ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol
Conditions: Critical COVID-19 With Respiratory Failure
Sponsor: APR Applied Pharma Research s.a.

 
Copyright NeuroRx, Inc. ©2020 All Rights Reserved 
 
 
 
 
EXPANDED ACCESS PROTOCOL 
 
Intermediate-size Patient Population 
 
 
 
For patients with Critical COVID-19 with respiratory 
failure who do not quality for Protocol RLF-100-001 
 
 
Protocol#: RLF-100-EA-1 
 
 
 
 

 
NeuroRx, Inc.  
 
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Expanded Access Protocol 
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Principal Investigatory 
Jihad Georges Youssef, MD 
Houston Methodist Hospital 
Houston, TX 
Study Sponsor 
 
NeuroRx, Inc. 
913 North Market Street, Suite 200 
Wilmington, DE  19801 
Contact: 
Jonathan C. Javitt, MD, MPH 
202-340-1352 
IND Number: 
Phase: 
IND 149152 
Expanded Access Protocol 
Version 
Date 
V.2.0    
Aug 15, 2020 
 
 
 

  
 
 
 
 
 
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SYNOPSIS 
Name of 
Investigational 
P
d
t
RLF-100  
Name of Active 
Ingredient: 
Aviptadil 
Reference Product(s):  Vasoactive Intestinal Polypeptide (synthetic) 
Title of Study: 
RLF-100-EA-1:  Expanded Access Protocol for Patients with Critical 
COVID-19 with Respiratory Failure Who do not Qualify for Protocol 
RLF-100-001 
Phase of 
Development: 
Phase 2b/3: Expanded Access 
Study Site(s): All active RLF-100-001 study sites and other sites upon application 
and qualification 
Total Participant 
Number: 
Up to 100 patients 
Study Duration: 28-day total follow-up 
Background and 
Rationale: 
RLF-100 is currently being studied in Protocol RLF100-001 in patients 
Critical COVID-19 with respiratory failure.  This Expanded Access 
Protocol is intended to provide RLF-100 to investigators for use in 
critically ill patients who do not qualify for the ongoing study. 
 
Objectives: 1. To provide RLF-100 to critically ill patients who do not quality for 
Study RLF-100-001. 
2. To collect safety data 
3. To collect effectiveness data 
Efficacy Endpoints: Primary Outcome Measures: 
1. Percent of patients alive and free of respiratory failure at 144 
hours from start of treatment 
2. Percent of patients with radiographic improvement at 96 hours 
from start of treatment 
Secondary outcome measures 
1. Days on ventilation or high flow post treatment 
2. Days in ICU post treatment 
3. 
Improvement on NIAID scale at 96 hours and 144 hours 
Study Design: Open-label, externally-controlled study in which patients treated with 
RLF-100 are compared to concurrent control patients treated with 
standard of care. 

  
 
 
 
 
 
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Inclusion Criteria: 1. Critical COVID-19 with respiratory failure by NIH/FDA 
definition requiring either mechanical ventilation, non-invasive 
ventilation, or high flow rate nasal cannula at minimum 20L flow 
and 50% FIO2. 
2. Age 18 years or higher 
3. Physician commitment to maximal Standard of Care treatment – 
as deemed necessary (i.e. patients on a “no code” status are not 
eligible). 
 
Inclusion Criteria for 
Expanded Access 
Protocol:  Patients 
may be enrolled into 
the Expanded Access 
Protocol if any of the 
following condition 
are present 
 
 
1. Pregnancy  
2. Mechanical ventilation for more than 7 days in primary cohort. 
Mechanical ventilation>21 days in the exploratory cohort 
3. Mean Arterial Pressure < 65 mm Hg with use of pressor per ICU 
protocol 
4. Irreversible condition (other than COVID-19) with projected 
fatal course  
5. ECMO 
6. Current or recent (within 30 d) enrollment in another 
investigational trial of anti-IL6 drug; 
7. Active diagnosis of Acquired immune deficiency syndrome; 
8. Transplant patients currently immunosuppressed;  
9. Chemotherapy-induced neutropenia (granulocyte count 
<1000/mm3);  
10. Cardiogenic shock; congestive heart failure – NYHA Class 3 or  
4; 
11. Recent myocardial infarction – within last 6 months and 
troponin > 0.5uria (urine output < 50 ml/d) or other signs of 
multi-organ failure; 
12. Severe liver disease with portal hypertension;  
13. Recent stroke or head trauma within last 12 months 
14. Increased intracranial pressure, or other serious neurologic 
disorder; 
15. Inability to access RLF-100_001 
Exclusion Criteria 1) Eligible for enrollment in Protocol  RLF-100-001 (NCT04311697) 
2) Liquid Diarrhea more than 3x/day; defined as more than 3 non-
bloody watery stools within a 24-hour period, requiring additional 
fluid and electrolyte supplementation 
3) Hypotension (i.e. Mean Arterial Pressure <65mmHg) that cannot be 
managed with pressors 
 
Safety Assessments: 
Adverse Events 
Serious Adverse Events 
Vital Signs 
Complete Blood Count 
ECG 
Dosage, Route of 
Administration, and 
Schedule: 
Three escalating doses of RLF-100 (Aviptadil): 50,100, and 150 
pmol/kg/hour administered over 12 hours via IV infusion on 

  
 
 
 
 
 
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successive days.  If side effects are detected during the infusion, dose 
reduced or halted.  
Statistical Methods: 
 
Primary endpoint: survival over 60 days by Kaplan Meier analysis 
Secondary endpoint: recovery from respiratory failure on cumulative 
probability distribution 
Secondary endpoint: NIAID 8 point ordinal scale 
 
PROTOCOL SIGNATURE PAGE 
I have read this protocol and agree to adhere to the requirements. I will provide copies of this 
protocol and all pertinent information to the study personnel under my supervision. I will 
discuss this material with them and ensure they are fully informed regarding the conduct of 
the study according to 21 CFR parts 50, 54, 56 and 812, 45 CFR 46, to GCP, as described in 
ICH guideline E6 and to hospital Institutional Review Boards. 
 
 
 
_____________________________ 
 
 
_____________________ 
Clinical Site Investigator Signature 
 
 
 
Date 
 
 
_____________________________ 
Clinical Site Investigator Printed Name 
 
 
_____________________________ 
 
 
_____________________ 
Investigator-Sponsor Signature  
 
 
Date 
 
 
_____________________________ 
Investigator-Sponsor Printed Name 
 
 

  
 
 
 
 
 
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TABLE OF CONTENTS 
 
 
SYNOPSIS................................................................................................................................................. 3 
 
PROTOCOL SIGNATURE PAGE .................................................................................................................. 5 
 
TABLE OF CONTENTS ............................................................................................................................... 6 
 
LIST OF ABBREVIATIONS .......................................................................................................................... 8 
 
INTRODUCTION ....................................................................................................................................... 9 
5.1 
EXECUTIVE SUMMARY ................................................................................................................................. 9 
5.2 
DEFINITION OF CRITICAL COVID-19 .............................................................................................................. 9 
5.3 
RLF-100 EXPERIMENTAL THERAPY IN COVID-19 .......................................................................................... 10 
5.4 
CLINICAL RATIONALE ................................................................................................................................. 10 
 
OBJECTIVES ........................................................................................................................................... 10 
6.1 
PRIMARY OBJECTIVE ................................................................................................................................. 10 
6.2 
SECONDARY OBJECTIVE ............................................................................................................................. 10 
 
STUDY DESIGN ....................................................................................................................................... 10 
7.1 
OVERVIEW .............................................................................................................................................. 10 
7.2 
DESIGN .................................................................................................................................................. 11 
7.3 
NUMBER OF PARTICIPANTS ........................................................................................................................ 11 
7.4 
STUDY DESIGN ......................................................................................................................................... 11 
7.5 
RLF-100 TREATMENT PROTOCOL ............................................................................................................... 12 
7.6 
ANTICIPATED RISK .................................................................................................................................... 12 
 
SELECTION OF SUBJECTS ........................................................................................................................ 13 
8.1 
STUDY POPULATION ................................................................................................................................. 13 
8.2 
INCLUSION CRITERIA .................................................................................................................................. 13 
8.3 
INCLUSION CRITERIA FOR EXPANDED ACCESS PROTOCOL ..................................................................................... 13 
8.4 
EXCLUSION CRITERIA .................................................................................................................................. 13 
 
RECRUITMENT, CONSENT & ENROLLMENT ............................................................................................ 14 
9.1 
RECRUITMENT & CONSENT PROCEDURES...................................................................................................... 14 
9.2 
OBTAINING INFORMED CONSENT ................................................................................................................ 14 
9.3 
PROTECTING CONFIDENTIALITY ................................................................................................................... 14 
9.4 
HIPAA COMPLIANCE ................................................................................................................................ 14 
9.5 
STANDARD OF CARE SUPPORT .................................................................................................................... 14 
9.6 
POPULATION BIAS .................................................................................................................................... 14 
9.7 
ENROLLMENT .......................................................................................................................................... 15 
9.8 
CHARGING FOR INVESTIGATIONAL PRODUCT .................................................................................................. 15 
 TREATMENT OF SUBJECTS ..................................................................................................................... 15 
10.1 
MAXIMAL STANDARD OF CARE ................................................................................................................... 15 
10.2 
PROPER STANDARD OF CARE (SOC) MANAGEMENT PRINCIPLES ....................................................................... 16 
10.3 
DOSING REGIMEN .................................................................................................................................... 16 
10.4 
POTENTIAL SIDE EFFECTS OF DRUG THERAPY ................................................................................................. 16 
 ASSESSMENT OF SAFETY ........................................................................................................................ 17 
11.1 
SERIOUS ADVERSE EVENTS ......................................................................................................................... 17 
11.2 
DEFINITION OF ADVERSE EVENTS ................................................................................................................ 17 
11.3 
DEFINITION OF A SERIOUS ADVERSE EVENT ................................................................................................... 17 
11.4 
RELATIONSHIP TO STUDY DRUGS ................................................................................................................. 18 
11.5 
RECORDING OF ADVERSE EVENTS ................................................................................................................ 18 
11.6 
REPORTING OF ADVERSE EVENTS................................................................................................................. 18 
11.7 
REPORTING OF SERIOUS ADVERSE EVENTS .................................................................................................... 18 
 ASSESSMENT OF EFFICACY .................................................................................................................... 19 

  
 
 
 
 
 
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12.1 
DATA COLLECTION ................................................................................................................................... 19 
12.2 
ASSESSMENTS OF ENDPOINTS ..................................................................................................................... 19 
 
Recovery from Respiratory Failure in Critical COVID-19 ............................................................. 19 
 
Improvement in SaO2 .................................................................................................................. 19 
 
Improvement on NIAID Scale ...................................................................................................... 19 
 
Chest x-ray .................................................................................................................................. 19 
 
Inflammatory Markers ............................................................................................................... 20 
 STATISTICAL ANALYSIS .......................................................................................................................... 20 
13.1 
STATISTICAL DESIGN AND ANALYSES ............................................................................................................ 20 
13.2 
DATA ANALYSIS ....................................................................................................................................... 20 
13.3 
INTERIM SAFETY ANALYSIS ......................................................................................................................... 20 
 HYPOTHESIS TESTS ................................................................................................................................ 20 
14.1 
TREATMENT COMPARISONS ....................................................................................................................... 20 
14.2 
PRIMARY HYPOTHESIS ............................................................................................................................... 20 
14.3 
PRIMARY EFFICACY ENDPOINT: RECOVERY FROM RESPIRATORY FAILURE ............................................................. 20 
14.4 
DECLARED SECONDARY EFFICACY ENDPOINT: SAO2. ....................................................................................... 21 
14.5 
SECONDARY EFFICACY ENDPOINT: NAIAD 8 POINT ORDINAL SCALE ................................................................... 21 
14.6 
SECONDARY LABORATORY EFFICACY ENDPOINTS: INFLAMMATORY MARKERS ....................................................... 21 
14.7 
OVERALL SAFETY ENDPOINTS...................................................................................................................... 21 
 SOURCE DATA & DOCUMENTS .............................................................................................................. 21 
15.1 
SOURCES OF RESEARCH MATERIALS ............................................................................................................. 21 
15.2 
PATIENT IDENTIFICATION ........................................................................................................................... 21 
15.3 
GENERAL CLINICAL DATA ........................................................................................................................... 21 
15.4 
DATA USED TO DETERMINE RESPIRATORY FAILURE ........................................................................................... 21 
15.5 
RADIOLOGY ............................................................................................................................................. 21 
15.6 
LABORATORY DATA .................................................................................................................................. 22 
15.7 
VITAL SIGNS, RESPIRATORY AND HEMODYNAMIC DATA ................................................................................... 22 
 STUDY MONITORING ............................................................................................................................. 22 
16.1 
STUDY MONITORING ................................................................................................................................ 22 
16.2 
MEDICAL MONITOR ................................................................................................................................. 22 
16.3 
AUDITS AND INSPECTIONS .......................................................................................................................... 22 
16.4 
INSTITUTIONAL REVIEW BOARD .................................................................................................................. 22 
 ETHICAL CONSIDERATIONS .................................................................................................................... 23 
17.1 
ETHICAL CONSIDERATIONS ......................................................................................................................... 23 
 
Anticipated benefits to participants and others ......................................................................... 23 
 
Anticipated risks to participants and others ............................................................................... 23 
17.2 
ETHICAL CONDUCT OF THE STUDY ............................................................................................................... 23 
17.3 
INFORMED CONSENT ................................................................................................................................ 23 
 DATA HANDLING & RECORD KEEPING ................................................................................................... 23 
18.1 
DATA CAPTURE ........................................................................................................................................ 23 
18.2 
DATA COLLECTION ................................................................................................................................... 24 
18.3 
RETENTION OF RECORDS ........................................................................................................................... 24 
18.4 
USE OF INFORMATION AND PUBLICATION POLICY ........................................................................................... 24 
 APPENDIX A; SCHEDULE OF EVENTS ...................................................................................................... 25 
 
List of Figures 
Figure 1 Study Schema ......................................................................................................................... 11 
Figure 2 Study Dosing .......................................................................................................................... 12 
 

  
 
 
 
 
 
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LIST OF ABBREVIATIONS 
AA 
 
 
Amino Acid 
ALI  
 
 
Acute Lung Injury 
ARDS  
 
Associated Acute Respiratory Distress Syndrome\ 
COVID-19 
 
Corona Virus Disease 2019 
ECMO  
 
Extracorporeal membrane Oxygenation 
ED  
 
 
Erectile Dysfunction  
EMR  
 
Electronic Medical Record 
Fas 
 
 
Cell Surface Death Receptor 
HCl 
 
 
Hydrogen Chloride 
ICU 
 
 
Intensive Care Unit 
ITT 
 
 
Intent-to-Treat 
IL 
 
 
Interleukin 
IND   
 
Investigational New Drug  
IV 
 
 
Intravenous 
SOC  
 
Maximal Intensive Care 
MERS  
 
Middle East Respiratory Syndrome 
MMRM 
 
Mixed model repeated measures 
RDR  
 
Respiratory Distress Ratio 
SOC  
 
Standard of Care 
SAE   
 
Serious Adverse Events 
SARS  
 
Severe Acute Respiratory Syndrome   
SARS-CoV-2  
SARS-Coronavirus 2 
TNFα   
 
Tumor Necrosis Factor Alpha 
VIP 
 
 
Vasoactive Intestinal Peptide 
 
 

  
 
 
 
 
 
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INTRODUCTION 
5.1 Executive Summary 
RLF-100 (aviptadil) is a synthetic form of Vasoactive Intestinal Polypeptide (VIP), a 
ubiquitous, naturally synthesized human peptide with extensively documented anti-
inflammatory, anti-cytokine cascade properties.  It has been granted FDA Fast Track 
Designation for treatment of Critical COVID-19 with Respiratory Failure. A phase 2/3 trial is 
underway that has passed its first evaluation at 30 patients for safety and futility.  This 
expanded access protocol is designed to offer access to investigational use of RLF-100 to 
patients who do not qualify for inclusion in Protocol  RLF-100-001 (NCT04311697) either 
on the basis of specific medical exclusions or because there is no accessible study site 
available to the prospective participant. 
5.2 Definition of Critical COVID-19 
In May 2020, FDA defined Critical COVID-19 to be used in clinical trials and disease 
staging as follows: 
Critical  
COVID-19 
• 
Positive testing by standard RT-PCR assay or an equivalent test 
• 
Evidence of critical illness, defined by at least one of the following:  
o 
Respiratory Failure defined on resource utilization requiring at least 
one of the following: 
▪ 
Endotracheal intubation and mechanical ventilation, oxygen 
delivered by high-flow nasal cannula (heated, humidified, oxygen 
delivered via reinforced nasal cannula at flow rates > 20 L/min 
with fraction of delivered oxygen ≥ 0.5), noninvasive positive 
pressure ventilation, ECMO, or clinical diagnosis of respiratory 
failure (i.e., clinical need for one of the preceding therapies, but 
preceding therapies not able to be administered in setting of 
resource limitation) 
o 
Shock (defined by systolic blood pressure <90 mmHg, or diastolic 
blood pressure <60 mmHg or requiring vasopressors) 
o 
Multi-organ dysfunction/failure 
 
Acute Lung Injury in COVID-19 is characterized by progressive failure of corporeal 
oxygenation, attributed on large part by SARS-CoV-2 infection of Alveolar Type II cells 
(Mason 2020). Extensive nonclinical studies document that 70% of VIP in the body binds to 
receptors on the Alveolar Type II cell, where VIP is known to block cytokine production and 
upregulate production of surfactant. 
 
Severity of COVID is associated with and graded by a progressively worsened state of 
oxygenation. This is seen in the PaO2/FIO2 ratio, which reflects the status of oxygenation for 
patients on high pressure oxygen and mechanical ventilation. In patients breathing room air, 
disease severity is assessed by SpO2. Many patients with Critical COVID meet the clinical 
definitions of Acute Respiratory Distress Syndrome (ARDS).  However, there is increasing 
recognition that respiratory distress in COVID-19 has different characteristics than ARDS in 
the setting of bacterial sepsis and other common presentations of ARDS. 
The pathologic hallmark of COVID-19 lung injury is diffuse alveolar damage, vascular 
endothelium damage, and damage to the surfactant-producing type II cells which results in 

  
 
 
 
 
 
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loss of the integrity of the alveolar-capillary barrier, transudation of protein-rich fluid across 
the barrier, pulmonary edema, and hypoxemia from intrapulmonary shunting. Typically, 
patients who have progressed to Critical COVID-19 require care in an intensive care unit 
(ICU). The mortality rate is variable but significant.  Deaths usually result from multisystem 
organ failure rather than lung failure alone. 
 
5.3 RLF-100 Experimental Therapy in COVID-19 
Under this protocol, patients with Critical COVID-19 will be treated with RLF-100 
(Aviptadil) with the aim to support pulmonary alveolar function, combat the cytokine-
induced inflammation, improve blood oxygenation, and reduce mortality.  
5.4 Clinical Rationale 
Given by intravenous infusion in appropriate concentrations, RLF-100-001 has been shown 
in clinical trials to have a manageable safety profile with no observed SAEs to date that 
would rise to the level of a black box warning.  
 
OBJECTIVES 
6.1 Primary Objective 
The primary objective of this study is to measure the effectiveness and safety of RLF-100 + 
maximal standard of care (SOC) in treating Critical COVID-19 with Respiratory Failure. 
6.2 Secondary Objective 
The key secondary objective is to test the hypothesis that RLF-100 improves blood 
oxygenation as measured by SaO2. 
 
STUDY DESIGN 
7.1 Overview 
This study, RLF100-EA-001, is an expanded access protocol for patients with Critical 
COVID-19 with respiratory failure who do not quality for Protocol RLF-100-001 
(NCT04311697), as posted on www.clinicaltrials.gov.  Patients who enroll in this study will be 
treated with RLF-100 + Maximal SOC. Aviptadil will be administered as a 12-hour IV 
infusion one thee consecutive days.  Primary endpoints will be measured at five (5) days post 
infusion with 28 days of follow-up. Patients with Critical COVID-19 infection who are not 
eligible for enrollment in Protocol RLF-100-001 will be offered the opportunity to participate 
in this study. 
 
Informed consent will be obtained from the patient or a responsible party. Once enrolled, 
patients will receive RLF-100 by IV infusion, each dose given over 12-hour period at the 
same time on consecutive days, in escalating doses from 50pmol/kg/hr to 150 pmol/kg/hr of 
RLF-100.    The primary outcome to be measured following RLF-100 infusion is recovery 
from respiratory failure by day 7. Numbers of participants surviving will be compared to 

  
 
 
 
 
 
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historical controls and to the placebo arm of Protocol RLF-100-001.  The declared secondary 
outcome to be measured following RLF-100 infusion will be improvement in blood oxygen 
saturation (SaO2) as measured by pulse oximetry. 
7.2 Design 
Open-label, expanded access protocol in patients with Critical COVID-19 and respiratory 
failure who do not meet the criteria for Protocol RLF-100-011 (NCT04311697) or cannot 
feasibly access an existing clinical trial site. 
 
Following informed consent, patients will be administered escalating doses of RLF-100 from 
50 pmol/kg/hour IV to 150 pmol/kg/hour as three (3) 12 hour infusions each at the same time 
of day on subsequent study days 1, 2, and 3.Vital signs and telemetry will be monitored 
throughout the infusion and for 48 hours after completion of all 3 infusions. Pulmonary, 
cardiovascular, hepatic, CNS, renal, and coagulation functions will be assessed daily for 5 
days, chest x-rays and plasma levels of selected cytokines will be requested as a condition of 
voluntary participation in this protocol. The primary efficacy outcome is recovery from 
respiratory failure secondary to Critical COVID-19. Secondary outcomes will include 
oxygenation levels and as other outcome measures.  
7.3 Number of Participants 
Initially, the study is limited to 100 participants.  As additional safety data emerge and 
availability of investigational product increases, the number of participants is expected to 
increase. 
7.4 Study Design 
 

  
 
 
 
 
 
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Figure 1 shows a graphical schema of the RLF100-001 protocol study design. 
 
7.5 RLF-100 Treatment Protocol 
Figure 2 shows a graphical flow chart of the RLF100-EA1 protocol study design. 
Note: If a determination is made to slow down the infusion rate by 50%, the next infusion 
would still be administered at the next 24-hour period, e.g., if infusion was started at 8:00 
AM and it runs for 18 hours, the next infusion should still take place at 8:00 AM the 
following day. 
7.6 Anticipated Risk 
Reported adverse events for intravenous aviptadil include hypotension, tachycardia, facial 
flushing and watery diarrhea. Pretreatment with Immodium is recommended and the use of a 
fecal management system is recommended if diarrhea develops. Hypotension is routinely 
managed per ICU protocol with pressors and the infusion may be slowed by up to 50% or 
halted if pressors are not effective in managing hypotension. See Flow Chart (Figure 2 
above). 

  
 
 
 
 
 
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SELECTION OF SUBJECTS 
8.1 Study Population 
The trial will be conducted in hospitalized patients with Critical COVID-19 by FDA/NIH 
criteria (section 6.2.) Subjects must either  
• be ineligible for Protocol RLF-100-001 based on specific exclusion criteria or  
• unable to access an active RLF-100-001 study site to participate in the study. 
 
8.2 Inclusion Criteria 
All patients entered this trial will have the diagnosis of Critical COVID-19. Subjects will be 
observed for a 1 to 24-hour period, during which time all inclusion criteria must be met. If all 
criteria are met once (not necessarily simultaneously), the patient will be enrolled and 
randomized to receive the study drug within 12 hours of the following entry criteria being 
fulfilled: 
1) Critical COVID-19 with respiratory failure by NIH/FDA definition requiring either 
mechanical ventilation, non-invasive ventilation, or high flow rate nasal cannula at 
minimum 20L flow and 50% FIO2. 
2) Age 18 years or higher 
3) Physician commitment to maximal Standard of Care treatment, as deemed necessary, i.e. 
patients on a “no code” status are not eligible. 
8.3 Inclusion Criteria for Expanded Access Protocol 
One or more of the below (which constitute exclusion criteria for Protocol RLF-100-001): 
1) Pregnancy  
2) Mechanical ventilation for more than 7 days 
3) Mean Arterial Pressure < 65 mm Hg with use of pressors per ICU protocol 
4) Irreversible condition (other than COVID-19) with projected fatal course  
5) ECMO 
6) Current or recent (within 30 d) enrollment in another investigational trial of anti-IL6 
drug 
7) Active diagnosis of Acquired immune deficiency syndrome 
8) Transplant patients currently immunosuppressed 
9) Chemotherapy-induced neutropenia (granulocyte count <1000/mm3) 
10) Cardiogenic shock; congestive heart failure – NYHA Class 3 or 4 
11) Recent myocardial infarction, within last 6 months and current troponin > 0.5 
12) Anuria (urine output < 50 ml/d) or other signs of multi-organ failure  
13) Severe liver disease with portal hypertension 
14) Recent stroke or head trauma within last 12 months 
15) Increased intracranial pressure, or other serious neurologic disorder 
16) Inability to access RLF-100_001 
8.4 Exclusion Criteria 
1) Eligible for enrollment in Protocol RLF-100-001. 
2) Liquid Diarrhea more than 3x/day; defined as more than 3 non-bloody watery stools 
within a 24-hour period, requiring additional fluid and electrolyte supplementation 

  
 
 
 
 
 
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RECRUITMENT, CONSENT & ENROLLMENT 
9.1 Recruitment & Consent Procedures 
Prospective participants will be screened for fulfillment of inclusion criteria by the Physician 
Investigator. Patients are likely to give consent in this setting. The PI or PI’s designee will 
seek consent from the patient’s responsible party, after explaining the procedure and consent 
form, approved by all participating sites. It should be noted that one feature of the COVID-19 
pandemic is that non-patients are barred from hospital premises. Therefore, informed consent 
from responsible parties will generally be obtained telephonically and signature may be 
obtained via an SMS text message or otherwise compliant consent systems. Consent will be 
documented by a witnessed, consent form, to be kept on file together with 
telephonic/electronic signature.  This does not preclude a site from obtaining consent via 
paper, if such arrangements can be made, e.g. fax.  Should the patient regain ability to 
consent, consent will be sought accordingly. 
9.2  Obtaining Informed Consent  
IRB-approved written informed consent forms (ICF) will be obtained from the responsible 
party of all subjects before any protocol-specified procedures are carried out. For entry into 
the study, all inclusion criteria must be met, and none of the exclusion criteria can be met. All 
signed ICF forms will be logged and kept in locked research cabinets under the supervision 
of the local Site PI and available for audit upon request.  
9.3 Protecting Confidentiality 
Any information obtained in this study will be treated as confidential and will be 
safeguarded. The data will be coded and kept in a secure location.  When published, the 
results of the study will be in a form that does not identify any of the patients. In compliance 
with federal regulations, the records of the study will be available to representatives of the 
Food and Drug Administration. 
9.4 HIPAA Compliance 
The study will be compliant with the Health Insurance Portability and Accountability Act 
(HIPAA), which protects the privacy and security of healthcare information. All personal 
identifying information (PII) will be securely stored and only accessible to healthcare 
providers and authorized personnel only.   
9.5 Standard of Care Support 
Supportive treatment in the ICU, including antibiotics, oxygen, mechanical ventilation, blood 
pressure-supporting medications, and all other standard of care interventions as needed, will 
be continued, regardless of participation in the study. 
9.6 Population Bias 
For unknown reasons, males are affected by severe COVID-19 symptoms twice (2X) as often 
as are females. It is likely that the enrollment in this trial will be consistent with that gender 

  
 
 
 
 
 
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difference. There is no evidence to suggest that RLF-100 will be differently tolerated based 
on race.  
9.7 Enrollment 
The initial total number of participants in the expanded access study will be 100. If the 
decision is made to continue the study beyond 100 patients, the amended protocol will be 
submitted to FDA.   
 
There is no mathematical sample size calculation because no hypothesis tests are planned. 
9.8 Charging for Investigational Product 
Because sponsor is a small, venture-backed biotechnology company, sponsor plans to charge 
for investigational product. Consistent with § 312.315, Sponsor will charge for direct drug 
costs, costs of monitoring the expanded access protocol under § 312.320, complying with 
protocol reporting requirements, and other administrative costs directly associated with the 
expanded access use § 312.8(d)(2).  Sponsor will further recover the fees paid to a third party 
for administering the intermediate-size patient population expanded access protocol, 
consistent with FDA’s interpretation of § 312.8(d)(2). 
 
Sponsor will provide to FDA documentation to show that its calculation is consistent with the 
requirements of § 312.8(d)(1), describing recovery of direct costs and, if applicable, the 
requirements of § 312.8(d)(2), describing certain additional costs that may be recovered for 
intermediate-size patient population expanded access uses or treatment INDs or protocols. 
This documentation must be accompanied by a statement that an independent, certified public 
accountant has reviewed and approved the calculations (§ 312.8(d)(3)). 
 TREATMENT OF SUBJECTS 
10.1 
Maximal Standard of Care 
All patients entered in the trial receive Maximal Standard of Care treatment and support, 
including fluids, antibiotics, vasoactive agents, non-invasive or mechanical ventilation, 
hemodialysis, surgery and other supportive measures. Unlike care under Protocol RLF-100-
001, treatment with extra-corporeal membrane oxygenation (ECMO) is not an exclusion 
criteria for this protocol and may in some cases be the basis for enrollment. Decisions 
regarding the use of intravenous fluids, cardiovascular and respiratory support, and surgical 
intervention are made by each patient's attending physician and are not dictated by the study 
protocol. At the completion of the three 12-hour infusions, patients are followed up for the 28 
days or until discharged from the hospital, whichever comes sooner. An attempt will be made 
to follow all patients for 28 days even after discharge, but it will not be practical during the 
Corona Pandemic either to bring patients back for post-discharge visits or to make home 
visits. Death while on life support vs. death following discharge from mechanical ventilation 
will be tracked separately. 

  
 
 
 
 
 
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10.2 
Proper Standard of Care (SOC) Management Principles 
Management principles are similar despite different etiologies. Oxygenation must be 
maintained, and the underlying cause of acute lung injury corrected. Meticulous attention is 
necessary to prevent nutritional depletion, O2 toxicity, superinfection, barotrauma, and renal 
failure, which may be worsened by intravascular volume depletion. While the diagnosis is 
being considered, life-threatening hypoxemia must be treated with a high FiO2 and monitored 
with repeated arterial blood gases or noninvasive oximetry. Prompt endotracheal intubation 
with mechanical ventilation and PEEP may be needed to deliver O2 if hypoxemia is refractory 
to O2 inhalation by face mask or nasal cannula. Despite the presence of alveolar edema, IV 
fluids should be given if needed to restore peripheral perfusion, urine output, and BP. 
Monitoring vascular volume is crucial because both hypovolemia and overhydration are 
deleterious. Physical findings and central venous pressure may be misleading in critically ill 
patients undergoing mechanical ventilation, and if severe hypoxemia persists, if skin perfusion 
is poor, if mentation is impaired, or if urinary output decreases (< 0.5 mL/kg/h), a reliable 
index of intravascular volume is needed immediately.  
 
ECMO is a lifesaving modality that may be used when mechanical ventilation is unable to 
support life.  Therefore, while ECMO is not an exclusion criterion for this study, ECMO is 
also not considered part of SOC for the purposes of this study based on its variable 
availability from one treatment facility to another. 
10.3 
Dosing Regimen 
The escalating dosing regimen for RLF-100 is shown in Figure 2.  Each infusion is planned 
for 12 hour duration, however, the infusion may be slowed by up to 50% (for an 18-hour total 
infusion time) at the discretion of the site personnel. Monitoring of vital signs and other 
safety measurements will be ongoing and decisions relating to dose-reduction or cessation 
will be based on the evaluation of these parameters. 
10.4 
 Potential Side Effects of Drug Therapy 
Signs and symptoms to look for: facial flushing, tachycardia, hypotension, diarrhea. These 
will be monitored for the duration of the infusion, and for 12 h afterward, by blood pressure 
and heart telemetry measurements and patient observation. One identified side-effect of 
Aviptadil infusion is watery diarrhea. As noted above, non-bloody watery diarrhea > 3x/day 
requiring additional fluids and electrolyte supplementation is an enrollment exclusion. Some 
investigators prefer to pretreat with Imodium. If watery diarrhea is observed during infusion, 
a fecal management system (i.e. rectal tube) should be used to monitor diarrhea and 
electrolyte content in order to ensure physiologic replacement of both fluid and electrolytes. 
Hypotension of >10mmHg that is not readily controlled with pressors is a basis for reducing 
the infusion rate by 50%.  If hypotension persists, the dosage for subsequent infusions should 
be decreased to the prior, tolerated dose of RLF-100. 

  
 
 
 
 
 
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 ASSESSMENT OF SAFETY 
11.1 
Serious Adverse Events  
Sponsor provides medical monitoring/consultation as part of this expanded access protocol.  
Investigators will be provided with contact numbers to reach medical monitors who are 
board-certified critical care physicians or otherwise highly qualified physicians on a 24/7/365 
basis.  Measurement of serious adverse events (SAE) will be the basis for assessing safety of 
RLF-100. All SAE’s will be recoded on an IRB approved SAE Report Form. The SAE 
Report Form will include the exact nature of the event and the circumstances of the subject at 
the time of the event, in addition to the usual information required to document AEs or SAEs. 
Data on all the above will be collected on separate eCRF pages. The latest version of the AE 
dictionary, MedDRA, will be used for the classification and analysis of AEs entered in the 
study database. For regulatory reporting, SAEs will be coded using MedDRA. 
11.2 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An AE does not 
necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) 
product. (Definition per ICH). AEs will be classified as expected/unexpected, drug-related, 
possibly drug-related, or non-drug related by the study safety monitor.  Flushing, Diarrhea 
and hypotension are expected generally on-serious AEs that are known physiologic effects of 
Vasoactive Intestinal Peptide. 
11.3 
Definition of a Serious Adverse Event 
The following criteria define a Serious Adverse Event: 
1) Death 
2) Life-threatening event 
3) Persistent or significant disability/incapacity 
 
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (e.g., death from anaphylaxis), the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a 
component of the study endpoint (e.g., all-cause mortality). In addition, the following 
variables will be collected for SAEs: 
 
• Date AE met criteria for SAE 
• Date investigator became aware of SAE 
• Explanation of seriousness of this AE 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Autopsy performed 

  
 
 
 
 
 
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• Causality assessment in relation to study procedure(s) 
• Causality assessment in relation to study drug 
• Causality assessment in relation to other medication 
• Description of AE 
11.4 
Relationship to Study Drugs 
Adverse events and SAEs will be collected from the time of signature of informed consent 
throughout the treatment period. The investigator will assess the causal relationship (i.e., the 
relationship to study treatment) between the investigational product and the AEs and answer 
“yes” or “no” to the question “Do you consider that there is a reasonable possibility that the 
event may have been caused by the investigational product?”. For SAEs, causal relationship 
will also be assessed.  
11.5 
Recording of Adverse Events 
Abnormal and clinically significant lab values will be reported as SAEs if they fulfill any of 
the SAE criteria or are the reason for discontinuation of treatment with the study drug. The 
principal investigator and the study biostatistician will establish the rules for what will 
constitute abnormal and clinically significant lab values based on established site-specific lab 
normal ranges. Adverse events, including abnormal lab values (clinically significant and 
clinically non-significant), will be review monthly for trends by the principal investigator and 
the medical monitor. Should any abnormal lab values exceed acceptable rates, the FDA will 
be notified within regulatory timelines. Wherever possible, the reporting investigator will use 
the clinical, rather than the laboratory term (e.g., anemia versus low hemoglobin value). 
11.6 
Reporting of Adverse Events 
All AEs and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated Informed Consent Form (ICF) is obtained until completion 
of the subject’s last study-related procedure. All events that meet the definition of a SAE will 
be reported as SAEs, regardless of whether they are protocol-specific assessments. All AEs, 
regardless of seriousness, severity, or presumed relationship to study drug, must be recorded 
using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses will be given when signs and symptoms are due to a common etiology. The 
sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
11.7 
 Reporting of Serious Adverse Events 
Reportable SAEs will be sent to the FDA by the sponsor. When a SAE is discovered, it will 
be reported immediately (within 24 business hours) to the Medical Monitor. Serious adverse 
events will be reported within 24 business hours of the site’s knowledge of the event to the 
IRB, Sponsor, Medical Monitor, and study site investigators. 

  
 
 
 
 
 
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 ASSESSMENT OF EFFICACY 
12.1 
Data Collection 
Data will be collected via the electronic medical record (EMR) or other hospital information 
system and ICU telemetry systems. Once collected, data will be transferred by study 
personnel to the IBM Watson electronic data capture system, which has been audited by FDA 
in connection with multiple drug approvals. GCP will be observed throughout, using 
sponsor’s quality system.  Extensive data not already defined in this protocol will be 
available for analysis via the EMR and telemetry systems. 
12.2 
Assessments of Endpoints 
 Recovery from Respiratory Failure in Critical COVID-19 
Recovery is defined as being able to maintain a physiologic oxygen saturation (SaO2) without the 
need for mechanical ventilation, non-invasive ventilation, or high-flow Nasal Oxygen above 20L/min.  
As per FDA guidelines, the definition is resource consumption-based and not tied to a specific SaO2 
 Improvement in SaO2 
The SaO2 following cessation of ventilation will be compared to the SaO2 that triggered the 
decision to institute ventilation. 
 Improvement on NIAID Scale 
The NIAID 8 point scale is: 
 
 Chest x-ray 
Investigators are requested to submit chest AP x-rays, which will generally be supine or 
sitting at day 0, 48-72 hours post first infusion, and day 7 or day of discharge, whichever 
comes sooner. Chest CT, if available should also be submitted 
 
 

  
 
 
 
 
 
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  Inflammatory Markers 
Cytokine studies will be performed by central lab.  Note that these are not declared efficacy 
or safety endpoints 
 STATISTICAL ANALYSIS 
13.1 
Statistical Design and Analyses 
Subjects will be compared to concurrent, open label control patients receiving Standard of 
Care.  Control patients will be enrolled only in centers where IRB authorization has been 
provided to use data from non-enrolled standard of care patients for comparison purposes.  
Survival will be assessed via Kaplan Meier lifetable and Cox Proportional Hazards model.  
Cumulative probability distribution of recovery from respiratory failure will be analyzed by 
Fisher’s Exact Test.  Difference in NIAID score will be assessed by linear regression model. 
13.2 
Data Analysis 
All patient data will be collected via the electronic medical record and in -house ICU 
telemetry systems.  Dedicated research personnel will extract data to a de-identified study 
database for statistical analysis. 
13.3 Interim Safety Analysis 
Upon completion of observations through Day 7 for the first 50 subjects, an analysis will be 
performed to assess safety. Safety determinations will entail a review of AEs and SAEs. Based on this 
evaluation, the sponsor will continue or expand the expanded access protocol.  
Should the program be expanded, the next safety evaluation will occur at 100 patients.   
 HYPOTHESIS TESTS  
14.1 
Treatment Comparisons 
Clinical outcomes will be compared both to concurrent controls and to published control 
groups from studies of other investigational agents. 
14.2 
Primary Hypothesis 
We hypothesize that RLF-100 improves survival and recovery  in patients with Critical 
COVID-19 and Respiratory Failure in the setting of severe comorbidity. 
14.3 
Primary Endpoint: Survival 
Survival is defined as not deceased from medical records and post-hospital inquiry 
14.4 
Secondary Efficacy Endpoint: Recovery from Respiratory 
Failure 
Recovery from Respiratory Failure is defined as not requiring mechanical ventilation, non-
invasive ventilation, or high-flow nasal oxygen of 20L or greater. 

  
 
 
 
 
 
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14.5 
Secondary Efficacy Endpoint: NAIAD 8 point ordinal scale 
Descriptive statistics will be published. 
14.6 
Declared Secondary Efficacy Endpoint: ICU days difference   
Difference in ICU days is ascertained from the medical record 
14.7 
Secondary Laboratory Efficacy Endpoints: Inflammatory 
Markers 
The secondary laboratory outcome measures are TNFα, IL6, and other inflammatory markers 
as measured in the central laboratory.   
14.8 
Overall Safety Endpoints 
All safety results will be presented to FDA  
 SOURCE DATA & DOCUMENTS 
15.1 
Sources of Research Materials 
The following source data and documents will be collected. All blood samples, except those 
taken for cytokine and arachidonate metabolite level monitoring, which would be part of this 
investigation, would be obtained in the normal course of clinical care of these patients as 
described above. 
15.2 
Patient Identification 
Patient name, medical record number, age, gender, height, weight, ethnic background, 
residence address with zip code will be collected. 
15.3 
General Clinical Data  
Primary diagnosis, coexisting diagnoses / conditions, hospital length of stay and outcome will 
be collected.  
15.4 
Data used to determine respiratory failure 
Resource use (room air, low flow O2, High Flow O2, non-invasive ventilation, mechanical 
ventilation, or ECMO) together with SaO2, PaO2/FiO2 ratio; PEEP/CPAP; must be entered 
into the IBM Cloud system in order for patient to be allowed to participate in the expanded 
access protocol 
15.5 
Radiology 
Chest X-ray images in Dicom quality will be requested from treating physicians.  Chest CT if 
performed will similarly be requested. 

  
 
 
 
 
 
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15.6 
Laboratory Data 
Arterial blood pH, PCO2, PO2; electrolytes (Na, K, Cl, HC03); renal function (BUN, serum 
creatinine); glucose, albumin & total plasma proteins; liver function tests; blood cell count; 
coagulation profile; lactic acid and serum osmolarity will be requested from treating 
physicians.  
15.7 
 Vital Signs, Respiratory and Hemodynamic Data 
Blood pressure (systolic, diastolic, mean), heart rate, respiratory rate must be entered in the 
IBM Watson Cloud system for ongoing participation. 
 STUDY MONITORING 
16.1 
Study Monitoring 
Under expanded access, sponsor is unable to provide active study monitoring.  However, 
sponsor is providing monitor support by a board-certified critical care physician available at 
all times. 
16.2 
Medical Monitor 
The Medical Monitor will review all SAEs, assess the benefits and risks of protocols on an 
ongoing basis, and work in collaboration with the IRB and DMC to identify safety signals 
and trends. In addition, the Medical Monitor will be available for site questions regarding 
inclusion/exclusion criteria, protocol conduct, and safety. Trained and qualified physicians 
will be available to provide coverage during times when the medical monitor is unavailable. 
Sites will be provided with the Medical Monitor’s cell phone number for emergency 
situations. Otherwise, sites are instructed to contact the Medical Monitor through email. All 
conversations with sites will be documented by the Medical Monitor and reviewed 
periodically by the sponsor. Each month the Medical Monitor will receive a listing of 
protocol violations for review and identification of possible trends.  
16.3 
Audits and Inspections 
Contracts with study sites will specify that sponsor or its representatives will have direct 
access to source data and documents for study monitoring. Additionally, the IRB and FDA 
may review source data following appropriate guidelines for this process. 
16.4 
 Institutional Review Board 
The study protocol and any amendments will be reviewed by the Advarra Institutional 
Review Board (IRB). The IRB will review the informed consent form, their updates (if any), 
and any written materials given to the participants. IRB approval will be obtained and 
documented prior to subject enrollment and screening. Before study initiation, the 
investigator must have written and dated approval from the IRB for the protocol, consent 
form, subject recruitment materials/process (e.g., advertisements), and any other written 
information to be provided to subjects. The investigators will provide the IRB with reports, 
updates, and other information (e.g., Safety Updates, Amendments, and Administrative 

  
 
 
 
 
 
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Letters) according to regulatory requirements and Institution procedures. A detailed list of 
required regulatory documents, to be submitted to the sponsor, will be sent upon final 
approval of the protocol. 
 ETHICAL CONSIDERATIONS 
17.1 
Ethical Considerations 
 Anticipated benefits to participants and others 
There are at present no satisfactory specific treatments Critical COVID-19 with Respiratory 
Failure. Based on early results in  RLF-100-001 and in patients treated under named-patient 
emergency access INDs approved by FDA, there is the possibility that RLF-100 may prove 
effective in increasing the rate of recovery from Critical COVID-19 with respiratory failure. 
 Anticipated risks to participants and others 
The only anticipated risks are due to the side-effects noted above of hypotension, tachycardia 
and watery diarrhea. Aviptadil has been evaluated in 4 species toxicology studies and the 
LD50 is more than 50x the exposure contemplated in this trial.  Thus far, no drug-related 
SAEs have been reported either in Protocol RLF-100-001 or under name-patient emergency 
use INDs. 
17.2 
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 and in compliance with the approved protocol. Sponsor is not 
in a position to monitor and insure compliance with GCP at the sites that will participate in 
this protocol. 
17.3 
 Informed Consent 
The patient’s legally authorized representative (LAR) must be capable of understanding the 
nature of this study and its potential risks, discomforts, and benefits. Study physicians will 
obtain consent after they have fully explained the study purpose and procedures, and the LAR 
has demonstrated an understanding of the protocol, willingness to participate, and 
competency to consent.  The investigator must ensure that subjects are clearly and fully 
informed about the purpose, potential risks, and other critical issues regarding clinical trials 
in which they volunteer to participate. Preparation of the site-specific consent form is the 
responsibility of the site Principal investigator and must include all elements required by CFR 
21 Part 50.25 and the IRB. 
 DATA HANDLING & RECORD KEEPING 
18.1 
Data Capture 
An investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on everyone 
treated with the investigational product or entered as a control in the investigation. 

  
 
 
 
 
 
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18.2 
Data Collection 
No manual data collection is anticipated in the ICU. Data will be extracted from the EMR 
and other sources by hospital clinical research staff in a HIPAA-compliant, de-identified 
manner and transferred to the IBM Watson Cloud EDC. 
18.3 
Retention of Records 
The investigator must retain investigational product disposition records and source 
documents for the maximum period required by applicable regulations and guidelines, or in 
accordance with institution procedures, and at least for 10 years. This is study practice in the 
study sites. 
18.4 
Use of Information and Publication Policy 
All publications will be reviewed by the sponsor for accuracy before submission to peer-
reviewed journals or scientific meetings. Abstracts will be submitted for review at least 10 
days before submission, and publications should be submitted for review at least 30 days 
before submission. The study will be posted to Clinicaltrials.gov, and results will be reported 
in accordance with Clinicaltrials.gov guidelines. 
 
 

  
 
 
 
 
 
   
 
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 APPENDIX A: SCHEDULE OF EVENTS 
  
Day 1 
Day 2 
Day 3 
Day 4 
and each day 
until discharge 
DIscharge Day 
EofS 
Procedures 
Screening  
1st 
Dosea 
During 
infusion 
2nd 
Dosea 
During 
infusion 
3rd 
Dosea 
During 
infusion 
Follow-Up 
Follow-Up 
D28 or 
day of 
discharge 
Informed Consent Process 
 X  
  
  
  
  
  
  
  
  
  
Evaluation of Exclusion & 
Inclusion Criteria 
 X  
  
  
  
  
  
  
  
  
  
Medical History/Demographics 
 X  
  
  
  
  
  
  
  
  
  
Confirm Eligibility and 
Randomization 
  
 X  
  
  
  
  
  
  
  
  
Vital Signs (Pulse, 
Respirations)b 
 X  
 X  
Xb 
 X  
Xb 
 X  
Xb 
 X 
 X 
  
Blood Pressurec 
 X  
 X  
  
 X  
  
 X  
  
  
  
  
Weight 
 X  
 X  
  
 X  
  
 X  
  
 X  
 X  
 X  
CNS Assessment 
 X  
 X  
  
  
  
 X  
  
 X  
 X  
 X  
IV Administration of Study 
Drug 
  
 X  
 X  
 X  
 X  
 X  
 X  
  
  
  
Chest X-ray 
X 
 
 
X (between 48-72 hr) 
Day 7 
X  
 
ICU Telemetry: ECG 
  
 X  
  
 X  
  
 X  
  
X 
 X 
  
PaO2/FiO2 Ratio  
 X  
 X  
  
 X  
  
 X  
  
 X  
 X  
 X  
CBC (Complete Blood Count 
with Differential & Platelets) 
 X  
 X  
  
 X  
  
 X  
  
 X  
 X  
X 
CMP (Complete Metabolic 
Panel) 
 X  
 X  
  
 X  
  
 X  
  
 X  
 X  
 X  
ABG (for PaO2/FiO2 ratio): pH, 
pCO2, pO2, CO2, HCO3 per 
ICU protocol 
  
 X  
 X  
 X  
 X  
 X  
 X  
 X  
 X  
 X  
Study Drug Pharmacy 
Dispensing 
  
 X  
  
 X  
  
 X  
  
  
  
  

  
 
 
 
 
 
   
 
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Day 1 
Day 2 
Day 3 
Day 4 
and each day 
until discharge 
DIscharge Day 
EofS 
Procedures 
Screening  
1st 
Dosea 
During 
infusion 
2nd 
Dosea 
During 
infusion 
3rd 
Dosea 
During 
infusion 
Follow-Up 
Follow-Up 
D28 or 
day of 
discharge 
Assess for Adverse Eventsd 
  
 X  
Xd 
 X  
Xd 
 X  
Xd 
 X  
X  
 X  
NIAID Ordinal Scale for 
Clinical Improvement 
  
X  
  
 X  
  
 X  
  
 X  
X 
 X  
 
Footnotes   
  
a 
Each dose is administered over 12 hours at the same time each day. Date and time of start and end of infusion will be recorded. 
b 
Pulse and respirations will be continuously monitored but will be recorded prior to and at 2, 4, 6, 8, 10 and 12-hour timepoints after each dose escalation 
c 
Blood pressure will be recorded prior to infusion and at 2, 4, 6, 8 and 12 hour timepoints throughout the infusion. 
d 
Infusion reactions/adverse events check at 2 hours, and then continuously throughout the 12-hour infusion period.  
e 
Collected pre-dose and at 1, 2, 12 hours for each infusion over 3 days, then daily on day 5 and 7 and day 28 / or day of discharge if 
sooner.