materials given to the patients. A list of all IRBs and contact information will be 
included in the study report. 
 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, GCP, and applicable regulatory 
requirements. 
 
Patient Information and Consent 
The PI, or designate, will obtain a freely given written consent from each patient or Legal 
Authorized Representative (LAR) after an appropriate explanation of the aims, methods, 
anticipated benefits, potential hazards, and any other aspects of the study that are relevant to the 
patient's or LAR’s decision to participate. The consent forms must be signed and dated by the 
patient or LAR before he/she is exposed to any protocol-specific procedure. 
The PI, or designee, will explain that the patients are completely free to refuse to enter the study 
or to withdraw from it at any time, without any consequences for their further care and without the 
need to justify. 
The patient or the patient’s LAR will receive a copy of the patient information and the signed 
informed consent form(s). 
The patient or the patient’s LAR will be informed if new information becomes available that may 
be relevant to his/her willingness to continue participation in the study. 
Each patient or patient’s LAR will be informed that a monitor, in accordance with applicable 
regulatory requirements, may review the portions of their source records and source data related 
to the study. Data protection and confidentiality will be handled in compliance with local laws. 
 
 


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3 
INTRODUCTION 
 
COVID-19 Background 
Recently, a global outbreak of a novel coronavirus named Severe Acute Respiratory Coronavirus 
2 (SARS-CoV-2; also listed as 2019-nCoV in the literature) and the disease it produces named 
Coronavirus Disease 2019 (COVID-19), has infected 2,355,676 total cases with 162,032 deaths 
globally (19-April-2020; Johns Hopkins, 2020). Similar to influenza, COVID-19 presents with 
fever > 100 °F, dry cough, difficulty breathing, and fatigue, and, in severe cases, bilateral 
pneumonia (Wu and McGoogan, 2020; Jin et al, 2020). Diagnosis of COVID-19, or any 
coronavirus, is based on the symptoms and confirmed through laboratory testing. Human-to-
human transmission of COVID-19 has rapidly occurred, urging individuals to exercise social and 
physical distancing (e.g., 6 feet apart). Those who may be infected yet asymptomatic highlight the 
need to implement social distancing for all people (Ahmed et al, 2018; Lau et al, 2020). Recently, 
there are two FDA-approved treatments, chloroquine and hydroxychloroquine ± azithromycin, to 
treat SARS-CoV-2 under emergency use authorization (CDC, 2020a).  However, there is neither 
FDA-approved antiviral therapy nor a vaccine authorized to treat or protect against COVID-19, 
yet more than 300 studies have been initiated looking at dozens of promising therapeutic 
interventions (Mullard, 2020). Patients with severe symptoms should go directly to an emergency 
department or contact their primary care provider and likely will be hospitalized, in particular if 
community-acquired viral pneumonia is diagnosed (Grasselli et al, 2020). Criteria for progressive 
COVID-19 disease vs. disease improvement/stabilization include (Liu et al, 2020):  
 Age (66 vs. 37 years, U=4.932, P=0.001) 
 History of smoking (27.3% vs. 3.0%, χ2=9.291, P=0.018) 
 Maximum body temperature at admission (38.2 °F vs. 37.5 °F, U=2.057, P=0.027) 
 Proportion with respiratory failure (54.5% vs. 20.9%, χ2=5.611, P=0.028) and respiratory 
rate (34 vs. 24 breaths/minute, U=4.030, P=0.004) 
 Receive high-level respiratory support (χ2=16.01, P=0.018) 
 C-reactive protein (38.9 vs. 10.6 mg/L, U=1.315, P=0.024) 
 Albumin (36.62 vs. 41.27 g/L, U=2.843, P=0.006). 
Others, including one report of 99 cases of COVID-19 in Wuhan China and another of 201 patients 
in the same area, found similar signs and symptoms to diagnose community-acquired viral 
pneumonia (Chen et al, 2020; Huang et al, 2020; Wu et al, 2020). 
Due to rapid escalation of this pandemic, clinicians and scientists have initiated experimental 
treatments for prevention and treatment of COVID-19. Raoult and colleagues recently described 
their findings on the effects of 600 mg hydroxychloroquine daily in attenuating the symptoms of 
COVID-19 and reducing viral load (Gautret et al, 2020). Depending upon the clinical picture of 
each patient, at the clinician’s discretion, azithromycin (Z-Pak 1500 mg over 5 days) was added to 
the regimen in this single arm, open-label, four site study at the Méditerranée Infection University 
Hospital Institute. A total of 20 hospitalized patients with confirmed COVID-19 infection were 
treated with hydroxychloroquine for up to 10 days and compared with 16 control patients. At Day 
6, 70% of hydroxychloroquine-treated patients were eradicated compared with 12.5% in the 


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control group (P=0.001). Remdesivir, an investigational antiviral with activity against SARS-
CoV-2 (Wang et al, 2020), manufactured by Gilead and undergoing compassionate trials, is being 
studied in a large ongoing clinical trial; cohorts studying the effects of individual and combination 
drugs, such as hydroxychloroquine, lopinavir/ritonavir, and interferon-ß-1A, are also being studied 
in this prospective, multinational trial involving 3100 patients (NCT04315948). Remdesivir was 
very recently authorized by the FDA on May 1, 2020 for the emergency use in the treatment of 
COVID-19 (FDA, 2020). 
There is also an ongoing post-exposure prophylaxis study with hydroxychloroquine and 
azithromycin (NCT04308668). In many cases (e.g., vitamin C infusions for the treatment of severe 
2019-nCoV pneumonia; NCT04264533), success of the treatments will not be known for several 
months to years.  
Despite these preliminary and uncontrolled reports of potential efficacy, none of the potential 
antiviral therapies under consideration are proven until proper placebo-controlled studies are 
completed. Furthermore, it is becoming apparent that once cytokine release syndrome and 
respiratory failure occur in COVID-19 patients, these events are believed to be largely virus-
independent and caused primarily by excessive and uncontrolled host immune/inflammatory 
responses (Moore and June, 2020; Henderson et al, 2020). A large proportion of patients with 
critical illness related to viral pneumonia still die despite appropriate antiviral therapy (Ayres, 
2020). Furthermore, uncontrolled host immune responses, also known as cytokine storms, drive 
the need for critical care, ventilatory support, and ensuing mortality from COVID-19.  
 
There is mounting evidence that organs other than, or in addition to lungs are damaged by COVID-
19 (Zhai et al, 2020; Klok et al, 2020; Shi et al, 2020). A recent report from 13 hospitals on Long 
Island NY involving 5,449 patients over a 5-week period highlights this issue (Hirsch et al, 2020). 
The vast majority of patients were diagnosed with acute kidney injury (AKI) within 1 month of 
mechanical ventilation in SARS-CoV-2-infected patients. The odds ratio for need for ventilation 
and AKI was 10.7. At the time of the publication, 780 (39%) were still admitted in the hospitals, 
519 (26%) had been discharged, and 694 (35%) had died. Other organs such as the liver, 
gastrointestinal tract, and the heart have been similarly compromised in COVID-19 patients. Thus, 
there is an urgent need to devise approaches to complement antiviral therapies to control the host 
immune/inflammatory response. 
 
Acute Respiratory Distress Syndrome 
Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory response to 
triggers such as infections and sepsis, resulting in acute lung injury (ALI) and respiratory failure 
(Jenne and Kubes, 2015; Thompson et al, 2017). The prevalence of ARDS in 459 ICUs from 50 
countries was 10.4% (3022 ARDS patients of 29,144 ICU patients; Bellani et al, 2016), with more 
than 75% being diagnosed with ARDS in the first 48 hours of admission to the ICU. This 
prevalence was divided into mild (30.9%), moderate ARDS (46.6%), and severe ARDS (23.4%). 
Hospital mortality was 34.9%, 40.3%, and 46.1% for those with mild, moderate, and severe ARDS, 
respectively. Others have reported a similar mortality rate (Cochi et al, 2016). The incidence of 
ARDS was highest in the United States (80.1 cases per 100,000 person-years) and lowest in Iceland 


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(3.65 cases per 100,000 person-years), likely due to patient characteristics including gender, race, 
and age, and early recognition of the signs and symptoms of ARDS (Pham and Rubenfield, 2017; 
Eworuke et al, 2018).  
Acute respiratory distress syndrome (ARDS) developed in 17–29% of hospitalized patients with 
COVID-19, and secondary infections developed in 10% (Huang et al, 2020; Chen et al, 2020). In 
one report, the median time from symptom onset to ARDS was 8 days (Wang et al, 2020). Among 
201 patients with confirmed COVID-19, 41.8% developed ARDS, and among these patients, 
52.4% died (Wu et al, 2020). Comorbidities, such as hypertension and diabetes, as well as those 
presenting with dyspnea, were found in patients who developed ARDS compared with those who 
did not. Risk factors for ARDS in this special population who died from ARDS-related disease 
were older age, neutrophilia, and underlying or evolving organ and coagulation dysfunction.  
The cascade of pattern recognition receptor activation, upregulation of pro-inflammatory 
cytokines, and ultimately recruitment of leukocytes to the affected tissue, in this case alveoli, 
results in the release of cytotoxins, ensuing cytotoxicity and cellular death. A number of 
interventions have been implemented over the last decade including (1) positive end-expiratory 
pressure (PEEP) to keep alveoli open for oxygenation of the deoxygenated blood, (2) induction of 
paralysis in the patient maintained on a lung-protective mechanical ventilator, and (3) prone 
positioning (patient lying face-down) for 16–18 hours per day to prevent primary aspiration (Festic 
et al, 2015; Albert, 2012). All interventions have reduced the mortality from 41% to 16%, however, 
these measures are supportive, at best, but at least reduce mortality in patients with ARDS. There 
remains no therapeutic modality to prevent the development of ARDS nor target its specific 
pathophysiology once diagnosed (Rawal et al, 2018). Trials with aspirin and inhaled 
budesonide/formoterol, amongst others, have been studied but despite some advances, mortality 
and morbidity remain high (Panka et al, 2017; Pais et al, 2018). Since 2010, ARDS mortality rates 
of in-hospital, ICU, 28/30-day, and 60-day mortality were 45, 38, 30, and 32%, respectively (Máca 
et al, 2017); thus, at least a third of patients with ARDS do not survive hospitalization. Others 
(Bellani et al, 2016) have shown mortality rates as high as 46% for those with severe ARDS, 
defined by a PaO2/FIO2 <100 mmHg based on the Berlin Definition (Ranieri et al, 2012).  
A keystone to preventing and managing ARDS is understanding the interaction between 
leukocytes, primarily neutrophils, and endothelial cells which line the vascular lumen of the lung 
allowing the exchange of oxygen between alveoli and blood (Mammoto and Mammoto, 2019). As 
part of the endothelial glycocalyx, which on its own may be a target in the cascade of events related 
to ARDS (Porras et al, 2018; Ozolina et al, 2016), these small capillary vessels provide a critical 
pathway for delivery of oxygen, nutrients, and cellular components to local tissues while also 
eliminating waste products carbon dioxide and blood. The recruitment of leukocytes to the site of 
injury in the lung actually results in “friendly fire” since cytokines expressed and released by 
neutrophils in response to the damaged cells by the disease state (e.g., infection) also result in 
“bystander” cytotoxicity of previously normal tissue and end-organ damage (Narasaraju et al, 
2011; Collins et al, 2013). Further, interactions between neutrophils and inflammatory mediators 
at the site of damage result in increased stiffness of the neutrophil and inability to deform due to 
rearrangement of the cytoskeleton within the capillary bed, leading to vascular congestion and 
ischemia (Doerschuk, 2000; Williams and Chambers, 2014). 


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Discovered by Arch Biopartners scientists, dipeptidase-1 (DPEP-1) is a vascular adhesion receptor 
for recruitment of neutrophils and other immune responders to organs of pathogenic inflammation, 
including the lung, liver, and kidneys (Choudhury et al, 2019). Thus, DPEP-1 is a viable target for 
therapeutic intervention to halt attraction of neutrophils as well abrogate binding of the neutrophil 
to endothelial cells (Figure 1). The therapeutic intervention of the LSALT peptide is discussed 
later, but it specifically binds to DPEP-1 and not DPEP-2 nor DPEP-3 (Figure 2). More 
information is found in Section 3.3. 
Figure 1.  Human neutrophils bound DPEP-1 COS1 monolayers with/without LSALT 
 
Used with permission (Choudhury et al, 2019). 
Figure 2.  LSALT peptide (green) binding to cells expressing DPEP1, DPEP2, DPEP3 
 
Used with permission (Choudhury et al, 2019). 
There is no cure for ARDS, only patient supportive strategies (American Lung Association, 2020). 
Current therapies include lung-protective ventilation with lower tidal volumes, thereby reducing 
neutrophil accumulation in the alveoli and lower concentrations of IL-6, IL-8, and TNFα (Parsons 
et al, 2005; Ranieri et al, 1999). Extracorporeal membrane oxygenation (ECMO) is often used for 
severe ARDS to allow lung healing/repair and reverse respiratory failure (Peek et al, 2009). High-
frequency oscillatory ventilation, with its rapid delivery of low tidal volumes and a respiratory rate 
in the range of 60 to 900 breaths/minute, has also been utilized in ARDS patients to avoid 
complications found with traditional ventilators (Meyers et al, 2019; Chan et al, 2007).  Other 
measures are outlined in Rawal et al, 2018. All interventions do not prevent ARDS, rather stabilize 
any ongoing lung injury, and in some cases, reduce overall mortality (Saguil and Fargo, 2012).  
It is important to understand that multi-organ dysfunction associated with ARDS, such as acute 
kidney injury (AKI; Cheng et al, 2020; Martinez-Rojas et al, 2020), cardiomyopathies (Shi et al, 
2020; Akhmerov and Marban, 2020), VTE (Llitjos et al, 2020; Zhai et al, 2020), acute liver failure 
(Xu et al, 2020; Lee et al, 2020), amongst others also occur alone in COVID-19. Some reports 
accurately suggest that ARDS also arises from non-pulmonary conditions including acute 
 
 


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pancreatitis, sepsis, trauma, pneumonia, burns, elective surgery, and amniotic fluid embolisms 
(Fan et al, 2018; Cutts et al, 2016). A recent review of 357 patients with ARDS who did not have 
acute or chronic renal impairment prior to ARDS (an exclusion criteria for their primary analysis) 
revealed the following facts:  
 68.3% developed AKI of which half (48.4%) were stage III severe AKI  
 Median time of onset was 4 days 
 Higher BMI (> 30 kg/m2), history of DM, high SOFA score (3 – 4), and acidosis were risk 
factors for Stage III AKI (Panitchote et al, 2019).  
Others have shown similar results associating ARDS with the development of nephropathies (Liu 
et al, 2012; Tignanelli et al, 2018; Darmon et al, 2014). ARDS is also associated with acute liver 
failure which increases in severity as the severity of ARDS increases (Kallet et al, 2019). In this 
single-center retrospective study, 1747 patients with ARDS were evaluated for prevalence, 
severity, and mortality by organ system. Up to four nonpulmonary organ dysfunctions were 
common at the onset of ARDS: trauma-associated ARDS had the lowest mortality rate and 
decreased in prevalence with increasing ARDS severity. In contrast, aspiration-associated ARDS 
had the highest mortality rate, second only to sepsis, which increased in prevalence with increasing 
severity. COVID-19 has been linked to pulmonary damage through the angiotensin-converting 
enzyme 2 (ACE2), which is the primary receptor of SARS-CoV-2 (Yang et al, 2020). Since ACE2 
is extensively expressed in the vascular endothelial cells of the heart, kidney, liver, intestine, and 
testis, amongst others, it is hypothesized that coronavirus will bind to ACE2 in these organs as 
well, resulting in multiple organ failure secondary to activated neutrophils expressing cytokines 
(Varga et al, 2020; Fu et al, 2020; Henderson et al, 2020). 
Since late 2019, intensivists treating COVID-19 patients have identified acute lung injury which 
approximates ARDS, largely a result of activated neutrophils at the infected alveolar endothelial 
level. The Berlin definition of mild ARDS is 200 mmHg < PaO2/FiO2 ≤ 300 mmHg with PEEP or 
CPAP ≥ 5 cm H2O (Table 1; Donahoe, 2011). However, when supplemental oxygen is 
administered to a patient, there are ways to determine whether a VQ mismatch is the source of 
poor oxygenation or if there is a right to left shunt that is causative. The rule of thumb for 
oxygenation improvement is that for every 10% change in FiO2, there should be an accompanying 
increase in the arterial PaO2 of 7 mmHg. For example, a patient is receiving 50% FiO2 by facemask 
and due to a drop in pulse oximetry, the patient is then placed on 100% by non-rebreather (mask). 
The expected increase in PaO2 related to the 50% increase in FIO2 (50→100) should be 35 mmHg 
(7x5=35). If the increase in PaO2 is not at least or greater than 35 mmHg, then there is a right to 
left shunt (Figure 3), suggesting an increased risk of cellular anaerobic metabolism at end organ, 
which could lead to the need for intubation. 
The NIAID Ordinal Scale could capture this information: 1) Death; 2) Hospitalized, on invasive 
mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on 
non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental 
oxygen; 5) Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen – no longer 
requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home 
oxygen; 8) Not hospitalized, no limitations on activities.  Any change from scale #4 to scale #3 
would suggest worsening respiratory status and likely progression to ARDS. This would be the 


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ideal time for intervention to prevent ARDS, although this scale does not obviate clinical 
judgement and the decision may occur prior to scale #4.  
In COVID-19 patients, review of arterial blood gas data at the time of admission to the ICU and 
pre-intubation, suggest there is a signal of uncoupling of the lungs ability to augment oxygenation. 
This inability is multifactorial related to poor diffusion, VQ mismatch caused by viral pneumonia, 
and microvascular thrombosis resulting in right to left shunt physiology (Gattinoni et al, 2020; 
Figure 3). Augmented PEEP in this setting can be deleterious, due to inappropriate redistribution 
of cardiac output to areas of thrombosis or poor diffusion caused by damage to the capillaries 
infected by COVID-19 (Greenland et al, 2020; Gattinoni et al, 2020), although others continue 
with moderate to high levels of PEEP in these patients (Matthay et al, 2020; Poston et al, 2020; 
Alhazzani et al, 2020). 
Scientists are also exploring the role of neutrophil extracellular traps (NETs) in pulmonary disease, 
including ventilator-associated nosocomial pneumonia, community-acquired pneumonia, virus-
related acute lung injury, and pneumonia-related ARDS (Mikacenic et al, 2018; Ebrahimi et al, 
2018; Lefrançais et al, 2018; Bendib et al, 2019; Twaddell et al, 2019). Indeed, Bendib and 
colleagues speculate on the potential of NETs as therapeutic targets in ARDS (Bendib et al, 2019). 
The formation of NETs has been linked to disease severity and mortality, including recruitment of 
macrophages to the active site which secrete IL-1ß which in turn induces IL-6. All-together, the 
ensuing cytokine storm leads to respiratory decompensation and other untoward events (Zhu et al, 
2020; Barnes et al, 2020; Kaplan and Radic, 2012; Henderson et al, 2020).  
By halting the upstream neutrophil-associated cascade of events, LSALT peptide may be an option 
to more fully understand the therapeutic benefits of NETs clinically as well as harm to normal 
tissue and organs. Further research with patient-centric outcomes will be a focus of subsequent 
research with LSALT peptide. 
Figure 3.  Respiratory system compliance is associated with right to left shunt fraction 
 
A. Respiratory system compliance of 50.2 ± 14.3 mL/cmH2O (N=16 patients) 
B. Shunt fraction of 0.50 ± 0.11 (Used with permission, Gattinoni et al, 2020) 


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As discussed above, reports are emerging during this viral crisis that damage to the lungs are in 
part due to an evolving cytokine storm (Mehta et al, 2020; Ruan et al, 2020; Yang Y et al, 2020). 
Biomarkers such as the interleukins (specifically interleukin-1ß, IL-1ra, IL-6, IFNɤ, and TNFα, 
amongst others), interferon gamma-induced protein 10 (CXCL10, IP-10), and serum ferritin are 
elevated in patients with COVID-19 with evolving acute lung injury (Xu et al, 2020; Ye et al, 
2020). We will study the prognostic value of these biomarkers and their relevance to the severity 
of ARDS (Jiang et al, 2005; Liu et al, 2020) and COVID-19 (Zhang et al, 2020; Cao X, 2020). 
Our study is focused on COVID-19 pneumonia which, not surprisingly, had higher prevalence and 
greater mortality with increasing severity of ARDS of all nonpulmonary etiologies, likely due to 
increasing hypoxemia, fluid overload, and ongoing ischemia. We will also assess multiple organ 
dysfunction to more broadly evaluate viral damage. Clearly there is an unmet medical need to find 
a therapeutic intervention to prevent the onset of ARDS and other acute organ dysfunction in 
patients with COVID-19. 
 Scoring systems 
3.2.1.1 Berlin ARDS definition 
ARDS was first described by Ashbaugh and colleagues in 1967, describing a syndrome 
characterized by the acute onset of dyspnea, severe hypoxemia, diffuse lung infiltrates, and 
decreased lung parenchymal system compliance in the absence of evidence for congestive heart 
failure (Ashbaugh et al, 1967; Cutts et al, 2016). In 1988, Murray et al. introduced the Lung Injury 
Score (LIS), an assessment tool for ARDS, which incorporates four parameters on a scale of 0 → 
4: (1) ratio of PaO2 to FiO2, (2) total respiratory compliance, (3) level of PEEP, and (4) extent of 
radiologic infiltrates (Murray et al, 1988). Six years later, the American-European Consensus 
Conference (AECC) on ARDS defined ARDS as respiratory failure of acute onset with a 
PaO2/FiO2 ratio < 200 mmHg independent of PEEP, bilateral infiltrates on front chest x-ray, and 
a pulmonary capillary wedge pressure ≤ 18 mmHg or no evidence of left atrial hypertension 
(Bernard et al, 1994; Raghavendran and Napolitano, 2011).  
The AECC definition was readily adopted by clinical researchers and clinicians; however, issues 
with the original definition required some adjustments, including PaO2/FiO2 ratios adjusted for 
ventilator settings, increase reliability of the chest x-ray criteria, and distinguishing hydrostatic 
edema (Phua et al, 2008). The European Society of Intensive Care Medicine endorsed by the 
Society of Clinical Care Medicine and the American Thoracic Society gained consensus on new 
guidelines known as the Berlin Definition (Ranieri et al, 2012; Ferguson et al, 2012). The degree 
of hypoxemia divided the Berlin Definition into three categories (Table 1).  
Table 1. The Berlin Definition of Acute Respiratory Distress Syndrome 
Acute Respiratory Distress Syndrome (ARDS) 
Timing
Within 1 week of a known clinical insult or new/worsening respiratory symptoms 
Chest imaginga
Bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules 
Origin of edema 
Respiratory failure not fully explained by cardiac failure or fluid overload 
Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor 
present 
Oxygenationb 
 
    Mild
200 mmHg < PaO2/FiO2 ≤ 300 mmHg with PEEP or CPAP ≥ 5 cm H2Oc 


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    Moderate
100 mmHg < PaO2/FiO2 ≤ 200 mmHg with PEEP ≥ 5 cm H2O
    Severe
PaO2/FiO2 ≤ 100 mmHg with PEEP ≥ 5 cm H2O
aChest radiograph or computed tomography scan 
bIf altitude is >1000 m, the correction factor should be calculated as follows: [PaO2/FiO2 x (barometric pressure/760)] 
cThis may be delivered noninvasively in the mild acute respiratory distress syndrome group 
3.2.1.2 Sequential Organ Failure Assessment score (SOFA) 
There are many quantitative scoring instruments to assess the number and severity of multiple 
organ dysfunctions, including the Denver Postinjury Multiple Organ Failure score (Sauaia et al, 
2009), Marshall Multiple Organ Dysfunction Score (MODS; Marshall et al, 1995), and the 
Predisposition, Infection, Response, and Organ Failure (PIRO) Sepsis Classification System 
(Granja et al, 2013), amongst others.  The sequential organ failure assessment score (SOFA score; 
Table 2), previously known as the sepsis-related organ failure assessment score (Vincent et al, 
1996), is used to track a patient's status during the stay in an ICU to determine the extent of organ 
function or rate of failure. This score has been compared with the other scoring systems, and with 
few exceptions, results in better sensitivity, specificity, and a balance between the two for mortality 
and organ dysfunction (Hutchings et al, 2017; Granja et al, 2013; Fröhlich et al, 2016; Soo  et al, 
209; Ulvik et al, 2007). The SOFA score is based on six different scores, one each for the 
respiratory, cardiovascular, hepatic, coagulation, renal, and neurologic systems.  
Table 2. The SOFA Score*  
 
 
LSALT peptide  
 Inflammation and Organ Injury 
Inflammation is a common pathway that contributes to the pathogenesis of many diseases caused 
by infection, allograft rejection, hypoxia, and autoimmunity. Although inflammation is regulated 
Organ System, 
Measurement 
SOFA score 
 
0 
1 
2 
3 
4 
Respiration 
PaO2/FiO2 
NL 
< 400 
< 300 
< 200a 
< 100a 
Coagulation 
Platelets 
x103/mm3 
NL 
< 150 
< 100 
< 50 
< 20 
Liver 
Bilirubin, mg/dL 
(µmol/L) 
NL 
1.2 – 1.9 
(20 – 32) 
2.0 – 5.9 
(33 – 101) 
6.0 – 119  
> 12.0 
> 204 
Cardiovascular 
Hypotension 
NL 
MAP < 70 
mmHg 
Dopamine ≤5 or 
dobutamine 
(any dose)b 
Dopamine >5 or 
epinephrine ≤0.1 or 
norepinephrine ≤0.1 
Dopamine >15 or 
epinephrine >0.1 or 
norepinephrine 
>0.1 
Central Nervous System 
Glasgow Coma Scale 
NL 
13 – 14  
10 – 12  
6 – 9  
< 6 
Renal  
Creatinine mg/dL 
(µmol/L) or 
Urine output 
NL 
1.2 – 1.9 
(110 – 170) 
2.0 – 3.4 
(171 – 299) 
3.5 – 4.9 
(300 – 440) 
or <500 mL/day 
>5.0 
(>440) 
or <200 mL/day 
*Source: Vincent et al, 1996 
NL = Normal 
aWith respiratory support (e.g., ventilator) 
bAdrenergic agents administered for at least 1 hour (doses given are µg/kg/min) 


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by many complex biological processes and can be activated by numerous microbial and non-
microbial stimuli, a common framework of events exists regardless of disease context which 
includes activation of pattern recognition receptors, upregulation of pro-inflammatory cytokines, 
and recruitment of leukocytes to affected tissues (Kopf et al, 2010; Nourshargh and Alon, 2014; 
Takeuchi and Akira, 2010). The interactions between recruited leukocytes and endothelial cells 
has been studied in detail to understand the exact processes that allows immune cells to bind to 
and infiltrate into injured or infected tissues. Endothelial receptors for leukocyte adhesion, 
including various selectins (e.g., E-selectin), integrins and members of the immunoglobulin family 
(e.g., PECAM1), have been identified yet other unknown receptors remain. Although 
inflammation is beneficial in eliminating microorganisms, abnormal and damaged cells during 
disease, it can also cause organ dysfunction and failure due to an excessive or unrelenting response 
that involves the overproduction of cytokines, cytotoxicity, and cell death (Kuchroo et al, 2012). 
LSALT, a peptide drug with the sequence NH3-LSALTPSPSWLKYKAL-COOH, binds to 
dipeptidase-1 (DPEP-1) but does not inhibit its biologic enzymatic activity, potentially minimizing 
off-target or other adverse effects. LSALT peptide inhibits leukocyte recruitment in multiple 
experimental disease models through the direct inhibition of leukocyte adhesion to DPEP-1 present 
in lungs, kidney, and liver (Choudhury et al, 2019; Figure 4). DPEP-1 represents a new molecular 
pathway for leukocyte adhesion discovered by Arch Biopartners scientists. 
Figure 4.  Graphic Illustration of Neutrophils Binding to DPEP-1. 
 
Used with permission (Choudhury et al, 2019). 
LSALT peptide was discovered by using an unbiased in vivo approach where a combinatorial 
phage display library17 was used to isolate specific peptide-displaying-phage that homed to the 
liver and lungs of mice during an inflammatory condition. In brief, neutrophils were isolated from 
C57/BL6 mice. RNA isolated from these neutrophils were then converted into cDNA. These 


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neutrophil-derived cDNA’s were then fused into the coat protein gene of T7 phage thereby 
generating a library called T7N. This resulted in a random pool of T7 phages which presented 
various neutrophil peptides on the surface. These phage display libraries were subtracted by 
depleting the phage that bound to background cells or primary murine unstimulated lung 
endothelium. Unbound phage were then isolated from the culture and injected into neutrophil-
depleted mice after lipopolysaccharide (LPS) stimulation. Phage that bound to the lung and liver 
endothelium were recovered, isolated and re-injected into another group of mice to enrich for the 
specific homing phage. This process was repeated five times in vivo to identify enriched phage 
clones that specifically homed to the lungs and liver. After isolation, phage were screened on the 
basis of their ability to inhibit neutrophil recruitment in the liver sinusoids in the presence of LPS 
by intravital microscopy. A specific peptide-displaying phage was isolated that inhibited the 
adhesion of neutrophils in the liver sinusoids in response to LPS in vivo. This phage subclone 
expressed the peptide NH3-LSALTPSPSWLKYKAL-COOH and designated as LSALT peptide.  
 Pre-Clinical Data for Dipeptidase-I and LSALT Peptide in AKI 
3.3.2.1 DPEP-1 expression and function in kidney, liver, and lung  
DPEP-1 expression and localization were characterized in renal tubular epithelial cells (TEC) 
cultured from human nephrectomy tissue samples were labeled with either zonula occludens-1 
(ZO-1), a tight junction protein found on TEC, and DPEP-1. Confocal microscopy confirmed the 
expression of DPEP-1 on the surface of TEC. Additional characterization of DPEP-1 using 
immunohistochemical analysis revealed high expression levels in mouse kidney epithelium and 
endothelium as well as expression in lung and liver endothelium. Similar expression patterns have 
been confirmed in human lung, liver, and kidney. Using immunoblotting, DPEP-1 expression was 
found in both total kidney lysates and isolated TEC which confirmed the microscopy findings. 
Although DPEP-1 is predicted to have a size of 42kDa, a 55kDa DPEP-1 protein was also detected 
due to the presence of a GPI anchor as well as post-translational glycosylation as demonstrated by 
the effects of PNGaseF. Functional activity of DPEP-1 was determined in various samples using 
fluorescent enzyme activity assay that demonstrated high levels of dipeptidase expression or 
activity in both human and mouse lung, liver, and kidney tissue. 
3.3.2.2 Specificity of LSALT Peptide binding to DPEP-1  
DPEP-1 as a binding target for LSALT peptide was confirmed by overexpressing rat, canine, or 
human DPEP-1 in Cos-1 cells and treated with fluorescently labeled LSALT peptide. Analysis 
with fluorescent confocal microscopy of these cells demonstrated that LSALT peptide was bound 
only to cells expressing DPEP-1. This specific interaction was confirmed using a biotin-labeled 
LSALT peptide immunoprecipitation assay of DPEP-1. Total protein lysates from DPEP-1 
overexpressing cells were treated with biotin-labeled LSALT peptide and the protein complex was 
pulled down with neutravidin conjugated beads before analysis by immunoblotting using anti-
DPEP-1 antibody. Immunoblot analysis revealed that DPEP-1 interacted with LSALT peptide but 
not non-specific control peptide indicating specificity of LSALT peptide binding to DPEP-1. 
To ensure LSALT peptide would not target similar proteins, other members of the dipeptidase 
family were also assessed. Human DPEP-1, DPEP-2, and DPEP-3 were transiently expressed in 


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Cos-1 cells before being treated with fluorescent-labeled LSALT peptide. Analysis by fluorescent 
microscopy revealed that LSALT peptide bound to DPEP-1 expressing cells but not DPEP-2 or 
DPEP-3 expressing cells. 
DPEP-1 enzyme activity was tested using a fluorometric assay originally described by Heywood 
and Hooper in 1995 (Heywood and Hooper, 1995). Enzymatic activity of DPEP-1 was confirmed 
in lysates from human, rat, and mouse derived DPEP-1 expressing cells. Cilastatin or 
penicillamine, known functional inhibitors of DPEP-1, abrogated the enzymatic activity of both 
human and mouse DPEP-1. When cells expressing human DPEP-1 were treated with LSALT 
peptide, no significant decrease in DPEP-1 enzymatic activity was detected indicating that LSALT 
peptide binds to DPEP-1 but does not inhibit its enzymatic activity.  
To determine whether the catalytic region of DPEP-1 was required for LSALT peptide interaction, 
a catalytically inert human DPEP-1 (E141D) was transiently expressed in Cos-1 cells and treated 
with fluorescent LSALT peptide. Analysis by fluorescent microscopy demonstrated removal of 
catalytic activity had no effect on LSALT peptide binding on cells as compared to normal DPEP-
1 or negative mutant controls (H215). Loss of enzymatic activity in the catalytically inert DPEP-
1 (E>D) was confirmed using the fluorometric assay (Gaber et al, 2011). Protein expression level 
of catalytically inert DPEP-1 (E141D) in Cos-1 cells was also confirmed by immunoblotting. 
In a human in vitro static neutrophil adhesion assay, LSALT peptide inhibited neutrophil adhesion 
to activated endothelium at concentrations as low as 1 μg/mL. 
3.3.2.3 DPEP-1 plays a role in renal ischemia reperfusion injury 
Renal ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). A reduction 
in renal blood flow followed by reperfusion during patient recovery occurs in numerous clinical 
contexts including cardiac surgery and kidney transplantation. Renal IRI results in inflammation 
that includes leukocyte infiltration, renal hemorrhage, and tubular cell necrosis. Inflammation 
plays a significant role in the pathophysiology of renal IRI, however there are currently no 
therapeutic strategies in human AKI that directly target this pathway. To determine the potential 
impact of LSALT peptide in renal IRI, a survival model of murine renal IRI was employed where 
a vascular clamp is placed on the renal pedicle of a unilateral nephrectomized mouse to induce 
warm ischemia and subsequently released to induce reperfusion injury. A significant inflammatory 
response can be observed in the kidney as early as 2 hours of renal IRI with large numbers of 
monocytes and neutrophils infiltrating into the tubular/interstitial space. Furthermore, because of 
immune cell infiltration and extravasation, loss of endothelial integrity can also be observed as 
blood vessels become leaky and no longer retain their web-like organization. 
Phenotypically, mice undergoing renal IRI developed oliguria/anuria over the course of 2 days due 
to loss of kidney function measured as an increase in serum creatinine (SCr). Treatment of mice 
with LSALT peptide (10 µg/kg) prior to renal IRI ameliorated AKI allowing mice to maintain 
normal urine output and preserving renal function. A similar effect on AKI was also seen with 
cilastatin (35 µg/kg), a chemical inhibitor of DPEP-1, albeit less effective than LSALT peptide. 


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Furthermore, dose response experiments demonstrated that LSALT peptide effectively inhibited 
the inflammatory response to renal IRI at a dose as low as 100 ng/kg. 
Use of another DPEP-1 targeting peptide, GFE-1 (10 µg/kg), also demonstrated protection against 
renal IRI induced inflammation in a similar manner as LSALT peptide (10 µg/kg; Choudhury 
thesis, 2018). 
3.3.2.4 DPEP-1 plays a role in lung & renal inflammation during endotoxemia and sepsis 
Sepsis is the result of overwhelming bacterial infection and systemic activation of inflammatory 
pathways. Accumulation of leukocytes in tissues/organs is responsible for many sepsis 
manifestations including lung injury (ARDS) and AKI.  
To evaluate the effect of the LSALT peptide in models of sepsis, mice were administered lethal 
doses of lipopolysaccharide (LPS) with or without pre-treatment with the LSALT peptide (given 
as a single dose before the LPS). All mice receiving LPS intravenously alone succumbed within 
48 hours. Mice pretreated with a single dose of LSALT peptide survived. Pathology of the lungs 
in mice LPS plus LSALT peptide demonstrated significantly less inflammation and injury 
compared to mice receiving LPS alone. Similarly, LSALT peptide prevented the accumulation of 
neutrophils and monocytes in the kidney. In a more physiologic model of sepsis, LSALT peptide 
was also protective in terms of survival and AKI. Mice underwent cecal ligation and puncture and 
followed for 48 hours. Mice were untreated (no antibiotics) or pre-treated with a single dose of the 
LSALT peptide. Mice receiving the LSALT peptide demonstrated less kidney inflammation at 6 
hours and improved kidney function and survival at 48 hours. Thus, LSALT peptide protects mice 
from the lethal effects of LPS. 
 Drug Metabolism and Pharmacokinetics 
Plasma levels of LSALT peptide were measured post-intravenous dosing of 100, 250, and 450 
mg/kg in rats.  Terminal elimination half-lives of 0.66 – 1.17 hr and MRTobs values of 0.58 – 0.85 
hr were observed for LSALT peptide. The AUC0-∞ was linear and close to proportional with dose. 
LSALT peptide is rapidly degraded in human plasma into smaller proteolytic fragments, likely 
from endopeptidase activity as measured by mass spectrometry. In mouse studies, at least one 
LSALT proteolytic fragment remains biologically active. Some of the proteolytic fragments have 
been detected in human plasma for as long as 120 minutes. LSALT peptide is undetectable in 
whole blood in the absence of phosphoric acid due to proteolytic digestion. LSALT peptide 
however is compatible with blood and does not induce red blood cell hemolysis. Work is ongoing 
to identify the LSALT peptide volume of distribution, tissue biodistribution, and excretion. 
 Toxicology and Safety 
The maximum tolerated dose (MTD) of LSALT peptide in mice and rats is 100 and 450 mg/kg, 
respectively, which is several logs above the minimum effective dose of 100 ng/kg to prevent 
organ inflammation and injury in mice. In dogs, the MTD of LSALT is 20 mg/kg. In all mouse 
studies, no LSALT peptide-related toxicity has been observed at therapeutic doses.  


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3.3.4.1 14-Day GLP Toxicology Studies 
3.3.4.1.1 Rat GLP Toxicology Study 
A GLP study assessed the potential toxicity and toxicokinetics of LSALT peptide when 
administered by intravenous injection to Sprague-Dawley rats once daily for 14 days. Three dose 
groups of 10, 30, and 50 mg/kg/day were evaluated. The control group was administered the 
vehicle used to prepare the LSALT peptide dosing formulations (0.9% sodium chloride, USP).  
The LSALT peptide dose formulations and the control vehicle were administered to rats by 
intravenous bolus injection at a dose volume of 1 mL/kg based on the most recent body weight of 
each animal. The progression or regression of any effects was evaluated during an additional 14-
day treatment-free, recovery period in the control and high-dose groups.  
Male and female rats [strain: Crl: CD® (SD) BR-Sprague-Dawley; Charles River] were acclimated 
for this study for 16 days. During the acclimation period, observations for clinical signs and 
ophthalmology were conducted and body weights as well as food consumption were measured.  
Following the pre-study evaluations, rats were randomized by body weight to control and test 
groups.  
There were no statistically significant differences in body weight, body weight changes, or food 
consumption between the treated and control groups during the study. Similarly, there were no 
ophthalmological or neurological findings considered to be related to treatment with the test item. 
Changes in hematology and clinical chemistry were mild, generally within normal ranges, and 
unlikely of clinical significance.  Further, there were no gross findings that could be related to the 
test item treatment. There were no statistically significant findings on organ weights that could be 
attributed to the test item treatment. 
LSALT peptide administered to Sprague-Dawley rats by intravenous bolus administration daily, 
for 14 days in the dose range of 10 to 50 mg/kg/day, was well-tolerated with no test-item-related 
effects observed upon evaluation of clinical observations, body weights, food consumption, 
clinical pathology (chemistry/hematology), gross pathology, or histopathology.  
The NOAEL in rats is 50 mg/kg. 
3.3.4.1.2 Dog GLP Toxicology Study 
A GLP study assessed the potential toxicology and toxicokinetics of LSALT peptide when 
administered by intravenous infusion to Beagle dogs once daily for 14 days. The control group 
was administered the vehicle used to prepare the LSALT peptide dosing formulations (0.9% 
sodium chloride, USP).  Three dose groups of 2.5, 7.5, and 15 mg/kg were evaluated. The LSALT 
peptide dose formulation and the control vehicle were administered to animals by intravenous 
infusion at a dose volume of 2 mL/kg based on the most recent body weight of each animal. The 
progression or regression of any effects was evaluated during an additional 14-day treatment-free, 
recovery period in the control and high dose groups. 
LSALT peptide administered to Beagle dogs by daily intravenous infusions for 14 days in the dose 
range of 2.5 to 7.5 mg/kg was well tolerated with no test-item related clinical observations noted. 


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The dose level of 15 mg/kg resulted in manifestation of pseudo-allergic (anaphylactoid) infusion 
reactions. The clinical signs appeared shortly after dosing and consisted of reddening of the skin 
around the eyes and mouth, head flicking, facial edema, hives/reddening on the pinnae, and/or 
reddened eyes and muzzle. Pseudo-allergic reactions were typically observed throughout the entire 
treatment phase duration. Affected animals were treated with diphenhydramine by IV injection. 
These reactions occurred during infusion and disappeared shortly after the infusion was completed. 
Other clinical signs were sporadic and not considered to be related to treatment with the test item. 
These reactions may likely diminish by lengthening the time of infusion for delivering daily doses 
≥ 15 mg/kg.  
Pseudo-allergic reactions following intravenous administration of peptides/proteins in dogs have 
been reported and occur in response to the infusion of biotherapeutics. Non-clinical infusion 
reactions do not necessarily predict responses in humans (Mease et al, 2017; Cohn et al, 2007; 
Roselló et al, 2017).  
Repeated dosing in the dose range of 2.5 to 15 mg/kg had no statistically significant effects. There 
were no differences in vital signs, body weight, or food consumption between the treated and 
control groups during the study. Changes in hematology and clinical chemistry were mild, 
generally within normal ranges, and unlikely of clinical significance. No changes in gross 
pathology and histopathology were attributed to the test item.  Gross findings noted upon necropsy 
of Main Study animals included a white-tan area of capsular thickening and contraction in the 
spleen of one mid-dose female and marked enlargement, redness, and protrusion of the right third 
eyelid in the eye of one high-dose female. These gross findings were considered incidental and 
unlikely to be test item-related. There were no statistically significant findings on organ weights 
that could be attributed to the test item treatment. 
The NOAEL in dogs is 2.5 mg/kg. 
 Preliminary Safety in Humans 
The first 6 cohorts of this study have been completed including subjects receiving a 5 mg dose 
daily for 3 consecutive days. No significant adverse effects were reported in any subjects receiving 
a single or multiple doses of the LSALT peptide (range 0.1 mg to 5 mg IV daily or IV daily for 3 
days). There were no drug-related clinical adverse events. No significant changes in clinical 
chemistry, hematology and other laboratory parameters were observed from baseline and 
compared to subjects receiving placebo. 


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 Pharmacokinetics 
Figure 5.  Intact LSALT peptide 5 mg single and multiple dose plasma concentrations 
 
As seen in Figure 5, there was rapid elimination of intact LSALT peptide after the end of the 
infusion (2 hours) with an estimated mean ± SD t½ of 0.41 ± 0.147 and 0.21 ± 0.0753 hours for 
the single dose and multiple dose, respectively. Apparent clearance was 580 ± 155 and 990 ± 146 
L/hr for the two regimens. 
 
Study Rationale 
According to a report by Asher Mullard, more than 180 clinical trials have emerged since the first 
description of SARS-CoV-2 in late 2019 in China (Mullard, 2020). A further 150 trials are in the 
wings to be started in the next few months. Thus, at least 300 trials will either be ongoing or 
initiated studying various cures for SARS-CoV-2, ranging from antivirals such as remdesivir, 
lopinavir, and ritonavir, to repurposed drugs such as hydroxychloroquine, azithromycin, and other 
immunomodulators, to cellular and vitamin interventions. The question raised in this article is: 
“Do we need 300 trials? Is that a good use of resources?” 
Coupled with this very recent article (published April 18, 2020) is an article by Janelle Ayres 
(published on April 17, 2020) questioning the priority of successful treatments of infectious 
diseases, which is obviously a primary endpoint of every ID study, without addressing concern for 
patients who progress to life-threatening sequelae of COVID-19 infections, including ARDS, 
septic shock, and multi-organ failure. These are serious conditions that result from immune 
responses to the virus (as discussed in the Introduction of this protocol). About one-quarter of 
patients presumably eradicated from a viral infection still die due to the underlying conditions 
resulting from host immune responses to the viral infection (Versluys and Boelens, 2018; Louis et 
al, 2012). Dr. Ayres asks a very important question in her article: It is equally as important to ask 


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the question: “How do we survive infections?” as it is to ask the familiar question: “How do we 
fight infections?”   
Acute respiratory distress syndrome (ARDS) is a devastating complication for patients infected 
with microorganisms, including COVID-19. Currently, there are no effective therapies to prevent 
or minimize ARDS. Inflammation is an important factor in the pathogenesis of lung injury related 
to viral pneumonia and COVID-19. Recent pathologic and molecular studies confirm a prominent 
role for neutrophils and other inflammatory cells in the pathogenesis of COVID-19 associated lung 
injury (Zhou et al, 2020; Varga et al 2020).  
Similarly, acute kidney injury (AKI) associated with COVID19 has important clinical implications 
with more than two thirds of patients experiencing prolonged hospitalization and/or death (Hirsch 
et al, 2020). While the pathophysiology of COVID19-associated AKI is not fully understood, 
inflammation related to direct viral infection of kidney cells, renal ischemia or systemic illness 
(sepsis or cytokine storm) are believed to play a role (Batlle et al, 2020; Diao et al, 2020). 
Given its favorable toxicology and clinical pharmacology profiles, the administration of LSALT 
peptide to target lung and kidney inflammation and prevent or minimize ARDS or AKI during a 
COVID-19 infection has the potential to provide a significant long-term clinical impact. During 
the course of their disease, approximately 17 – 42% of COVID-19 hospitalized patients develop 
ARDS within 8 days of admission and almost half of those patients died while hospitalized (Chen 
et al, 2020; Huang et al, 2020; Wang et al, 2020; Wu et al, 2020). 36.6% of patients developed 
AKI in the series by Hirsch with more than two thirds of patients dying or requiring prolonged 
hospitalization. Of the patients who were discharged, a large proportion were left with significant 
kidney dysfunction (Hirsch et al, 2020). How many had cleared the virus is unknown from the 
literature.  
Clearly, a therapeutic intervention that prevents life-threatening ARDS is needed. Even a 20 – 30% 
reduction in ARDS incidence or severity during COVID-19 would have a significant impact on 
clinical outcomes and health systems, including mortality, critical care, and ventilatory capacity. 
LSALT peptide has shown activity in animal models of inflammation including lung, kidney, and 
liver injury in the context of bacterial sepsis and its safety profile has been well-described in 
healthy adult subjects. Thus, the critical next step is the proof-of-concept Phase 2 study in 
hospitalized patients with COVID-19. We are attempting to answer the question: “How do we 
survive infections?” 
 
Dose Justification 
In order to identify a potential starting dose in the Phase 2 clinical trial in adult patients with 
COVID-19 using the existing data, toxicology data from the 14-day dog toxicology study were 
relied on; these are considered to be the most appropriate as the NOAEL in rats (50 mg/kg) is 
much less sensitive than the dog. In the 14-day dog toxicology study, the NOAEL dose was 
established as 2.5 mg/kg/day. The FDA’s Guidance for Industry entitled “Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers” (FDA, 2005) was used to determine the human equivalent dose (HED) for an infected 


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adult weighing 70 kg. This patient represents the mid-range of the weight of COVID-19 patients 
intended to be included in the Phase 2 trial. The dog NOAEL dose of 2.5 mg/kg/day converts to a 
HED of 1.4 mg/kg/day. Applying a safety factor of 10 results in an initial starting dose of 
approximately 0.14 mg/kg/day or 10 mg/day. The study dose of 5 mg over 2 hours is substantially 
less than the HED and safe according to the Phase 1 results.  
4 
STUDY OBJECTIVES AND ENDPOINTS 
 
Study Objectives 
 Primary Objective 
To evaluate the proportion of subjects alive and free of respiratory failure (e.g., need for non-
invasive or invasive mechanical ventilation, high flow oxygen [≥ 6 L/minute], or ECMO) and free 
of the need for continued renal replacement therapy (RRT) on Day 28. The need for continued 
RRT at Day 28 will be defined as either dialysis in the past 3 days (Day 26, 27, or 28) or an eGFR1 
on Day 28 <10 mL/min/1.73 m2. 
 Secondary Objectives 
To evaluate the following: 
 Incidence and time to mild, moderate, and severe ARDS between treatment groups 
 Ventilation-free days 
 Time on nasal canula or oxygen mask 
 28-day mortality– both all-cause and attributable 
 ICU length of stay (in days) 
 Hospitalization length of stay (in days) 
 Virologic clearance rate 
 Incidence of other organ disorders 
 Need and duration for extracorporeal membrane oxygenation (ECMO) 
 Vasopressor-free days 
 Clinical improvement in chest x-rays  
 Change in baseline modified Medical Research Council (mMRC) dyspnea scale  
 SOFA scores assessed periodically 
 Change from baseline in liver function tests (ALT, AST, and/or total bilirubin) 
 Change from baseline in SCr and eGFR  
 
1 eGFR is calculated from the serum creatinine according to the eGFRCKD-EPI equation (Levey et al, 2009):  
eGFR (mL/min/1.73 m2) = 141 × min(Scr/κ,1)α × max(Scr/κ, 1) - 1.209 × 0.993Age × 1.018 [if female] * 1.159 
[if black], where Scr = serum creatinine; κ = 0.7 for females and 0.9 for males; α = -0.329 for females and -0.411 
for males; min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.  


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 Change from baseline in highly-sensitive troponin (hs-troponin) 
 Change from baseline ACT, aPTT, and/or PT/INR levels 
 Change from baseline for antiviral immunoglobulins (IgG, IgM, and IgA) at EOS. 
 Health Outcomes Objective 
 Total healthcare costs from admission to discharge (Omer et al, 2020). 
 Exploratory Objectives 
 Change in serum cytokines including IL-1α, hs-troponin, and ferritin levels, as well as other 
exploratory biomarkers drawn at the same time as LSALT peptide levels. 
 Change in baseline antiviral immunoglobulins (IgG, IgM, IgA) at EOS. 
 Pharmacokinetics of LSALT peptide and fragments (metabolites) over the study period. 
 
Study Endpoints 
 Primary Efficacy Endpoint 
To evaluate the proportion of subjects alive and free of respiratory failure (e.g., need for non-
invasive or invasive mechanical ventilation, high flow oxygen [≥ 6 L/min], or ECMO) and free of 
the need for continued renal replacement therapy (RRT) on Day 28. The need for continued RRT 
at Day 28 will be defined as either dialysis in the past 3 days (Day 26, 27, or 28) or an eGFR on 
Day 28 <10 mL/min/1.73 m2.  
 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
 All-cause mortality 
 The presence and severity of ADRS as an ordinal outcome of the proportion of patients 
who have none, mild, moderate, or severe ARDS  
 Time to each of mild, moderate, and severe ARDS 
 The number of ventilation-free days and ECMO-free days 
 Time on nasal canula or oxygen mask 
 Length of stay in ICU and hospital (admission to discharge)  
 Virologic clearance rate  
 Worst PaO2/FiO2 ratio following enrollment  
 Change in PaO2/FiO2 ratio 
 Vasopressor-free days 
 Change from maximal radiographic damage to EOT 
 Change in baseline mMRC score 


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 Change in APACHE II score 
 Proportion of patients with extrapulmonary organ dysfunction using the daily SOFA score 
 Change in liver function tests (ALT, AST, total bilirubin) 
 Change in renal function tests (SCr, eGFR) 
 Change in hs-troponin levels 
 Change in ACT, aPTT, and/or PT/INR values 
 Change in antiviral IgG, IgA, and IgM levels.  
 Health Outcomes endpoint: 
 Total healthcare costs from admission to discharge between treatment groups. 
 Exploratory Endpoints: 
  Change in serum cytokines including IL-1α, IL-1ß, and ferritin levels, as well as other 
exploratory biomarkers drawn at the same time as LSALT peptide concentrations. 
 Change in baseline antiviral immunoglobulins (IgG, IgM, IgA) at EOS. 
 Safety Endpoints 
Safety endpoints include: 
 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory tests 
 Vital signs 
 Physical examinations 
 12-lead ECG 
 Radiologic findings. 
5 
INVESTIGATIONAL PLAN 
 
Overall Study Design and Plan – Description 
This is a global, multicenter, randomized, double-blind, placebo-controlled, proof of concept study 
of LSALT peptide as prevention of acute respiratory distress syndrome (ARDS) and acute kidney 
injury in patients infected with SARS-CoV-2 (COVID-19).  
After assessing the risk of ARDS and satisfying all inclusion and exclusion criteria, the patient 
will be randomized to 5 mg LSALT peptide or blinded placebo to be given intravenously once 
daily for a maximum of 14 days. Physical and respiratory examinations, vital signs, and adverse 
events will be recorded throughout the study, including Day 28 (EOS). Blood chemistries, 
hematology, coagulation, urinalysis, ECG, SARS-CoV-2 tests, eGFR, and chest x-ray (CXR) will 
be assessed at Day 1 (Screening/Baseline) prior to initiation of study drug, and on Day 3, EOT, 
and at EOS, as well as when clinically indicated. The ECG at EOS will only be obtained if 


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clinically indicated. An additional CXR will be obtained at time of clinical improvement. 
Cytokines/biomarkers and pharmacokinetics (PK) will be assessed at Day 1 (Screening/Baseline) 
prior to initiation of study drug, and on Days 1, 3, and EOT at 1 (mid-dose) and 2 hours (end of 
infusion) of drug therapy, and a single blood sample at EOS for cytokines/biomarkers only. Where 
applicable, a urinary pregnancy test will be obtained at Screening in women of childbearing 
potential. When clinically indicated, questionnaires (APACHE II, SOFA) will be obtained at 
Baseline, EOT, and EOS; venous blood gas (VBG) or HCO3 (bicarbonate) levels may be 
substituted for arterial blood gas (ABG) if it is standard-of-care (SOC) or in the patient’s best 
interest, and results in comparable APACHE II and SOFA scores (Brown et al, 2016). Other 
questionnaires (Berlin Definition and modified Medical Research Council Dyspnea Scale) will be 
assessed at Baseline, Day 3, EOT, and EOS. IgG, IgA, and IgM antiviral antibodies will be 
collected at Baseline and EOS. Patients will be maintained on the SOC per institutional guidelines, 
including prophylaxis or treatment of VTE, throughout the study.  
Patients will be randomized to one of two blinded treatment regimens: 
1. 100 mL of 5 mg IV LSALT peptide infusion over 2 hours daily 
2. 100 mL of drug-free IV saline infusion over 2 hours daily. 
Duration of therapy will be a maximum of 14 days. Patients will be maintained on the standard of 
care (SOC) for the treatment of COVID-19 as defined by institutional guidelines and/or physician 
practice. Co-morbidities and concomitant medications will be reviewed daily and documented in 
the patient’s eCRF. The risk of venous thromboembolism (VTE), a potential consequence of 
SARS-CoV-2 infection, will be assessed and prophylaxis will be included as SOC for every patient 
(Zhai et al, 2020; Klok et al, 2020). Please refer to antithrombotic therapy in patients with COVID-
19 (COVID-19 Treatment Guidelines Panel, Antithrombotic Therapy in Patients with COVID-19, 
p197; 17-December-2020).   
 
Number of Patients (Planned) 
Thirty (30) patients will be randomized to active drug (LSALT peptide) and 30 patients will be 
randomized to matching placebo. Patients and, if necessary, the Legal Authorized Representative 
(LAR), the Investigational Staff, and the Sponsor and its representatives will not know the 
randomization schemata. The Pharmacist at the site will be unblinded and prepare drug/placebo 
for injection.  
A Data and Safety Monitoring Board (DSMB) will evaluate patients on a continuing basis for 
primarily safety assessments but also the adequacy of treatment based upon clinical data of the 
patient, target drug concentrations, and data obtained from the AB001 PK study in healthy subjects 
to offer recommendations to the Sponsor. In the absence of adverse events or any safety issues 
during the course of study, the DSMB may recommend continuance or suspension of the study 
due to futility or safety issues. The DSMB will meet at least monthly if not more frequently based 
upon enrollment throughout the study period.  Per protocol, at no time will patients be dosed for 
more than 14 days of therapy. The DSMB Charter will outline all processes for changes to the 
protocol and protocol design prior to the first patient being enrolled into study.  


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Discussion of Study Design 
This double-blind, placebo-controlled, proof-of-concept Phase 2 study is designed to evaluate 
LSALT peptide compared with placebo in a defined number of adult hospitalized patients with the 
diagnosis of COVID-19. This is a 1:1 randomization comparing 5 mg LSALT peptide daily with 
matching placebo. LSALT peptide or drug-free saline will begin immediately once the patient 
meets all inclusion/exclusion criteria at the start of hospitalization and followed with physical and 
respiratory exams, blood chemistries, coagulation, hematology, ECGs, SARS-CoV-2 tests, CXRs, 
biomarkers, and PK will be recorded periodically throughout the 28 day study. When clinically 
indicated, questionnaires (APACHE II, SOFA) will be obtained at Baseline, EOT, and EOS; 
venous blood gas (VBG) or HCO3 (bicarbonate) levels may be substituted for arterial blood gas 
(ABG) if it is SOC or in the patient’s best interest, and results in comparable APACHE II and 
SOFA scores (Brown et al, 2016). Other questionnaires (Berlin Definition and modified Medical 
Research Council Dyspnea Scale) will be assessed at Baseline, Day 3, EOT, and EOS. Patients 
will be maintained on SOC, including prophylaxis or treatment for VTE, per institutional 
guidelines throughout the study. Dosing will end on Day 14, or at cure or increasing severity of 
ARDS, or at death. Patients will be followed clinically, and safety and efficacy measures will be 
recorded at end of study (EOS; Day 28) or death, whichever occurs first. 
 
Selection of Study Population 
 Inclusion Criteria 
Eligible patients must fulfill the following inclusion criteria: 
1. Male or female hospitalized patients between 18 and 80 years of age at time of consent. 
2. Clinical and laboratory diagnosis of COVID-19 infection. Patients must be positive for the 
SARS-CoV-2 by Real-Time Reverse Transcriptase (RT)-PCR Diagnostic Panel or have an 
existing complication secondary to SARS-CoV-2 infection which was positive within 2 weeks 
of entry into the study. Further, patients must have at least two of the following three 
symptoms: 
 Fever (oral temperature ≥ 100.4 °F [> 38 °C]) with or without chills 
 Dyspnea or difficulty breathing (≥ 2 on mMRC dyspnea scale) 
 Nonproductive cough (Stokes et al, 2020), 
 Or other signs and symptoms of established complications to SARS-CoV-2 infection (e.g., 
coagulopathy, cardiomyopathy, acute kidney injury [AKI], and/or acute liver injury) within 
the limits of Exclusion Criteria #8.  
3. Patients must present with moderate to severe illness as defined below: 
 Moderate illness: Patients who have evidence of lower respiratory disease by clinical 
assessment or imaging and an oxygen saturation (SpO2) > 93% on room air at sea level 
 Severe illness: Patients who have a respiratory frequency > 30 breaths per minute (bpm), 
SpO2 ≤ 93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction 
of inspired oxygen (PaO2/FiO2) < 300, or lung infiltrates > 50% (COVID-19 Treatment 
Guidelines Panel, 2020).   
4. APACHE II score < 20 or establishment of survivability of the patient beyond 48 hours 


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following randomization. 
5. Therapies which have been shown to be beneficial and are included in standard-of-care 
COVID-19 treatment guidelines (e.g., those of WHO or NIH, or institutional guidelines) are 
permitted. 
6. Sexually active women of child-bearing potential (WCBP) must be using a medically 
acceptable method of birth control throughout the study and for at least 1 day following the 
end of study, and have a negative urine pregnancy test at the Screening visit. A WCBP is 
defined as a female who is biologically capable of becoming pregnant. A medically acceptable 
method of birth control includes intrauterine devices in place for at least 3 months, surgical 
sterilization, or the implant (ACOG, 2020). In patients who are not sexually active, abstinence 
is an acceptable form of birth control and urine will be tested per protocol. Women who are of 
nonchild-bearing potential, i.e., post-menopause, must have this condition captured in their 
medical history. Pregnant women and nursing mothers are excluded from this study. 
7. Patient or Legally Authorized Representative (LAR) is available and willing to give written 
informed consent, after being properly informed of the nature and risks of the study and prior 
to engaging in any study-related procedures. 
 Exclusion Criteria 
The presence of any of the following excludes a patient from study enrollment: 
1. Known sensitivity, allergy, or previous exposure to LSALT peptide. 
2. Exposure to any investigational drug or device <90 days prior to entry into study.  
3. Treatment with immunomodulators or immunosuppressant drugs, including but not limited to 
IL-6 inhibitors, TNF inhibitors, anti-IL-1 immunomodulators, and JAK inhibitors within five 
half-lives or 30 days (whichever is longer) prior to randomization and throughout the study 
period. However, should any of these treatments become SOC and incorporated into clinical 
treatment guidelines (e.g., those of WHO or NIH, or institutional guidelines), the treatment is 
permitted. Further, low-dose oral prednisone (≤ 20 mg/day) and inhaled steroids (e.g., for 
treatment of asthma) are allowed in the study. 
4. Anticipated transfer to another hospital or medical center within 72 hours, which is not a study 
site. 
5. Uncontrolled or poorly-treated active hepatitis B (HBV), hepatitis C (HepC), or HIV infection. 
Those subjects who are positive for HBV, HepC, or HIV but are well-controlled with low viral 
loads are allowed to participate in the study: 
 HBV low viral load defined as <20,000 IU/mL 
 HepC low viral load defined as <800,000 IU/mL 
 HIV low viral load defined as <5000 copies/mL.   
6. Participation in another drug or device study at any time during this study, for example: 
 Ulinastatin 200,000 IU or greater (ClinicalTrials.org NCT03089957) 
 High dose intravenous Vitamin C (ClinicalTrials.org NCT042645333) 


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 Budesonide and formoterol (Festic et al, 2017) 
 Bevacizumab to prevent ARDS (NCT01314066) 
 Dornase alfa to reduce hypoxemia in ventilated trauma patients (Pottecher et al, 2020). 
7. As indicated in the inclusion criteria, pregnant female patients are excluded from study. 
Further, female patients who are nursing are excluded from study.   
8. Has any medical condition considered to be clinically significant and could potentially affect 
patient safety or study outcome, including but not limited to:  
 Acute kidney injury (Thomas et al, 2015) or chronic kidney disease (stage-4 and stage-5 
renal impairment [Wongrakpanich et al, 2017; Agarwal, 2016]; hemodialysis or eGFR < 
30 mL/min/1.73 m2; [CKD-EPI equation; Levey et al, 2009) 
 End-stage malignancy undergoing treatment 
 Immunocompromised patients or those with medical/surgical conditions (e.g., solid organ 
transplantation) which require chronic immunosuppression 
 Chronic hematologic disease which, in the opinion of the PI, prohibits the patient from 
entering into study  
 Acute liver injury with AST and/or ALT levels greater than 3x ULN, unless recent injury 
(within 2 weeks) likely due to COVID-19 infection  
 History of coagulopathy of unknown etiology, as defined by abnormal ACT (only if part 
of SOC), aPTT, and/or PT/INR values at least 2-fold outside normal limits, and currently 
present at screening, and/or 
 End-stage lung disease, acute lung injury, very severe chronic obstructive pulmonary 
disease (COPD) as assessed by the GOLD criteria (GOLD Stage IV; Vogelmeier et al, 
2017), or mechanical ventilation. 
 Removal of Patient from Therapy 
Reasons for permanent discontinuation of treatment include the following: 
 Patient experiences two or more Grade 2 toxicities or one or more Grade 3 or 4 toxicity 
considered by the PI to be associated with LSALT peptide treatment (CTCAE v5.0, 2017) 
 Patient requests to discontinue treatment or patient withdrawal of consent 
 PI considers that it is not in the best interest of the patient to continue treatment due to an 
adverse event.  
 Protocol deviation requiring discontinuation of study treatment for safety reasons, and/or 
 Pregnancy. 
Patients who discontinue treatment for any reason (except withdrawal of consent from study 
participation) will not be discontinued from the study and will continue to be followed for all 


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assessments until Day 28, or if not possible then for all assessments necessary to determine the 
value of the primary endpoint at Day 28.  
5.4.3.1 Procedures for Early Termination of Treatment 
For any discontinuation, the PI will obtain all the required details and document the date and the 
main reason for the premature termination. If the reason for discontinuation is an AE, the specific 
event or the main laboratory abnormality will be recorded in the electronic case report form 
(eCRF). The PI will make thorough efforts to document the outcome. The PI will attempt to 
continue to follow the patient for the full duration of the study and continue planned assessments. 
If circumstances prevent the patient from completing all scheduled evaluations, every attempt will 
be made to complete all procedures listed in Section 8.2.5. 
6 
STUDY PRODUCT 
 
Study Medication Supply 
LSALT peptide and matching placebo will be sent to the sites per the randomization schemata. 
Drug receipt/administration logs and temperature logs will be maintained by the study site using 
the Drug Accountability Form. The unblinded Pharmacist/designate will ensure that the total 
number of vials in the drug dispatch log is present in the shipment from the Sponsor. The 
Pharmacist/designate will also ensure that there is no evidence of breakage of the drug vials. The 
Sponsor/designate must be notified immediately if any discrepancy is identified in the drug or 
temperature log or if any breakage occurs. 
 Description and Formulation of Study Product 
LSALT peptide will be supplied to the study site in aqueous solution at -20°C as a single 
concentration (1 mg/mL) in a glass vial with restricted access to the site Pharmacist or designate. 
The LSALT peptide vials will be labeled in English or the local language in the country of study 
and according to local regulations (Appendix 1). 
 Study Drug Dosage and Preparation 
LSALT peptide or an equivalent volume of 0.9% sodium chloride (NaCl) will be diluted in 0.9% 
sodium chloride solution to a volume of 100 mL mini-IV bag by an unblinded Pharmacist or 
designate. The drug will be infused into the patient through a peripheral 18, 20, or 22 g intravenous 
catheter or through a central line over 2 hours and under the supervision of the study investigator. 
 Pharmacy records 
The unblinded Pharmacist or designate will be responsible for ensuring that the study site 
maintains an accurate record of the LSALT peptide inventory using the Drug Accountability Form. 
A coded label will be affixed to the patient eCRF to identify placebo and LSALT peptide-treated 
subjects. 
 Conditions for Storage and Use 
All study medication will be stored in the research pharmacy prior to dispensing, or in a locked 
freezer accessible only to the pharmacy team. Study drug (LSALT peptide and commercially-
available drug-free saline) should be stored frozen at -20°C (-4°F) in a temperature-monitored 


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freezer; a record of daily temperatures during the study will be reviewed by the Sponsor or 
delegate. Refer to the Pharmacy Manual on specifics of storage and other related information. 
 
Study Drug Administration 
The dose will be one of the following for each patient:  
A. 100 mL of 5 mg IV LSALT peptide infusion over 2 hours once daily 
B. 100 mL drug-free IV saline infusion over 2 hours once daily.   
The frozen study drugs (LSALT peptide or saline) will be warmed to room temperature by the 
unblinded Pharmacist before dispensing to the investigators for adding to the infusion bags. As 
warming time may vary, every effort should be made to allow ample time to the unblinded 
Pharmacist for the completion of the warming procedure. Post-preparation, the drug product and 
placebo will be stored for no longer than 4 hours at room temperature (68°F/20°C) or no longer 
than 24 hours when refrigerated (35°F/2°C) prior to administration to the patient to minimize the 
risk of excessive growth of adventitious microbial contamination. Times of post-preparation to 
infusion and storage temperatures will be documented in the pharmacy records and eCRF.  
Study drug will be administered once daily at a consistent time throughout the study. A missed 
dose of study medication can be administered up to 8 hours before the next scheduled dose; 
otherwise, the missed dose should not be administered to the patient and the deviation should be 
noted on the eCRF.  
 Patient Numbering 
Each patient will be assigned a unique 6-digit patient number by the study staff. The patient 
number will consist of a 3-digit clinical investigational site number assigned by the Sponsor, 
followed by a 3-digit patient number (e.g., 001) assigned by the study staff. 
The clinical site and/or pharmacy, if applicable, is responsible for maintaining a current log of 
patient number assignments and bottle numbers of the investigational product administered to each 
patient. The patient’s unique patient number is required to be entered on all clinical investigation 
documentation (i.e., eCRFs, labeling of clinical materials and samples containers, drug 
accountability logs, etc.). 
 Method of Assigning Patients to Treatment Groups 
This is a double-blind, placebo-controlled study. The actual treatment given to individual patients 
is determined by a randomization schedule. A fixed block randomization schedule will be prepared 
to assign patients to 1 of 2 treatments: LSALT peptide 5 mg once daily or matching placebo in a 
1:1 allocation ratio. 
 Dispensing, Compliance and Accountability 
The study drug must be used only as directed in the protocol. The Pharmacist/delegate will keep 
accurate records of the quantities of the study drug dispensed/distributed, used, and returned by 
each patient in the eCRF system. 
The Sponsor or delegate will provide drug product accountability forms to assist the 
Pharmacist/delegate, when applicable, in maintaining current and accurate inventory records 


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covering receipt, dispensing, and the return of study drug supplies. When a shipment is received, 
the Pharmacist will verify the quantities received and return the acknowledgment to the Arch 
Biopartners Clinical Trial Material (CTM) Coordinator. The drug product will not be used without 
Arch Biopartners or designate approval in writing. The unblinded Pharmacist will record study 
drug accountability which includes the coded identification of the patient to whom the study drug 
is dispensed, the quantity and the date of dispensing, and any returned or unused study drug, as 
well as a full record of CTM storage temperatures. This record is in addition to any study drug 
accountability information recorded on the eCRF. These records will be readily available for 
inspection by an unblinded monitor and/or Arch Biopartners audits and are open to regulatory 
authority inspection at any time. 
Noncompliance is defined as receiving less than 80% or more than 120% of study drug during the 
study period. Noncompliance should be discussed with the Project Manager, or delegate, and is to 
be noted both in the source documentation and in the eCRF.  
At the end of the study, all unused study drug will be destroyed on site according to site procedures. 
If the site does not have procedures in place for on-site destruction, the study drug will be returned 
to the Arch Biopartners CTM Coordinator or designate for destruction. 
Based on entries in the site electronic study drug accountability forms, it must be possible to 
reconcile study drug delivered with those used and returned. All study drug must be accounted for 
and all discrepancies investigated and documented appropriately. 
The unblinded Pharmacist is responsible for maintaining accountability for the receipt, dispensing, 
and return of all study medication to the clinic. 
 
Prior and Concomitant Therapy 
Medications having the potential to interfere with the evaluation of efficacy or safety are excluded 
throughout the trial (review Sections 5.4.1 Inclusion criteria and 5.4.2 Exclusion criteria). Current 
therapies which have been shown to be efficacious and are included in standard COVID-19 
treatment guidelines (e.g., WHO or US NIH, institutional guidelines) are permitted if not part of 
another investigational study. All concomitant medication usage needs to be documented in the 
eCRF. 
7 
EFFICACY AND SAFETY ASSESSMENTS 
 
Efficacy Assessments 
 Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects alive and free of respiratory failure 
(e.g., need for non-invasive or invasive mechanical ventilation, high flow oxygen [≥ 6 L/minute], 
or ECMO) and free of the need for continued renal replacement therapy (RRT) on Day 28. The 
need for continued RRT at Day 28 will be defined as either dialysis in the past 3 days (Day 26, 27, 
or 28) or an eGFR on Day 28 <10 mL/min/1.73 m2. 
 Secondary Efficacy Endpoints 
 All-cause mortality 


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 The presence and severity of ADRS as an ordinal outcome of the proportion of patients 
who have none, mild, moderate, or severe ARDS  
 Time to each of mild, moderate, and severe ARDS 
 The number of ventilation-free days and ECMO-free days 
 Time on nasal canula or oxygen mask 
 Length of stay in ICU and hospital (admission to discharge)  
 Virologic clearance rate  
 Worst PaO2/FiO2 ratio following enrollment  
 Change in PaO2/FiO2 ratio 
 Vasopressor-free days 
 Change from maximal radiographic damage to EOT 
 Change in baseline mMRC score 
 Change in APACHE II score 
 Proportion of patients with extrapulmonary organ dysfunction using the daily SOFA score 
 Change in liver function tests (ALT, AST, total bilirubin) 
 Change in renal function tests (SCr, eGFR) 
 Change in hs-troponin levels 
 Change in ACT, aPTT, and/or PT/INR values 
 Change in antiviral IgG, IgA, and IgM levels.  
 Health Outcomes endpoint 
 Total healthcare costs from admission to discharge between treatment groups. 
 Exploratory Endpoints 
 Change in serum cytokines including IL-1α, IL-1ß, and ferritin levels, as well as other 
exploratory biomarkers drawn at the same time as LSALT peptide concentrations. 
 Change in baseline antiviral immunoglobulins (IgG, IgM, and IgA) at EOS. 
Additional measures may be added. Data will be analyzed for the modified intent-to-treat (mITT) 
and per protocol (PP) populations. 


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Pharmacokinetic Variables 
Blood samples for determination of LSALT peptide concentrations and related metabolites 
(degradation products) and cytokines will be obtained at Baseline prior to initiation of drug, and 
at the mid-point of the 2-hour drug infusion and immediately following the end of the 2-hour 
infusion on Days 1, 3, and EOT A single blood sample will be obtained at EOS for measurement 
of cytokines/biomarkers only. 
 
Safety Assessment 
Safety will be assessed by changes from Baseline in: 
 TEAEs 
 Clinical laboratory tests (Appendix 2) 
 Vital signs including pulse rate, blood pressure, body temperature, respiration rate, body 
weight  
 Physical examinations 
 12-lead ECG 
 Radiologic findings. 
Additional assessments may be conducted as considered appropriate. Clinical labs, vital signs, 
ECG measurements, and radiologic findings may be repeated if needed to corroborate or refute 
abnormal findings. Both the original and replicate assessments should be recorded in the eCRF. 
 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient participating in a clinical 
trial. An AE can be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of the study medication, whether or not considered related to the study 
medication. AEs will be collected from the initiation of treatment until 30 days following the final 
dose. Pre-existing known clinically significant conditions observed at screening should be 
recorded as medical history. 
This definition also includes accidental injuries, reasons for any change in medication (drug and/or 
dose), reasons for re-admission to a hospital, or reasons for surgical procedures (unless for minor 
elective surgery for a pre-existing condition). It also includes adverse events commonly observed 
and adverse events anticipated based on the pharmacological effect of the study medication. Any 
laboratory abnormality assessed as clinically significant by the PI must be recorded as an adverse 
event. 
A treatment-emergent adverse event (TEAE) is also defined as any adverse event occurring after 
start of study medication and within the time of residual drug effect (30 days after the last 
administration of the study medication), or a pre-treatment adverse event or pre-existing medical 
condition that worsens in intensity after start of study medication and within the time of residual 
drug effect. 


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Adverse events should be recorded as diagnoses, if available. If not, separate sign(s) and 
symptom(s) are recorded. One diagnosis/symptom should be entered per record. 
Note that death is not an adverse event but the cause of death is. An exception is the adverse event 
of sudden death of unknown cause. Note that hospitalization is not an adverse event; however, the 
reason for hospitalization is. Procedures are not adverse events; the reasons for conducting the 
procedures are. In general, only the reason for conducting the procedure will be captured as an 
adverse event. However, if deemed necessary by the PI, a procedure can be captured along with 
the reason for conducting the procedure. 
An overdose or medication error is not an adverse event unless it is temporally associated with an 
unfavorable or unintended sign or symptom. 
While pregnancy in and of itself is not a SAE, for the purposes of this trial, should a pregnancy 
occur in a subject or subject’s partner, it should be reported on a Pregnancy Reporting form within 
24 hrs of being aware and be followed until an outcome is received. 
7.3.1.1 Serious Adverse Events 
Each AE is to be classified by the PI as serious or non-serious. A serious adverse event (SAE) is 
any untoward medical occurrence or effect that occurs at any dose: 
 Results in death 
 Is life-threatening (i.e., an immediate risk of death) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is associated with a congenital anomaly/birth defect 
 Is an important medical event. 
An adverse event caused by an overdose or medication error is considered serious if a criterion 
listed in the definition above is fulfilled. 
Important adverse events that may not result in death, may not be life-threatening, or do not require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient’s safety or may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
Serious adverse events also include any other event that the PI or Sponsor judges to be serious or 
which is defined as serious by the regulatory agency. 
The PI is to report all directly observed adverse events and all adverse events spontaneously 
reported by the trial patient using concise medical terminology.  


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7.3.1.2 Procedures for Assessing, Recording, and Reporting Adverse Events and Serious 
Adverse Events 
Throughout the duration of the study, the PI will closely monitor each patient for evidence of drug 
intolerance and for the development of clinical or laboratory evidence of adverse events. All AEs 
(expected or unexpected) which occur during the course of the study, whether observed by the PI 
or by the patient, and whether or not thought to be drug-related, will be reported and followed until 
resolution or until they become stable. 
The description of the AE will include description of the event, start date, stop date, intensity, if it 
was serious, relationship to test drug, change in test drug dosage, if the patient died, and if 
treatment was required. Events will be recorded as one of the following severity/causality 
categories below (CTCAE v5.0): 
Severity
Definition
Mild (Grade 1) 
Asymptomatic or mild symptoms, clinical or diagnostic observations only; intervention not 
indicated  
Moderate (Grade 2) 
Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL (e.g., meal preparation, shopping, using telephone, managing money, etc.)
Severe (Grade 3) 
Medically significant but not immediately life-threatening; prolongation of hospitalization 
indicated; disabling; limited self-care (e.g., bathing, dressing, feeding self, using toilet, etc.)
Very severe (Grade 4)
Life-threatening consequences; urgent intervention indicated
Death (Grade 5)
Death related to AE
Category
Definition
Unrelated 
Clearly and incontrovertibly due only to extraneous causes and does not meet criteria listed 
under possible or probable.
Unlikely 
Does not follow a reasonable temporal sequence from administration. May have been 
produced by the patient’s clinical state or by environmental factors or other therapies 
administered.
Possible 
Follows a reasonable temporal sequence from administration but may have been also 
produced by the patient’s clinical state, environmental factors or other therapies 
administered.
Probable 
Clear-cut temporal association with administration with improvement on cessation of 
investigational medicinal product or reduction in dose. Reappears upon rechallenge. 
Follows a known pattern of response to the investigational medicinal product.
Definitely 
There is evidence of exposure to the test product, for example, reliable history or acceptable 
compliance assessment; the temporal sequence of the AE onset relative to the drug is 
reasonable; the AE is most likely to be explained by the drug treatment than by another 
cause; the challenge is positive; re-challenge (if feasible) is positive; the AE shows a pattern 
consistent with previous knowledge of the drug treatment.
Adverse events with the causality assessed as possible, probable, and definitely are categorized as 
related to study medication and are called adverse drug reactions. 
7.3.1.2.1 Serious Adverse Events (SAE) Reporting 
Any SAE will be reported to the Sponsor or designate via telephone, fax, e-mail, or in-person, 
within 24 hours of knowledge by the Investigator, and then in writing as soon as possible, but no 
later than 7 calendar days after first knowledge of the SAE. 
The notification must be directed to the following for North American sites: 
Peter Polos, MD 


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Peter.Polos@SyneosHealth.com 
(908) 963-7783 
and 
SafetyReporting@SyneosHealth.com or 
FAX: (877) 464-7787 
For Turkish sites, the following should be contacted: 
Yaprak Çalğar, MD 
YaprakC@MonitorCRO.com 
90 (545) 261 19 75 
and 
ab002pharmacovigilance@monitorcro.com.  
7.3.1.2.2 Fatal or Life-threatening Serious, Unexpected Adverse Drug Reactions 
The Sponsor or designate is responsible for notifying regulatory agencies of fatal or life-
threatening serious, unexpected adverse drug reactions (by telephone, facsimile transmission or in 
writing) as soon as possible, but no later than 7 calendar days after becoming aware of the 
information. Additionally, within 8 days after having informed the agency(ies), a complete report 
must be submitted, including an assessment of the importance and implication of any findings. 
Syneos Health Canada will handle notifications to the Canadian regulatory agency on behalf of 
the Sponsor. 
It is the responsibility of the clinical site to report as soon as possible, but no later than 7 calendar 
days after first knowledge by the Investigator, fatal or life-threatening serious, unexpected adverse 
drug reactions to the Independent Ethics Committee (IEC) responsible for the study. 
7.3.1.2.3 Other Suspected, Unexpected, Serious Adverse Drug Reactions (SUSAR) 
The Sponsor is responsible for notifying regulatory agencies of all other suspected, unexpected, 
serious adverse drug reactions that are neither fatal nor life-threatening as soon as possible, but no 
later than 15 calendar days after becoming aware of the information. Syneos Health Canada will 
handle notifications to the Canadian regulatory agency on behalf of the Sponsor. 
 Other Assessments 
7.3.2.1 Clinical Laboratory Tests (Appendix 2) 
 Hematology Complete blood count: total white blood cell count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, and basophils), total red blood cells 
(RBC, hemoglobin [Hgb], hematocrit, mean corpuscular volume, mean corpuscular Hgb, 
and mean corpuscular Hgb concentration), and platelets. 
 Biochemistry Sodium, potassium, glucose, blood urea nitrogen, chloride, creatinine and 
eGFR, calcium, bilirubin (total), alkaline phosphatase, aspartate transaminase, alanine 


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transaminase, gamma-glutamyl transferase, total protein, albumin, and carbon dioxide 
(CO2). 
 Coagulation Activated Partial Thromboplastin Time (aPTT), Prothrombin time (PT), 
International Normalized Ratio (INR), and activated clotting (or coagulation) time (ACT), 
the latter only if part of SOC at the investigational site. 
 Urinalysis Dipstick for presence of blood, glucose, ketones, and protein; pH, color (if 
applicable), transparency, specific gravity, and urobilinogen. 
Blood and urine samples will be obtained at Screening, and prior to the drug infusion on Days 3, 
EOT, and at EOS, and as clinically indicated for evaluation of blood chemistries, hematology, 
coagulation, and urinalysis. 
7.3.2.2 LSALT Peptide and Metabolite Pharmacokinetics 
Blood samples will be drawn at Baseline prior to initiation of drug administration, at the mid-point 
(1 hour) of the 2-hour infusion and immediately following the end of the 2-hour infusion on Days 1, 3, 
and at EOT for measurement of LSALT peptide and metabolite(s) analysis (See Section 8.1 Study 
Flow Chart). The time of the blood sample collection and the time of the most recent dose prior to 
the blood sample collection will be recorded accurately on the eCRF. Samples of blood will be 
centrifuged to obtain plasma; refer to the Laboratory Manual for Pharmacokinetic Sample 
Collection. 
7.3.2.3 Measurement of Cytokines and Other Biomarkers 
Blood samples will be drawn at Baseline prior to initiation of drug administration, at the mid-point 
(1 hour) of the 2-hour infusion and immediately following the end of the 2-hour infusion on Days 
1, 3, EOT, and a single blood draw at EOS for measurement of cytokines and other biomarkers 
(See Section 8.1 Study Flow Chart). Samples will be analyzed for the following biomarkers: IL-
1α, IL-1β, hs-troponin, and ferritin levels, as well as other exploratory biomarkers.  Please refer to 
the Laboratory Manual for more specific instructions. 
7.3.2.4 Cardiovascular Assessments 
Vital signs including supine pulse rate and blood pressure will be measured at Screening, and on 
Days 3, EOT, and EOS. ECGs (12-lead) will be recorded at Baseline pre-dose, Day 3, EOT, and 
at EOS (if clinically indicated). Highly-sensitive troponin levels will be compared from baseline 
and between treatment groups throughout the study (refer above to Section 7.3.2.3). 
7.3.2.5 Pulmonary Assessments 
Chest x-rays will be obtained at Baseline, Day 3, at time of clinical improvement, at EOT, at EOS, 
and where clinically indicated. All x-rays will be recorded in the eCRF. Chest CT will be obtained 
as per clinical practice at the study site. 
 
 


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8 
STUDY PROCEDURES AND FLOW CHART 
 
Study Flow Chart 
Calendar 
Admissiona 
Admissionb 
Treatment 
Period
Treatment 
Period
EOT 
EOS 
Day
1
1
1 – 14  (max)
3 
Variable
28±3
Sign informed consent 
X
Assign screening number
X
Inclusion/exclusion criteria
X
Review demographics
X
Review medical history
X
Concomitant medsc 
X
X
X
X
X
Physical examc
X
X
X
X
X
Respiratory examc
X
X
X
X
X
Urine pregnancy in WCBP
X
Clinical labs/Urine testsc,d 
X
X
X
X
12-lead ECGe
X
X
X
X
Vital signsc,f
X
X
X
X
X
eGFRb,d
X
X
X
X
SARS-CoV-2 testing swabsc,g
X
X
X
X 
Chest x-rayh
X
X
X
X
PK and biomarker samplesi 
X
X
X
X
Randomization
X
Study drug administration
X
X
X
X
AE assessments
X
X
X
X
X
SARS-CoV-2 IgG, IgA, IgM levels
X
X
Berlin Definitionj,k 
X
X
X
X
SOFA scorej,l
X
X
X
X
mMRC scorej,m 
X
X
X
X
APACHE II scorej,n
X
X
X
X
Health Outcomes
X
a Screening to determine eligibility (prior to randomization) 
b Baseline after Screening and prior to the start of study drug unless otherwise indicated. 
c Performed at Screening, Day 3, and EOT prior to drug administration, and at EOS. 
d Hematology, biochemistry, coagulation, and urinalysis will be obtained and eGFR will be calculated 
(Appendix 2), and when clinically indicated. 
e 12-Lead ECG (supine) will be recorded at time 0 (pre-dose) at Screening, Day 3, EOT, and at EOS (only 
if clinically indicated). Also, an ECG will be obtained during the study when clinically indicated. 
f Blood pressure (supine), pulse rate (supine), body temperature, respiration rate (supine), actual body 
weight (kg), and height (cm). Note: Height will only be measured at Screening.  
g Swabs (nasal, throat, sputum, or lower respiratory tract) at Screening, Day 3, EOT, and EOS.  
h Chest x-rays at Baseline (Day 1), Day 3, at time of clinical improvement, at EOT, and EOS. A chest x-
ray will also be obtained if clinically warranted and recorded in the eCRF.  
i Blood draws at Baseline pre-dose, at the mid-point (1 hr) and at the end of 2-hr infusion of study drug on 
Days 1, 3, and EOT, and a single blood draw at EOS. 
j Obtained at Baseline, Day 3, when clinically indicated, at EOT, and at EOS. 
k  Appendix 3 
l Appendix 4 
m Appendix 5 
n Appendix 6 


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Study Visits 
 Screening (Day 1a) 
 Obtain written informed consent from the patient 
 Assign screening number 
 Review Inclusion/Exclusion criteria with the patient 
 Collect demographics and medical history 
 Document concomitant drugs, including drug name, dose, and frequency  
 Urine pregnancy test for female patients of child-bearing potential 
 Perform physical examination including respiratory exam 
 Laboratory tests including hematology, biochemistry, coagulation, and urinalysis 
 12-lead ECG  
 Measure vital signs, including blood pressure (sitting), pulse rate, body temperature, 
respiration rate, actual body weight (kg), and height (cm) 
 Swab nasal, throat, sputum, or lower respiratory tract source for SARS-CoV-2.  
 Calculate eGFR  
 Baseline Visit (Day 1b) 
 Obtain chest x-ray 
 Collect blood samples (5 mL each) at Baseline prior to start of drug infusion, at one hour 
post start of infusion, and end of the daily 2-hour drug infusion for PK, cytokines, and 
antibody analysis. Prepare the samples per Section 7.3.2.2. 
 Review and record any TEAEs 
 Complete the (1) Berlin Definition (Appendix 3), (2) SOFA score (Appendix 4), (3) 
modified Medical Research Council Dyspnea Scale (Appendix 5), and (4) APACHE II 
score (Appendix 6) pre-dose.  
 Randomize the patient 
 Administer IV drug over 2 hours (after completion of all other assessments and procedures 
on Day 1) 
 During Treatment Period (Days 1, 2, 4 – 14 (maximum)) 
 Document concomitant drugs, including drug name, dose, and frequency 


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 Perform physical examination including respiratory exam 
 Measure vital signs, including blood pressure (sitting), pulse rate, body temperature, 
respiration rate, and actual body weight (kg) daily or as clinically indicated – note: no need 
to document height. 
 Administer IV drug over 2 hours 
 Review and record any TEAEs. 
 During Treatment Period (Day 3 and EOT, and when clinically indicated) 
 Document concomitant drugs, including drug name, dose, and frequency 
 Perform physical examination including respiratory exam 
 Obtain chest x-ray on Day 3, in the event of clinical improvement, and at EOT, and when 
clinically indicated 
 12-lead ECG  
 Laboratory tests including hematology, biochemistry, coagulation, and urinalysis on Day 
3, EOT, and if clinically indicated 
 Measure vital signs, including blood pressure (sitting), pulse rate, body temperature, 
respiration rate, and actual body weight (kg) daily or as clinically indicated – note: no need 
to document height. 
 Calculate eGFR  
 Administer IV drug over 2 hours 
 Collect blood samples (5 mL each) at mid-point and end of the 2-hour drug infusion for 
PK and biomarker analysis. Prepare the samples per Section 7.3.2.2. 
 Review and record any TEAEs 
 Swab nasal, throat, sputum, or lower respiratory tract source for SARS-CoV-2 on Days 4, 
7, 10, and 14 (if necessary). 
 Complete the (1) Berlin Definition (Appendix 3), (2) SOFA score (Appendix 4), and (3) 
modified Medical Research Council Dyspnea Scale (Appendix 5), and (4) APACHE II 
score (Appendix 6; only if clinically indicated).  


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 End of Treatment (EOT) 
The EOT visit refers to the completion of the last dose of study drug.  All study assessments 
outlined during the Treatment Period are to be performed.  For a complete list of assessments, refer 
to the Study Flow Chart.   
 End of Study (Day 28 EOS ± 3 days)  
 Document concomitant drugs, including drug name, dose, and frequency 
 Perform physical examination including respiratory exam 
 Laboratory tests including hematology, biochemistry, coagulation, and urinalysis, and 
antiviral antibodies (IgG, IgM, IgA) 
 Collect blood sample in the morning for biomarker analyses. Prepare the samples per 
Section 7.3.2.2. 
 12-lead ECG (if clinically indicated) 
 Obtain chest x-ray 
 Measure vital signs, including blood pressure (sitting), pulse rate, body temperature, 
respiration rate, and actual body weight (kg) 
 Calculate eGFR  
 Review and record any TEAEs 
 Swab nasal, throat, sputum, or lower respiratory tract source for SARS-CoV-2 if not 
eradicated on Day 14. 
 Complete the (1) Berlin Definition (Appendix 3), (2) SOFA score (Appendix 4), and (3) 
modified Medical Research Council Dyspnea Scale (Appendix 5), and (4) APACHE II 
score (Appendix 6) on Day 28 (EOS). 
 Record healthcare resource utilization.  
 Premature Withdrawal / Early Termination Visit 
All attempts should be made to perform all the tests for Day 28 at the Withdrawal/Early 
Termination visit for patients who may withdraw consent for further participation in the study 
before completion. 
 Unscheduled Visits 
If a patient returns to the site prior to their next scheduled study visit for assessment of an adverse 
event (e.g., before Day 28), or at the request of the Investigator, the Unscheduled Visit forms of 
the eCRF should be completed. Procedures and examinations conducted at the Unscheduled Visit 


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are at the discretion of the Investigator. If the patient withdraws consent for further participation 
at the Unscheduled Visit, the eCRF forms for the Premature Withdrawal / Early Termination Visit, 
and the End of Study Form should be completed rather than the Unscheduled Visit form. 
 Appropriateness of Measurements 
Prevention of ARDS will reduce morbidity and mortality in infected patients, amongst others. 
 Data Quality Assurance 
Steps to be taken to assure the accuracy and reliability of data include the selection of qualified 
PIs and appropriate study centers, review of protocol procedures with the PI and associated 
personnel prior to the study, and periodic monitoring and site audits by the Sponsor or their 
designee. The data will be entered into the clinical trial database and verified for accuracy. 
9 
STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
 
Determination of Sample Size 
The sample size (n=60) was determined based on medical judgement and a desire to assess safety 
in a limited number of patients, prior to further study and patient availability: 30 patients (active) 
and 30 patients (placebo). 
 
Patient Populations 
 Full Analysis Set (FAS) 
The Full Analysis Set is defined as patients who received any amount of at least one dose of study 
medication, with assignment to treatment as randomized. 
 Per Protocol (PP) Population 
The Per Protocol population is defined as patients who meet all inclusion/exclusion criteria, were 
within the acceptable compliance range (≥80% and ≤120%), and completed the study with no 
major protocol violations.  The Per Protocol population will be finalized prior to breaking the blind 
for final reporting. 
 Safety Population 
The safety population is defined as all patients who received at least one dose (partial or complete) 
of the study medication, assigned to treatment according to the treatment actually received. 
 
Statistical Methods 
In general, continuous variables will be summarized with descriptive statistics (the number of 
non‑missing values [n], mean, median, standard deviation [SD], minimum, and maximum). All 
categorical variables will be summarized with frequency counts and percentages, as applicable.   
A detailed statistical analysis plan (SAP) will be developed which will describe all analyses to be 
performed. The SAP will be finalized prior to database lock and unblinding. 


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 Demographic, Medical, and Disease History 
All baseline characteristics, demographics, and medical history (by body system) will be 
summarized by treatment within each age cohort as well as overall. For continuous variables, n, 
mean, standard deviation, median, minimum, and maximum will be presented. For categorical 
variables, frequency counts and percentages will be presented. No formal statistical analysis 
methods will be employed. 
Summary and/or data listings of the prior, concomitant medications, in particular AEDs, and class 
of medication will be provided. 
 Efficacy Analyses 
The primary efficacy endpoint is the proportion of subjects alive and free of respiratory failure 
(e.g., need for non-invasive or invasive mechanical ventilation, high flow oxygen (≥ 6 L/minute), 
or ECMO) and free of the need for continued renal replacement therapy (RRT) on Day 28. The 
need for continued RRT at Day 28 will be defined as either dialysis in the past 3 days (Day 26, 27, 
or 28) or an eGFR on Day 28 <10 mL/min/1.73 m2.       
Analyses for the primary and the key secondary endpoints will be performed on the FAS and PP 
populations, with the analysis on the FAS as the primary analysis; all other efficacy endpoints will 
be analyzed on the FAS population only. 
Time to event variables will be summarized using Kaplan-Meier survival curves and compared 
between treatment groups using either Log-rank tests or Cox’s Proportional Hazard model 
adjusting for baseline covariates, as necessary.  For continuous variables assessed at multiple time 
points a Mixed Model Repeated Measures (MMRM) approach will be used or Analysis of 
Covariance (ANCOVA) if assessed at a single time point post-baseline.  For categorical endpoints 
Cochran-Mantel-Haenszel (CMH) methods will be used, or a logistic regression approach, in the 
case of continuous covariates.  
Additional details regarding precise endpoint definitions (including transformations, as 
applicable), analysis model specifications and alpha-level control for primary and important 
secondary endpoints associated with multiplicity will be provided in the SAP, to be finalized prior 
to unblinding the study.  
 Pharmacokinetic Analysis 
All plasma concentration data will be summarized using N, mean, SD, % coefficient of variation, 
median, minimum, and maximum by treatment and cohort. Attempts will be made to correlate 
LSALT peptide concentrations with cytokine levels. 
 Safety Analysis 
9.3.4.1 Adverse Events 
All safety analyses will be conducted on all patients who are in the Safety Population. AEs will be 
coded to system organ class and preferred term using MedDRA version 20.0 or higher. All AEs 
occurring after the initiation of the study treatment (TEAEs) will be collected, including events 
present at baseline that worsened during the study. 


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AEs will be summarized by treatment group to provide comparison among the treatment groups 
with respect to incidence of AEs (the number of patients reporting at least one episode of a specific 
AE), incidence of AEs by severity within body system, incidence of AEs by attribution within 
body system, and incidence of AEs causing withdrawal and incidence of SAEs. Regarding severity 
and attribution summaries, the most extreme outcome (highest severity and closest to study drug 
related) will be used for those patients who experience the same AE on more than one occasion. 
Written narratives will be provided for all serious, unexpected, or other significant AEs that are 
judged to be of special interest because of their clinical importance. 
9.3.4.2 Clinical Laboratory 
Clinical Laboratory examination will be performed prior to treatment and during treatment. 
Descriptive statistics will be presented for the observed values and change from baseline of each 
of the clinical laboratory results by treatment and visit. Shift tables describing abnormality shifts 
from baseline to after treatment and follow-up (Day 28) will be created. 
9.3.4.3 Vital Signs, ECG, and Chest X-rays 
Vital signs, 12-lead ECG parameters, and chest x-rays will be summarized using descriptive 
statistics by treatment including changes from baseline. 
 Interim Analysis 
No interim analysis apart from that provided to the DSMB for the purpose of ensuring safety of 
patients will be conducted.  
 Study Stopping Rules 
The progress of the study will be monitored by the DSMB  on an ongoing basis according to the 
DSMB Charter with meetings at monthly intervals or more frequently dependent upon the rate of 
enrollment. These meetings will include an assessment of differences in the number of subjects 
with an unfavorable outcome for the primary endpoint, as well as observed imbalances in severity 
or risk factors and the totality of data, including adverse event profiles not associated with an 
unfavorable primary endpoint value.  Consideration will also be given to the limited information 
available in the early stages of the study and a potential for unfavorable trends with very few 
subjects due to chance alone. 
9.3.6.1 Safety Indices 
 The observed adverse event profile of the patients on the treatment arm exceeding the incidence 
and/or severity of adverse events observed in the placebo arm to a significant degree at any 
time during the study. 
 Primary endpoint: there will be no more than a 1-subject difference in the number of subjects 
with an unfavorable outcome for the primary endpoint after the first 6 subjects completed 
active treatment compared with placebo (in favor of placebo). Subsequently, for the total 
number of 18 subjects, there will be no more than a 2-subject difference in the primary endpoint 
(in favor of placebo) and no more than a 3-subject difference for the remaining subjects.  
Otherwise, the DSMB will consider stopping the study for safety reasons.   


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For the primary endpoint, each of these scenarios is considered unlikely in the presence of at least 
a modest relative reduction in the incidence rate of only 20 percent (i.e., a rate of 22.4% for LSALT 
from an assumed incidence rate of 28% for placebo), with probabilities in the range of 6% or less 
for these unfavorable outcomes at the end of each cohort, under this assumption. 
 Missing Data  
Although significant missing data with respect to the primary endpoint is not anticipated for a 
study of this duration (due to the nature of the endpoint), methods for handling missing data and 
intercurrent events, including for secondary endpoints will be specified in the SAP.  These methods 
will be consistent with missing data due to death as having a worst possible outcome.    
10 QUALITY CONTROL AND QUALITY ASSURANCE 
 Source Data and Records 
Source data are all the information in original records and certified copies of original records of 
clinical findings, observations, laboratory reports, data sheets provided by the Sponsor or other 
activities in the study, which are necessary for the reconstruction and evaluation of the study. The 
PI will permit study-related monitoring, audit(s), IRB review(s), and regulatory inspection(s), with 
direct access to all the required source records. 
All study records will be retained for a period of time as defined by the regulatory authority for 
the country in which the investigation is conducted. Generally, this means at least 2 years following 
the date on which the drug is approved by the regulatory authority for marketing for the purposes 
that were the subject of the investigation. In other situations, (e.g., where the investigation is not 
in support of or as part of an application for a research or marketing permit), a period of 2 years 
following the date on which the entire clinical program is completed, terminated, or discontinued 
or the investigational application under which the investigation is being conducted is terminated 
or withdrawn by the regulatory authorities. 
In the event the PI retires, relocates, or for any other reason withdraws from the responsibility for 
maintaining records for the period of time required, custody of the records may be transferred to 
any other person who will accept responsibility for the records. Notice of such a transfer must be 
given in writing to the Sponsor. The PI must contact the Sponsor prior to disposal of any records 
related to this study. 
 Reporting of Results 
The electronic Case Report Form (eCRF) is an integral part of the study and subsequent reports. 
The eCRF must be used to capture all study data recorded in the patient’s medical record. The 
eCRF must be kept current to reflect patient status during the course of the study. 
The monitor is responsible for performing on-site monitoring at regular intervals throughout the 
study to verify adherence to the protocol; verify adherence to local regulations on the conduct of 
clinical research; and ensure completeness, accuracy, and consistency of the data entered in the 
eCRF. 


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Arch Biopartners or its designate will monitor completed eCRFs. An eCRF will also be completed 
for each screened patient. 
All protocol-required information collected during the study must be entered by the PI, or 
designated representative, in the eCRF, an internet-based electronic data collection system. All 
details of the eCRF completion and correction will be explained to the PI and his staff. The 
management module of the eCRF includes edit check and query systems that seamlessly integrate 
with the data entry system. All modifications to the data in the eCRF are tracked by an electronic 
audit trail (date and identity of the person making the change are instantaneously recorded). The 
eCRF will be 21CFR Part 11 compliant. 
If the PI authorizes other persons to make entries in the eCRF, the names, positions, and signatures 
of these persons must be supplied to the Sponsor. 
The PI, or designated representative, should complete the eCRF as soon as possible after data are 
collected, preferably on the same day that a study patient is seen for an examination, treatment, or 
any other study procedure. Any outstanding entries must be completed immediately after the final 
examination. By design, an explanation must be provided for all missing data, altered data, and/or 
out of range data. 
The completed eCRF must be reviewed and signed by the PI named in the study protocol or by a 
designated sub-Investigator. 
Final monitored and audited eCRFs will be provided by the Sponsor to the sites at the end of the 
study in the format of a PDF file. 
 Confidentiality of Patient Data 
The PI will ensure that the confidentiality of the patients' data will be preserved. In the eCRF or 
any other documents submitted to the Sponsor, the patients will not be identified by their names, 
but by an identification system, which consists of a uniquely assigned number in the study. The PI 
will maintain documents not meant for submission to the Sponsor (e.g., the confidential patient 
identification code and the signed informed consent forms) in strict confidence. 
11 REPORTING AND PUBLICATION 
 Confidentiality of Study Data 
Any information relating to the study drug or the study, including any data and results from the 
study, will be the exclusive property of the Sponsor. The PI and any other persons involved in the 
study will protect the confidentiality of this proprietary information belonging to Arch Biopartners.


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13 APPENDICES 
 Appendix 1.  Bottle Label 
Sample labels for the study drug are illustrated below in Figure 6 and Figure 7. Labels will be 
adapted in accordance with local regulatory and language requirements. 
Figure 6:  Vial Labels 
Study #AB002           LSALT Peptide – 4.95 mg 
0.9 mg/mL (5.5 mL fill in 10 mL Clear Vial) 
Mfg. Date: 21SEP2018             Lot Number: LE550C02R1 
Store at (-15°C to -25°C) 
LSALT Peptide Solution for IV Administration –  
Use as per sponsor instructions 
Sponsor: Arch Biopartners Inc. 
(Toronto. ON, M4T 2M5, Canada) 
Caution: New Drug – Limited by Federal (or United States)  
law to investigational use only 
Trial Subject ID#:  ____________________ 
 
 
VIAL LABEL: TURKISH TRANSLATION 
Klinik çalışma #AB002           LSALT Peptide – 4.95 mg 
0.9 mg/mL (5.5 mL dolum miktarı, 10 mL şeffaf flakonda) 
Üretim tarihi: 21EYL2018             Seri no: LE550C02R1 
-15°C ila -25°C arasındaki ısılarda saklanmalıdır 
LSALT Peptid solüsyonu; Sadece IV uygulama için –  
Çalışma destekleyicisinin yönergeleri doğrultusunda uygulanmalıdır 
Destekleyici : Arch Biopartners Inc. 
(Toronto. ON, M4T 2M5, Canada) 
Dikkat: Araştırma İlacıdır - Sadece klinik araştırma için kullanılmalıdır 
Çalışma hasta numarası #:  ____________________ 
 
 
 
 


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Figure 7:  Outside Carton Labels 
 
 
 
 
 
Study #AB002 
LSALT Peptide – 4.95mg/vial 
0.9mg/mL (5.5mL fill in 10mL Clear Vial) 
Mfg. Date: 21SEP2018 
Lot Number: LE550C02R1 
Store at (-15°C to -25°C) 
LSALT Peptide Solution for IV Administration - Use as per sponsor instructions 
Sponsor: Arch Biopartners Inc. 
(Toronto. ON, M4T 2M5, Canada,) 
Caution: New Drug – Limited by Federal  
(or United States) law to investigational use only 
Number of vials per carton: 100 
Carton #: ____________________  
                   
CARTON LABEL: TURKISH TRANSLATION
Klinik çalışma #AB002 
LSALT Peptid – 4.95mg/flakon 
0.9mg/mL (5.5mL dolum miktarı, 10mL şeffaf flakonda) 
Üretim tarihi: 21EYL2018 
Seri no: LE550C02R1 
-15°C ila -25°C arasındaki ısılarda saklanmalıdır 
LSALT Peptid solüsyonu; Sadece IV uygulama için –  
Çalışma destekleyicisinin yönergeleri doğrultusunda uygulanmalıdır 
Destekleyici: Arch Biopartners Inc. 
(Toronto. ON, M4T 2M5, Canada,) 
Dikkat: Araştırma İlacıdır - Sadece klinik araştırma için kullanılmalıdır 
Her karton kutuda 100 flakon vardır 
Karton kutu #: ____________________  
                   


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 Appendix 2.  Clinical Laboratory Tests 
Clinical Chemistry 
Hematology 
Coagulation 
Urinalysis 
Total bilirubin 
Hemoglobin 
Activated clotting time* 
pH* 
AST (SGOT) 
Hematocrit 
aPTT 
Color* 
ALT (SGPT) 
Erythrocytes 
Prothrombin time 
Transparency 
BUN 
Leukocytes + Diff 
INR 
Specific gravity 
Glucose 
Thrombocytes 
 
Urobilinogen 
Potassium 
 
 
Ketones 
Sodium 
 
 
Protein 
Calcium 
 
 
Glucose 
Alkaline phosphatase 
 
 
Hemoglobin 
Chloride 
 
 
 
Creatinine & eGFR (calc) 
 
 
 
Gamma-glutamyl 
transferase 
 
 
 
Total protein 
 
 
 
Albumin 
 
 
 
CO2 
 
 
 
ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen; aPTT = activated 
partial prothrombin time; Diff = differential; INR = International normalized ratio; CO2 = carbon dioxide; 
eGFR (calc) = estimated glomerular filtration rate 
*Only if SOC 
 


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 Appendix 3.  Berlin Definition 
Acute Respiratory Distress Syndrome (ARDS) 
Timing
Within 1 week of a known clinical insult or new/worsening respiratory symptoms 
Chest imaginga
Bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules 
Origin of edema 
Respiratory failure not fully explained by cardiac failure or fluid overload 
Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor 
present 
Oxygenationb 
 
    Mild
200 mmHg < PaO2/FiO2 ≤ 300 mmHg with PEEP or CPAP ≥ 5 cm H2Oc 
    Moderate
100 mmHg < PaO2/FiO2 ≤ 200 mmHg with PEEP ≥ 5 cm H2O
    Severe
PaO2/FiO2 ≤ 100 mmHg with PEEP ≥ 5 cm H2O
aChest radiograph or computed tomography scan 
bIf altitude is >1000 m, the correction factor should be calculated as follows: [PaO2/FiO2 x (barometric pressure/760)] 
cThis may be delivered noninvasively in the mild acute respiratory distress syndrome group 
 
 


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 Appendix 4.  Sequential Organ Failure Assessment (SOFA) score 
 
 
 


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 Appendix 5.  Modified Medical Research Council (mMRC) Dyspnea Scale 
 
 
 
 


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  Appendix 6.  Acute Physiology and Chronic Health Evaluation II score