Conditions: COVID-19
Keywords: COVID-19 ARDS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate whether inhaled epoprostenol given via a breath actuated delivery system will help improve oxygen levels and treatment outcomes in patients with COVID-19 who are on mechanical ventilation.

Detailed description:
This study will evaluate the potential therapeutic benefit of VentaProst in treating patients with COVID-19 at risk for respiratory and/ or cardiac/circulatory failure. This is a double-blind, placebo controlled study of VentaProst in 10 confirmed COVID-19 patients compared to 10- COVID-19 placebo patients to assess the efficacy and safety of VentaProst given over 10 days at varying doses.

Arms:
arm 1: Up to 10 days of inhaled epoprostenol delivered by a breath actuated dedicated delivery system for patients with COVID-19 who are mechanically ventilated. arm 2: Up to 10 days of inhaled 0.9% sodium chloride solution delivered by a breath actuated dedicated delivery system for patients with COVID-19 who are mechanically ventilated.

Interventions: intervention 1: VentaProst (inhaled epoprostenol delivered via a dedicated delivery system)
Intervention descriptions: intervention 1: VentaProst delivered for up to 10 days via mechanical ventilation at a dose range that may be up or down titrated to a patient's clinical condition.

Protocol document:
Prot_SAP_000.pdf: 
VentaProst™ 
Clinical Study Report 
 
APC-VPCOV-CLN-001 
16.1.1 
Protocol and Protocol Amendments 
 
This section contains the following documents: 
APC-VPCOV-CLN-001 Clean-FINAL-22Jun2020 
APC-VPCOV-CLN-001 Amend-1 21Jul2020-signed 
APC-VPCOV-CLN-001 Amend-2 03Nov2020-Clean-Final 
APC-VPCOV-CLN-001 Amend-3 14Dec2020-Clean-Final 


 
 
 
 
PROTOCOL TITLE 
TITLE: OPEN LABEL STUDY TO ASSESS THE EFFICACY AND 
SAFETY 
OF 
VENTAPROST 
(INHALED 
EPOPROSTENOL 
DELIVERED 
VIA 
DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING 
MECHANICAL 
VENTILATION  
PROTOCOL  NUMBER 
APC-VPCOV-CLN-001 
INVESTIGATIONAL 
PRODUCT 
VentaProst™ 
INDICATION 
Reduction of respiratory, cardiac or circulatory failure in patients with 
COVID-19 
PHASE 
Phase 2a 
SPONSOR 
Aerogen Pharma Limited 
1660 S Amphlett Boulevard, Suite 360 
San Mateo, CA 94402 
United States 
MEDICAL MONITOR 
Veronica Franco, MD, MSPH 
APPROVAL DATE 
22 June 2020 
GCP STATEMENT 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) and all applicable local Good 
Clinical Practices (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
CONFIDENTIALITY 
STATEMENT 
This document is confidential as it contains proprietary information 
of Aerogen Pharma.  Any viewing or disclosure of such information 
that is not authorized in writing by the Aerogen Pharma is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 22 Jun 2020 
Confidential 
Page 2 of 52 
SPONSOR PROTOCOL APPROVAL PAGE 
 
PROTOCOL TITLE 
AN OPEN LABEL STUDY TO ASSESS THE EFFICACY AND 
SAFETY 
OF 
VENTAPROST 
(INHALED 
EPOPROSTENOL 
DELIVERED 
VIA 
DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING 
MECHANICAL 
VENTILATION  
PROTOCOL NUMBER  
APC-VPCOV-CLN-001 
APPROVAL DATE 
22 June 2020 
 
 
________________________________________________________________________ 
Judy Doto, RN, BSN 
 
 
 
 
 
 
Date 
Head of Clinical Operations 
Aerogen Pharma 
 
________________________________________________________________________ 
Jim Fink PhD, RRT, FCCP 
 
 
 
 
 
Date 
Chief Scientific Officer  
Aerogen Pharma 
 
________________________________________________________________________ 
Plamena Entcheva-Dimitrov, PhD, RAC 
 
 
 
 
Date 
Head of Regulatory and Medical Affairs 
Aerogen Pharma 
 
 
________________________________________________________________________ 
Andy Clark PhD  
 
 
 
 
 
 
Date 
Vice President and General Manager 
Aerogen Pharma 
22Jun2020
22 JUN 2020
22 Jun 2020
22 JUN 2020


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 22 Jun 2020 
Confidential 
Page 3 of 52 
 
INVESTIGATOR’S SIGNATURE PAGE 
PROTOCOL TITLE 
AN OPEN LABEL STUDY TO ASSESS THE EFFICACY AND 
SAFETY 
OF 
VENTAPROST 
(INHALED 
EPOPROSTENOL 
DELIVERED 
VIA 
DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING 
MECHANICAL 
VENTILATION  
PROTOCOL NUMBER  
APC-VPCOV-CLN-001 
APPROVAL DATE 
22 June 2020 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations 
of the protocol and in accordance with ICH-GCPs and all applicable local guidelines. 
 
________________________________________________________________________ 
Principal Investigator (printed/typed) 
 
 
 
 
 
 
 
 
 
 
________________________________________________________________________ 
Principal Investigator Signature 
 
 
 
 
 
Date 
 
 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 22 Jun 2020 
Confidential 
Page 4 of 52 
1. 
CLINICAL PROTOCOL SYNOPSIS 
Sponsor 
Aerogen Pharma 
Protocol No. 
APC-VPCOV-CLN-001 
Title of Study 
Open label study to assess the efficacy and safety of VentaProst (Inhaled epoprostenol 
delivered via dedicated delivery system) in subjects with COVID-19 requiring mechanical 
ventilation.  
Study Centers 
One clinical site in the US 
Phase 
Phase 2a 
Objectives 
 
Primary Objective: 
The primary objective of this study is the reduction of respiratory, cardiac or circulatory 
failure in patients with confirmed COVID-19. 
Secondary Objectives: 
The secondary objective in this study is to evaluate the effects of VentaProst on improvement 
in oxygenation and improvement in clinical outcomes.  
 
The study will also evaluate the effects of VentaProst on inflammatory parameters in subjects 
with confirmed COVID-19. 
Study Design 
 
This study will evaluate the potential therapeutic benefit of VentaProst in treating patients 
with COVID-19 at risk for the progression of respiratory and/ or cardiac/circulatory failure. 
This is an open label study of VentaProst in 10 confirmed COVID-19 patients compared to 20 
COVID-19 historical control patients to assess the efficacy and safety of VentaProst at an 
initial dose of 13.6 ng/kg/min (A range from 3.4-30.6 ng/kg/min may be administered based 
on the investigator discretion) for a maximum of 10 days at the discretion of the Investigator.  
The patient will be followed through Day 28 to assess clinical outcomes.   
Patients will be enrolled into the study within 24 hours of being placed on a mechanical 
ventilator.  Patients will be administered VentaProst using the dedicated delivery system 
which allows up and down titration of the inhaled epoprostenol to achive hemodynamic and 
oxygenation stability.  The starting dose will be initiated at 13.6 ng/kg/min.  Based on 
hemodynamic and oxygenation parameters, the dose can be increased in 3.4 ng/kg/min 
increments up to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.  The 
titration table below shows the typical up titration and also shows downward titration  steps 
for VentaProst while patients are on mechanical ventilation.   
Table 1: Overview of Titration and Weaning Guidelines 
Uptitration Guideline  
Downward Titration / 
Weaning Guideline* 
Start Dose: 13.6 ng/kg/min 
1st Step Up Dose (17.0) 
2nd Step Up Dose (20.4) 
3rd Step Up Dose (23.8) 
Start Dose: 13.6 ng/kg/min 
1st Step Down dose (10.2) 
2nd Step Down Dose (6.8) 
3rd Step Down dose (3.4) 


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4th Step Up Dose (27.2) 
5th Step Up Dose (30.6) 
 
*If the patient has been up-titrated weaning should occur from that level in 3.4 ng/kg/min decrements.  
Patients will be weaned from VentaProst slowly due to concern that VentaProst is providing 
significant clinical benefit and to avoid rebound vasoconstriction.  During weaning, doses will 
be decreased in steps of 3.4 ng/kg/min increments, with a minimum of 15 minutes between 
changes. The VentaProst weaning process should occur in isolation to other treatment changes 
(no changes in inotropes, vasopressors, or vasodilators) whenever possible. Patients will be 
observed closely before, during, and after dose changes. In the event patients demonstrate 
signs of hemodynamic instability  or a decrease in oxygenation indicated by pulse oximetry 
during downward titration, the VentaProst dose will be returned to its previous level. Once 
patients have been stable for at least 15 minutes, repeat attempts at dose reduction may be 
undertaken.  The process will continue until patients are fully weaned from VentaProst.  
Patients will be monitored for safety and PD efficacy throughout VentaProst administration. 
Number/Type 
of Patients 
Approximately 30 patients will be enrolled in this study. 
10 COVID-19 positive study participants will receive VentaProst and will be compared to 20 
COVID-19 positive historical control patients who have received standard of care (SOC) 
therapy. 
For retrospective comparison, each treatment patient will be matched to 2 confirmed COVID-
19 historical controls treated at the clinical center between February 2020 and end of this 
study using the following criteria whenever available: comparable age,  similar degree of 
disease severity (e.g. similar organ damage, similar co-morbidities, similar oxygenation 
status), on Mechanical Ventilation in ICU.  
Inclusion 
Criteria 
 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men Age ≥18 years old (no upper limit)  
2. Confirmed COVID-19 positive by RT-PCR test 
3. Patients who require invasive mechanical ventilation.  
4. Enrolled into study within 24 hours of being placed on mechanical ventilation  
5. Consent or professional consent obtained 
6. Duration of shortness of breath must be within the previous 14 days.   
7. Female subjects of childbearing potential must have a negative pre-treatment 
pregnancy test (serum or urine).  
8. Willing and able to comply with treatment schedule and follow-up. 
 
Exclusion 
Criteria 
 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. 
Patients on ECMO support. 
2. 
Patients receiving another inhalation research medication or inhaled nitric oxide.  
3. 
 Not expected to survive for 48 hours. 
4. 
Pregnant (positive pregnancy test in a pre-dose examination) or breastfeeding  
5. 
Open tracheostomy. 
6. 
Clinical contra-indication, as deemed by the attending physician. 
7. 
Allergy to Epoprostenol and its diluent 


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8. 
Using inhaled vasodilators  at baseline.  
9. 
Patients who are hemodynamically unstable as determined by investigator  
10. Patients with  significant hemoptysis as determined by investigator 
Study 
Treatment(s) 
Patients will receive VentaProst via mechanical ventilator, starting at 13.6 ng/kg/min.  If 
determined by the treating physician, the VentaProst can be up titrated to 30.6 ng/kg/min (in 
3.4 ng/kg/min increments).  At the Investigator’s discretion, the patient will be weaned off the 
drug in 3.4 ng/kg/min increments.  Medication can be administered up to 10 days.   
Duration of 
Treatment 
The duration of study participation for each patient is as follows:  
• 
Screening: up to 14 days 
• 
Treatment: up to 10 days 
• 
Follow up: 28 days 
Criteria for 
Evaluation 
 
Primary Endpoint  
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• 
Requires VV ECMO   
• 
Inability to extubate patient within 10 days or reintubation within < 24 
hours 
• 
Change in S/F, oxygenation index and P/F ratio (≥15%) from baseline to 12 
hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• 
Need to begin inotropic or 10% increase in current vasopressor therapy 
• 
Worsening hemodynamic parameters  
• 
Cardiac troponin > 20% from baseline   
• 
BNP ≥ 15% of baseline 
• 
Need for temporary mechanical circulatory support (IABP, Impella) 
• 
Requires VA ECMO 
Secondary Endpoints: 
1. Improvement in oxygenation defined as any one of the following: 
• 
Stabilization of PaO2/FIO2 >250 
• 
Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
 
2. Improved clinical outcomes defined as one of more of the following:  
• 
Shorter time to extubation following the site’s extubation protocol 
• 
Free from reintubation 
• 
Reduction in ICU days 
• 
Reduction in the number of re-admissions to the ICU due to COVID-19 
within 28 days. 
• 
Reduction in hospital days 
• 
Mortality (28 Days) defined as Cardiopulmonary mortality or mortality 
from all causes. 
3. Safety and tolerability 
• 
Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 


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Page 7 of 52 
CT or Chest X-rays, vital signs, ventilatory and oxygenation parameters, 
and laboratory tests. 
Exploratory endpoints will include (where available): 
1. 
Change in LDH 
2. 
Change in fibrinogen 
3. 
Change in WBC count including lymphocytes and neutrophil subsets 
4. 
Change in triglycerides 
5. 
Change in ferritin 
6. 
Change in CRP / ESR 
7. 
Change in IL-6 
8. 
Change in D-Dimer 
Ventilatory 
Parameters 
OSU SOC: 
Ventilator Type (GE) 
Parameters to monitor are:  
1. Ventilator Mode 
2. FiO2 
3. Inspiratory Time 
4. Mean Airway Pressure 
5. Peak Inspiratory Pressure 
6. Positive End Expiratory Pressure 
7. Respiratory Rate 
8. Tidal Volume 
Criteria for 
Stopping 
VentaProst 
Treatment 
Individual patients stopping criteria: At any time during VentaProst administration, patients 
may be removed from study treatment and placed on standard of care (SoC) therapy if they 
meet one or more of the following pre-defined criteria leading to a deterioration in their 
condition: 
• 
Severe hypotension as evidenced by a systolic BP < 90 mmHg  or MAP < 60 mmHG 
for >2 hours from the start of VentaProst 
• 
Need for VV ECMO 
• 
Need to increase existing vasopressor therapy by more than 25% 
• 
Worsening in oxygenation, ventilatory, or hemodynamic parameters that in the 
opinion of the investigator the patient should be removed from study treatment 
• 
Hemoptysis 
• 
If a clinically inadequate response to VentaProst is observed 
 
Study stopping criteria: If 3 patients are removed from the study for any of the above 
conditions, the study will stop further enrollment and an investigation will be conducted to 
determine the cause of the events.  An independent safety evaluation will also be conducted.  
If it is suspected that the investigational product has caused the events, the study will be 
terminated. 
Independent Safety Evaluation: Independent safety evaluation will be conducted by a 
licensed physician who is not involved in the VentaProst COVID-19 clinical study or the 
sponsoring organization.   
Statistical 
Methods 
All patients who are enrolled in the study and who receive at least one dose of VentaProst will 
be included in the intent-to-treat (ITT) analyses of pharmacodynamic and safety data.  All 
available data will be used and missing data will not be estimated or carried forward in any 


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Page 8 of 52 
statistical summary or analyses. 
Descriptive summary statistics include the number of patients, mean, median, percent 
coefficient of variation (% CV) (if required), standard deviation, and minimum and maximum 
values (quantitative variables) or the number of patients and percentages by category 
(qualitative variables). Changes will be assessed as the difference between baseline 
measurements and the appropriate post-dose measurements unless otherwise specified.  Mean 
differences between active and historical control groups will be assessed and significance will 
be determined on the basis of a 95% CI.   
No formal estimate of the sample size has been made. This is an exploratory study and the 
number of patients was selected to enable an adequate clinical assessment of 
pharmacodynamic, safety, and tolerability parameters without presenting undue risk to a large 
number of patients. 
Efficacy 
Analysis 
Efficacy will be secondarily determined by summarizing success or failure to meet any of the 
primary or secondary endpoints as compared to the matching historical controls.   
Safety 
Analyses 
Safety data will be summarized for both treatment group and historical control (when 
available) group using frequencies and incidence rates.  Safety will be assessed through 
monitoring of adverse events (AEs), serious adverse events (SAEs), chest CTs or chest X-
rays, laboratory tests, oxygenation and ventilatory parameters,  and vital signs.   


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Page 9 of 52 
Table 2: Schedule of Assessments and Procedures 
 
 
 
Screening 
VentaProst -
Day 1 
 
VentaProst Days 2-10 
 
End of 
Study  
 
 
 
Study Procedures 
Within 14 
Days 
Prior to 
Baseline 
 
 
 
Baseline
- 0 Hr 
 
 
 
12 
hrs 
 
 
 
D-2 
 
 
 
D-3 
 
 
 
D-4 
 
 
 
D-5 
 
 
 
D-6 
 
 
 
D-7 
 
 
 
D-8  
 
 
 
D-9 
 
 
 
D-10 
 
Day 28 
(+/- 
2 
days) 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication History/ 
Prior Meds 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Height1 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Chest CT Scan or 
CXR 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Clinical Laboratory 
Sampling2 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy Test 
(Serum or Urine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RT-PCR + for 
COVID-19 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Administer 
VentaProst 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oxygenation 
Measurements4 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Ventilator 
Parameters5 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
AE/SAE  
Monitoring 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
 
X 
 
X 
 
X 
Concomitant 
Medications 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Prone position 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1  Height only performed at screening 
2 Clinical Labs include: Safety labs: CBC (lymphocyte and neutrophil counts), Full Chemistry Panel (including LFTs) and PT/PTT drawn 
Screening, Day 1-12 hours, Days 5 & 10.  Triglycerides, LDH, ferritin, fibrinogen, CRP, ESR, IL-6, D-Dimer, troponin, BNP drawn at 
Screening, Day 1-12 hours and Day 10. 
3 Vital signs: Prior to initiating VentaProst, Days 1-10 twice daily (morning and evening) at the same time to reduce exposure to Health 
Care Professionals to include; temperature, pulse rate, blood pressure. 
4 Continuous SpO2 via pulse oximetry 
5 Ventilator Parameters will be collected twice daily along with vital signs and  include: Ventilator Type, Ventilator Mode, FiO2, Inspiratory 
Time, Mean Airway Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume and Respiratory Rate  
6Time Prone Position – 16 hours per day per OSU protocol 


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Page 10 of 52 
TABLE OF CONTENTS 
INVESTIGATOR’S SIGNATURE PAGE ....................................................... 3 
1. 
CLINICAL PROTOCOL SYNOPSIS ............................................... 4 
TABLE OF CONTENTS ......................................................................... 10 
LIST OF ACRONYMS, ABBREVIATIONS AND 
DEFINITION OF TERMS ...................................................................... 13 
2. 
BACKGROUND AND RATIONALE ............................................. 15 
2.1 
Introduction ................................................................................. 15 
2.2 
VentaProst .................................................................................... 17 
2.2.1 Nonclinical Experience ..................................................... 17 
2.2.2 Clinical Experience ........................................................... 17 
2.2.3 Summary of Pharmacokinetic Results ............................ 17 
2.2.4 Summary of Clinical Results ........................................... 18 
2.2.5 Summary of Known and Potential Risks of 
Inhaled Epoprostenol Administration ........................................ 19 
2.2.6 Dosing Rationale for VentaProst...................................... 19 
3. 
STUDY OBJECTIVES.................................................................... 21 
3.1 
Primary Objective ........................................................................ 21 
3.2 
Secondary Objectives ................................................................... 21 
3.3 
Study Design ................................................................................ 21 
3.4 
Duration of Participation ............................................................ 21 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..................... 22 
4.1 
Inclusion Criteria ......................................................................... 22 
4.2 
Exclusion Criteria ........................................................................ 22 
4.3 
Re-Screening of Patients ............................................................. 23 
4.4 
Removal of Patients from Therapy or Assessment ..................... 23 
4.4.1 Criteria for Stopping VentaProst Treatment ................... 23 
5. 
STUDY TREATMENTS ................................................................. 24 
5.1 
Identity of Medication Component of the 
Investigational Product .......................................................................... 24 
5.1.1 Storage Condition ............................................................. 24 
5.2 
Treatments Administered ............................................................ 24 
5.3 
Study Medication Supply, Preparation, and 
Administration ....................................................................................... 24 
5.3.1 Study Medication Supply ................................................. 24 
5.3.2 Study Medication Preparation ......................................... 25 
5.3.3 Study Medication Administration.................................... 25 
5.3.4 Study Medication Weaning .............................................. 26 
5.4 
Identity of the Device Component of the 
Investigational Product .......................................................................... 26 


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5.4.1 Identity of Device .............................................................. 26 
5.4.2 Ventilator Settings ............................................................ 30 
5.4.3 Device Supply ................................................................... 30 
5.4.4 Device Replacement ......................................................... 31 
5.4.5 Device Malfunction or Failure ......................................... 31 
5.5 
Blinding ........................................................................................ 31 
5.6 
Prior and Concomitant Therapy ................................................. 31 
5.6.1 Prohibited Concomitant Therapy .................................... 31 
5.7 
Investigational Product (IP) Supplies and 
Accountability ......................................................................................... 31 
6. 
CRITERIA FOR EVALUATION ..................................................... 32 
6.1 
Primary Endpoint ........................................................................ 32 
6.2 
Secondary Endpoints ................................................................... 33 
6.3 
Exploratory endpoints will include (where available): .............. 33 
6.4 
Appropriateness of Measurements ............................................. 34 
7. 
SAFETY ASSESSMENTS .............................................................. 34 
7.1 
General Safety Procedures .......................................................... 34 
7.1.1 Vital Signs and Weight Measurements ........................... 34 
7.1.2 Physical Examination ...................................................... 34 
7.1.3 Laboratory Measurements ............................................... 34 
7.1.4 Chest Assessments ........................................................... 34 
7.1.5 Time Prone Protocol ......................................................... 35 
7.2 
Adverse Events ............................................................................ 35 
7.2.1 Definitions......................................................................... 35 
7.2.2 Grading of Adverse Events ............................................... 35 
7.2.3 Relationship to Study Medication/Study 
Device/Procedure ......................................................................... 35 
7.2.4 AE Outcomes .................................................................... 36 
7.2.5 Laboratory Test and other Test Abnormalities 
as Adverse Events ........................................................................ 36 
7.2.6 Serious Adverse Events .................................................... 36 
7.2.7 Reporting for SAEs (24 Hours) ........................................ 37 
7.3 
Reporting of Pregnancy ............................................................... 38 
8. 
PHARMACOKINETIC ASSESSMENTS ...................................... 38 
9. 
SCHEDULE OF ASSESSMENTS AND 
PROCEDURES ....................................................................................... 38 
9.1 
Study Evaluation Timepoints ..................................................... 38 
9.1.1 Screening (within 14 days prior to Baseline 
Day 1) 38 
9.1.2 Days 1-10 Treatment ........................................................ 39 
9.1.3 Day 28/End of Study (EOS) .............................................. 41 
9.2 
Data Collection ............................................................................ 41 


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9.3 
Clinical Data Management ......................................................... 41 
9.4 
Database Quality Assurance ....................................................... 41 
10. 
STATISTICAL CONSIDERATIONS .................................... 41 
10.1 
Statistical Methods ...................................................................... 41 
10.2 
Determination of Sample Size ..................................................... 41 
10.3 
Analyses Sets ............................................................................... 41 
10.4 
Demographic and Other Baseline Characteristics ..................... 42 
10.5 
Criteria for Evaluation ................................................................ 42 
10.5.1 Primary Efficacy Endpoint ............................................. 42 
10.5.2 Secondary Efficacy Endpoints ........................................ 42 
1. 
Improvement in oxygenation defined as any one of 
the following: .......................................................................................... 42 
10.5.3 Key Exploratory Endpoints include: .............................. 43 
10.6 
Extent of Exposure ...................................................................... 43 
10.7 
Safety Analyses ............................................................................ 43 
10.7.1 Adverse Events ............................................................... 43 
10.7.2 Laboratory Values........................................................... 44 
10.7.3 Vital Signs ....................................................................... 44 
10.8 
The Procedure for Revising the Statistical Analysis 
Plan 44 
11. ADMINISTRATIVE PROCEDURES AND 
INSTRUCTIONS .................................................................................... 44 
11.1 
Ethics ............................................................................................ 44 
11.1.1 Institutional Review Boards/Independent 
Ethics Committees ....................................................................... 44 
11.1.2 Ethical Conduct of the Study ......................................... 45 
11.1.3 Patient Information and Informed Consent .................. 45 
11.2 
Administrative Procedures .......................................................... 46 
11.2.1 Changes to the Protocol .................................................. 46 
11.2.2 Adherence to the Protocol ............................................... 46 
11.2.3 Monitoring Procedures ................................................... 46 
11.2.4 Recording of Data ........................................................... 47 
11.2.5 Data Storage and Retention of Records ......................... 47 
11.2.6 Handling of Investigational Product .............................. 48 
11.2.7 Publication of Results ..................................................... 48 
11.2.8 Disclosure and Confidentiality ....................................... 48 
11.2.9 Discontinuation of Study ................................................ 49 
11.2.10 Patient Insurance and Indemnity ................................ 49 
12. 
REFERENCES ...................................................................... 50 
 
 


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List of Figures and Tables 
Table 1: 
Overview of Titration and Weaning Guidelines 
4 
Table 2: 
Schedule of Assessments and Procedures 
9 
Table 3: 
Medication Administration Titration Guidelines 
25 
Figure 1: 
Drug Delivery System 
28 
Figure 2: 
Aerogen Pharma Controllers 
29 
Figure 3: 
VentaProst Device Placement in the Gas Pathway 
30 
 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
AE 
Adverse |Event 
ALI 
Acute Lung Injury 
ALT (SGPT) 
Alanine Aminotransferase (serum glutamic pyruvic transaminase) 
AP 
Alkaline Phosphatase 
ARDS 
Acute Respiratory Distress Syndrome 
AST (SGOT) 
Aspartate Aminotransferase (serum glutamic oxaloacetic transaminase)   
bpm 
Beats Per Minute 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
cAMP 
Cyclic Adenosine Monophosphate 
CI 
Cardiac Index (L/min/m2) 
CO 
Cardiac Output (L/min) 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Concentration 
CPB 
Cardiopulmonary Bypass 
CRA 
Clinical Research Associate 
CRF 
Case Report Form   
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CVP 
Central Venous Pressure (mm Hg) 
DCF 
Data Collection Form 
DNR 
Do Not Resuscitate  
dPAP 
Diastolic Pulmonary Arterial  Pressure (mm Hg) 
dSAP 
Diastolic Systemic Arterial Pressure (mm Hg) 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 


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Abbreviation 
Term 
ESR 
Erythrocyte Sedimentation Rate 
ETT 
Endotracheal Tube 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCP 
Good Clinical Practice 
HME 
Heat-Moisture Exchanger 
HR 
Heart Rate (bpm) 
IABP 
Intra-aortic Balloon Pump 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ICU 
Intensive Care Unit 
IL-6 
Interleukin 6 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LAR 
Legally Authorized Representative  
LDR 
Lung Dosing Rate 
LFT 
Liver Function Test 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mPAP 
Mean Pulmonary Arterial Pressure (mm Hg) 
mSAP 
Mean Systemic Arterial Pressure (mm Hg) 
NC 
Nasal Cannula 
ng 
Nanogram 
OR 
Operating Room 
OTC 
Over-the-Counter 
PAH 
Pulmonary Arterial Hypertension 
PaO2 
Partial Pressure of Oxygen in Arterial Blood 
PAP 
Pulmonary Arterial Pressure (mm Hg) 
PCWP 
Pulmonary Capillary Wedge Pressure 
PD 
Pharmacodynamic 
PEEP 
Positive End Expiratory Pressure 
PH 
Pulmonary Hypertension 
PIP 
Peak Inspiratory Pressure 
PK 
Pharmacokinetic 
 
PP 
Per Protocol 
PGI2 
Prostaglandin I2 (epoprostenol) 
PVR 
Pulmonary Vascular Resistance (dyn/sec/cm5) 
RBC 
Red Blood Cell (count) 
RH 
Right Heart 
RHF 
Right Heart Failure 


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Abbreviation 
Term 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
RVSWI 
Right Ventricular Stroke Work Index 
SAE 
Serious Adverse Event 
SaO2 
Arterial Oxygen Saturation 
sPAP 
Systolic Pulmonary Arterial Pressure (mm Hg) 
sSAP 
Systolic Systemic Arterial Pressure (mm Hg) 
SE 
Standard Error 
SOP 
Standard Operating Procedures 
SOC 
Standard of Care 
SpO2 
Oxygen Saturation by Pulse Oximetry 
SVR 
Systemic Vascular Resistance 
TEAE 
Treatment-Emergent Adverse Event 
TEE 
Transesophageal Echocardiogram 
TPG 
Transpulmonary Gradient 
t1/2 
Half-Life 
TLD 
Total Lung Dose 
ULN 
Upper Limit of Normal 
VA-ECMO 
Veno-arterial Extracorporeal Membrane Oxygenation 
VentaProst 
VentaProst™ – Drug/device combination product consisting of aerosolized 
epoprostenol delivered via dedicated drug delivery system 
VentaProst Nebulizer 
The nebulizer assembly that is part of the VentaProst delivery system  
VTE 
Venous Thromboemobolism 
VV ECMO 
Venovenous Extracorporeal Membrane Oxygenation 
WBC 
White Blood Cell (count) 
WHO 
World Health Organization 
 
 
BACKGROUND AND RATIONALE 
2.1 
Introduction 
COVID-19 is a rapidly emerging pathogen that has recently been declared a pandemic by 
the World Health Organization (WHO). No targeted therapeutic treatments for 
coronavirus (COVID-19) have been identified.  Symptoms range from mild upper 
respiratory tract infection to profound hypoxia, severe pneumonia, ARDS and death. 
Progression of end stage disease is unpredictable with high fatality rates in mechanically 
ventilated patients as a result of multi-organ failure.   Among patients who require 
hospitalization, mortality may be 5% to 15%, and for those who become critically ill, 
reported mortality ranges from 22% to 62%.     
 
Prostacyclin therapy—available in oral, inhaled, and intravenous forms—is an analogue 
which mimics endogenous prostacyclin (PGI2). Prostacyclin binds to its receptor (a G-
protein coupled receptor) found on the surface of vascular smooth muscle and platelets, 
activates cyclic adenosine monophosphate (cAMP), and results in inhibition of platelet 


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aggregation, vascular smooth muscle relaxation and vasodilation of the pulmonary 
arteries (Mitchell, Ali et al. 2008). Prostacyclins are most commonly used in the 
treatment of PAH due to their potent vasodilatory effects. In addition, prostacyclin 
analogs also inhibit platelet aggregation and may reduce prothrombotic effects of 
endothelin. 
The rationale for use of vasodilators in COVID-19 patients rests on their rapid local 
effect on the pulmonary vasculature, which has shown to lead to increased oxygenation in 
other diseases, such as PAH (Higenbottam, Wheeldon et al. 1984) and post-surgical PH 
(De Wet, Affleck et al. 2004).  Epoprostenol has the additional advantage over inhaled 
nitric oxide in that it may be directly administered through a standard ventilator (closed-
circuit). 
 
The rationale for aerosolized prostacyclin use in COVID-19 patients experiencing 
hypoxia leading to cardiac failure is two-fold:  
(1) inhaled prostacyclin therapy has been used in the treatment of ARDS and has been 
shown to improve oxygenation and ventilation-perfusion mismatch (see Section 9).  
Prostacyclins, such as epoprostenol, promote pulmonary vasodilation via a cyclic 
adenosine monophosphate-mediated decrease in intracellular calcium (Figure 4).  While 
it has not been associated with improved outcomes, such as mortality, and it’s use in 
ARDS is off-label, it may be used in severe life-threatening hypoxemia refractory to 
conventional ARDS management, such as has been seen in COVID-19. 
(2) The second potential benefit of prostacyclin therapy in the management of COVID-19 
is to mitigate direct SARS-CoV-2-associated coagulopathy.  Prostacyclins have anti-
inflammatory (Dewachter 2012) and antiplatelet aggregation properties1.  Microvascular 
thrombosis and large vessel venous thromboembolism have been described anecdotally 
and in case reports of corona virus infected patients and abnormal coagulation parameters 
are associated with increased mortality (Giannis, Ziogas et al. 2020). Inhibition of platelet 
aggregation occurs with prostacyclin therapy and may mitigate thrombosis in situ seen in 
PAH itself, and potentially in patients with COVID-19 associated respiratory illness. 
Literature data with both inhaled NO and inhaled epoprostenol in ARDS, acute lung 
injury and severe hypoxemia show improvement of oxygenation (Afshari, Bastholm Bille 
et al. 2017), (Dzierba, Abel et al. 2014), decrease of pulmonary arterial pressure (Fuller, 
Mohr et al. 2015) and in some cases improvement in clinical outcomes such as shorter 
time on mechanical ventilation and shorter time in ICU (Ammar, Bauer et al. 2015).  
However, due to the heterogeneity of the population and the severity of the disease, not 
all studies agree on the effectiveness of inhaled epoprostenol, particularly to reduce 
mortality in ARDS (Adhikari, Dellinger et al. 2014), (Afshari, Bastholm Bille et al. 2017).  
Meta-analyses have concluded that the quality of the currently published data for the use 
of inhaled vasodilators in ARDS, ALI and refractory hypoxemia is insufficient to 
definitely conclude for or against their use (Afshari, Bastholm Bille et al. 2017), (Fuller, 
Mohr et al. 2015). 
 
This study will evaluate the potential therapeutic benefit of VentaProst in treating patients 
with COVID-19 at risk for the progression of respiratory and/or cardiac/circulatory 
failure. This open-label study will assess the efficacy and safety of VentaProst at a range 
of 3.4-30.6 ng/kg/min (based on the investigator discretion) for a maximum of 10 days at 
the discretion of the Investigator.  The patient will be followed through Day 28 to assess 


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their clinical status.   
 
2.2 
VentaProst 
2.2.1 
Nonclinical Experience 
Refer to the current Investigator’s Brochure (IB) for details of nonclinical pharmacology 
and toxicology studies with VentaProst. 
2.2.2 
Clinical Experience 
There have been no clinical trials to date with VentaProst in COVID-19 patients (see 
Section 2.2.4 below for summary of clinical data with VentaProst in cardiac surgery 
patients). 
2.2.3 
Summary of Pharmacokinetic Results  
Epoprostenol undergoes rapid chemical hydrolysis under physiological conditions to 
yield 6-keto-PGF1α and is also subject to enzymatic degradation.  As such, it is only 
possible to evaluate the PK using radioactively labeled drug. Studies using 3H-
epoprostenol sodium indicate half-life is generally less than 3 minutes with an I.V. bolus, 
and with I.V. infusion, plasma steady-state concentrations were achieved within 15 
minutes of initiation of the infusions, and steady-state concentrations increased linearly 
with increasing infusion rate.  Tissue distribution studies indicate the highest levels of 
radioactivity were observed in the kidney, liver, and small intestine and the lowest levels 
were observed in brain and adipose tissue.  Epoprostenol-derived material is rapidly 
excreted into urine and feces after dosing with epoprostenol sodium. 
 
There is only one study in the literature that reports the PK of inhaled epoprostenol.  The 
study by Haraldsson (Haraldsson, Kieler-Jensen et al. 2000) was designed to evaluate the 
effects of inhaled epoprostenol on platelet aggregation after surgery.  No differences were 
seen in 6-keto-PGF1α levels with two dose levels of epoprostenol compared to placebo 
over six hours of administration in the ICU.  Epoprostenol deposition in the lungs was not 
quantified, but the aerosol was administered only during the inspiratory phase of 
mechanical ventilation.  The blood levels of 6-keto-PGF1α by enzyme immunoassay in 
this study were reported to be several times higher than other levels reported in the 
literature.   
 
In 2017, Stanford University’s Department of Cardiac Surgery conducted an 
observational study (IND129777, Report# APC-VP-CLN-004) investigating the levels of 
6-keto-PGF1α in cardiac surgery patient requiring CPB.  Sixteen patients were enrolled; 
eight did not received inhaled epoprostenol, eight received aerosolized epoprostenol at a 
nominal starting dose of 50 ng/kg/min.   
 
Plasma levels determined in aerosol epoprostenol naïve patients indicates that cardiac 
surgery procedures, including CPB, result in elevated endogenous levels of both 6-keto-
PGF1α and thromboxane B2.  Delivery of aerosol epoprostenol in patients resulted in a 
further elevation of 6-keto-PGF1α levels, but not thromboxane B2. 
 
While it proved difficult to delineate the endogenous and exogenous contributions of 


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aerosol delivery during surgery, 6-keto-PGF1α levels declined rapidly in aerosol naïve 
patients during ICU stay.  Examination of the 6-keto-PGF1α levels during weaning, after 
this endogenous decline, indicate that the overall aerosol delivery efficiency, nebulized to 
absorbed (deposited lung dose), is less than 8%.  That is, out of a nominal dosing rate of 
50 ng/kg/min only 4 ng/kg/min actually reaches the lungs and gets absorbed. 
Comparison to recently published data (Nicolas, Krause et al. 2012) investigating 6-keto-
PGF1α levels during steady state I.V. administration of Flolan indicates that the systemic 
exposure from aerosol delivery in cardiac surgery is similar to, or lower, than that 
experienced from intravenous administration of the approved Flolan product. 
 
The findings of this observational PK study with inhaled epoprostenol are sufficient to 
make a correlation to historical systemic exposure levels with intravenous administered 
Flolan (the reference listed drug) and show levels of exposure similar to, or lower than, 
the currently approved intravenous product.   
  
2.2.4 
Summary of Clinical Results 
The safety and tolerability of VentaProst were evaluated in a Phase 2a Clinical Study in 
cardiac surgery patients “A Two-Part Pharmacodynamic Study to Compare VentaProstTM 
(Epoprostenol Solution for Inhalation via Custom Drug Delivery System) Dosing to 
Conventionally Administered Aerosolized Epoprostenol Dosing in Cardiac Surgery 
Patients” (NCT03122730).  
 
Overall, 15 patients were exposed to doses of VP from 3.4 to 20.4 ng/kg/min in this study.  
Administration of VP in this dose range was well-tolerated.  Overall, there were 2 
patients (28.6%) in Part I and 1 patient (12.5%) in Part II who experienced a total of 7 
TEAEs.  All 7 TEAEs were assessed by the investigator as related to the surgical 
procedure and as unrelated to the study drug and unrelated to the device.  No deaths 
occurred during the study.  A total of 3 patients had 1 SAE each.  All 3 SAEs were 
considered to be unrelated to the study drug or the study device.   
 
Seven patients were evaluated in Part I to determine the effective dose equivalence 
between VP delivered at 17 ng/kg/min and off-label aerosolized Veletri administered at 
50 ng/kg/min during mechanical ventilation.  In all patients, VP 17 ng/kg/min was found 
to be equivalent either by calculation of effect compared with aerosolized Veletri 50 
ng/kg/min or the investigators’ judgement.  In most patients, no differences were 
observed in oxygen saturation ranges between VP and aerosolized Veletri treatments at 
the same FiO2 while on the ventilator. The investigator determined that oxygenation, 
assessed by oxygen saturation measurements, did not change disproportionately with 
ventilator operating parameters on VP compared with aerosolized Veletri. 
 
Eight patients were evaluated in Part II of the study to identify the optimal dose of VP.  In 
the investigator’s judgement, the optimal VP dose was determined to be 6.8 ng/kg/min in 
2 patients, 10.2 ng/kg/min in 3 patients, and 13.6 ng/kg/min in 3 patients, which is the 
minimal dose that reliably produced a maximum hemodynamic response in all patients. 
   
There have been no clinical trials to date with VentaProst in COVID-19 patients. 


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See IB for additional clinical information regarding inhaled epoprostenol. 
2.2.5 
Summary of Known and Potential Risks of Inhaled Epoprostenol 
Administration 
Safety of inhaled epoprostenol in cardiothoracic surgery patients is remarkable.  In the 
reported literature to date, there were no reports of serious or life-threatening drug-related 
safety events.  Due to its mechanism of action, inhaled epoprostenol may theoretically 
cause increased bleeding (anti-platelet mechanism) or systemic vasodilation consequent 
to spill over into the central circulatory system, but no such events have been reported.  
Some accounts of the use of inhaled prostacyclin in the chronic setting (e.g. iloprost for 
PAH) report transient events as listed on the approved product labeling.  These include 
cough, headache, flushing, and an influenza-like syndrome.  However, these types of 
events are unlikely to be reported due to sedation in the ICU setting. 
VentaProst may result in hypotension, which will be monitored via frequent   assessments 
of oxygenation, ventilatory and hemodynamic parameters and vital signs. Worsening 
oxygenation is a theoretic concern through worsened ventilation/ perfusion matching. 
This will be monitored through continuous pulse oximetry throughout the administration 
of the inhaled epoprostenol. 
 
Risks to subjects in this study are related to common procedures performed (e.g., 
venipuncture) and the documented adverse events (AEs) listed in the current 
Investigator’s Brochure. These risks are communicated to the subjects in the consent 
forms. There may be additional risks that are currently unknown.  
 
The benefits of the study may include targeted lung vasodilation and improved 
oxygenation, potential anti-platelet effects on the lung vasculature, reduction in disease 
progression, avoidance of greater oxygen needs and early weaning off mechanical 
ventilation. If the drug does have such properties, then this may aid recovery, improve 
outcomes and enable an earlier discharge from the hospital.  
There is no funding awarded to the patients participating in this study. 
 
2.2.6 
Dosing Rationale for VentaProst 
Literature on the current use of aerosolized epoprostenol in cardiac surgery and in ARDS 
shows a wide range and technically variable dosing for lowering PVR (Rao, Ghadimi et 
al. 2018), (Kallet, Burns et al. 2017), (Fuller, Mohr et al. 2015).  Most of the experience 
is with continuous nebulization by commercially available nebulizers in various positions 
in mechanical ventilator circuits at doses of 50 ng/kg/min.  Unlike the commercially 
available nebulizer systems, the VentaProst delivery platform aerosolizes epoprostenol 
only during the inspiratory cycle of the ventilator and administers respirable sized aerosol 
droplets (3-5 µm) in close proximity to the ETT of mechanically ventilated patients.  
 
The assumed effect of the current continuous dosing regimen of 50 ng/kg/min is that the 
hemodynamic response is maximized and that no further improvements would be seen by 
increasing the dose.  The initial in vitro estimate of the equivalent VentaProst (VP) dose 
to a 50 ng/kg/min conventional dose of continuously aerosolized Veletri was 17 


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ng/kg/min, which was the starting dose in Part I of the APC-VP-CLN-001 Phase 2a study 
conducted by Aerogen Pharma.  During Part I of the study, it was determined that this 
dose is equivalent to 50 ng/kg/min epoprostenol delivered off-label via a generic 
nebulizer and continuous delivery.  In Part II of the APC-VP-CLN-001 Phase 2a study, 
the VP dose escalation started from an initial dose of 3.4 ng/kg/min (20% of the 
equivalent dose).  The dose was then increased in 3.4 ng/kg/min increments.  Part II of 
the study was designed to demonstrate that the dose-response plateau could be achieved 
using lower VP doses than the initial estimated equivalent dose in Part I.  Doses up to 
30.6 ng/kg/min were approved for use in the study. In Part I of the study one patient, per 
the investigator discretion, received a 20.4 ng/kg/min dose.  In Part II of the study it was 
determined that the optimal VP dose of 6.8 ng/kg/min in 2 patients, 10.2 ng/kg/min in 3 
patients, and 13.6 ng/kg/min in 3 patients provided stable hemodynamic response.  Based 
on these data,  the recommended starting dose of VP, will be 13.6 ng/kg/min, as this dose 
is anticipated to produce the maximum hemodynamic response. 
The proposed nominal dosing regimen for this COVID-19 trial is for up to 10 days of 
breath-synchronized aerosol delivery with a starting dose of 13.6 ng/kg/min drug and 
range between 10.2 and 30.6 ng/kg/min.  Lower doses can also be used depending on the 
clinical state of the patient and the discretion of the physician.  Of this nominal dosing 
rate approximately 30% will reach and deposit in the lung.  Thus, the maximum Lung 
Dosing Rate (LDR) is ~10 ng/kg/min and the maximum Total Lung Dose (TLD) is ~ 144 
µg/kg (Refer to VP IB Edition 6 dated 17-Jun-2020).  
The inhalation toxicology program for VentaProst, originally designed for the cardiac 
surgery indication, covered a maximum LDR of 320 ng/kg/min and 60 ng/kg/min and a 
maximum TLD of 1091.4 µg/kg and 172.8 µg/kg in rats and dogs respectively.  The LDR 
and TLD margins over the proposed maximum clinical exposure are thus 32 and 6, and 
7.6 and 1.2, in rats and dogs respectively.   


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3. 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is the reduction of respiratory, cardiac or circulatory 
failure in patients with confirmed COVID-19. 
3.2 
Secondary Objectives 
The secondary objective in this study is to evaluate the effects of VentaProst on 
improvement in oxygenation, improvement in clinical outcomes and safety and 
tolerability.  
 
The study will also evaluate the effects of VentaProst on inflammatory parameters in 
subjects with confirmed COVID-19.  
3.3 
Study Design 
This study will evaluate the potential therapeutic benefit of VentaProst in treating patients 
with COVID-19 at risk for the progression of respiratory and/or cardiac/circulatory 
failure. This is an open label study of VentaProst in 10 confirmed COVID-19 patients 
compared to 20 historical control confirmed COVID-19 patients to assess the efficacy 
and safety of VentaProst.  Patients will be enrolled within 24 hours of being placed on 
mechanical ventilation and may have VentaProst given for up to 10 days.     The patient 
will be followed through Day 28 to assess clinical outcomes.   
 
The proposed dosing regimen for the COVOD-19 trial is for up to 10 days of breath-
synchronized aerosol delivery with a starting dose of 13.6 ng/kg/min drug.  Based on 
hemodynamic and oxygenation parameters, the dose can be titrated in 3.4 ng/kg/min 
steps up to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min while 
patients are on mechanical ventilation.  Titration guidelines are provided in Section 5.3.3.   
Patients will be weaned from VentaProst slowly due to concern that VentaProst is 
providing significant clinical benefit and to avoid a rebound vasoconstriction.  During 
weaning, doses will be decreased in steps of 3.4 ng/kg/min increments, with a minimum 
of 15 minutes between changes. The VentaProst weaning process should occur in 
isolation to other treatment changes (no changes in inotropes, vasopressors, or 
vasodilators) whenever possible. Patients will be observed closely before, during, and 
after dose changes. In the event patients demonstrate signs of hemodynamic instability or 
a decrease in oxygenation by pulse oximetry during downward titration, the VentaProst 
dose will be returned to its previous level. Once patients have been stable for at least 15 
minutes, repeat attempts at dose reduction may be undertaken.  The process will continue 
until patients are fully weaned from VentaProst.  Patients will be monitored for safety 
and efficacy throughout VentaProst administration. 
3.4 
Duration of Participation 
Patients who meet entry criteria will be entered into the study and the duration of study 
participation for each patient is listed below. The duration of study participation for each 
patient is as follows:  
• Screening: up to 14 days 


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• Treatment: up to 10 days 
• Follow up: 28 days 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Approximately 30 patients will be enrolled in this study.  Ten study participants with a 
positive RT-PCR for COVID-19 and are mechanically ventilated will receive VentaProst 
and will be compared to twenty matching historical control patients with a positive RT-
PCR for COVID-19 who have received standard of care (SOC) therapy. 
Each treatment patient will be matched to 2 confirmed COVID-19 historical controls 
treated at the clinical center between February 2020 and end of this study using the 
following criteria whenever available: comparable age,  similar degree of disease severity 
(e.g. similar organ damage, similar co-morbidities, similar oxygenation status), on 
Mechanical Ventilation in ICU.  
Patients who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study medication.  
4.1 
Inclusion Criteria 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men Age ≥18 years old (no upper limit)  
2. Confirmed COVID-19 positive by RT-PCR test 
3. Patients who require invasive mechanical ventilation.  
4. Enrolled into study within 24 hours of being placed on mechanical ventilation  
5. Consent or professional consent obtained 
6. Duration of shortness of breath must be within the previous 14 days.   
7. Female subjects of childbearing potential must have a negative pre-treatment 
pregnancy test (serum or urine).  
8. Willing and able to comply with treatment schedule and follow-up. 
4.2 
Exclusion Criteria 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. Patients on ECMO support. 
2. Patients receiving another inhalation research medication or inhaled nitric oxide.  
3. Not expected to survive for 48 hours. 
4. Pregnant (positive pregnancy test in a pre-dose examination) or breastfeeding  
5. Open tracheostomy. 
6. Clinical contra-indication, as deemed by the attending physician. 
7. Allergy to Epoprostenol and its diluent 
8. Using inhaled vasodilators at baseline.  


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9. Patients who are hemodynamically unstable as determined by investigator  
10. Patients with  significant hemoptysis as determined by investigator 
4.3 
Re-Screening of Patients 
Patients may not be enrolled more than once.   
4.4 
Removal of Patients from Therapy or Assessment 
Aerogen Pharma or the Investigator may discontinue patients from the study at any time 
for safety or administrative reasons.   
The End of Treatment Study procedures (at Day 10) are to be completed for all patients 
who discontinue from the study (except Screen Failure patients).  
The Investigator will promptly explain to the patient or their LAR that the study will be 
discontinued for the patient and provide appropriate medical treatment and other 
necessary measures for the patient.   
Patients who discontinue early from the study will be discontinued for one of these 
primary reasons:  Adverse events, patient death, lost to follow-up, patient withdrew 
consent, protocol violation, lack of efficacy, investigator decision, study terminated by 
sponsor, screen failure, or other.  Study disposition information will be collected on the 
Patient Disposition DCF. 
4.4.1 
Criteria for Stopping VentaProst Treatment 
Individual patients stopping criteria: At any time during VentaProst administration, 
patients may be removed from study treatment and placed on standard of care (SoC) 
therapy if they meet one or more of the following pre-defined criteria leading to a 
deterioration in their condition: 
 
• Severe hypotension as evidenced by a systolic BP < 90 mmHg  or MAP < 60 
mmHG for >2 hours from the start of VentaProst 
• Need for VV ECMO 
• Need to increase existing vasopressor therapy by more than 25% 
• Worsening oxygenation, ventilatory, or hemodynamic parameters that in the 
opinion of the investigator the patient should be removed from study treatment 
• Hemoptysis 
• If a clinically inadequate response to VentaProst is observed 
 
Study stopping criteria: If 3 patients are removed from the study for any of the above 
conditions, the study will stop further enrollment and investigation will be conducted to 
determine the cause of the events.  An independent safety evaluation will also be 
conducted.  If it is suspected that the investigational product has caused the events, the 
study will be terminated. 
 


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Independent Safety Evaluation: Independent safety evaluation will be conducted by a 
licensed physician who is not involved in the VentaProst COVID-19 clinical study or the 
sponsoring organization.   
5. 
STUDY TREATMENTS 
5.1 
Identity of Medication Component of the Investigational Product 
The study medication of VentaProst, Flolan (epoprostenol sodium), is manufactured by 
GlaxoSmithKline and has been analyzed and released according to their specifications.  
The Flolan will be procured by OSU on behalf of Aerogen Pharma and stored in the 
Investigational Pharmacy.  The labelling of Flolan for this clinical trial will follow the 
protocols and procedures set forth by OSU’s Investigational Pharmacy. Aerogen Pharma 
will provide labels to the pharmacy for labeling Flolan after it has been reconstituted per 
the VentaProst COVID pharmacy manual. 
Drug Substance Name 
Epoprostenol Sodium 
Chemical Name 
5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-
oic acid. 
Molecular Formula 
C20H31NaO5 
Structural Formula 
 
Molecular Weight 
374.45 
 
5.1.1 
Storage Condition 
Both the vials of study medication and sterile diluent buffer should be stored between 20o 
to 25oC (68o to 77oF) with excursions permitted to 15° to 30°C (59° to 86°F) and kept in 
the supplied carton to protect the product from light.  Study medication will be stored in a 
secure, controlled-access location at the study sites. 
5.2 
Treatments Administered 
Patients will receive VentaProst via mechanical ventilator, at an initial dose of 13.6 
ng/kg/min.  If determined by the treating physician, the VentaProst can be up titrated to 
30.6 ng/kg/min or down titrated to 3.4 ng/kg/min (in 3.4 ng/kg/min increments).  At the 
Investigator’s discretion, the patient will be weaned off the drug in 3.4 ng/kg/min 
decrements.  VentaProst can be administered up to 10 days.   
5.3 
Study Medication Supply, Preparation, and Administration 
5.3.1 
Study Medication Supply 
The medicinal component of VentaProst, Flolan, is already approved for I.V. delivery.  
The dosage form is a vial of 1.5 mg epoprostenol as a lyophilizate and the required pH 12 


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Sterile Flolan diluent per the currently approved packet insert (NDA20-444/ Supplement 
241).  Flolan and its diluent are not re-formulated by Aerogen Pharma.  Flolan is used 
with the same diluent system and reconstituted per the approved packet insert.   
Flolan and diluent container closure (glass vial and stopper/crimp-pH 12 Sterile Diluent 
for Flolan comes in a plastic bottle for mixing) and secondary packaging (cardboard box) 
are not being altered, including the information on the vial and box label and the 
information in the approved Flolan packet insert.  This preserves the approved drug 
labeling information per NDA 20-444.  
 
The patient number, dose number, date and time of dose administration will be recorded 
in the study medication dispensing logs. 
5.3.2 
Study Medication Preparation 
Refer to the VentaProst-COVID Pharmacy Manual for preparation of the study 
medication for aerosol administration. 
Prior to use, reconstituted solutions of epoprostenol sodium must be protected from light 
and must be refrigerated at 2° to 8°C (36° to 46°F) if not used immediately.  Do not 
freeze reconstituted solutions of epoprostenol sodium for injection and discard any 
reconstituted solution that has been frozen. Discard any reconstituted solution if it has 
been refrigerated for more than 8 days. 
Freshly prepared reconstituted solutions or reconstituted solutions that have been stored 
at 2°C to 8°C (36°F to 46°F) for no longer than 8 days can be administered up to 48 
hours at up to 30°C (86°F). 
5.3.3 
Study Medication Administration  
In the ICU, patients will be started on an initial dose of VentaProst of 13.6 ng/kg/min to 
be administered through the VentaProst delivery system.  The patient may have their 
VentaProst dose titrated up or down in 3.4 ng/kg/min increments (refer to VentaProst 
Pharmacy Manual) as clinically indicated every 5 to 15 minutes as clinically indicated to 
a dose range of 3.4-30.6 ng/kg/min. 
Table 3: Medication Administration Titration Guidelines 
Uptitration Guideline  
Downward Titration / Guideline 
Start Dose: 13.6 ng/kg/min 
1st Step Up Dose (17.0) 
2nd Step Up Dose (20.4) 
3rd Step Up Dose (23.8) 
4th Step Up Dose (27.2) 
5th Step Up Dose (30.6) 
Start Dose: 13.6 ng/kg/min 
1st Step Down dose (10.2) 
2nd Step Down Dose (6.8) 
3rd Step Down dose (3.4) 
 
 
 
 
1 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020444s024lbl.pdf  


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5.3.4 
Study Medication Weaning 
Patients will be weaned from VentaProst slowly due to concern that VentaProst is 
providing significant clinical benefit and to avoid a rebound vasoconstriction.  Doses will 
be decreased in steps of 3.4 ng/kg/min with a minimum of 15 minutes between changes 
until drug has been discontinued.  The VentaProst weaning process should occur in 
isolation to other treatment changes (no changes in inotropes, vasopressors, or 
vasodilators) whenever possible. Patients will be observed closely before, during, and 
after dosing changes. In the event patients demonstrate signs of hemodynamic instability 
or a decrease in oxygenation indicated by pulse oximetry  during downward titration, the 
VentaProst dose will be returned to its previous level. Once patients have been stable for 
at least 15 minutes, repeat attempts at dose reduction may be undertaken.  The process 
will continue until patients are fully weaned from VentaProst.  Patients will be monitored 
for safety and efficacy throughout VentaProst administration. 
5.4 
Identity of the Device Component of the Investigational Product 
5.4.1 
Identity of Device 
The Phase 2a VentaProst drug delivery system is designed to accurately and precisely 
administer aerosol to the lungs of critically ill patients who require support via 
mechanical ventilation.  The aerosol generator’s fundamental operating mechanism and 
materials of construction will be similar to the 510(k)-cleared Aeroneb Solo System 
(K120939, K103635, K070642, Aerogen Ltd) and it is being designed for compatibility 
with the range of ventilators found in the OR and ICU. 
5.4.1.1 VentaProst Aerosol Delivery to Ventilated Patients 
The VentaProst clinical study drug delivery system (Figure 1) consists of reusable and 
single-patient use disposable elements: 
 
1. Reusable multi-patient use components consist of two electronic controllers, 
Aerogen Solo Nebulizer Cable, and Sensirion Flow Sensor Cable.  When used 
together, they synchronize aerosol generation with the patient’s inspiratory pattern 
through a single-patient use, disposable administration kit. 
o Aerogen Pro-X, is a commercially available device (K1209392) cleared 
for use to continuously operate the disposable Aerogen Solo nebulizer. 
(item #1 Figure 1). 
o Aerogen Pharma Controller (AP Controller) is an investigational device, 
which synchronizes aerosol generation with the ventilator inspiratory 
cycle (item #2 on Figure 1).  This controller was tested to demonstrate its 
safety for use under IND129777.  
 
 
 
2 The product names for the Aerogen commercial products changed from the term “Aeroneb”, to the brand 
name “Aerogen”.  A Note to File was submitted to FDA and receipt was acknowledged by the Branch 
Office 
 


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o Aerogen Solo Nebulizer Cable 
o Sensirion Flow Sensor Cable 
2. Single-patient disposable kit: 
o Aerogen Solo nebulizer (item #3 on Figure 1) is a commercially available, 
low mass and low profile vibrating mesh aerosol generator (K070642) 
cleared for use with the Aerogen Pro-X controller and Aerogen 
Continuous Nebulization Tube Set (CNTS).  
o Aerogen CNTS and syringe (items #4 and 5 on Figure 1) is a 
commercially available device (K103635) cleared for use to connect to the 
Aerogen Solo and deliver medication from the drug reservoir (syringe) to 
the mesh the nebulizer.   
o Flow sensor and cable connected to the Aerogen Pharma Controller (AP 
Controller, item #7 on Figure 1).  This is a new component of the system, 
which was tested to demonstrate safety for use in a clinical study.  
The VentaProst delivery system will be used in conjunction with a commercially 
available and FDA-cleared syringe pump (item #8 on Figure 1).  In general, any available 
syringe pump, which (1) is compatible with the Aerogen Continuous Nebulization Tube 
Set (CNTS syringe and tubing), and (2) is capable of delivering medication to the 
vibrating mesh nebulizer within the range of 0.4 to 2.4 mL/h as required to deliver the 
doses specified in the APC-VPCOV-CLN-001 Pharmacy Manual. For purposes of the 
VPCOV study, Aerogen Pharma will supply  the Perfusor® Space Infusion Syringe Pump 
System from B.Braun (Figure 1).  This particular syringe pump is FDA-cleared 
(K093913), it is compatible with the CNTS syringe (items #4 on Figure 1) and is able to 
deliver fluids in the rage of 0.4 to 2.4 mL/h.  It is worth noting that on 11 April 2020, this 
pump received EUA for use in the tracheal delivery of continuous nebulized medications 
into a nebulizer to treat patients of all ages with or suspected of having the Coronavirus 
Disease 2019 (COVID-19)3.   
 
 
 
 
 
3 https://www.fda.gov/media/136894/download  
 


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Figure 1: Drug Delivery System 
 
The Aerogen Pro-X (item #1, Figure 1), Aerogen Solo (item #3, Figure 1) are mounted on 
an I.V. pole at the patient’s bedside.  The two controllers and Aerogen CNTS (items #4 
and 5, Figure 1) are routinely used as a system within their intended use.  The sensor and 
nebulizer are connected into specific locations of the inspiratory limb of the ventilator 
pre- and post the humidifier, respectively (see Figure 2).  The addition of the AP 
Controller and an off-the shelf Sensirion flow sensor enables the VentaProst system to 
synchronize aerosol delivery with the inspiratory cycle of the ventilator (Figures 1 and 2).   
 
Figure 2 illustrates the AP Controller, which is similar to the commercially available 
Aerogen Pro-X controller in form, size, weight and materials used for the upper and 
lower shells.  The AP Controller uses the same AC/DC adapter and cable as used in the 
commercial Aerogen Pro-X controller.  The packaging used for the AP Controller is same 
as packaging validated by Aerogen Ltd. for the commercially available Aerogen Pro-X 
system.  Functionality of the AP Controller was tested in design verification studies 
(IND129777).  Two dials (Figure 2) are used to: (1) set the flow threshold for 
nebulization triggering during the inspiratory cycle of the ventilator, accommodating 
initial ventilator baseline bias flows, and (2) set the duration of nebulization during the 
inspiratory cycle (a detailed description of the mechanism of action of the AP Controller 
is presented in IND129777).   
 
 


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A. Diagram of Aerogen Pharma Controller 
(left side view) 
 
 
B. Diagram of Aerogen Pharma Controller (right 
side view) 
C. Flow Trigger Dial settings 
D. Aerosol Duration Dial settings 
 
Figure 2: Aerogen Pharma Controllers 
Prior to VentaProst administration, the study medication will be reconstituted in the 
recommended diluent buffer and placed into two 60 mL CNTS syringes per the VPCOV 
Pharmacy Manual.  These syringes should be protected from light.  The user will attach 
the syringe to the CNTS tubing and prime the tube set so that the formulation reaches the 
Aerogen Solo, producing aerosol generation.  The CNTS syringe set will be placed in a B 
Braun Perfusor Space Infusion syringe pump.  The 15-mm T-Piece with nebulizer is 
placed between the ventilator circuit and the ETT (Figure 2).  The user will select the 
pump rate to deliver the recommended dose based on the ideal body weight in kilograms 
(kg) dispensed to achieve the dose rate in ng/kg/min.  The corresponding pump flow rate 
in mL/hour will be calculated based on initial dose of Flolan in ng/kg/min. The user will 
be able to adjust this recommended dose up or down (per protocol) by changing pump 
rate prior to selecting dose and initiating delivery.  The selected dose will then be 
dispensed by the pump to the receiving surface of the mesh, resulting in generation of an 
aerosol with a volume median diameter in the range of 2 to 5 µm.  The Aerogen Pharma 
Controller monitors the patient’s breathing pattern and user adjusts the knob (on left) to 
initiate aerosol generation at the beginning of the breathing cycle.  The knob on right sets 
the duration of aerosol generation within each breath.   
The VentaProst device is designed to be compatible with standard intensive care unit 


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(ICU) equipment.  The following site-specific equipment will be needed to deliver the 
therapy: B.Braun syringe pump, ventilator, endotracheal tube (ETT), humidifier, 
ventilator circuit.  This equipment is standard for critical care medicine. 
  
Figure 3 - VentaProst Device Placement in the Gas Pathway 
5.4.2 
Ventilator Settings 
The device is designed for use with standard adult ventilator settings.  An intermittent 
positive pressure ventilatory mode (i.e., not constant positive airway pressure [CPAP] or 
t-piece) is required to activate the device to deliver aerosol during the inspiration phase.  
A Heat-Moisture Exchanger (HME) may be used in the device circuit.   
The site will utilize OSU’s Standard of Care (SOC) mechanical ventilation guidelines for 
care of patients for COVID-19 with ARDS.  The following ventilator parameters will be 
assessed daily while on VentaProst:  Ventilator type, Mode, FiO2, Inspiratory Time, Mean 
Airway Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, 
Respiratory Rate and Tidal Volume. 
5.4.3 
Device Supply 
All device supplies will be provided by Aerogen Pharma Limited. The serial numbers for 
the controllers, flow sensor, and nebulizer will also be recorded in an IP accountability 
dispensing log. 


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Used and unused devices will be inventoried and returned to the Sponsor or Sponsor’s 
designee. 
5.4.4 
Device Replacement 
Devices may be replaced at any time if there a suspicion of malfunction, but must be 
replaced if: 
• The investigator suspects that, due to device malfunction, less than 90% of the 
total dose of study medication is being delivered.  Reduced doses must be 
estimated and recorded in the patient’s medical record and source documentation.   
• The investigator suspects the device is not performing optimally for any reason. 
5.4.5 
Device Malfunction or Failure 
One device (Aerogen Pro-X controller, Aerogen Pharma Breath Controller, Flow Sensor, 
Solo nebulizer, CNTS syringe, and associated components) is expected to perform 
throughout the duration of study treatment.  If the controllers, Flow Sensor, CNTS 
syringe, or the Solo nebulizer are not functioning optimally for any reason, instructions 
for trouble-shooting provided in the device instruction for use manual should be followed.  
If one or more devices need to be replaced, the reason should be documented in the 
patient’s medical record, dispensing log, and Device Performance Issues Form.  
Additional devices are provided for this purpose.  The unique serial numbers of the new 
components will be recorded in the patient’s medical record, dispensing log, and the 
source documentation. 
For device malfunction or complaints, complete the Device Performance Issues Log and 
submit to the Sponsor at Complaints@aerogenpharma.com within 48 hours.  Failed 
devices will be set aside from the general supplies, inventoried and returned to the 
Sponsor or the Sponsor’s designee. 
5.5 
Blinding 
Since this is an open-label study, there will be no blinding of the study medication. 
5.6 
Prior and Concomitant Therapy 
For patients who receive study medication, any medication (including over-the-counter 
[OTC] medications) or therapy administered to the patient during the course of the study 
(starting at Screening and 14  days prior) will be recorded on the Prior and Concomitant 
Therapy data collection forms.  The Investigator will record any AE on the AE data 
collection forms for which a concomitant medication/therapy was administered. 
5.6.1 Prohibited Concomitant Therapy 
Other inhaled vasodilators besides VentaProst. 
5.7 
Investigational Product (IP) Supplies and Accountability 
Investigational product supplies will not be sent to the Investigator(s) until the following 
documentation has been received by the Sponsor: 


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• Written proof of approval of the protocol and its informed consent forms (ICFs) 
by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for 
the institution where the study is to be conducted. 
• An Investigator-signed and dated FDA Form 1572. 
• A signed and dated curriculum vitae of the Principal Investigator including a copy 
of the Principal Investigator’s current medical license (required in the US) or 
medical registration number on curriculum vitae. 
The Investigator and study staff will be responsible for the accountability of all IP 
supplies (dispensing, inventory, and record keeping) following Aerogen Pharma 
instructions and adhere to Good Clinical Practice (GCP) guidelines as well as local 
and/or regional requirements. 
Under no circumstances will the Investigator allow the IP to be used other than as 
directed by this protocol.  IP will not be administered to any individual who is not 
enrolled into the study. 
An accurate and timely record of the receipt of all IP; dispensing of IP to the patient; 
collection of unused IP; and subsequent return of unused IP to Aerogen Pharma must be 
maintained.  This includes, but may not be limited to: (a) documentation of receipt of IP, 
(b) IP dispensing log, (c) IP accountability log, (d) all shipping service receipts, and (e) 
documentation of returned IP to the Sponsor.  All forms will be provided by Aerogen 
Pharma.  Any comparable forms that the investigational site wishes to use must be 
approved by Aerogen Pharma. 
The supplies and inventory records must be made available, upon request, for inspection 
by the designated representative of Aerogen Pharma, a representative of the FDA, or a 
representative of a non-US health authority.  All used and unused IP are to be returned to 
Aerogen Pharma at the conclusion of the study.   
6. 
CRITERIA FOR EVALUATION 
6.1 
Primary Endpoint 
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• Requires VV ECMO   
• Inability to extubate within 10 days or reintubation within < 24 hours 
• Change in S/F, oxygenation index and P/F ratio (>15%) from baseline to 
12 hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
1. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• Need to begin inotropic 10% increase in current vasopressor therapy 
• Worsening hemodynamic parameters  


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• Cardiac troponin >20% from baseline  
• BNP > 15% of baseline 
• Need for temporary mechanical circulatory support (IABP, Impella) 
• Requires VA ECMO 
6.2 
Secondary Endpoints 
1. Improvement in oxygenation defined as any one of the following: 
• Stabilization of PaO2/FIO2 >250 
• Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
2. Improved clinical outcomes defined as one of more of the following: 
• Time to extubation following the site’s extubation protocol 
• Free from re-intubation 
• Reduction in ICU days 
• Reduction in the number of re-admissions to the ICU due to COVID-19   
within 28 days 
• Reduction in total hospital days  
• Mortality [28 days] defined as Cardiopulmonary mortality or mortality 
from all causes  
3. Safety and tolerability 
• Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory/oxygenation parameters,  and 
laboratory tests. 
6.3 
Exploratory endpoints will include (where available): 
• Change in LDH 
• Change in fibrinogen 
• Change in WBC count including lymphocytes and neutrophil subsets 
• Change in triglycerides 
• Change in ferritin 
• Change in CRP / ESR 
• Change in IL-6 
• Change in D-Dimer  
 


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6.4 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used and generally 
recognized as reliable, accurate, and relevant in studies of cardiac and respiratory 
function. 
7. 
SAFETY ASSESSMENTS 
Safety will be assessed through monitoring of adverse events (AEs) and serious adverse 
events (SAEs),  laboratory tests, chest assessments (Chest CT or Chest X-ray), 
oxygenation/ventilatory parameters, and vital signs.  Safety assessment frequency is 
shown in the Schedule of Assessments and Procedures. 
7.1 
General Safety Procedures 
7.1.1 
Vital Signs and Weight Measurements 
Vital sign measurements, including systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR) [beats per minute], respiratory rate (breaths per minute), 
and body temperature (in Celsius) will be obtained twice daily Days 1-10 or  as clinically 
indicated.  Weight (kg) will be obtained at the time of Screening and at Day 10 or end of 
VP treatment.  Height will be obtained at the time of Screening.  If unable to obtain 
height, the study staff will use the best reported historical height from patient or LAR. 
7.1.2 
Physical Examination 
A physical examination will be conducted at the screening visit and will include 
assessments of general appearance; skin and lymphatics; eyes, ears, nose, throat; 
cardiovascular system; respiratory system; abdomen/gastrointestinal system; urological 
system; musculoskeletal and neurological systems.  Other body systems may be 
examined as clinically indicated. 
7.1.3 
Laboratory Measurements 
Clinical laboratory measurements to be performed are listed below.  The Schedule of Assessments 
and Procedures shows the time points at which blood will be collected for clinical laboratory tests and 
pregnancy testing.  The Baseline for laboratory tests is the Screening assessment. 
Category 
Parameters 
Hematology-CBC with diff 
Hemoglobin, hematocrit, RBC, WBC with differential 
(neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, 
basophils), platelets  
Full Chemistry Panel 
 
Electrolytes 
Sodium, potassium, chloride, bicarbonate, calcium 
Liver function tests 
AST, ALT, AP, total bilirubin 
Renal function parameters 
BUN, creatinine 
Coagulation Studies 
PT/PTT, D-Dimer 
Other 
Serum or urine pregnancy test, RT-PCR for COVID-19, 
ESR, 
Troponin, 
BNP, 
fibrinogen, 
ferritin, 
LDH, 
Triglycerides, D-Dimer, IL-6, and CRP 
7.1.4 
Chest Assessments 
A Chest CT or Chest X-ray will be obtained at Screening and Day 5. 


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7.1.5 
Time Prone Protocol 
The time prone protocol is a standard of care in OSU’s ICU.  This will be in place for all 
days that patients are within the ICU. 
7.2 
Adverse Events 
7.2.1 
Definitions 
Adverse events are any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment.  For the purposes of this study, this will include unanticipated 
medical events in the judgment of the investigator.  A pre-existing condition or symptom 
is one that is present at the start of the study and is reported as part of the patient’s 
medical history.  A pre-existing condition or symptom should be reported as an AE only 
if its frequency, intensity or character worsens during study treatment. 
All AEs that occur from the time of the first dose of study medication through the End of 
Study (Day 28) will be recorded and reported as Treatment-Emergent Adverse Events 
(TEAE).  All AEs must be appropriately documented in the patient’s medical 
chart/source documentation and on the DCFs.  When known, investigators should report 
syndromes rather than list symptoms associated with the syndrome. 
All AEs that are ongoing at the conclusion of the study should be followed until: a) 
resolution/stable sequelae; b) the Investigator determines that it is no longer clinically 
significant; or, c) the study patient is lost to follow-up.  If no follow-up is provided, the 
Investigator must provide a written justification. 
7.2.2 
Grading of Adverse Events 
The severity of each AE will be categorized using the following criteria: 
• Grade 1 (Mild):  usually transient; requires no special treatment and does not 
interfere with the patient’s daily activities. 
• Grade 2 (Moderate):  produces a low level of inconvenience to the patient and 
may interfere with daily activities.  These AEs are usually ameliorated by simple 
therapeutic measures. 
• Grade 3 (Severe):  interrupts daily activity and requires systemic drug therapy or 
other medical treatment. 
7.2.3 
Relationship to Study Medication/Study Device/Procedure 
The Investigator must assess the relationship of each reported AE.  The Investigator must 
make an assessment of the relationship of the AE to the study medication/study 
device/procedure using the following scale: 
• Unrelated:  The AE is definitely not or unlikely to be associated with study 
medication/study device/procedure and is judged due to causes other than the 
study medication/study device/procedure. 
• Related:  The AE is possibly or probably related with study medication/study 
device/procedure.    


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7.2.4 
AE Outcomes 
The following terms and definitions are used in assessing the final outcome of an AE:  
• Recovered/Resolved - The patient has fully recovered, or by medical or surgical 
treatment, the condition has returned to the level observed at the first trial-related 
activity. 
• Recovering/Resolving - The condition is improving and the patient is expected to 
recover from the event. 
• Recovered/Resolved with sequelae - The patient has recovered from the 
condition, but with lasting effect due to a disease, injury, treatment or procedure. 
If a sequela meets an SAE criterion, the AE must be reported as an SAE. 
• Not recovered/Not resolved - The condition of the patient has not improved and 
the symptoms are unchanged, or the outcome is not known at the time of 
reporting. 
• Fatal - This term is only applicable if the patient died from a condition related to 
the reported AE. Outcomes of other reported AEs in a patient before he/she died 
should be assessed as “recovered”, “recovering”, “recovered with sequelae” or 
“not recovered”.  An AE with fatal outcome must be reported as an SAE. 
7.2.5 
Laboratory Test and other Test Abnormalities as Adverse Events 
A laboratory or other test (chest assessments, vital signs) abnormality should be reported 
as an AE if the Investigator considers the abnormality an AE or if the abnormality is 
associated with accompanying symptoms, requires medical/surgical intervention, leads to 
a change in study treatment, or results in discontinuation from the trial. When possible, 
syndromes not laboratory values, should be reported as AEs.  For example, elevated 
hepatic transaminases associated with hepatitis should be reported as “hepatitis” and 
decreased hemoglobin and hematocrit requiring iron supplementation should be recorded 
as “anemia.”  Prior to reporting as an AE, abnormal tests should be repeated to verify the 
accuracy of the original result. 
7.2.6 
Serious Adverse Events 
The Investigator is required to determine if each AE is a Serious Adverse Event (SAE).  
An SAE is any AE occurring after the first dose of study medication and results in any of 
the following outcomes: 
• Death, or 
• Is life-threatening, or 
• Prolongation of existing hospitalization, or 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 


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judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
In the event of death, the cause of death should be recorded as the SAE (death is an 
outcome, not the AE itself). 
Any planned procedures that require admission to hospital as well as any planned elective 
procedures (e.g., angioplasty) are not considered SAEs (unless the underlying condition 
has worsened or the procedure results in a worsening of the patient’s condition).  In 
addition, pregnancy that occurs during the course of the study or absence of a treatment 
effect will also not be considered to be an SAE and will be collected on a separate CRF. 
7.2.7 
Reporting for SAEs (24 Hours) 
Regardless of causality, an SAE must be followed clinically until resolution or 
stabilization.   
All SAEs after the first dose of study medication through Day 28 of the study must be 
reported to the Sponsor or the Sponsor’s representative within 24 hours of the 
investigational site’s knowledge of the occurrence.  The investigational site will email a 
Serious Adverse Event Report (SAER) to the Sponsor and the Medical Monitor.    
Investigational sites will be provided with SAER forms.  The Medical Monitor will work 
closely with the Sponsor to properly assess and report the SAE.  
The SAE information emailed to the Sponsor or the Sponsor’s representative will include 
the following (as available): 
• Patient Number, Investigator name, and Site Number 
• SAE information:  event term, onset date, severity, and causal relationship 
• Basic demographic information (e.g., age, gender, weight) 
• The outcomes attributable to the event (death, a life-threatening adverse drug 
experience, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, other important medical event[s]) 
• A summary of relevant test results, pertinent laboratory data, and any other 
relevant medical history 
• The first and last dates of study medication administration 
• A statement whether study medication was discontinued or study medication 
administration schedule modified 
• A statement whether event recurred after reintroduction of study medication if 
administration had been discontinued or withheld 
• Supplemental anonymized information may include the following hospital 
records:  laboratory results, radiology reports, progress notes, admission and 
emergency room notes, holding/observation notes, discharge summaries, autopsy 
reports, and death certificates 


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Supplemental information may be transmitted using a follow-up report and should not 
delay the initial report. 
For regulatory purposes, initial reports of SAEs should be transmitted within the 
prescribed time frame as long as the following minimum information is available:  patient 
number, suspect study medication, reporting source, and an event or outcome that can be 
identified as being both serious and unexpected for which the Investigator can make a 
relationship assessment. 
7.3 
Reporting of Pregnancy 
Any pregnancy where the estimated date of conception occurs either prior to the End of 
Study must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study medication 
exposure, this should be reported regardless of the length of time that has passed since the 
exposure to study treatment. 
An induced abortion or a spontaneous abortion is considered to be an SAE and should be 
reported in the same timeframe and in the same format as all other SAEs. 
Pregnancies must be reported as soon as possible but no later than one business day by 
email.  
All pregnancies must be followed to outcome.  The outcome of the pregnancy must be 
reported as soon as possible but not later than 24 hours of the investigational site’s 
knowledge of the outcome. 
8. 
PHARMACOKINETIC ASSESSMENTS 
Not applicable. 
9. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
The assessments and procedures for this study are described in detail below and 
presented in the Schedule of Assessments and Procedures located behind the Synopsis. 
9.1 
Study Evaluation Timepoints 
9.1.1 Screening (within 14 days prior to Baseline Day 1) 
Potential study patients will be recruited by the study staff from patients.  The following 
assessments will occur prior to study enrollment: 
• Informed consent prior to any study procedures or assessments being performed. 
• Demographic Information 
• Medical History  
• Physical Exam 


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• Prior Medication History 
• Chest CT or Chest X-ray 
• Inclusion/Exclusion Eligibility Assessment (including assessment of shortness of 
breath within the last 14 days) 
• Serum/Urine Pregnancy Test (if woman of childbearing potential) 
• Clinical Laboratory Sampling to include: Full Chemistry Panel including LFTs, 
CBC with Diff including neutrophils and lymphocytes, PT/PTT, Triglycerides, 
LDH, ferritin, fibrinogen, CRP, ESR, IL-6, troponin, BNP, D-Dimer, and RT-
PCR for COVID-19 
• Vital Signs  
• Height & Weight (If height can’t be obtained, use the best reported historical 
height) 
9.1.2 Days 1-10 Treatment  
9.1.2.1 Baseline-Day 1 (0 Hour) 
 
• Continue evaluation eligibility by assessing Inclusion/Exclusion Criteria. 
• Subjects will receive VentaProst, for a maximum of 10 days, as clinically 
indicated at the discretion of the Investigator.  VentaProst dose will begin at 13.6 
ng/kg/min and can be titrated up to 30.6 ng/kg/min or down to 3.4 ng/kg/min as 
clinically warranted.  The B.Braun syringe pump will be set to the appropriate 
dose utilizing the subject’s sex and height (ideal body weight).  
• Vital signs will be assessed twice daily in AM and PM while on VentaProst.  
Efforts will be made to obtain vital signs at the same time each day.  Vital signs 
include: temperature, pulse rate, respiration rate and blood pressure.  
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily while on VentaProst:  Ventilator 
Type, Vent Mode, FiO2, Inspiratory time, Mean Airway Pressure, Peak 
Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume, and 
Respiratory Rate 
• Time Prone Position-16 hours per day per OSU Protocol 
9.1.2.2 Day 1-12 hours 
• Clinical Laboratory Sampling to include: Full Chemistry Panel including LFTs, 
CBC with Diff including neutrophils and lymphocytes, PT/PTT, Triglycerides, 
LDH, ferritin, fibrinogen, CRP, ESR, IL-6, troponin, BNP, and D-Dimer. 
• Continue to administer VentaProst if clinically indicated. 


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• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Oxygenation measurement via continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily while on VP:  Ventilator Type, Vent 
Mode, FiO2, Inspiratory time, Mean Airway Pressure, Peak Inspiratory Pressure, 
Positive End Expiratory Pressure, Tidal Volume, and Respiratory Rate 
• Vital signs will be assessed twice daily in AM and PM.  Efforts will be made to 
obtain vital signs at the same time each day.  Vital signs include: temperature, 
pulse rate, and blood pressure.  
• Time Prone Position-16 hours per day per OSU Protocol 
9.1.2.3 Days 2-10 (While on VentaProst) 
• Continue to administer VentaProst if clinically indicated. 
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Oxygenation measurement via continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily: Ventilator Type, Vent Mode, FiO2, 
Inspiratory time, Mean Airway Pressure, Peak Inspiratory Pressure, Positive End 
Expiratory Pressure, Tidal Volume, and Respiratory Rate 
• Vital signs will be assessed twice daily in AM and PM.  Efforts will be made to 
obtain vital signs at the same time each day.  Vital signs include: temperature, 
pulse rate, and blood pressure.  
• Time Prone Position-16 hours per day per OSU Protocol 
• Full Chemistry Panel including LFTs, CBC with Diff including neutrophils and 
lymphocytes, PT/PTT and RT-PCR for COVID-19. (Day 5 only) 
• Chest CT or Chest X-ray (Day 5 only) 
• Full Chemistry Panel including LFTs, CBC with Diff including neutrophils and 
lymphocytes, PT/PTT, Triglycerides, LDH, ferritin, fibrinogen, CRP, ESR, IL-6, 
troponin, BNP, D-Dimer, and RT-PCR for COVID-19 (Day 10 only).  
• Obtain weight. (Day 10 only or at end of VP dosing) 
9.1.2.4 Weaning  
Patients will be weaned from VentaProst slowly due to concern that VentaProst is 
providing significant clinical benefit and to avoid a rebound effect.  Doses will be 


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decreased in steps of 3.4 ng/kg/min increments  with a minimum of 15 minutes 
between changes until VentaProst is discontinued.   
 
9.1.3 
Day 28/End of Study (EOS)  
•    Assess AEs/SAEs  
•    Assess Mortality 
•    Assess concomitant medications 
9.2 
Data Collection 
Investigator or designee will enter the information required by the protocol onto source 
documents and enter data into data collection forms (DCFs) in an excel spreadsheet 
provided by Aerogen Pharma. 
9.3 
Clinical Data Management 
Data from source documents will be verified against the DCF and any discrepancies will 
be clarified and resolved with study staff. 
9.4 
Database Quality Assurance 
All databases will be remotely monitored by the Sponsor due to the COVID-19 
pandemic. Should restrictions be lifted at OSU, an on-site visit may occur if all parties 
are in agreement. 
10. 
 STATISTICAL CONSIDERATIONS 
10.1 
Statistical Methods 
A Statistical Analysis Plan will be not be developed as this is an exploratory trial.  Any 
statistical evaluation will be handled internally by Aerogen Pharma or their designee. 
10.2 
Determination of Sample Size 
The number of patients has been selected to enable an adequate clinical assessment of 
pharmacodynamics, safety, and tolerability parameters without presenting undue risk to a 
large number of patient’s being exposed to this investigational product. 
10.3 
Analyses Sets 
All patients who are enrolled in the study and who receive at least one dose of VentaProst 
will be included in the intent-to-treat (ITT) analyses of pharmacodynamic and safety data.  
All available data will be used and missing data will not be estimated or carried forward 
in any statistical summary or analyses. 
Descriptive summary statistics include the number of patients, mean, median, percent 
coefficient of variation (% CV) (if required), standard deviation, and minimum and 
maximum values (quantitative variables) or the number of patients and percentages by 
category (qualitative variables).  Changes will be assessed as the difference between 
baseline measurements and the appropriate post-dose measurements unless otherwise 


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specified.  Mean differences between active and historical control groups (when 
available) will be assessed and significance will be determined on the basis of a 95% CI.  
Individual patient listings of data will also be provided to allow for review of all 
pharmacodynamic, safety, and tolerability parameters. 
10.4 
Demographic and Other Baseline Characteristics 
Continuous demographic and other baseline characteristics (such as age, weight, and 
height) will be summarized using n, mean, SD, median, minimum, and maximum.  
Qualitative characteristics (such as gender and race) will be summarized by counts and 
percentages.   
10.5 
Criteria for Evaluation 
10.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint:  
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• Requires VV ECMO   
• Inability to extubate patient within 10 days or reintubation within <24 
hours 
• Change in S/F, oxygenation index and P/F ratio (>15%) from baseline to 
12 hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• Need to begin inotropic or 10% increase in current vasopressor therapy 
• Worsening hemodynamic parameters  
• Cardiac troponin >20 % from baseline   
• BNP > 15% of baseline 
• Need for temporary mechanical circulatory support (IABP, Impella) 
• Requires VA ECMO 
10.5.2 
Secondary Efficacy Endpoints 
Key secondary endpoints include: 
1. Improvement in oxygenation defined as any one of the following: 
• 
Stabilization of PaO2/FIO2 >250 
• Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
2. Improved clinical outcomes defined as one of more of the following:  


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• Time to extubation following the site’s extubation protocol 
• Free from reintubation 
• Reduction in ICU days 
• Reduction in the number of re-admissions to the ICU due to COVID-19   
within 28 days 
• Reduction in total hospital days  
• Mortality [28 days] defined as Cardiopulmonary mortality or mortality 
from all causes  
3. Safety 
• Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory/oxygenation parameters,  and 
laboratory tests. 
10.5.3 
Key Exploratory Endpoints include: 
• Change in LDH 
• Change in fibrinogen 
• Change in WBC count including lymphocytes and neutrophil subsets 
• Change in triglycerides 
• Change in ferritin 
• Change in CRP / ESR 
• Change in IL-6 
• Change in D-Dimer  
 
10.6 
Extent of Exposure 
Exposure data will be summarized by using frequencies and percentages. 
10.7 
Safety Analyses 
Safety measurements include AE/SAEs, vital signs, chest assessments (Chest CT or 
Chest X-ray), laboratory tests, and oxygenation/ventilatory parameters.  Safety data will 
be summarized by using frequencies and incidence rates.   
10.7.1 
Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim 
description (Investigator term) using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be presented by preferred term nested within System Organ Class.  
Verbatim description and all MedDRA level terms, including the lower level terms, for 
all AEs will be contained in the data listings of the clinical study report (CSR).  


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AEs will be summarized by presenting the incidence of AEs.  Although a MedDRA term 
may be reported more than once for a patient, that patient will be counted only one time 
in the incidence count for that MedDRA term. 
Treatment-emergent adverse events (TEAEs) will be analyzed.  AEs that are not 
treatment-emergent will be listed.  A TEAE is defined as  
• AEs that emerge during treatment, having been absent at pretreatment, or  
• Reemerge during treatment, having been present at pretreatment but stopped 
prior to treatment, or  
• Worsen in severity or frequency during treatment relative to the pretreatment 
state, when the AE is continuous. 
10.7.2 
Laboratory Values 
Clinical laboratory results post-Baseline will be evaluated for markedly abnormal values.  
For the incidence of markedly abnormal laboratory values, each patient may be counted 
once in the laboratory parameter value high and in the laboratory parameter low 
categories as applicable.  Descriptive summary statistics (e.g. mean, SD, median, 
minimum, maximum) for laboratory values and changes from baseline will be evaluated. 
10.7.3 
Vital Signs 
Vital sign values will be evaluated on an individual basis by patient.  Abnormal vital sign 
values will be identified as those outside (above or below) the reference range.  
Descriptive summary statistics (e.g., mean, SD, median, minimum, maximum) for vital 
sign parameters and changes from Baseline will be evaluated. 
10.8 
The Procedure for Revising the Statistical Analysis Plan 
Not Applicable. 
11. 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS 
11.1 
Ethics 
11.1.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an IRB or IEC constituted and functioning in accordance with 
International Conference on Harmonization (ICH) E6, Section 3, and any local 
regulations, i.e., Federal Regulations, Title 21 Code of Federal Regulations (CFR) Part 
56.  Any protocol amendment and/or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval (except for changes involving only logistical or 
administrative aspects of the study (e.g., change in CRA[s], change of telephone 
number[s]).  Documentation of IRB/IEC compliance with the ICH and any local 
regulations regarding constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC Chairman must be sent to the 
Principal Investigator with a copy to the Sponsor prior to study start and the release of 


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any investigational products to the site by the Sponsor or its designee (ICH E6, Section 
4.4).  If the IRB/IEC decides to suspend or terminate the study, the Investigator will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator 
or Sponsor, depending on local regulatory obligations.  If the Investigator is required to 
report to the IRB/IEC, he/she will forward a copy to the Sponsor at the time of each 
periodic report.  The Investigator or the Sponsor will submit, depending on local 
regulations, periodic reports and inform the IRB/IEC of any reportable AEs per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
Investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required. 
11.1.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating practices of Aerogen 
Pharma (or designee), which are designed to ensure adherence to GCP guidelines as 
required by the following: 
• ICH - E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonization of Pharmaceuticals for Human Use. 
• US CFR dealing with clinical studies (21 CFR, including parts 50 and 56 
concerning Informed Patient Consent and IRB regulations). 
11.1.3 
Patient Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each patient or their legally authorized representative (LAR), the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, and currently available alternative treatments.  Each 
patient must be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written 
in non-technical language.  The patient or their LAR should understand the statement 
before signing and dating it and will be given a copy of the signed document.  The patient 
or their LAR will be asked to sign an informed consent prior to any study-specific 
procedures being performed.  No patient can enter the study before his/her informed 
consent has been obtained.  Due to the COVID-19 pandemic and restrictions on hospital 
visitors, informed consent may be obtained via telephone or video conference call if the 
patient is incapacitated or sedated due to the severity of their illness.  A witness for the 
study team should be present when a call or video conference is occurring with the 
patient’s LAR.  This process should be carefully documented in the subject’s medical 
records. 
An unsigned copy of an IRB/IEC and Sponsor-approved written informed consent must 
be prepared in accordance with ICH E 6, Section 4, and all applicable local regulations, 


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i.e., Federal Regulations, Title 21, CFR Part 50, and provided to the Sponsor.  Each 
patient or their LAR must sign an approved informed consent prior to study participation.  
The form must be signed and dated by the appropriate parties.  The original signed ICF 
for each patient will be verified by the Sponsor and kept in the study center’s 
investigational site files. 
The patient should be informed in a timely manner if new information becomes available 
that might be relevant to the patient’s willingness to continue participation in the trial.  
The communication of this information should be documented. 
11.2 
Administrative Procedures 
11.2.1 
Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  
Protocols will be followed as written. 
Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the Sponsor before implementation.  Amendments 
specifically affecting the safety of patients, the scope of the investigation, or the scientific 
quality of the study require additional approval by the applicable IRBs/IECs of all 
investigational sites and, as required, by the regulatory authority.  These requirements 
should in no way prevent any immediate action from being taken by the Investigator, or 
by the Sponsor, in the interest of preserving the safety of all patients included in the 
study.  If an immediate change to the protocol is felt by the Investigator to be necessary 
for safety reasons, the  Medical Monitor must be notified promptly and the IRB/IEC for 
the site must be informed as soon as possible. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval, but the IRB/IEC must be kept informed of such 
changes.  In these cases, the Sponsor will send a letter to the site for forwarding on to the 
IRB/IEC detailing such changes. 
11.2.2 
Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
11.2.3 
Monitoring Procedures 
The Sponsor or Sponsor’s representative will maintain contact with the Investigator and 
designated staff by telephone, letter, and/or email between study visits.  Monitoring visits 
to each investigational site will be conducted by the sponsor either remotely or in person.  
In accordance with ICH E6, Section 6.10, source documents include, but are not limited 
to the following: 
• Clinic, office, hospital charts. 
• Copies or transcribed health care provider notes which have been certified for 
accuracy after production. 


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• Recorded data from automated instruments such as mechanical ventilators, x-
rays, and other imaging reports, e.g., sonograms, computed tomography scans, 
magnetic resonance images, radioactive images, ECGs, rhythm strips, 
electroencephalographs, polysomnography, pulmonary function tests (regardless 
of how these images are stored, including microfiche and photographic 
negatives). 
• Records of telephone contacts. 
• Diaries or evaluation checklists. 
• Investigational product distribution and accountability logs maintained in 
pharmacies or by research personnel. 
• Laboratory results and other laboratory test outputs, e.g., serum pregnancy test 
result documentation. 
• Correspondence regarding a study patient’s treatment between physicians or 
memoranda sent to the IRBs/IECs. 
• CRF components (e.g., questionnaires) that are completed directly by patients 
and serve as their own source. 
11.2.4 
Recording of Data 
In order to provide the Sponsor with accurate, complete, and legible records following 
criteria are to be maintained.  The Investigator will enter the information required by the 
protocol onto the data collection forms (DCFs)  provided by the sponsor as agreed upon 
with the research staff. 
11.2.5 
Data Storage and Retention of Records 
 
The circumstances of completion or termination of the study notwithstanding, the 
Investigator has the responsibility to retain all study documents, including but not limited 
to the protocol, copies of data collection forms (DCFs) , Investigator's Brochure, 
regulatory agency registration documents, e.g., FDA 1572 form, ICFs, and IRB/IEC 
correspondence.  The investigational site should plan on retaining study documents as 
follows: 
• For at least two years following the date a marketing application is approved for 
the investigational product for the indication for which it is being investigated, or 
• Until two years after the investigation is formally discontinued and no application 
is to be filed or if the application is not approved. 
It is requested that at the completion of the required retention period, or should the 
Investigator retire or relocate, the Investigator contacts the Sponsor, allowing the Sponsor 
the option of permanently retaining the study records. 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Data will be coded (de-identified), stored in a secure electronic database during and after 


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the study, and will not be shared with unauthorized persons. The principal investigator 
and co-investigator will have access to the data to review and analyze the data, as 
described in this protocol. For the protection and privacy of the patients, no identifying 
information will be released. 
 
Data will be retained and possibly used in the future for further analysis. All identifiers 
will be removed and not be shared at any time. 
 
11.2.6 
Handling of Investigational Product 
All IP will be procured by OSU on behalf of Aerogen Pharma and maintained within the 
site’s Investigational Pharmacy.  It will be inventoried and stored according to their 
protocols and procedures.   Since Flolan will be procured by OSU, the drug should not be 
dispensed to patients in the VentaProst COVID trial (APC-VPCOV-CLN-001) until a 
favorable IRB approval has been obtained by the OSU IRB and a study initiation visit has 
been conducted by the Sponsor.  Investigation product supplies must be kept in an 
appropriate secure area (e.g., locked cabinet) and stored according to the conditions 
specified on the investigational product labels.  The Investigator (or designated 
pharmacist) must maintain an accurate record of the shipment and dispensing of the IP in 
an IP accountability log, a copy of which must be given to the Sponsor at the end of the 
study.  An accurate record of the date and amount of IP dispensed to each patient must be 
available for inspection at any time.  The assigned sponsor representative will review 
these documents along with all other study conduct documents at an appropriate interval 
of visit to the investigational site once IP has been received by the investigational site.  
Due to COVID-19 a physical inventory of IP (drug and device supplies) may not be 
possible.  If at all possible, an inventory of supplies should be conducted via video 
conferencing.  If video conferencing is not possible, study staff will inventory supplies 
and provide documentation to Aerogen Pharma. 
All IP supplies are to be used only for this protocol and not for any other purpose.  The 
Investigator (or designated pharmacist) must not destroy any IP product labels or any 
partly used or unused IP supply without Sponsor authorization.  At the conclusion of the 
study and as appropriate during the course of the study, the Investigator (or designated 
pharmacist) will return or properly dispose of all used and unused IP. Unused 
investigational device components will be returned to Aerogen Pharma at the conclusion 
of the study. 
11.2.7 
Publication of Results 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each Investigator and Aerogen Pharma, as appropriate. 
11.2.8 
Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the course 
of this study will be kept confidential by the Investigator, the Investigator’s staff, and 
IRB/IEC and will not be disclosed in whole or in part to others or used for any purpose 
other than reviewing or performing the study without the written consent of the Sponsor.  


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No data collected as part of this study will be utilized in any written work, including 
publications, without the written consent of Sponsor.  These obligations of confidentiality 
and non-use shall in no way diminish such obligations as set forth in the Confidentiality 
Agreement between the Sponsor and the Investigator.  All persons assisting in the 
performance of this study must be bound by the obligations of confidentiality and non-
use set forth in the Confidentiality Agreement between the Investigator and Sponsor 
(provided by the Sponsor). 
11.2.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.   
The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the Investigator terminates or suspends a trial without prior agreement of the 
Sponsor, the Investigator should inform the Institution where applicable, and the 
Investigator/Institution should promptly inform the Sponsor and the IRB/IEC and should 
provide the Sponsor and the IRB/IEC a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 
11.2.10 Patient Insurance and Indemnity 
The Sponsor will provide the insurance in accordance with local guidelines and 
requirements as a minimum for the patients participating in this study. 


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12. 
REFERENCES 
 
Adhikari, N. K., R. P. Dellinger, S. Lundin, D. Payen, B. Vallet, H. Gerlach, K. J. 
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not reduce mortality in patients with acute respiratory distress syndrome regardless 
of severity: systematic review and meta-analysis." Crit Care Med 42(2): 404-412. 
 
Afshari, A., A. Bastholm Bille and M. Allingstrup (2017). "Aerosolized 
prostacyclins for acute respiratory distress syndrome (ARDS)." Cochrane 
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Ammar, M. A., S. R. Bauer, S. N. Bass, M. Sasidhar, R. Mullin and S. W. Lam 
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Treatment of ARDS." Ann Pharmacother 49(10): 1105-1112. 
 
De Wet, C. J., D. G. Affleck, E. Jacobsohn, M. S. Avidan, H. Tymkew, L. L. Hill, P. 
B. Zanaboni, N. Moazami and J. R. Smith (2004). "Inhaled prostacyclin is safe, 
effective, and affordable in patients with pulmonary hypertension, right heart 
dysfunction, and refractory hypoxemia after cardiothoracic surgery." J Thorac 
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Dewachter, C., Laurence Dewachter , Marie Vercruyssen , Benoit Rondelet , Dean 
P. Schraufnagel , Serge Brimioulle , Francois Kerbaul , Robert Naeije (2012). 
"Inflammatory Processes In Load-Induced Right Ventricular Failure - Anti-
Inflammatory Effects Of Epoprostenol." American Journal of Respiratory and 
Critical Care Medicine A3462(185). 
 
 
 


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Dzierba, A. L., E. E. Abel, M. S. Buckley and I. Lat (2014). "A review of inhaled 
nitric oxide and aerosolized epoprostenol in acute lung injury or acute respiratory 
distress syndrome." Pharmacotherapy 34(3): 279-290. 
 
Fuller, B. M., N. M. Mohr, L. Skrupky, S. Fowler, M. H. Kollef and C. R. 
Carpenter (2015). "The use of inhaled prostaglandins in patients with ARDS: a 
systematic review and meta-analysis." Chest 147(6): 1510-1522. 
 
Giannis, D., I. A. Ziogas and P. Gianni (2020). "Coagulation disorders in 
coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons 
from the past." J Clin Virol 127: 104362. 
 
Haraldsson, A., N. Kieler-Jensen, H. Wadenvik and S. E. Ricksten (2000). 
"Inhaled prostacyclin and platelet function after cardiac surgery and 
cardiopulmonary bypass." Intensive Care Med 26(2): 188-194. 
 
Higenbottam, T., D. Wheeldon, F. Wells and J. Wallwork (1984). "Long-term 
treatment of primary pulmonary hypertension with continuous intravenous 
epoprostenol (prostacyclin)." Lancet 1(8385): 1046-1047. 
 
Kallet, R. H., G. Burns, H. Zhuo, K. Ho, J. S. Phillips, L. P. Pangilinan, V. Yip, A. 
Gomez and M. S. Lipnick (2017). "Severity of Hypoxemia and Other Factors That 
Influence the Response to Aerosolized Prostacyclin in ARDS." Respir Care 62(8): 
1014-1022. 
 
Mitchell, J. A., F. Ali, L. Bailey, L. Moreno and L. S. Harrington (2008). "Role of 
nitric oxide and prostacyclin as vasoactive hormones released by the 
endothelium." Exp Physiol 93(1): 141-147. 
 
 


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 22 Jun 2020 
Confidential 
Page 52 of 52 
 
Nicolas, L. B., A. Krause, M. M. Gutierrez and J. Dingemanse (2012). "Integrated 
pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects." Br 
J Clin Pharmacol 74(6): 978-989. 
 
Rao, V., K. Ghadimi, W. Keeyapaj, C. A. Parsons and A. T. Cheung (2018). 
"Inhaled Nitric Oxide (iNO) and Inhaled Epoprostenol (iPGI2) Use in 
Cardiothoracic Surgical Patients: Is there Sufficient Evidence for Evidence-Based 
Recommendations?" J Cardiothorac Vasc Anesth 32(3): 1452-1457. 
 


PROTOCOL TITLE 
TITLE: DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING MECHANICAL VENTILATION  
PROTOCOL  NUMBER 
APC-VPCOV-CLN-001 
INVESTIGATIONAL 
PRODUCT 
VentaProst™ 
INDICATION 
Reduction of respiratory, cardiac or circulatory failure in patients with 
COVID-19 
PHASE 
Phase 2a 
SPONSOR 
Aerogen Pharma Limited 
1660 S Amphlett Boulevard, Suite 360 
San Mateo, CA 94402 
United States 
MEDICAL MONITOR 
Matthew Exline, MD 
AMENDMENT #1 
APPROVAL DATE 
21 July 2020 
GCP STATEMENT 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) and all applicable local Good 
Clinical Practices (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
CONFIDENTIALITY 
STATEMENT 
This document is confidential as it contains proprietary information 
of Aerogen Pharma.  Any viewing or disclosure of such information 
that is not authorized in writing by the Aerogen Pharma is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 


Aerogen Pharma 
Protocol Number APC-VPCOV-CLN-001 
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 2 of 52 
SPONSOR PROTOCOL APPROVAL PAGE 
PROTOCOL TITLE 
PROTOCOL NUMBER 
APC-VPCOV-CLN-001 
AMENDMENT #1 
APPROVAL DATE 
21 July 2020 
________________________________________________________________________ 
Judy Doto, RN, BSN 
Date 
Head of Clinical Operations 
Aerogen Pharma 
________________________________________________________________________ 
Jim Fink PhD, RRT, FCCP 
 
 
 
 
 
Date 
Chief Scientific Officer  
Aerogen Pharma 
________________________________________________________________________ 
Plamena Entcheva-Dimitrov, PhD, RAC 
 
 
 
 
Date 
Head of Regulatory and Medical Affairs 
Aerogen Pharma 
________________________________________________________________________ 
Andy Clark PhD  
Date 
Vice President and General Manager 
Aerogen Pharma 
21 July 2020
21 July 2020
21 JUL 2020
A DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA 
DEDICATED DELIVERY SYSTEM) IN SUBJECTS WITH 
COVID-19 REQUIRING MECHANICAL VENTILATION  
21 JUL 2020


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 3 of 52 
 
INVESTIGATOR’S SIGNATURE PAGE 
PROTOCOL TITLE 
A DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING MECHANICAL VENTILATION  
PROTOCOL NUMBER  
APC-VPCOV-CLN-001 
AMENDMENT #1 
APPROVAL DATE 
21July 2020 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations 
of the protocol and in accordance with ICH-GCPs and all applicable local guidelines. 
 
________________________________________________________________________ 
Principal Investigator (printed/typed) 
 
 
 
 
 
 
 
 
 
 
________________________________________________________________________ 
Principal Investigator Signature 
 
 
 
 
 
Date 
 
 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 4 of 52 
1. 
CLINICAL PROTOCOL SYNOPSIS 
Sponsor 
Aerogen Pharma 
Protocol No. 
APC-VPCOV-CLN-001 
Title of Study 
Double-blind, placebo controlled study to assess the efficacy and safety of VentaProst 
(Inhaled epoprostenol delivered via dedicated delivery system) in subjects with COVID-19 
requiring mechanical ventilation.  
Study Centers 
One clinical site in the US 
Phase 
Phase 2a 
Objectives 
 
Primary Objective: 
The primary objective of this study is the reduction of respiratory, cardiac or circulatory 
failure in patients with confirmed COVID-19. 
Secondary Objectives: 
The secondary objective in this study is to evaluate the effects of VentaProst on improvement 
in oxygenation and improvement in clinical outcomes.  
 
The study will also evaluate the effects of VentaProst on inflammatory parameters in subjects 
with confirmed COVID-19. 
Study Design 
 
This is a double-blind, placebo controlled study of VentaProst (Active) as compared to 
placebo (Control).  Active is inhaled epoprostenol administered via the VentaProst delivery 
system in 10 COVID-19 positive patients. Control is inhaled 0.9% sodium chloride solution 
administered via the VentaProst delivery system in 10 COVID-19 positive patients.  
Throughout the remainder of the protocol both Active and Control will be referred to as 
“study drug”.  This study will evaluate the potential therapeutic benefit of VentaProst  in 
treating patients with COVID-19 who require mechanical ventilation and are at risk for the 
progression of respiratory and/ or cardiac/circulatory failure.  This study will assess the 
efficacy and safety of VentaProst at an initial dose of 13.6 ng/kg/min (A range from 3.4-30.6 
ng/kg/min may be administered as clinically required for a maximum of 10 days at the 
discretion of the Investigator.  Patients will be followed through Day 28 to assess clinical 
outcomes.   
Patients will be consented and randomized to either the Active or Control group within 24 
hours of being placed on a mechanical ventilator.  Patients will be administered study drug 
using the VentaProst delivery system which allows up and down titration of study drug to 
achieve hemodynamic and oxygenation stability.  The starting dose of study drug will be 
initiated at 13.6 ng/kg/min.  Based on hemodynamic and oxygenation parameters, the dose of 
study drug can be increased in 3.4 ng/kg/min increments up to a maximum of 30.6 ng/kg/min 
or down to a minimum of 3.4 ng/kg/min.  Study drug will be administered based on the pump 
rate calculated for active treatment in mL/hr.  The titration table below (Table 1) shows the 
typical up and down titration steps for study drug.    
 
 
 
 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 5 of 52 
Table 1: Overview of Titration and Weaning Guidelines 
 
Up titration Guideline*  
 
Downward Titration / 
Weaning Guideline** 
Start Dose: 13.6 ng/kg/min 
1st Step Up Dose (17.0) 
2nd Step Up Dose (20.4) 
3rd Step Up Dose (23.8) 
4th Step Up Dose (27.2) 
5th Step Up Dose (30.6) 
Start Dose: 13.6 ng/kg/min 
1st Step Down dose (10.2) 
2nd Step Down Dose (6.8) 
3rd Step Down dose (3.4) 
 
* The study drug will be administered based on the pump rate calculated for active treatment in 
mL/hr.**If the patient has been up-titrated weaning should occur from that level in 3.4 ng/kg/min 
decrements.  
Patients will be weaned from study drug slowly to avoid rebound vasoconstriction.    During 
weaning, doses will be decreased in steps of 3.4 ng/kg/min increments, with a minimum of 15 
minutes between changes. The weaning process should occur in isolation to other treatment 
changes (no changes in inotropes, vasopressors, or vasodilators) whenever possible. Patients 
will be observed closely before, during, and after dose changes. In the event patients 
demonstrate signs of hemodynamic instability  or a decrease in oxygenation indicated by 
pulse oximetry during downward titration, the dose will be returned to its previous level. 
Once patients have been stable for at least 15 minutes, repeat attempts at dose reduction may 
be undertaken.  The process will continue until patients are fully weaned.  Patients will be 
monitored for safety and efficacy throughout study drug administration. 
Number/Type 
of Patients 
Approximately 20 COVID-19 positive patients requiring mechanical ventilation will be 
enrolled in this study. 
Patients will be randomized to either VentaProst Active (aerosolized epoprostenol 
administered via the VentaProst delivery system) or VentaProst Control (aerosolized 0.9% 
sodium chloride solution administered via the VentaProst delivery system). 
 
Inclusion 
Criteria 
 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men Age ≥18 years old (no upper limit)  
2. Confirmed COVID-19 positive by RT-PCR test 
3. Patients who require invasive mechanical ventilation.  
4. Enrolled into study within 24 hours of being placed on mechanical ventilation  
5. Consent or professional consent obtained 
6. Duration of shortness of breath must be within the previous 14 days.   
7. Female subjects of childbearing potential must have a negative pre-treatment 
pregnancy test (serum or urine). 
8. Received or currently receiving dexamethasone for the treatment of COVID. 
9. Willing and able to comply with treatment schedule and follow-up. 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 6 of 52 
 
Exclusion 
Criteria 
 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. 
Patients on ECMO support. 
2. 
Patients receiving another inhalation research medication or inhaled nitric oxide.  
3. 
 Not expected to survive for 48 hours. 
4. 
Pregnant (positive pregnancy test in a pre-dose examination) or breastfeeding  
5. 
Open tracheostomy. 
6. 
Clinical contra-indication, as deemed by the attending physician. 
7. 
Allergy to Epoprostenol and its diluent 
8. 
Using inhaled vasodilators  at baseline.  
9. 
Patients who are hemodynamically unstable as determined by investigator  
10. Patients with  significant hemoptysis as determined by investigator 
Study 
Treatment(s) 
Patients will receive study drug via mechanical ventilator, starting at 13.6 ng/kg/min.  If 
determined by the treating physician, study drug can be up titrated in 3.4 ng/kg/min 
increments to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.  At the 
Investigator’s discretion, the patient will be weaned off the drug in 3.4 ng/kg/min increments. 
Study drug will be administered based on the pump rate calculated for active treatment in 
mL/hr.  Study drug  can be administered up to 10 days.   
Duration of 
Treatment 
The duration of study participation for each patient is as follows:  
• 
Screening: up to 14 days 
• 
Treatment: up to 10 days 
• 
Follow up: 28 days 
Criteria for 
Evaluation 
 
Primary Endpoint  
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• 
Requires VV ECMO   
• 
Inability to extubate patient within 10 days or reintubation within < 24 
hours 
• 
Change in S/F, oxygenation index and P/F ratio (≥15%) from baseline to 12 
hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• 
Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 
• 
Worsening hemodynamic parameters  
• 
Cardiac troponin > 20% from baseline   
• 
BNP ≥ 15% of baseline 
• 
Need for temporary mechanical circulatory support (IABP, Impella) 
• 
Requires VA ECMO 
Secondary Endpoints: 
1. Improvement in oxygenation defined as any one of the following: 
• 
Stabilization of PaO2/FIO2 >250 
• 
Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 7 of 52 
2. Improved clinical outcomes defined as one of more of the following:  
• 
Shorter time to extubation following the site’s extubation protocol 
• 
Free from reintubation 
• 
Reduction in ICU days 
• 
Reduction in the number of re-admissions to the ICU due to COVID-19 
within 28 days. 
• 
Reduction in hospital days Mortality (28 Days) defined as Cardiopulmonary 
mortality or mortality from all causes. 
 
3. Safety and tolerability: 
• 
Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory and oxygenation parameters, 
and laboratory tests. 
Exploratory endpoints will include (where available): 
1. 
Change in LDH 
2. 
Change in fibrinogen 
3. 
Change in WBC count including lymphocytes and neutrophil subsets 
4. 
Change in triglycerides 
5. 
Change in ferritin 
6. 
Change in CRP / ESR 
7. 
Change in IL-6 
8. 
Change in D-Dimer 
Changes in these parameters will be assessed for each patient from baseline to end of 
study as well as changes between the active and control groups. 
Ventilatory 
Parameters 
OSU SOC: 
Ventilator Type (GE) 
Parameters to monitor are:  
1. Ventilator Mode 
2. FiO2 
3. Inspiratory Time 
4. Mean Airway Pressure 
5. Peak Inspiratory Pressure 
6. Positive End Expiratory Pressure 
7. Respiratory Rate 
8. Tidal Volume 
Criteria for 
Stopping 
VentaProst 
Treatment 
Individual patients stopping criteria: At any time during study drug administration, patients 
may be removed from study treatment and placed on standard of care (SoC) therapy if they 
meet one or more of the following pre-defined criteria leading to a deterioration in their 
condition: 
• 
Severe hypotension as evidenced by a systolic BP < 90 mmHg  or MAP < 60 mmHG 
for >2 hours from the start of VentaProst 
• 
Need for VV ECMO 
• 
Need to increase existing vasopressor therapy by more than 25% 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 8 of 52 
• 
Worsening in oxygenation, ventilatory, or hemodynamic parameters that in the 
opinion of the investigator the patient should be removed from study treatment 
• 
Massive hemoptysis thought to be clinically significant and not related to 
endotracheal tube trauma 
• 
Pulmonary edema 
• 
If a clinically inadequate response to treatment is observed 
 
Study stopping criteria: If 3 patients are removed from the study for any of the above 
conditions, the study will stop further enrollment and an investigation will be conducted to 
determine the cause of the events.  An independent safety evaluation will also be conducted.  
If it is suspected that the investigational product has caused the events, the study will be 
terminated. 
Independent Safety Evaluation: Independent safety evaluation will be conducted by a 
licensed physician who is not involved in the VentaProst COVID-19 clinical study or the 
sponsoring organization.   
Statistical 
Methods 
All patients who are enrolled in the study and who receive at least one dose of study drug will 
be included in the intent-to-treat (ITT) analyses of pharmacodynamic and safety data.  All 
available data will be used and missing data will not be estimated or carried forward in any 
statistical summary or analyses. 
Descriptive summary statistics include the number of patients, mean, median, percent 
coefficient of variation (% CV) (if required), standard deviation, and minimum and maximum 
values (quantitative variables) or the number of patients and percentages by category 
(qualitative variables). Changes will be assessed as the difference between baseline 
measurements and the appropriate post-dose measurements unless otherwise specified.  Mean 
differences between active and historical control groups will be assessed and significance will 
be determined on the basis of a 95% CI.   
No formal estimate of the sample size has been made. This is an exploratory study and the 
number of patients was selected to enable an adequate clinical assessment of 
pharmacodynamic, safety, and tolerability parameters without presenting undue risk to a large 
number of patients. 
Efficacy 
Analysis 
Efficacy will be secondarily determined by summarizing success or failure to meet any of the 
primary or secondary endpoints as compared to Control treatment.   
Safety 
Analyses 
Safety data will be summarized for both treatment groups including frequencies and incidence 
rates.  Safety will be assessed through monitoring of adverse events (AEs), serious adverse 
events (SAEs), chest CTs or chest X-rays, laboratory tests, oxygenation and ventilatory 
parameters,  and vital signs.   


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 9 of 52 
Table 2: Schedule of Assessments and Procedures 
 
 
 
Screening 
VentaProst -
Day 1 
 
VentaProst Days 2-10 
 
End of 
Study 
 
 
 
Study Procedures 
Within 14 
Days 
Prior to 
Baseline 
 
 
 
Baseline
- 0 Hr 
 
 
 
12 
hrs 
 
 
 
D-2 
 
 
 
D-3 
 
 
 
D-4 
 
 
 
D-5 
 
 
 
D-6 
 
 
 
D-7 
 
 
 
D-8  
 
 
 
D-9 
 
 
 
D-10 
 
Day 28 
(+/- 
2 
days) 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication History/ 
Prior Meds 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Height1 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Chest CT Scan or 
CXR 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Clinical Laboratory 
Sampling2 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy Test 
(Serum or Urine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RT-PCR + for 
COVID-19 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Administer 
VentaProst 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oxygenation 
Measurements4 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Ventilator 
Parameters5 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
AE/SAE  
Monitoring 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
 
X 
 
X 
 
X 
Concomitant 
Medications 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Prone position 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1  Height only performed at screening 
2 Clinical Labs include: Safety labs: CBC (lymphocyte and neutrophil counts), Full Chemistry Panel (including LFTs) and PT/PTT drawn Screening, Day 1-
12 hours, Days 5 & 10.  Triglycerides, LDH, ferritin, fibrinogen, CRP, ESR, IL-6, D-Dimer, troponin, BNP drawn at Screening, Day 1-12 hours and D-10. 
3 Vital signs: Prior to initiating VentaProst, Days 1-10 twice daily (morning and evening) at the same time to reduce exposure to Health Care Professionals to 
include; temperature, pulse rate, blood pressure. 
4 Continuous SpO2 via pulse oximetry 
5 Ventilator Parameters will be collected twice daily along with vital signs and  include: Ventilator Type, Ventilator Mode, FiO2, Inspiratory Time, Mean 
Airway Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume and Respiratory Rate  
6Time Prone Position – 16 hours per day per OSU protocol 


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 10 of 52 
TABLE OF CONTENTS 
INVESTIGATOR’S SIGNATURE PAGE ....................................................... 3 
1. 
CLINICAL PROTOCOL SYNOPSIS ............................................... 4 
TABLE OF CONTENTS ......................................................................... 10 
LIST OF ACRONYMS, ABBREVIATIONS AND 
DEFINITION OF TERMS ...................................................................... 13 
2. 
BACKGROUND AND RATIONALE ............................................. 16 
2.1 
Introduction ................................................................................. 16 
2.2 
VentaProst .................................................................................... 17 
2.2.1 Nonclinical Experience ..................................................... 17 
2.2.2 Clinical Experience ........................................................... 17 
2.2.3 Summary of Pharmacokinetic Results ............................ 17 
2.2.4 Summary of Clinical Results ........................................... 18 
2.2.5 Summary of Known and Potential Risks of 
Inhaled Epoprostenol Administration ........................................ 19 
2.2.6 Dosing Rationale for VentaProst...................................... 20 
3. 
STUDY OBJECTIVES.................................................................... 21 
3.1 
Primary Objective ........................................................................ 21 
3.2 
Secondary Objectives ................................................................... 21 
3.3 
Study Design ................................................................................ 21 
3.4 
Duration of Participation ............................................................ 21 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..................... 22 
4.1 
Inclusion Criteria ......................................................................... 22 
4.2 
Exclusion Criteria ........................................................................ 22 
4.3 
Re-Screening of Patients ............................................................. 23 
4.4 
Removal of Patients from Therapy or Assessment ..................... 23 
4.4.1 Criteria for Stopping VentaProst Treatment ................... 23 
5. 
STUDY TREATMENTS ................................................................. 24 
5.1 
Identity of Medication Component of the 
Investigational Product .......................................................................... 24 
5.1.1 Storage Condition ............................................................. 24 
5.2 
Treatments Administered ............................................................ 24 
5.3 
Study Medication Supply, Preparation, and 
Administration ....................................................................................... 24 
5.3.1 Study Medication Supply ................................................. 24 
5.3.2 Study Medication Preparation ......................................... 25 
5.3.3 Study Medication Administration.................................... 25 
5.3.4 Study Medication Weaning .............................................. 26 
5.4 
Identity of the Device Component of the 
Investigational Product .......................................................................... 26 


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5.4.1 Identity of Device .............................................................. 26 
5.4.2 Ventilator Settings ............................................................ 31 
5.4.3 Device Supply ................................................................... 31 
5.4.4 Device Replacement ......................................................... 31 
5.4.5 Device Malfunction or Failure ......................................... 31 
5.5 
Blinding ........................................................................................ 32 
5.6 
Prior and Concomitant Therapy ................................................. 32 
5.6.1 Prohibited Concomitant Therapy .................................... 32 
5.7 
Investigational Product (IP) Supplies and 
Accountability ......................................................................................... 32 
6. 
CRITERIA FOR EVALUATION ..................................................... 33 
6.1 
Primary Endpoint ........................................................................ 33 
6.2 
Secondary Endpoints ................................................................... 33 
6.3 
Exploratory endpoints will include (where available): .............. 34 
6.4 
Appropriateness of Measurements ............................................. 34 
7. 
SAFETY ASSESSMENTS .............................................................. 34 
7.1 
General Safety Procedures .......................................................... 35 
7.1.1 Vital Signs and Weight Measurements ........................... 35 
7.1.2 Physical Examination ...................................................... 35 
7.1.3 Laboratory Measurements ............................................... 35 
7.1.4 Chest Assessments ........................................................... 35 
7.1.5 Time Prone Protocol ......................................................... 35 
7.2 
Adverse Events ............................................................................ 35 
7.2.1 Definitions......................................................................... 35 
7.2.2 Adverse Events of Special Interest (AESI) ...................... 36 
7.2.3 Grading of Adverse Events ............................................... 36 
7.2.4 Relationship to Study Medication/Study 
Device/Procedure ......................................................................... 36 
7.2.5 AE Outcomes .................................................................... 36 
7.2.6 Laboratory Test and other Test Abnormalities 
as Adverse Events ........................................................................ 37 
7.2.7 Serious Adverse Events .................................................... 37 
7.2.8 Reporting for SAEs (24 Hours) ........................................ 38 
7.3 
Reporting of Pregnancy ............................................................... 39 
8. 
PHARMACOKINETIC ASSESSMENTS ...................................... 39 
9. 
SCHEDULE OF ASSESSMENTS AND 
PROCEDURES ....................................................................................... 39 
9.1 
Study Evaluation Timepoints ..................................................... 39 
9.1.1 Screening (within 14 days prior to Baseline 
Day 1) 39 
9.1.2 Days 1-10 Treatment ........................................................ 40 
9.1.3 Day 28/End of Study (EOS) .............................................. 42 


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9.2 
Data Collection ............................................................................ 42 
9.3 
Clinical Data Management ......................................................... 42 
9.4 
Database Quality Assurance ....................................................... 42 
10. 
STATISTICAL CONSIDERATIONS .................................... 42 
10.1 
Statistical Methods ...................................................................... 42 
10.2 
Determination of Sample Size ..................................................... 42 
10.3 
Analyses Sets ............................................................................... 42 
10.4 
Randomization ............................................................................. 43 
10.5 
Demographic and Other Baseline Characteristics ..................... 43 
10.6 
Criteria for Evaluation ................................................................ 43 
10.6.1 Primary Efficacy Endpoint ............................................. 43 
10.6.2 Secondary Efficacy Endpoints ........................................ 44 
1. 
Improvement in oxygenation defined as any one of 
the following: .......................................................................................... 44 
10.6.3 Key Exploratory Endpoints include: .............................. 44 
10.7 
Extent of Exposure ...................................................................... 44 
10.8 
Safety Analyses ............................................................................ 45 
10.8.1 Adverse Events ............................................................... 45 
10.8.2 Laboratory Values........................................................... 45 
10.8.3 Vital Signs ....................................................................... 46 
10.9 
The Procedure for Revising the Statistical Analysis 
Plan 46 
11. ADMINISTRATIVE PROCEDURES AND 
INSTRUCTIONS .................................................................................... 46 
11.1 
Ethics ............................................................................................ 46 
11.1.1 Institutional Review Boards/Independent 
Ethics Committees ....................................................................... 46 
11.1.2 Ethical Conduct of the Study ......................................... 46 
11.1.3 Patient Information and Informed Consent .................. 47 
11.2 
Administrative Procedures .......................................................... 47 
11.2.1 Changes to the Protocol .................................................. 47 
11.2.2 Adherence to the Protocol ............................................... 48 
11.2.3 Monitoring Procedures ................................................... 48 
11.2.4 Recording of Data ........................................................... 49 
11.2.5 Data Storage and Retention of Records ......................... 49 
11.2.6 Handling of Investigational Product .............................. 49 
11.2.7 Publication of Results ..................................................... 50 
11.2.8 Disclosure and Confidentiality ....................................... 50 
11.2.9 Discontinuation of Study ................................................ 50 
11.2.10 Patient Insurance and Indemnity ................................ 50 
12. 
REFERENCES ...................................................................... 51 
 


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List of Figures and Tables 
Table 1: 
Overview of Titration and Weaning Guidelines 
4 
Table 2: 
Schedule of Assessments and Procedures 
9 
Table 3: 
Administration Titration Guidelines 
26 
Table 4:  
Example of Up Titration for male with Ideal Body Weight of 70 kg  
26 
Figure 1: 
Drug Delivery System 
28 
Figure 2: 
Aerogen Pharma Controllers 
29 
Figure 3: 
VentaProst Device Placement in the Gas Pathway 
30 
 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
Active  
Inhaled epoprostenol administered via the VentaProst delivery system 
AE 
Adverse |Event 
ALI 
Acute Lung Injury 
ALT (SGPT) 
Alanine Aminotransferase (serum glutamic pyruvic transaminase) 
AP 
Alkaline Phosphatase 
ARDS 
Acute Respiratory Distress Syndrome 
AST (SGOT) 
Aspartate Aminotransferase (serum glutamic oxaloacetic transaminase)   
bpm 
Beats Per Minute 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
cAMP 
Cyclic Adenosine Monophosphate 
CI 
Cardiac Index (L/min/m2) 
CO 
Cardiac Output (L/min) 
Control  
Inhaled 0.9% sodium chloride solution, USP administered via the VentaProst delivery 
system 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Concentration 
CPB 
Cardiopulmonary Bypass 
CRA 
Clinical Research Associate 
CRF 
Case Report Form   
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CNTS 
Continuous Nebulization Tube Set 
CVP 
Central Venous Pressure (mm Hg) 
DCF 
Data Collection Form 


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Abbreviation 
Term 
DNR 
Do Not Resuscitate  
dPAP 
Diastolic Pulmonary Arterial  Pressure (mm Hg) 
dSAP 
Diastolic Systemic Arterial Pressure (mm Hg) 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
ESR 
Erythrocyte Sedimentation Rate 
ETT 
Endotracheal Tube 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCP 
Good Clinical Practice 
HME 
Heat-Moisture Exchanger 
HR 
Heart Rate (bpm) 
IABP 
Intra-aortic Balloon Pump 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ICU 
Intensive Care Unit 
IL-6 
Interleukin 6 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LAR 
Legally Authorized Representative  
LDR 
Lung Dosing Rate 
LFT 
Liver Function Test 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mPAP 
Mean Pulmonary Arterial Pressure (mm Hg) 
mSAP 
Mean Systemic Arterial Pressure (mm Hg) 
NC 
Nasal Cannula 
ng 
Nanogram 
OR 
Operating Room 
OTC 
Over-the-Counter 
PAH 
Pulmonary Arterial Hypertension 
PaO2 
Partial Pressure of Oxygen in Arterial Blood 
PAP 
Pulmonary Arterial Pressure (mm Hg) 
PCWP 
Pulmonary Capillary Wedge Pressure 
PD 
Pharmacodynamic 
PEEP 
Positive End Expiratory Pressure 
PH 
Pulmonary Hypertension 
PIP 
Peak Inspiratory Pressure 
PK 
Pharmacokinetic 
 
PP 
Per Protocol 


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Abbreviation 
Term 
PGI2 
Prostaglandin I2 (epoprostenol) 
PVR 
Pulmonary Vascular Resistance (dyn/sec/cm5) 
RBC 
Red Blood Cell (count) 
RH 
Right Heart 
RHF 
Right Heart Failure 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
RVSWI 
Right Ventricular Stroke Work Index 
SAE 
Serious Adverse Event 
SaO2 
Arterial Oxygen Saturation 
sPAP 
Systolic Pulmonary Arterial Pressure (mm Hg) 
sSAP 
Systolic Systemic Arterial Pressure (mm Hg) 
SE 
Standard Error 
SOP 
Standard Operating Procedures 
SOC 
Standard of Care 
SpO2 
Oxygen Saturation by Pulse Oximetry 
Study Drug 
Active or Control Treatment 
SVR 
Systemic Vascular Resistance 
TEAE 
Treatment-Emergent Adverse Event 
TEE 
Transesophageal Echocardiogram 
TPG 
Transpulmonary Gradient 
t1/2 
Half-Life 
TLD 
Total Lung Dose 
ULN 
Upper Limit of Normal 
VA-ECMO 
Veno-arterial Extracorporeal Membrane Oxygenation 
VentaProst 
VentaProst™ – Drug/device combination product consisting of aerosolized epoprostenol 
delivered via dedicated drug delivery system 
VentaProst 
Nebulizer 
The nebulizer assembly that is part of the VentaProst delivery system  
VTE 
Venous Thromboemobolism 
VV ECMO 
Venovenous Extracorporeal Membrane Oxygenation 
WBC 
White Blood Cell (count) 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 


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BACKGROUND AND RATIONALE 
2.1 
Introduction 
COVID-19 is a rapidly emerging pathogen that has recently been declared a pandemic by 
the World Health Organization (WHO). No targeted therapeutic treatments for 
coronavirus (COVID-19) have been identified.  Symptoms range from mild upper 
respiratory tract infection to profound hypoxia, severe pneumonia, ARDS and death. 
Progression of end stage disease is unpredictable with high fatality rates in mechanically 
ventilated patients as a result of multi-organ failure.   Among patients who require 
hospitalization, mortality may be 5% to 15%, and for those who become critically ill, 
reported mortality ranges from 22% to 62%.     
 
Prostacyclin therapy—available in oral, inhaled, and intravenous forms—is an analogue 
which mimics endogenous prostacyclin (PGI2). Prostacyclin binds to its receptor (a G-
protein coupled receptor) found on the surface of vascular smooth muscle and platelets, 
activates cyclic adenosine monophosphate (cAMP), and results in inhibition of platelet 
aggregation, vascular smooth muscle relaxation and vasodilation of the pulmonary 
arteries (Mitchell, Ali et al. 2008). Prostacyclins are most commonly used in the 
treatment of PAH due to their potent vasodilatory effects. In addition, prostacyclin 
analogs also inhibit platelet aggregation and may reduce prothrombotic effects of 
endothelin. 
The rationale for use of vasodilators in COVID-19 patients rests on their rapid local 
effect on the pulmonary vasculature, which has shown to lead to increased oxygenation in 
other diseases, such as PAH (Higenbottam, Wheeldon et al. 1984) and post-surgical PH 
(De Wet, Affleck et al. 2004).  Epoprostenol has the additional advantage over inhaled 
nitric oxide in that it may be directly administered through a standard ventilator (closed-
circuit). 
 
The rationale for aerosolized prostacyclin use in COVID-19 patients experiencing 
hypoxia leading to cardiac failure is two-fold:  
 
(1) inhaled prostacyclin therapy has been used in the treatment of ARDS and has been 
shown to improve oxygenation and ventilation-perfusion mismatch (see Section 9).  
Prostacyclins, such as epoprostenol, promote pulmonary vasodilation via a cyclic 
adenosine monophosphate-mediated decrease in intracellular calcium (Figure 4).  While 
it has not been associated with improved outcomes, such as mortality, and it’s use in 
ARDS is off-label, it may be used in severe life-threatening hypoxemia refractory to 
conventional ARDS management, such as has been seen in COVID-19. 
 
(2) The second potential benefit of prostacyclin therapy in the management of COVID-19 
is to mitigate direct SARS-CoV-2-associated coagulopathy.  Prostacyclins have anti-
inflammatory (Dewachter 2012) and antiplatelet aggregation properties1.  Microvascular 
thrombosis and large vessel venous thromboembolism have been described anecdotally 
and in case reports of corona virus infected patients and abnormal coagulation parameters 
are associated with increased mortality (Giannis, Ziogas et al. 2020). Inhibition of platelet 
aggregation occurs with prostacyclin therapy and may mitigate thrombosis in situ seen in 
PAH itself, and potentially in patients with COVID-19 associated respiratory illness. 


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Literature data with both inhaled NO and inhaled epoprostenol in ARDS, acute lung 
injury and severe hypoxemia show improvement of oxygenation (Afshari, Bastholm Bille 
et al. 2017), (Dzierba, Abel et al. 2014), decrease of pulmonary arterial pressure (Fuller, 
Mohr et al. 2015) and in some cases improvement in clinical outcomes such as shorter 
time on mechanical ventilation and shorter time in ICU (Ammar, Bauer et al. 2015).  
However, due to the heterogeneity of the population and the severity of the disease, not 
all studies agree on the effectiveness of inhaled epoprostenol, particularly to reduce 
mortality in ARDS (Adhikari, Dellinger et al. 2014), (Afshari, Bastholm Bille et al. 2017).  
Meta-analyses have concluded that the quality of the currently published data for the use 
of inhaled vasodilators in ARDS, ALI and refractory hypoxemia is insufficient to 
definitely conclude for or against their use (Afshari, Bastholm Bille et al. 2017), (Fuller, 
Mohr et al. 2015). 
 
This study will evaluate the potential therapeutic benefit of VentaProst in treating patients 
with COVID-19 at risk for the progression of respiratory and/or cardiac/circulatory 
failure. This double-blind, placebo controlled study will assess the efficacy and safety of 
VentaProst at a range of 3.4-30.6 ng/kg/min for a maximum of 10 days at the discretion 
of the Investigator.  The patient will be followed through Day 28 to assess their clinical 
status.   
 
2.2 
VentaProst 
2.2.1 
Nonclinical Experience 
Refer to the current Investigator’s Brochure (IB) for details of nonclinical pharmacology 
and toxicology studies with VentaProst. 
2.2.2 
Clinical Experience 
There have been no clinical trials to date with VentaProst in COVID-19 patients (see 
Section 2.2.4 below for summary of clinical data with VentaProst in cardiac surgery 
patients). 
2.2.3 
Summary of Pharmacokinetic Results  
Epoprostenol undergoes rapid chemical hydrolysis under physiological conditions to 
yield 6-keto-PGF1α and is also subject to enzymatic degradation.  As such, it is only 
possible to evaluate the PK using radioactively labeled drug. Studies using 3H-
epoprostenol sodium indicate half-life is generally less than 3 minutes with an I.V. bolus, 
and with I.V. infusion, plasma steady-state concentrations were achieved within 15 
minutes of initiation of the infusions, and steady-state concentrations increased linearly 
with increasing infusion rate.  Tissue distribution studies indicate the highest levels of 
radioactivity were observed in the kidney, liver, and small intestine and the lowest levels 
were observed in brain and adipose tissue.  Epoprostenol-derived material is rapidly 
excreted into urine and feces after dosing with epoprostenol sodium. 
 
There is only one study in the literature that reports the PK of inhaled epoprostenol.  The 
study by Haraldsson (Haraldsson, Kieler-Jensen et al. 2000) was designed to evaluate the 
effects of inhaled epoprostenol on platelet aggregation after surgery.  No differences were 
seen in 6-keto-PGF1α levels with two dose levels of epoprostenol compared to placebo 


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over six hours of administration in the ICU.  Epoprostenol deposition in the lungs was not 
quantified, but the aerosol was administered only during the inspiratory phase of 
mechanical ventilation.  The blood levels of 6-keto-PGF1α by enzyme immunoassay in 
this study were reported to be several times higher than other levels reported in the 
literature.   
 
In 2017, Stanford University’s Department of Cardiac Surgery conducted an 
observational study (IND129777, Report# APC-VP-CLN-004) investigating the levels of 
6-keto-PGF1α in cardiac surgery patient requiring CPB.  Sixteen patients were enrolled; 
eight did not received inhaled epoprostenol, eight received aerosolized epoprostenol at a 
nominal starting dose of 50 ng/kg/min.   
 
Plasma levels determined in aerosol epoprostenol naïve patients indicates that cardiac 
surgery procedures, including CPB, result in elevated endogenous levels of both 6-keto-
PGF1α and thromboxane B2.  Delivery of aerosol epoprostenol in patients resulted in a 
further elevation of 6-keto-PGF1α levels, but not thromboxane B2. 
 
While it proved difficult to delineate the endogenous and exogenous contributions of 
aerosol delivery during surgery, 6-keto-PGF1α levels declined rapidly in aerosol naïve 
patients during ICU stay.  Examination of the 6-keto-PGF1α levels during weaning, after 
this endogenous decline, indicate that the overall aerosol delivery efficiency, nebulized to 
absorbed (deposited lung dose), is less than 8%.  That is, out of a nominal dosing rate of 
50 ng/kg/min only 4 ng/kg/min actually reaches the lungs and gets absorbed. 
Comparison to recently published data (Nicolas, Krause et al. 2012) investigating 6-keto-
PGF1α levels during steady state I.V. administration of Flolan indicates that the systemic 
exposure from aerosol delivery in cardiac surgery is similar to, or lower, than that 
experienced from intravenous administration of the approved Flolan product. 
 
The findings of this observational PK study with inhaled epoprostenol are sufficient to 
make a correlation to historical systemic exposure levels with intravenous administered 
Flolan (the reference listed drug) and show levels of exposure similar to, or lower than, 
the currently approved intravenous product.   
  
2.2.4 
Summary of Clinical Results 
The safety and tolerability of VentaProst were evaluated in a Phase 2a Clinical Study in 
cardiac surgery patients “A Two-Part Pharmacodynamic Study to Compare VentaProstTM 
(Epoprostenol Solution for Inhalation via Custom Drug Delivery System) Dosing to 
Conventionally Administered Aerosolized Epoprostenol Dosing in Cardiac Surgery 
Patients” (NCT03122730).  
 
Overall, 15 patients were exposed to doses of VP from 3.4 to 20.4 ng/kg/min in this study.  
Administration of VP in this dose range was well-tolerated.  Overall, there were 2 
patients (28.6%) in Part I and 1 patient (12.5%) in Part II who experienced a total of 7 
TEAEs.  All 7 TEAEs were assessed by the investigator as related to the surgical 
procedure and as unrelated to the study drug and unrelated to the device.  No deaths 
occurred during the study.  A total of 3 patients had 1 SAE each.  All 3 SAEs were 
considered to be unrelated to the study drug or the study device.   


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Seven patients were evaluated in Part I to determine the effective dose equivalence 
between VP delivered at 17 ng/kg/min and off-label aerosolized Veletri administered at 
50 ng/kg/min during mechanical ventilation.  In all patients, VP 17 ng/kg/min was found 
to be equivalent either by calculation of effect compared with aerosolized Veletri 50 
ng/kg/min or the investigators’ judgement.  In most patients, no differences were 
observed in oxygen saturation ranges between VP and aerosolized Veletri treatments at 
the same FiO2 while on the ventilator. The investigator determined that oxygenation, 
assessed by oxygen saturation measurements, did not change disproportionately with 
ventilator operating parameters on VP compared with aerosolized Veletri. 
 
Eight patients were evaluated in Part II of the study to identify the optimal dose of VP.  In 
the investigator’s judgement, the optimal VP dose was determined to be 6.8 ng/kg/min in 
2 patients, 10.2 ng/kg/min in 3 patients, and 13.6 ng/kg/min in 3 patients, which is the 
minimal dose that reliably produced a maximum hemodynamic response in all patients. 
   
There have been no clinical trials to date with VentaProst in COVID-19 patients. 
See IB for additional clinical information regarding inhaled epoprostenol. 
2.2.5 
Summary of Known and Potential Risks of Inhaled Epoprostenol 
Administration 
Safety of inhaled epoprostenol in cardiothoracic surgery patients is remarkable.  In the 
reported literature to date, there were no reports of serious or life-threatening drug-related 
safety events.  Due to its mechanism of action, inhaled epoprostenol may theoretically 
cause increased bleeding (anti-platelet mechanism) or systemic vasodilation consequent 
to spill over into the central circulatory system, but no such events have been reported.  
Some accounts of the use of inhaled prostacyclin in the chronic setting (e.g. iloprost for 
PAH) report transient events as listed on the approved product labeling.  These include 
cough, headache, flushing, and an influenza-like syndrome.  However, these types of 
events are unlikely to be reported due to sedation in the ICU setting. 
VentaProst may result in hypotension, which will be monitored via frequent   assessments 
of oxygenation, ventilatory and hemodynamic parameters and vital signs. Pulmonary 
edema and pulmonary bleeding are potential risks due to the drug’s mode of action (refer 
to Section 7.2.2).  Worsening oxygenation is a theoretic concern through worsened 
ventilation/ perfusion matching. This will be monitored through continuous pulse 
oximetry throughout the administration of the inhaled epoprostenol.  
 
Risks to subjects in this study are related to common procedures performed (e.g., 
venipuncture) and the documented adverse events (AEs) listed in the current 
Investigator’s Brochure. These risks are communicated to the subjects in the consent 
forms. There may be additional risks that are currently unknown.  
 
The benefits of the study may include targeted lung vasodilation and improved 
oxygenation, potential anti-platelet effects on the lung vasculature, reduction in disease 
progression, avoidance of greater oxygen needs and early weaning off mechanical 
ventilation. If the drug does have such properties, then this may aid recovery, improve 


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outcomes and enable an earlier discharge from the hospital.  
There is no funding awarded to the patients participating in this study. 
2.2.6 
Dosing Rationale for VentaProst 
Literature on the current use of aerosolized epoprostenol in cardiac surgery and in ARDS 
shows a wide range and technically variable dosing for lowering PVR (Rao, Ghadimi et 
al. 2018), (Kallet, Burns et al. 2017), (Fuller, Mohr et al. 2015).  Most of the experience 
is with continuous nebulization by commercially available nebulizers in various positions 
in mechanical ventilator circuits at doses of 50 ng/kg/min.  Unlike the commercially 
available nebulizer systems, the VentaProst delivery platform aerosolizes epoprostenol 
only during the inspiratory cycle of the ventilator and administers respirable sized aerosol 
droplets (3-5 µm) in close proximity to the ETT of mechanically ventilated patients.  
 
The assumed effect of the current continuous dosing regimen of 50 ng/kg/min is that the 
hemodynamic response is maximized and that no further improvements would be seen by 
increasing the dose.  The initial in vitro estimate of the equivalent VentaProst (VP) dose 
to a 50 ng/kg/min conventional dose of continuously aerosolized Veletri was 17 
ng/kg/min, which was the starting dose in Part I of the APC-VP-CLN-001 Phase 2a study 
conducted by Aerogen Pharma.  During Part I of the study, it was determined that this 
dose is equivalent to 50 ng/kg/min epoprostenol delivered off-label via a generic 
nebulizer and continuous delivery.  In Part II of the APC-VP-CLN-001 Phase 2a study, 
the VP dose escalation started from an initial dose of 3.4 ng/kg/min (20% of the 
equivalent dose).  The dose was then increased in 3.4 ng/kg/min increments.  Part II of 
the study was designed to demonstrate that the dose-response plateau could be achieved 
using lower VP doses than the initial estimated equivalent dose in Part I.  Doses up to 
30.6 ng/kg/min were approved for use in the study. In Part I of the study one patient, per 
the investigator discretion, received a 20.4 ng/kg/min dose.  In Part II of the study it was 
determined that the optimal VP dose of 6.8 ng/kg/min in 2 patients, 10.2 ng/kg/min in 3 
patients, and 13.6 ng/kg/min in 3 patients provided stable hemodynamic response.  Based 
on these data,  the recommended starting dose of VP, will be 13.6 ng/kg/min, as this dose 
is anticipated to produce the maximum hemodynamic response. 
The proposed nominal dosing regimen for this COVID-19 trial is for up to 10 days of 
breath-synchronized aerosol delivery with a starting dose of study drug 13.6 ng/kg/min. 
Based on hemodynamic and oxygenation parameters, the dose can be titrated in 3.4 
ng/kg/min steps up to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 
ng/kg/min while patients are on mechanical ventilation.  Of this nominal dosing rate 
approximately 30% will reach and deposit in the lung.  Thus, the maximum Lung Dosing 
Rate (LDR) is ~10 ng/kg/min and the maximum Total Lung Dose (TLD) is ~ 144 µg/kg 
(Refer to VP IB Edition 6 dated 17-Jun-2020).  
The inhalation toxicology program for VentaProst, originally designed for the cardiac 
surgery indication, covered a maximum LDR of 320 ng/kg/min and 60 ng/kg/min and a 
maximum TLD of 1091.4 µg/kg and 172.8 µg/kg in rats and dogs respectively.  The LDR 
and TLD margins over the proposed maximum clinical exposure are thus 32 and 6, and 
7.6 and 1.2, in rats and dogs respectively.   


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3. 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is the reduction of respiratory, cardiac or circulatory 
failure in patients with confirmed COVID-19. 
3.2 
Secondary Objectives 
The secondary objective in this study is to evaluate the effects of VentaProst on 
improvement in oxygenation, improvement in clinical outcomes and safety and 
tolerability.  
The study will also evaluate the effects of VentaProst on inflammatory parameters in 
subjects with confirmed COVID-19.  
3.3 
Study Design 
This is a double-blind, placebo controlled study of VentaProst (Active) as compared to 
placebo (Control).  Active is inhaled epoprostenol administered via the VentaProst 
delivery system in 10 COVID-19 positive patients. Control is inhaled 0.9% sodium 
chloride solution administered via the VentaProst delivery system in 10 COVID-19 
positive patients.  Throughout the remainder of the protocol both Active and Control will 
be referred to as “study drug”.  This study will evaluate the potential therapeutic benefit 
of VentaProst  in treating patients with COVID-19 who require mechanical ventilation 
and are at risk for the progression of respiratory and/ or cardiac/circulatory failure.  This 
study will assess the efficacy and safety of VentaProst at an initial dose of 13.6 ng/kg/min 
(A range from 3.4-30.6 ng/kg/min may be administered as clinically required for a 
maximum of 10 days at the discretion of the Investigator.  Patients will be followed 
through Day 28 to assess clinical outcomes.   
Patients will be consented and randomized to either the Active or Control group within 24 
hours of being placed on mechanical ventilation.  Patients will be administered study 
drug using the VentaProst delivery system which allows up and down titration of study 
drug to achieve hemodynamic and oxygenation stability.  The starting dose of study drug 
will be initiated at 13.6 ng/kg/min.  Based on hemodynamic and oxygenation parameters, 
the dose of study drug can be increased in 3.4 ng/kg/min increments up to a maximum of 
30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.     
All study staff with the exception of the unblinded pharmacist and Sponsor CRA will be 
blinded to which treatment regimen a patient has been assigned.  Titration and weaning 
will be performed the same for all patients.  Study drug will be administered based on the 
pump rate calculated for active treatment in mL/hr. Titration guidelines are provided in 
Section 5.3.3 and Table 3. 
3.4 
Duration of Participation 
Patients who meet entry criteria will be entered into the study and the duration of study 
participation for each patient is listed below. The duration of study participation for each 
patient is as follows:  
• Screening: up to 14 days 
• Treatment: up to 10 days 
• Follow up: 28 days 


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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Approximately 20 COVID-19 positive patients requiring mechanical ventilation will be 
enrolled in this study.  Ten study participants will be randomized to either Active (inhaled 
epoprostenol administered via the VentaProst delivery system) treatment or Control 
(inhaled 0.9% sodium chloride solution administered by the VentaProst delivery system 
at calculated rates (mL/hr) used for the aerosolized epoprostenol). Study drug will 
indicate both Active and Control treatments. 
Patients who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to enroll into the study.   
4.1 
Inclusion Criteria 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men Age ≥18 years old (no upper limit)  
2. Confirmed COVID-19 positive by RT-PCR test 
3. Patients who require invasive mechanical ventilation.  
4. Enrolled into study within 24 hours of being placed on mechanical ventilation  
5. Consent or professional consent obtained 
6. Duration of shortness of breath must be within the previous 14 days.   
7. Female subjects of childbearing potential must have a negative pre-treatment 
pregnancy test (serum or urine).  
8. Received or currently receiving dexamethasone therapy for COVID-19 
9. Willing and able to comply with treatment schedule and follow-up. 
4.2 
Exclusion Criteria 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. Patients on ECMO support. 
2. Patients receiving another inhalation research medication or inhaled nitric oxide.  
3. Not expected to survive for 48 hours. 
4. Pregnant (positive pregnancy test in a pre-dose examination) or breastfeeding  
5. Open tracheostomy. 
6. Clinical contra-indication, as deemed by the attending physician. 
7. Allergy to Epoprostenol and its diluent 
8. Using inhaled vasodilators at baseline.  
9. Patients who are hemodynamically unstable as determined by investigator  
10. Patients with  significant hemoptysis as determined by investigator 


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4.3 
Re-Screening of Patients 
Patients may not be enrolled more than once.   
4.4 
Removal of Patients from Therapy or Assessment 
Aerogen Pharma or the Investigator may discontinue patients from the study at any time 
for safety or administrative reasons.   
The End of Treatment Study procedures (Day 10) are to be completed for all patients 
who discontinue from the study (except Screen Failure patients).  
The Investigator will promptly explain to the patient or their LAR that the study will be 
discontinued for the patient and provide appropriate medical treatment and other 
necessary measures for the patient.   
Patients who discontinue early from the study will be discontinued for one of these 
primary reasons:  Adverse events, patient death, lost to follow-up, patient withdrew 
consent, protocol violation, lack of efficacy, investigator decision, study terminated by 
sponsor, screen failure, or other.  Study disposition information will be collected on the 
Patient Disposition DCF. 
4.4.1 
Criteria for Stopping VentaProst Treatment 
Individual patients stopping criteria: At any time during study drug administration , 
patients may be removed from study treatment and placed on standard of care (SoC) 
therapy if they meet one or more of the following pre-defined criteria leading to a 
deterioration in their condition: 
 
• Severe hypotension as evidenced by a systolic BP < 90 mmHg  or MAP < 60 
mmHG for >2 hours from the start of VentaProst 
• Need for VV ECMO 
• Need to increase existing vasopressor therapy by more than 25% 
• Worsening oxygenation, ventilatory, or hemodynamic parameters that in the 
opinion of the investigator the patient should be removed from study treatment 
• Massive hemoptysis thought to be clinically significant and not due to 
endotracheal tube trauma 
• Pulmonary Edema 
• If a clinically inadequate response is observed 
 
Study stopping criteria: If 3 patients are removed from the study for any of the above 
conditions, the study will stop further enrollment and investigation will be conducted to 
determine the cause of the events.  An independent safety evaluation will also be 
conducted.  If it is suspected that the investigational product has caused the events, the 
study will be terminated. 
Independent Safety Evaluation: Independent safety evaluation will be conducted by a 
licensed physician who is not involved in the VentaProst COVID-19 clinical study or the 
sponsoring organization.   


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5. 
STUDY TREATMENTS 
5.1 
Identity of Medication Component of the Investigational Product 
The study medication  VentaProst, Flolan (epoprostenol sodium), is manufactured by 
GlaxoSmithKline and has been analyzed and released according to their specifications.   
The labelling of Flolan and placebo for this clinical trial will follow the protocols and 
procedures set forth by OSU’s Investigational Drug Services (IDS).   The Control for this 
study is 0.9% sodium chloride solution, USP from the OSU IDS stock and will be labeled 
in a blinded manner per the IDS protocols for maintenance of study blind. 
Drug Substance Name 
Epoprostenol Sodium 
Chemical Name 
5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-
oic acid. 
Molecular Formula 
C20H31NaO5 
Structural Formula 
 
Molecular Weight 
374.45 
 
5.1.1 
Storage Condition 
Both the vials of study medication and sterile diluent buffer should be stored between 20o 
to 25oC (68o to 77oF) with excursions permitted to 15° to 30°C (59° to 86°F) and kept in 
the supplied carton to protect the product from light.  Study medication will be stored in a 
secure, controlled-access location at the study sites. 
The 0.9% sodium chloride solution will be stored according the the product labelling. 
5.2 
Treatments Administered 
Patients will receive study drug via mechanical ventilator, starting at 13.6 ng/kg/min.  If 
determined by the treating physician, study drug can be up titrated in 3.4 ng/kg/min 
increments to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.  At 
the Investigator’s discretion, the patient will be weaned off the drug in 3.4 ng/kg/min 
increments. Study drug will be administered based on the pump rate calculated for the 
active treatment but delivered in mL/hr.  Study drug  can be administered up to 10 days.   
5.3 
Study Medication Supply, Preparation, and Administration 
5.3.1 
Study Medication Supply 
The medicinal component of VentaProst, Flolan, (epoprostenol sodium), is already 
approved for I.V. delivery.  The dosage form is a vial of 1.5 mg epoprostenol as a 


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lyophilizate and the required pH 12 Sterile Flolan diluent per the currently approved 
packet insert (NDA20-444/ Supplement 24 1).  Flolan and its diluent (pH 12 Sterile 
Diluent) are not re-formulated by Aerogen Pharma.  Flolan is used with the same diluent 
system and reconstituted per the approved packet insert.  
Flolan and diluent container closure (glass vial and stopper/crimp-pH 12 Sterile Diluent 
for Flolan comes in a plastic bottle for mixing) and secondary packaging (cardboard box) 
are not being altered, including the information on the vial and box label and the 
information in the approved Flolan packet insert.  This preserves the approved drug 
labeling information per NDA 20-444.  
Placebo will be a corresponding volume of  0.9% sodium chloride solution from the OSU 
IDS stock. 
5.3.2 
Study Medication Preparation 
Refer to the VentaProst-COVID Pharmacy Manual for preparation of study drug solution.. 
Prior to use, drug solutions  must be protected from light and refrigerated at 2° to 8°C 
(36° to 46°F) if not used immediately.  Do not freeze drug solutions and discard any  
drug solution that has been frozen. Discard any drug solutions if refrigerated for more 
than 8 days.  Control, (0.9% sodium chloride solution) will be placed in identical syringes 
and masked according OSU IDS procedures for blinded studies. 
5.3.3 
Study Medication Administration  
In the ICU, patients will be started on study drug administered via the VentaProst 
delivery system at an initial dose administered at 13.6 ng/kg/min.  Study Drug Study drug 
may be titrated up or down in 3.4 ng/kg/min increments (refer to VentaProst Pharmacy 
Manual) as clinically indicated to a dose range of 3.4-30.6 ng/kg/min.  Study drug will be 
administered based on the pump rate calculated for the active treatment in mL/hr.  Study 
drug  can be administered up to 10 days.   
1 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020444s024lbl.pdf  
APC-VPCOV-CLN-001 21 Jul 2020 
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Table 3:  Administration Titration Guidelines 
Up titration Guideline  
Downward Titration / Guideline 
Start Dose: 13.6 ng/kg/min 
1st Step Up Dose (17.0) 
2nd Step Up Dose (20.4) 
3rd Step Up Dose (23.8) 
4th Step Up Dose (27.2) 
5th Step Up Dose (30.6) 
Start Dose: 13.6 ng/kg/min 
1st Step Down dose (10.2) 
2nd Step Down Dose (6.8) 
3rd Step Down dose (3.4) 
 
All study drug will be administered per the calculated pump rate for the active treatment in ml/hr 
 
Table 4-Example of Up Titration for male with Ideal Body Weight of 70 kg  
Initial Dose Rate 
Initial Pump Rate 
New Dose Rate 
New Pump Rate 
13.6 ng/kg/min 
1.89 mL/hr 
13.6 ng/kg/min 
1.89 mL/hr 
17.0 ng/kg/min 
2.39 mL/hr 
20.4 ng/kg/min 
2.86 mL/hr 
23.8 ng/kg/min 
3.33 mL/hr 
27.2 ng/kg/min 
 
3.81 mL/hr 
30.6 ng/kg/min 
4.28 mL/hr 
              Active drug is prepared with 50 mL in each syringe at a concentration of 30,000 ng/mL. 
              All study drug will be administered per the calculated pump rate for the active treatment in ml/hr. 
 
5.3.4 
Study Medication Weaning 
Patients will be weaned from study drug slowly to avoid rebound vasoconstriction.   
During weaning, doses will be decreased in steps of 3.4 ng/kg/min increments, with a 
minimum of 15 minutes between changes. The weaning process should occur in isolation 
to other treatment changes (no changes in inotropes, vasopressors, or vasodilators) 
whenever possible. Patients will be observed closely before, during, and after dose 
changes. In the event patients demonstrate signs of hemodynamic instability  or a 
decrease in oxygenation indicated by pulse oximetry during downward titration, the dose 
will be returned to its previous level. Once patients have been stable for at least 15 
minutes, repeat attempts at dose reduction may be undertaken.  The process will continue 
until patients are fully weaned.  Patients will be monitored for safety and efficacy 
throughout study drug administration. 
5.4 
Identity of the Device Component of the Investigational Product 
5.4.1 
Identity of Device 
The Phase 2a VentaProst drug delivery system is designed to accurately and precisely 
administer aerosol to the lungs of critically ill patients who require support via 
mechanical ventilation.  The aerosol generator’s fundamental operating mechanism and 
materials of construction will be similar to the 510(k)-cleared Aeroneb Solo System 
(K120939, K103635, K070642, Aerogen Ltd) and it is being designed for compatibility 
with the range of ventilators found in the OR and ICU. 


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5.4.1.1 VentaProst Aerosol Delivery to Ventilated Patients 
The VentaProst delivery system (Figure 1) consists of reusable and single-patient use 
disposable elements: 
1. Reusable multi-patient use components consist of two electronic controllers with 
power supplies, Aerogen Solo Nebulizer Cable, and Sensirion Flow Sensor Cable.  
When used together, they synchronize aerosol generation with the patient’s 
inspiratory pattern through a single-patient use, disposable administration kit. 
o Aerogen Pro-X, is a commercially available device (K1209392) cleared 
for use to continuously operate the disposable Aerogen Solo nebulizer. 
(item #1 Figure 1). 
o Aerogen Pharma Controller (AP Controller) is an investigational device, 
which synchronizes aerosol generation with the ventilator inspiratory 
cycle (item #2 on Figure 1).  This controller was tested to demonstrate its 
safety for use under IND129777.  
o Aerogen Solo Nebulizer Cable 
o Sensirion Flow Sensor Cable 
2. Single-patient disposable kit: 
o Aerogen Solo nebulizer (item #3 on Figure 1) is a commercially available, 
low mass and low profile vibrating mesh aerosol generator (K070642) 
cleared for use with the Aerogen Pro-X controller and Aerogen 
Continuous Nebulization Tube Set (CNTS).  
o Aerogen CNTS and syringe (items #4 and 5 on Figure 1) is a 
commercially available device (K103635) cleared for use to connect to the 
Aerogen Solo and deliver medication from the drug reservoir (syringe) to 
the mesh the nebulizer.   
o Flow sensor and cable connected to the Aerogen Pharma Controller (AP 
Controller, item #7 on Figure 1).  This is a new component of the system, 
which was tested to demonstrate safety for use in a clinical study.  
The VentaProst delivery system will be used in conjunction with a commercially 
available and FDA-cleared syringe pump (item #8 on Figure 1).  In general, any available 
syringe pump, which (1) is compatible with the Aerogen Continuous Nebulization Tube 
Set (CNTS syringe and tubing), and (2) is capable of delivering medication to the 
vibrating mesh nebulizer within the range of 0.4 to 12.0 mL/h as required to deliver the 
doses specified in the APC-VPCOV-CLN-001 Pharmacy Manual. For purposes of the 
VPCOV study, Aerogen Pharma will supply  the Perfusor® Space Infusion Syringe Pump 
System from B.Braun (Figure 1).  This particular syringe pump is FDA-cleared 
(K093913), it is compatible with the CNTS syringe (items #4 on Figure 1) and is able to 
 
 
 
2 The product names for the Aerogen commercial products changed from the term “Aeroneb”, to the brand 
name “Aerogen”.  A Note to File was submitted to FDA and receipt was acknowledged by the Branch 
Office 
 


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deliver fluids in the rage of 0.4 to 12.0 mL/h.  It is worth noting that on 11 April 2020, 
this pump received EUA for use in the tracheal delivery of continuous nebulized 
medications into a nebulizer to treat patients of all ages with or suspected of having the 
Coronavirus Disease 2019 (COVID-19)3.   
Figure 1: Drug Delivery System 
The Aerogen Pro-X (item #1, Figure 1), Aerogen Solo (item #3, Figure 1) are mounted on 
an I.V. pole at the patient’s bedside.  The two controllers and Aerogen CNTS (items #4 
and 5, Figure 1) are routinely used as a system within their intended use.  The sensor and 
nebulizer are connected into specific locations of the inspiratory limb of the ventilator 
pre- and post the humidifier, respectively (see Figure 2).  The addition of the AP 
Controller and an off-the shelf Sensirion flow sensor enables the VentaProst system to 
synchronize aerosol delivery with the inspiratory cycle of the ventilator (Figures 1 and 2).  
Figure 2 illustrates the AP Controller, which is similar to the commercially available 
3 https://www.fda.gov/media/136894/download 


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Aerogen Pro-X controller in form, size, weight and materials used for the upper and 
lower shells.  The AP Controller uses the same AC/DC adapter and cable as used in the 
commercial Aerogen Pro-X controller.  The packaging used for the AP Controller is same 
as packaging validated by Aerogen Ltd. for the commercially available Aerogen Pro-X 
system.  Functionality of the AP Controller was tested in design verification studies 
(IND129777).  Two dials (Figure 2) are used to: (1) set the flow threshold for 
nebulization triggering during the inspiratory cycle of the ventilator, accommodating 
initial ventilator baseline bias flows, and (2) set the duration of nebulization during the 
inspiratory cycle (a detailed description of the mechanism of action of the AP Controller 
is presented in IND129777).   
 
 
A. Diagram of Aerogen Pharma Controller 
(left side view) 
 
 
B. Diagram of Aerogen Pharma Controller (right 
side view) 
C. Flow Trigger Dial settings 
D. Aerosol Duration Dial settings 
 
Figure 2: Aerogen Pharma Controllers 
Prior to administration, study drug will be prepared per the VP COVID Pharmacy Manual 
and placed into a 60 mL CNTS syringe.  The syringe will be labeled to maintain the study 
blind.  The user will attach the syringe to the CNTS tubing and prime the tube set so that 
the formulation reaches the Aerogen Solo, producing aerosol generation.  The CNTS 
syringe set will be placed in a B Braun Perfusor Space Infusion syringe pump.  The 15-
mm T-Piece with nebulizer is placed between the ventilator circuit and the ETT (Figure 
2).  The user will select the pump rate (mL/hr) to deliver the recommended dose based on 


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the ideal body weight in kilograms (kg) dispensed to achieve the dose rate in ng/kg/min 
for active treatment.  The control treatment’s corresponding pump flow rate in mL/hour 
will be calculated based on initial dose of Flolan in ng/kg/min. All study drug will be 
administered per the calculated pump rate for active treatment in ml/hr.  The user will be 
able to adjust this recommended dose up or down (per protocol) by changing pump rate 
prior to selecting dose and initiating delivery.  The selected dose will then be dispensed 
by the pump to the receiving surface of the mesh, resulting in generation of an aerosol 
with a volume median diameter in the range of 2 to 5 µm.  The Aerogen Pharma 
Controller monitors the patient’s breathing pattern and user adjusts the knob (on left) to 
initiate aerosol generation at the beginning of the breathing cycle.  The knob on right sets 
the duration of aerosol generation within each breath.   
 
The VentaProst device is designed to be compatible with standard intensive care unit 
(ICU) equipment.  The following site-specific equipment will be needed to deliver the 
therapy: B.Braun syringe pump (provided by Aerogen Pharma), ventilator, endotracheal 
tube (ETT), humidifier, ventilator circuit.  This equipment is standard for critical care 
medicine. 
  
Figure 3 - VentaProst Device Placement in the Gas Pathway 
 


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5.4.2 
Ventilator Settings 
The device is designed for use with standard adult ventilator settings.  An intermittent 
positive pressure ventilatory mode (i.e., not constant positive airway pressure [CPAP] or 
t-piece) is required to activate the device to deliver aerosol during the inspiration phase.
A Heat-Moisture Exchanger (HME) may be used in the device circuit.
The site will utilize OSU’s Standard of Care (SOC) mechanical ventilation guidelines for 
care of patients for COVID-19 with ARDS.  The following ventilator parameters will be 
assessed daily while on VentaProst:  Ventilator type, Mode, FiO2, Inspiratory Time, Mean 
Airway Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, 
Respiratory Rate and Tidal Volume. 
5.4.3 
Device Supply 
All device supplies will be provided by Aerogen Pharma Limited (including the B.Braun 
Syringe Pump). The serial numbers for the controllers, flow sensor, and nebulizer will 
also be recorded in an IP accountability dispensing log. 
Used and unused devices will be inventoried and returned to the Sponsor or Sponsor’s 
designee. 
5.4.4 
Device Replacement 
Devices may be replaced at any time if there a suspicion of malfunction, but must be 
replaced if: 
•
The investigator suspects that, due to device malfunction, less than 90% of the
total dose of study drug has been delivered.  Reduced doses must be estimated
and recorded in the patient’s medical record and source documentation.
•
The investigator suspects the device is not performing optimally for any reason.
5.4.5 
Device Malfunction or Failure 
One device (Aerogen Pro-X controller, Aerogen Pharma Breath Controller, Flow Sensor, 
Solo nebulizer, CNTS tubing and syringe, and associated components) is expected to 
perform throughout the duration of study treatment.  If the controllers, Flow Sensor, 
CNTS tubing and syringe, or the Solo nebulizer are not functioning optimally for any 
reason, instructions for trouble-shooting provided in the device instruction for use manual 
should be followed.  If one or more devices need to be replaced, the reason should be 
documented in the patient’s medical record, dispensing log, and Device Performance 
Issues Form.  Additional devices are provided for this purpose.  The unique serial 
numbers of the new components will be recorded in the patient’s medical record, 
dispensing log, and the source documentation. 
For device malfunction or complaints, complete the Device Performance Issues Log and 
submit to the Sponsor at Complaints@aerogenpharma.com within 48 hours.  Failed 
devices will be set aside from the general supplies, inventoried and returned to the 
Sponsor or the Sponsor’s designee. 


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5.5 
Blinding 
Clinical and research staff and Sponsor will be blinded to Active or Control dose 
assignments with the exception of the pharmacy staff and an unblinded Sponsor CRA.  
Should unblinding be necessary, the medical monitor for this study will work with the 
unblinded pharmacist or unblinded CRA to unblind the patient.  
Active treatment (Flolan) is clear in color when reconstituted and Control treatment 
(0.9% sodium chloride solution) is also clear in color to maintain the study blind.  The 
Control and Active treatments will be placed in identical 60 mL syringes and labelled in a 
blinded manner prior to leaving the pharmacy. 
5.6 
Prior and Concomitant Therapy 
For patients who receive study drug, any medication (including over-the-counter [OTC] 
medications or other investigational therapies) or therapy administered to the patient 
during the course of the study (starting at Screening and 14  days prior) will be recorded 
on the Prior and Concomitant Therapy data collection forms.  The Investigator will 
record any AE on the AE data collection forms for which a concomitant 
medication/therapy was administered. 
5.6.1 Prohibited Concomitant Therapy 
Other inhaled vasodilators. 
5.7 
Investigational Product (IP) Supplies and Accountability 
Investigational product supplies will not be sent to the Investigator(s) until the following 
documentation has been received by the Sponsor: 
• Written proof of approval of the protocol and its informed consent forms (ICFs) 
by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for 
the institution where the study is to be conducted.  (Due to COVID-19 and the 
availability of the Active study medication, the study medication will be sent to 
the OSU pharmacy and held in quarantine until IRB approval and the completion 
of Study Initiation Visit (SIV), which may be conducted remotely or in person.  A 
NTF will be sent to OSU pharmacy instructing that the study medication not be 
released for use until Sponsor notification.) 
• An Investigator-signed and dated FDA Form 1572. 
• A signed and dated curriculum vitae of the Principal Investigator including a copy 
of the Principal Investigator’s current medical license (required in the US) or 
medical registration number on curriculum vitae. 
The Investigator and study staff will be responsible for the accountability of all IP 
supplies (dispensing, inventory, and record keeping) following Aerogen Pharma 
instructions and adhere to Good Clinical Practice (GCP) guidelines as well as local 
and/or regional requirements. 
Under no circumstances will the Investigator allow the IP to be used other than as 
directed by this protocol.  IP will not be administered to any individual who is not 
enrolled into the study. 


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An accurate and timely record of the receipt of all IP; dispensing of IP to the patient; 
collection of unused IP; and subsequent return of unused IP to Aerogen Pharma must be 
maintained.  This includes, but may not be limited to: (a) documentation of receipt of IP, 
(b) IP dispensing log, (c) IP accountability log, (d) all shipping service receipts, and (e) 
documentation of returned IP to the Sponsor.  All forms will be provided by Aerogen 
Pharma.  Any comparable forms that the investigational site wishes to use must be 
approved by Aerogen Pharma. 
The supplies and inventory records must be made available, upon request, for inspection 
by the designated representative of Aerogen Pharma, a representative of the FDA, or a 
representative of a non-US health authority.  All used and unused IP are to be returned to 
Aerogen Pharma at the conclusion of the study.   
6. 
CRITERIA FOR EVALUATION 
6.1 
Primary Endpoint 
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• Requires VV ECMO   
• Inability to extubate within 10 days or reintubation within < 24 hours 
• Change in S/F, oxygenation index and P/F ratio (>15%) from baseline to 
12 hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
1. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 
• Worsening hemodynamic parameters  
• Cardiac troponin >20% from baseline  
• BNP > 15% of baseline 
• Need for temporary mechanical circulatory support (IABP, Impella) 
• Requires VA ECMO 
6.2 
Secondary Endpoints 
1. Improvement in oxygenation defined as any one of the following: 
• Stabilization of PaO2/FIO2 >250 
• Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
2. Improved clinical outcomes  defined as one of more of the following: 
• Time to extubation following the site’s extubation protocol 


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• Free from re-intubation 
• Reduction in ICU days 
• Reduction in the number of re-admissions to the ICU due to COVID-19   
within 28 days 
• Reduction in total hospital days  
• Mortality [28 days] defined as Cardiopulmonary mortality or mortality 
from all causes  
3. Safety and tolerability 
• Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory/oxygenation parameters,  and 
laboratory tests. 
6.3 
Exploratory endpoints will include (where available): 
• Change in LDH 
• Change in fibrinogen 
• Change in WBC count including lymphocytes and neutrophil subsets 
• Change in triglycerides 
• Change in ferritin 
• Change in CRP / ESR 
• Change in IL-6 
• Change in D-Dimer  
Changes in these parameters will be assessed for each patient from baseline to 
end of study as well as changes between the active and control groups. 
 
6.4 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used and generally 
recognized as reliable, accurate, and relevant in studies of cardiac and respiratory 
function. 
7. 
SAFETY ASSESSMENTS 
Safety will be assessed through monitoring of adverse events (AEs) and serious adverse 
events (SAEs),  laboratory tests, chest assessments (Chest CT or Chest X-ray), 
oxygenation/ventilatory parameters, and vital signs.  Safety assessment frequency is 
shown in the Schedule of Assessments and Procedures. 


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7.1 
General Safety Procedures 
7.1.1 
Vital Signs and Weight Measurements 
Vital sign measurements, including systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR) [beats per minute], respiratory rate (breaths per minute), 
and body temperature (in Celsius) will be obtained twice daily Days 1-10 or  as clinically 
indicated.  Weight (kg) will be obtained at the time of Screening and at Day 10 or end of 
VP treatment.  Height will be obtained at the time of Screening.  If unable to obtain 
height, the study staff will use the best reported historical height from patient or LAR. 
7.1.2 
Physical Examination 
A physical examination will be conducted at the screening visit and will include 
assessments of general appearance; skin and lymphatics; eyes, ears, nose, throat; 
cardiovascular system; respiratory system; abdomen/gastrointestinal system; urological 
system; musculoskeletal and neurological systems.  Other body systems may be 
examined as clinically indicated. 
7.1.3 
Laboratory Measurements 
Clinical laboratory measurements to be performed are listed below.  The Schedule of Assessments 
and Procedures shows the time points at which blood will be collected for clinical laboratory tests and 
pregnancy testing.  The Baseline for laboratory tests is the Screening assessment. 
Category 
Parameters 
Hematology-CBC with diff 
Hemoglobin, hematocrit, RBC, WBC with differential 
(neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, 
basophils), platelets  
Full Chemistry Panel 
 
Electrolytes 
Sodium, potassium, chloride, bicarbonate, calcium 
Liver function tests 
AST, ALT, AP, total bilirubin 
Renal function parameters 
BUN, creatinine 
Coagulation Studies 
PT/PTT 
Other 
Serum or urine pregnancy test, RT-PCR for COVID-19, 
ESR, 
Troponin, 
BNP, 
fibrinogen, 
ferritin, 
LDH, 
Triglycerides, D-Dimer, IL-6, and CRP 
7.1.4 
Chest Assessments 
A Chest CT or Chest X-ray will be obtained at Screening and Day 5. 
7.1.5 
Time Prone Protocol 
The time prone protocol is a standard of care in OSU’s ICU.  This will be in place for all 
days that patients are within the ICU. 
7.2 
Adverse Events 
7.2.1 
Definitions 
Adverse events are any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment.  For the purposes of this study, this will include unanticipated 
medical events in the judgment of the investigator.  A pre-existing condition or symptom 


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is one that is present at the start of the study and is reported as part of the patient’s 
medical history.  A pre-existing condition or symptom should be reported as an AE only 
if its frequency, intensity or character worsens during study treatment. 
All AEs that occur from the time of the first dose of study medication through the End of 
Study (Day 28) will be recorded and reported as Treatment-Emergent Adverse Events 
(TEAE).  All AEs must be appropriately documented in the patient’s medical 
chart/source documentation and on the DCFs.  When known, investigators should report 
syndromes rather than list symptoms associated with the syndrome. 
All AEs that are ongoing at the conclusion of the study should be followed until: a) 
resolution/stable sequelae; b) the Investigator determines that it is no longer clinically 
significant; or, c) the study patient is lost to follow-up.  If no follow-up is provided, the 
Investigator must provide a written justification. 
7.2.2 
Adverse Events of Special Interest (AESI) 
Pulmonary edema and  pulmonary hemorrhage are AEs of special interest due to the 
mode of action of epoprostenol.  If an AE of special interest occurs, the Sponsor will be 
notified of this occurrence within 24 hours. 
7.2.3 
Grading of Adverse Events 
The severity of each AE will be categorized using the following criteria: 
• Grade 1 (Mild):  usually transient; requires no special treatment and does not 
interfere with the patient’s daily activities. 
• Grade 2 (Moderate):  produces a low level of inconvenience to the patient and 
may interfere with daily activities.  These AEs are usually ameliorated by simple 
therapeutic measures. 
• Grade 3 (Severe):  interrupts daily activity and requires systemic drug therapy or 
other medical treatment. 
7.2.4 
Relationship to Study Medication/Study Device/Procedure 
The Investigator must assess the relationship of each reported AE.  The Investigator must 
make an assessment of the relationship of the AE to the study drug/study 
device/procedure using the following scale: 
• Unrelated:  The AE is definitely not or unlikely to be associated with study 
medication/study device/procedure and is judged due to causes other than the 
study medication/study device/procedure. 
• Related:  The AE is possibly or probably related with study medication/study 
device/procedure.    
7.2.5 
AE Outcomes 
The following terms and definitions are used in assessing the final outcome of an AE:  
• Recovered/Resolved - The patient has fully recovered, or by medical or surgical 
treatment, the condition has returned to the level observed at the first trial-related 


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activity. 
• Recovering/Resolving - The condition is improving and the patient is expected to 
recover from the event. 
• Recovered/Resolved with sequelae - The patient has recovered from the 
condition, but with lasting effect due to a disease, injury, treatment or procedure. 
If a sequela meets an SAE criterion, the AE must be reported as an SAE. 
• Not recovered/Not resolved - The condition of the patient has not improved and 
the symptoms are unchanged, or the outcome is not known at the time of 
reporting. 
• Fatal - This term is only applicable if the patient died from a condition related to 
the reported AE. Outcomes of other reported AEs in a patient before he/she died 
should be assessed as “recovered”, “recovering”, “recovered with sequelae” or 
“not recovered”.  An AE with fatal outcome must be reported as an SAE. 
7.2.6 
Laboratory Test and other Test Abnormalities as Adverse Events 
A laboratory or other test (chest assessments, vital signs) abnormality should be reported 
as an AE if the Investigator considers the abnormality an AE or if the abnormality is 
associated with accompanying symptoms, requires medical/surgical intervention, leads to 
a change in study treatment, or results in discontinuation from the trial. When possible, 
syndromes not laboratory values, should be reported as AEs.  For example, elevated 
hepatic transaminases associated with hepatitis should be reported as “hepatitis” and 
decreased hemoglobin and hematocrit requiring iron supplementation should be recorded 
as “anemia.”  Prior to reporting as an AE, abnormal tests should be repeated to verify the 
accuracy of the original result. 
7.2.7 
Serious Adverse Events 
The Investigator is required to determine if each AE is a Serious Adverse Event (SAE).  
An SAE is any AE occurring after randomization and through Day 28 and results in any 
of the following outcomes: 
• Death, or 
• Is life-threatening, or 
• Prolongation of existing hospitalization, or 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
In the event of death, the cause of death should be recorded as the SAE (death is an 
outcome, not the AE itself). 


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Any planned procedures that require admission to hospital as well as any planned elective 
procedures (e.g., angioplasty) are not considered SAEs (unless the underlying condition 
has worsened or the procedure results in a worsening of the patient’s condition).  In 
addition, pregnancy that occurs during the course of the study or absence of a treatment 
effect will also not be considered to be an SAE and will be collected on a separate CRF. 
7.2.8 
Reporting for SAEs (24 Hours) 
Regardless of causality, an SAE must be followed clinically until resolution or 
stabilization.   
All SAEs after randomization and through Day 28 of the study must be reported to the 
Sponsor or the Sponsor’s representative within 24 hours of the investigational site’s 
knowledge of the occurrence.  The investigational site will email a Serious Adverse 
Event Report (SAER) to the Sponsor and the Medical Monitor.    Investigational sites 
will be provided with SAER forms.  The Medical Monitor will work closely with the 
Sponsor to properly assess and report the SAE.  
The SAE information emailed to the Sponsor or the Sponsor’s representative will include 
the following (as available): 
• Patient Number, Investigator name, and Site Number 
• SAE information:  event term, onset date, severity, and causal relationship 
• Basic demographic information (e.g., age, gender, weight) 
• The outcomes attributable to the event (death, a life-threatening adverse drug 
experience, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, other important medical event[s]) 
• A summary of relevant test results, pertinent laboratory data, and any other 
relevant medical history 
• The first and last dates of study drug administration. 
• A statement whether study medication was discontinued or study medication 
administration schedule modified 
• A statement whether event recurred after reintroduction of study medication if 
administration had been discontinued or withheld 
• Supplemental anonymized information may include the following hospital 
records:  laboratory results, radiology reports, progress notes, admission and 
emergency room notes, holding/observation notes, discharge summaries, autopsy 
reports, and death certificates 
Supplemental information may be transmitted using a follow-up report and should not 
delay the initial report. 
For regulatory purposes, initial reports of SAEs should be transmitted within the 
prescribed time frame as long as the following minimum information is available:  patient 
number, suspect study medication, reporting source, and an event or outcome that can be 


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identified as being both serious and unexpected for which the Investigator can make a 
relationship assessment. 
7.3 
Reporting of Pregnancy 
Any pregnancy where the estimated date of conception occurs either prior to the End of 
Study must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, 
this should be reported regardless of the length of time that has passed since the exposure 
to study treatment.  The medical monitor may decide that unblinding of the patient 
treatment assignment may be necessary. 
An induced abortion or a spontaneous abortion is considered to be an SAE and should be 
reported in the same timeframe and in the same format as all other SAEs. 
Pregnancies must be reported as soon as possible but no later than one business day by 
email.  
All pregnancies must be followed to outcome.  The outcome of the pregnancy must be 
reported as soon as possible but not later than 24 hours of the investigational site’s 
knowledge of the outcome. 
8. 
PHARMACOKINETIC ASSESSMENTS 
Not applicable. 
9. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
The assessments and procedures for this study are described in detail below and 
presented in the Schedule of Assessments and Procedures located behind the Synopsis. 
9.1 
Study Evaluation Timepoints 
9.1.1 Screening (within 14 days prior to Baseline Day 1) 
Potential study patients will be recruited by the study staff from patients.  The following 
assessments will occur prior to study enrollment: 
• Informed consent prior to any study procedures or assessments being performed. 
• Demographic Information 
• Medical History  
• Physical Exam 
• Prior Medication History 
• Chest CT or Chest X-ray 
• Inclusion/Exclusion Eligibility Assessment (including assessment of shortness of 
breath within the last 14 days) 


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• Serum/Urine Pregnancy Test (if woman of childbearing potential) 
• Clinical Laboratory Sampling to include: Full Chemistry Panel including LFTs, 
CBC with Diff including neutrophils and lymphocytes, PT/PTT, Triglycerides, 
LDH, ferritin, fibrinogen, CRP, ESR, IL-6, troponin, BNP, D-Dimer, and RT-
PCR for COVID-19 
• Vital Signs  
• Height & Weight (If height can’t be obtained, use the best reported historical 
height) 
9.1.2 Days 1-10 Treatment  
9.1.2.1 Randomization 
• Evaluate that the patient continues to be  eligibile for the study by assessing 
Inclusion/Exclusion Criteria. 
• Once eligibility has been confirmed, a Subject number beginning with 101 and 
rising sequentially will be assigned to the next enrolled subject. 
• A blinded order for the Investigational Drug Services group will be generated by 
EPIC for the next sequential subject to be randomized.  
• The unblinded pharmacist will prepare the treatment assignment (Active or 
Control) for the next assigned Subject number. 
• The reconstituted study drug will be protected from light and labelled in a blinded 
manner to ensure maintenance of the study blind. 
• Subjects will be randomized to receive either Active or Control for a maximum of 
10 days, as clinically indicated and at the discretion of the Investigator. 
9.1.2.2 Baseline-Day 1 (0 Hour) 
 
• Continue evaluation eligibility by assessing Inclusion/Exclusion Criteria. 
•   Study drug treatment will begin at a starting dose of 13.6 ng/kg/min based on the 
concentration used to calculate Active treatment in mL/hr and can be titrated up to 
30.6 ng/kg/min or down to 3.4 ng/kg/min as clinically warranted.  The B.Braun 
syringe pump will be set to the appropriate dose in mL/hr utilizing the subject’s 
sex and height (ideal body weight).  
• Vital signs will be assessed twice daily in AM and PM while on study drug.  
Efforts will be made to obtain vital signs at the same time each day.  Vital signs 
include: temperature, pulse rate, respiration rate and blood pressure.  
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily while on study drug:  Ventilator 
Type, Vent Mode, FiO2, Inspiratory time, Mean Airway Pressure, Peak 
Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume, and 
Respiratory Rate 
• Time Prone Position-16 hours per day per OSU Protocol 


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9.1.2.3 Day 1-12 hours 
• Clinical Laboratory Sampling to include: Full Chemistry Panel including LFTs, 
CBC with Diff including neutrophils and lymphocytes, PT/PTT, Triglycerides, 
LDH, ferritin, fibrinogen, CRP, ESR, IL-6, troponin, BNP, and D-Dimer. 
• Continue to administer study drug if clinically indicated. 
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Oxygenation measurement via continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily while on study drug:  Ventilator 
Type, Vent Mode, FiO2, Inspiratory time, Mean Airway Pressure, Peak 
Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume, and 
Respiratory Rate 
• Vital signs will be assessed twice daily in AM and PM.  Efforts will be made to 
obtain vital signs at the same time each day.  Vital signs include: temperature, 
pulse rate, and blood pressure.  
• Time Prone Position-16 hours per day per OSU Protocol 
9.1.2.4 Days 2-10 (While on study drug) 
• Continue to administer study drug if clinically indicated. 
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Oxygenation measurement via continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily: Ventilator Type, Vent Mode, FiO2, 
Inspiratory time, Mean Airway Pressure, Peak Inspiratory Pressure, Positive End 
Expiratory Pressure, Tidal Volume, and Respiratory Rate 
• Vital signs will be assessed twice daily in AM and PM.  Efforts will be made to 
obtain vital signs at the same time each day.  Vital signs include: temperature, 
pulse rate, and blood pressure.  
• Time Prone Position-16 hours per day per OSU Protocol 
• Full Chemistry Panel including LFTs, CBC with Diff including neutrophils and 
lymphocytes, PT/PTT and RT-PCR for COVID-19. (Day 5 only) 
• Chest CT or Chest X-ray (Day 5 only) 


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• Full Chemistry Panel including LFTs, CBC with Diff including neutrophils and 
lymphocytes, PT/PTT, Triglycerides, LDH, ferritin, fibrinogen, CRP, ESR, IL-6, 
troponin, BNP, D-Dimer, and RT-PCR for COVID-19 (Day 10 only).  
• Obtain weight. (Day 10 only or at end of study drug dosing) 
9.1.2.5 Weaning  
See Section 5.3.4 and Table 3 for weaning guidelines.  
 
9.1.3 
Day 28/End of Study (EOS)  
•    Assess AEs/SAEs  
•    Assess Mortality 
•    Assess concomitant medications 
9.2 
Data Collection 
Investigator or designee will enter the information required by the protocol onto source 
documents and enter data into data collection forms (DCFs) in an excel spreadsheet 
provided by Aerogen Pharma. 
9.3 
Clinical Data Management 
Data from source documents will be verified against the DCF and any discrepancies will 
be clarified and resolved with study staff. 
9.4 
Database Quality Assurance 
All data will be remotely monitored by the Sponsor due to the COVID-19 pandemic. 
Should restrictions be lifted at OSU, an on-site visit may occur if all parties are in 
agreement. 
10. 
 STATISTICAL CONSIDERATIONS 
10.1 
Statistical Methods 
A Statistical Analysis Plan will be not be developed as this is an exploratory trial.  Any 
statistical evaluation will be handled internally by Aerogen Pharma or their designee. 
10.2 
Determination of Sample Size 
The number of patients has been selected to enable an adequate clinical assessment of 
pharmacodynamics, safety, and tolerability parameters without presenting undue risk to a 
large number of patient’s being exposed to this investigational product. 
10.3 
Analyses Sets 
All patients who are enrolled in the study and who receive at least one dose of study drug  
will be included in the intent-to-treat (ITT) analyses of pharmacodynamic and safety data.  
All available data will be used and missing data will not be estimated or carried forward 


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in any statistical summary or analyses. 
Descriptive summary statistics include the number of patients, mean, median, percent 
coefficient of variation (% CV) (if required), standard deviation, and minimum and 
maximum values (quantitative variables) or the number of patients and percentages by 
category (qualitative variables).  Changes will be assessed as the difference between 
baseline measurements and the appropriate post-dose measurements unless otherwise 
specified.  Mean differences between active and control groups (when available) will be 
assessed and significance will be determined on the basis of a 95% CI.  Individual patient 
listings of data will also be provided to allow for review of all pharmacodynamic, safety, 
and tolerability parameters. 
10.4 
Randomization 
Patients will be randomized 1:1. A randomization schedule will be provided to the 
unblinded pharmacist.  Should unblinding be requested due to a medical emergency, the 
unblinded pharmacist will work with the medical monitor or Sponsor unblinded CRA to 
obtain the required information. 
10.5 
Demographic and Other Baseline Characteristics 
Continuous demographic and other baseline characteristics (such as age, weight, and 
height) will be summarized using n, mean, SD, median, minimum, and maximum.  
Qualitative characteristics (such as gender and race) will be summarized by counts and 
percentages.   
10.6 
Criteria for Evaluation 
10.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint:  
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• Requires VV ECMO   
• Inability to extubate patient within 10 days or reintubation within <24 
hours 
• Change in S/F, oxygenation index and P/F ratio (>15%) from baseline to 
12 hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 
• Worsening hemodynamic parameters  
• Cardiac troponin >20 % from baseline   
• BNP > 15% of baseline 


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• Need for temporary mechanical circulatory support (IABP, Impella) 
• Requires VA ECMO 
10.6.2 
Secondary Efficacy Endpoints 
Key secondary endpoints include: 
1. Improvement in oxygenation defined as any one of the following: 
• 
Stabilization of PaO2/FIO2 >250 
• Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
2. Improved clinical outcomes  defined as one of more of the following:  
• Time to extubation following the site’s extubation protocol 
• Free from reintubation 
• Reduction in ICU days 
• Reduction in the number of re-admissions to the ICU due to COVID-19   
within 28 days 
• Reduction in total hospital days  
• Mortality [28 days] defined as Cardiopulmonary mortality or mortality 
from all causes  
3. Safety 
• Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory/oxygenation parameters,  and 
laboratory tests. 
10.6.3 
Key Exploratory Endpoints include: 
• Change in LDH 
• Change in fibrinogen 
• Change in WBC count including lymphocytes and neutrophil subsets 
• Change in triglycerides 
• Change in ferritin 
• Change in CRP / ESR 
• Change in IL-6 
• Change in D-Dimer  
Changes in these parameters will be assessed for each patient from baseline to 
end of study as well as changes between the active and control groups. 
10.7 
Extent of Exposure 
Exposure data will be summarized by using frequencies and percentages. 


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10.8 
Safety Analyses 
Safety measurements include AE/SAEs, vital signs, chest assessments (Chest CT or 
Chest X-ray), laboratory tests, and oxygenation/ventilatory parameters.  Safety data will 
be summarized by using frequencies and incidence rates.   
10.8.1 
Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim 
description (Investigator term) using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be presented by preferred term nested within System Organ Class.  
Verbatim description and all MedDRA level terms, including the lower level terms, for 
all AEs will be contained in the data listings of the clinical study report (CSR).  
AEs will be summarized by presenting the incidence of AEs.  Although a MedDRA term 
may be reported more than once for a patient, that patient will be counted only one time 
in the incidence count for that MedDRA term. 
Treatment-emergent adverse events (TEAEs) will be analyzed.  AEs that are not 
treatment-emergent will be listed.  A TEAE is defined as  
• AEs that emerge during treatment, having been absent at pretreatment, or  
• Reemerge during treatment, having been present at pretreatment but stopped 
prior to treatment, or  
• Worsen in severity or frequency during treatment relative to the pretreatment 
state, when the AE is continuous. 
Adverse events of special interest (AESI) will be analyzed.   An AESI is defined as: 
• Serious or non-serious adverse that is one of scientific and medical    concern 
specific to the sponsor’s product for which ongoing monitoring   and rapid 
communication by the investigator to the sponsor is required 
• Events or symptoms thought to potentially be associated with the investigational 
compound, device, or disease under study, or 
• Can arise with any use of a drug/device (e.g. off-label use, use in combination 
with another approved drug), with any route of administration, formulation, or 
dose, including an overdose. 
 
10.8.2 
Laboratory Values 
Clinical laboratory results post-Baseline will be evaluated for markedly abnormal values.  
For the incidence of markedly abnormal laboratory values, each patient may be counted 
once in the laboratory parameter value high and in the laboratory parameter low 
categories as applicable.  Descriptive summary statistics (e.g. mean, SD, median, 
minimum, maximum) for laboratory values and changes from baseline will be evaluated. 


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10.8.3 
Vital Signs 
Vital sign values will be evaluated on an individual basis by patient.  Abnormal vital sign 
values will be identified as those outside (above or below) the reference range.  
Descriptive summary statistics (e.g., mean, SD, median, minimum, maximum) for vital 
sign parameters and changes from Baseline will be evaluated. 
10.9 
The Procedure for Revising the Statistical Analysis Plan 
Not Applicable. 
11. 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS 
11.1 
Ethics 
11.1.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an IRB or IEC constituted and functioning in accordance with 
International Conference on Harmonization (ICH) E6, Section 3, and any local 
regulations, i.e., Federal Regulations, Title 21 Code of Federal Regulations (CFR) Part 
56.  Any protocol amendment and/or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval (except for changes involving only logistical or 
administrative aspects of the study (e.g., change in CRA[s], change of telephone 
number[s]).  Documentation of IRB/IEC compliance with the ICH and any local 
regulations regarding constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC Chairman must be sent to the 
Principal Investigator with a copy to the Sponsor prior to study start.  If the IRB/IEC 
decides to suspend or terminate the study, the Investigator will immediately send the 
notice of study suspension or termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator 
or Sponsor, depending on local regulatory obligations.  If the Investigator is required to 
report to the IRB/IEC, he/she will forward a copy to the Sponsor at the time of each 
periodic report.  The Investigator or the Sponsor will submit, depending on local 
regulations, periodic reports and inform the IRB/IEC of any reportable AEs per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
Investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required. 
11.1.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating practices of Aerogen 
Pharma (or designee), which are designed to ensure adherence to GCP guidelines as 
required by the following: 
• ICH - E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonization of Pharmaceuticals for Human Use. 


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• US CFR dealing with clinical studies (21 CFR, including parts 50 and 56 
concerning Informed Patient Consent and IRB regulations). 
11.1.3 
Patient Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each patient or their legally authorized representative (LAR), the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, and currently available alternative treatments.  Each 
patient must be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written 
in non-technical language.  The patient or their LAR should understand the statement 
before signing and dating it and will be given a copy of the signed document.  The patient 
or their LAR will be asked to sign an informed consent prior to any study-specific 
procedures being performed.  No patient can enter the study before his/her informed 
consent has been obtained.  Due to the COVID-19 pandemic and restrictions on hospital 
visitors, informed consent may be obtained via telephone or video conference call if the 
patient is incapacitated or sedated due to the severity of their illness.  A witness for the 
study team should be present when a call or video conference is occurring with the 
patient’s LAR.  This process should be carefully documented in the subject’s medical 
records. 
An unsigned copy of an IRB/IEC and Sponsor-approved written informed consent must 
be prepared in accordance with ICH E 6, Section 4, and all applicable local regulations, 
i.e., Federal Regulations, Title 21, CFR Part 50, and provided to the Sponsor.  Each 
patient or their LAR must sign (or give verbal consent with study staff witnessing the 
verbal consent) an approved informed consent prior to study participation.  The form 
must be signed and dated by the appropriate parties.  The original signed ICF for each 
patient will be verified by the Sponsor and kept in the study center’s investigational site 
files. 
The patient should be informed in a timely manner if new information becomes available 
that might be relevant to the patient’s willingness to continue participation in the trial.  
The communication of this information should be documented. 
11.2 
Administrative Procedures 
11.2.1 
Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  
Protocols will be followed as written. 
Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the Sponsor before implementation.  Amendments 
specifically affecting the safety of patients, the scope of the investigation, or the scientific 
quality of the study require additional approval by the applicable IRBs/IECs of all 
investigational sites and, as required, by the regulatory authority.  These requirements 


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should in no way prevent any immediate action from being taken by the Investigator, or 
by the Sponsor, in the interest of preserving the safety of all patients included in the 
study.  If an immediate change to the protocol is felt by the Investigator to be necessary 
for safety reasons, the  Medical Monitor must be notified promptly and the IRB/IEC for 
the site must be informed as soon as possible. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval, but the IRB/IEC must be kept informed of such 
changes.  In these cases, the Sponsor will send a letter to the site for forwarding on to the 
IRB/IEC detailing such changes. 
11.2.2 
Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
11.2.3 
Monitoring Procedures 
The Sponsor or Sponsor’s representative will maintain contact with the Investigator and 
designated staff by telephone, letter, and/or email between study visits.  Monitoring visits 
to each investigational site will be conducted by the sponsor either remotely or in person.  
In accordance with ICH E6, Section 6.10, source documents include, but are not limited 
to the following: 
• Clinic, office, hospital charts. 
• Copies or transcribed health care provider notes which have been certified for 
accuracy after production. 
• Recorded data from automated instruments such as mechanical ventilators, x-
rays, and other imaging reports, e.g., sonograms, computed tomography scans, 
magnetic resonance images, radioactive images, ECGs, rhythm strips, 
electroencephalographs, polysomnography, pulmonary function tests (regardless 
of how these images are stored, including microfiche and photographic 
negatives). 
• Records of telephone contacts. 
• Diaries or evaluation checklists. 
• Investigational product distribution and accountability logs maintained in 
pharmacies or by research personnel. 
• Laboratory results and other laboratory test outputs, e.g., serum pregnancy test 
result documentation. 
• Correspondence regarding a study patient’s treatment between physicians or 
memoranda sent to the IRBs/IECs. 
• CRF components (e.g., questionnaires) that are completed directly by patients 
and serve as their own source. 


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11.2.4 
Recording of Data 
In order to provide the Sponsor with accurate, complete, and legible records following 
criteria are to be maintained.  The Investigator will enter the information required by the 
protocol onto the data collection forms (DCFs)  provided by the sponsor as agreed upon 
with the research staff. 
11.2.5 
Data Storage and Retention of Records 
 
The circumstances of completion or termination of the study notwithstanding, the 
Investigator has the responsibility to retain all study documents, including but not limited 
to the protocol, copies of data collection forms (DCFs) , Investigator's Brochure, 
regulatory agency registration documents, e.g., FDA 1572 form, ICFs, and IRB/IEC 
correspondence.  The investigational site should plan on retaining study documents as 
follows: 
• For at least two years following the date a marketing application is approved for 
the investigational product for the indication for which it is being investigated, or 
• Until two years after the investigation is formally discontinued and no application 
is to be filed or if the application is not approved. 
It is requested that at the completion of the required retention period, or should the 
Investigator retire or relocate, the Investigator contacts the Sponsor, allowing the Sponsor 
the option of permanently retaining the study records. 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Data will be coded (de-identified), stored in a secure electronic database during and after 
the study, and will not be shared with unauthorized persons. The principal investigator 
and co-investigator will have access to the data to review and analyze the data, as 
described in this protocol. For the protection and privacy of the patients, no identifying 
information will be released.  Data will be retained and possibly used in the future for 
further analysis. All identifiers will be removed and not be shared at any time. 
11.2.6 
Handling of Investigational Product 
Investigational study drug (Flolan) will be inventoried and maintained within the site’s 
Investigational Drug Services .  It will be stored according to their protocols and 
procedures.   The study drug should not be dispensed to patients in the VentaProst 
COVID trial (APC-VPCOV-CLN-001) until a favorable IRB approval has been obtained 
by the OSU IRB and a study initiation visit has been conducted by the Sponsor.  
Investigational device  supplies must be kept in an appropriate secure area (e.g., locked 
cabinet) and stored according to the conditions specified on the investigational product 
labels.  The Investigator (or designated pharmacist) must maintain an accurate record of 
the shipment and dispensing of the IP (both device and drug) in an IP accountability log, 
a copy of which must be given to the Sponsor at the end of the study.  An accurate record 
of the date and amount of IP dispensed to each patient must be available for inspection at 
any time.  The assigned sponsor representative will review these documents along with 
all other study conduct documents at an appropriate interval of visit to the investigational 


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site once IP has been received by the investigational site.  Due to COVID-19 a physical 
inventory of IP (drug and device supplies) may not be possible.  If at all possible, an 
inventory of supplies should be conducted via video conferencing.  If video conferencing 
is not possible, study staff will inventory supplies and provide documentation to Aerogen 
Pharma. 
All IP supplies (with the exception of OSU stock 0.9% sodium chloride solution supplies) 
are to be used only for this protocol and not for any other purpose.  The Investigator (or 
designated pharmacist) must not destroy any IP product labels or any partly used or 
unused IP supply without Sponsor authorization.  At the conclusion of the study and as 
appropriate during the course of the study, the Investigator (or designated pharmacist) 
will return or properly dispose of all used IP. Unused investigational device and drug 
components will be returned to Aerogen Pharma at the conclusion of the study. 
11.2.7 
Publication of Results 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each Investigator and Aerogen Pharma, as appropriate. 
11.2.8 
Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the course 
of this study will be kept confidential by the Investigator, the Investigator’s staff, and 
IRB/IEC and will not be disclosed in whole or in part to others or used for any purpose 
other than reviewing or performing the study without the written consent of the Sponsor.  
No data collected as part of this study will be utilized in any written work, including 
publications, without the written consent of Sponsor.  These obligations of confidentiality 
and non-use shall in no way diminish such obligations as set forth in the Confidentiality 
Agreement between the Sponsor and the Investigator.  All persons assisting in the 
performance of this study must be bound by the obligations of confidentiality and non-
use set forth in the Confidentiality Agreement between the Investigator and Sponsor 
(provided by the Sponsor). 
11.2.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.   
The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the Investigator terminates or suspends a trial without prior agreement of the 
Sponsor, the Investigator should inform the Institution where applicable, and the 
Investigator/Institution should promptly inform the Sponsor and the IRB/IEC and should 
provide the Sponsor and the IRB/IEC a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 
11.2.10 Patient Insurance and Indemnity 
The Sponsor will provide the insurance in accordance with local guidelines and 
requirements as a minimum for the patients participating in this study. 


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 51 of 52 
12. 
REFERENCES 
Adhikari, N. K., R. P. Dellinger, S. Lundin, D. Payen, B. Vallet, H. Gerlach, K. J. Park, S. 
Mehta, A. S. Slutsky and J. O. Friedrich (2014). "Inhaled nitric oxide does not reduce 
mortality in patients with acute respiratory distress syndrome regardless of severity: 
systematic review and meta-analysis." Crit Care Med 42(2): 404-412. 
 
Afshari, A., A. Bastholm Bille and M. Allingstrup (2017). "Aerosolized prostacyclins for 
acute respiratory distress syndrome (ARDS)." Cochrane Database Syst Rev 7: CD007733. 
 
Ammar, M. A., S. R. Bauer, S. N. Bass, M. Sasidhar, R. Mullin and S. W. Lam (2015). 
"Noninferiority of Inhaled Epoprostenol to Inhaled Nitric Oxide for the Treatment of 
ARDS." Ann Pharmacother 49(10): 1105-1112. 
 
De Wet, C. J., D. G. Affleck, E. Jacobsohn, M. S. Avidan, H. Tymkew, L. L. Hill, P. B. 
Zanaboni, N. Moazami and J. R. Smith (2004). "Inhaled prostacyclin is safe, effective, 
and affordable in patients with pulmonary hypertension, right heart dysfunction, and 
refractory hypoxemia after cardiothoracic surgery." J Thorac Cardiovasc Surg 127(4): 
1058-1067. 
 
Dewachter, C., Laurence Dewachter , Marie Vercruyssen , Benoit Rondelet , Dean P. 
Schraufnagel , Serge Brimioulle , Francois Kerbaul , Robert Naeije (2012). 
"Inflammatory Processes In Load-Induced Right Ventricular Failure - Anti-Inflammatory 
Effects Of Epoprostenol." American Journal of Respiratory and Critical Care Medicine 
A3462(185). 
 
Dzierba, A. L., E. E. Abel, M. S. Buckley and I. Lat (2014). "A review of inhaled nitric 
oxide and aerosolized epoprostenol in acute lung injury or acute respiratory distress 
syndrome." Pharmacotherapy 34(3): 279-290. 
 
Fuller, B. M., N. M. Mohr, L. Skrupky, S. Fowler, M. H. Kollef and C. R. Carpenter 
(2015). "The use of inhaled prostaglandins in patients with ARDS: a systematic review 
and meta-analysis." Chest 147(6): 1510-1522. 


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 21 Jul 2020 
Confidential 
Page 52 of 52 
 
Giannis, D., I. A. Ziogas and P. Gianni (2020). "Coagulation disorders in coronavirus 
infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past." J 
Clin Virol 127: 104362. 
 
Haraldsson, A., N. Kieler-Jensen, H. Wadenvik and S. E. Ricksten (2000). "Inhaled 
prostacyclin and platelet function after cardiac surgery and cardiopulmonary bypass." 
Intensive Care Med 26(2): 188-194. 
 
Higenbottam, T., D. Wheeldon, F. Wells and J. Wallwork (1984). "Long-term treatment of 
primary 
pulmonary 
hypertension 
with 
continuous 
intravenous 
epoprostenol 
(prostacyclin)." Lancet 1(8385): 1046-1047. 
 
Kallet, R. H., G. Burns, H. Zhuo, K. Ho, J. S. Phillips, L. P. Pangilinan, V. Yip, A. Gomez 
and M. S. Lipnick (2017). "Severity of Hypoxemia and Other Factors That Influence the 
Response to Aerosolized Prostacyclin in ARDS." Respir Care 62(8): 1014-1022. 
 
Mitchell, J. A., F. Ali, L. Bailey, L. Moreno and L. S. Harrington (2008). "Role of nitric 
oxide and prostacyclin as vasoactive hormones released by the endothelium." Exp 
Physiol 93(1): 141-147. 
 
Nicolas, L. B., A. Krause, M. M. Gutierrez and J. Dingemanse (2012). "Integrated 
pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects." Br J Clin 
Pharmacol 74(6): 978-989. 
 
Rao, V., K. Ghadimi, W. Keeyapaj, C. A. Parsons and A. T. Cheung (2018). "Inhaled 
Nitric Oxide (iNO) and Inhaled Epoprostenol (iPGI2) Use in Cardiothoracic Surgical 
Patients: Is there Sufficient Evidence for Evidence-Based Recommendations?" J 
Cardiothorac Vasc Anesth 32(3): 1452-1457. 
 


 
 
 
PROTOCOL TITLE 
TITLE: DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING MECHANICAL VENTILATION  
PROTOCOL  NUMBER 
APC-VPCOV-CLN-001 
INVESTIGATIONAL 
PRODUCT 
VentaProst™ 
INDICATION 
Reduction of respiratory, cardiac or circulatory failure in patients with 
COVID-19 
PHASE 
Phase 2a 
SPONSOR 
Aerogen Pharma Limited 
1660 S Amphlett Boulevard, Suite 360 
San Mateo, CA 94402 
United States 
MEDICAL MONITOR 
Matthew Exline, MD 
AMENDMENT #2 
APPROVAL DATE 
03 November 2020 
GCP STATEMENT 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) and all applicable local Good 
Clinical Practices (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
CONFIDENTIALITY 
STATEMENT 
This document is confidential as it contains proprietary information 
of Aerogen Pharma.  Any viewing or disclosure of such information 
that is not authorized in writing by the Aerogen Pharma is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 


Aerogen Pharma 
Protocol Number APC-VPCOV-CLN-001 
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 2 of 52 
SPONSOR PROTOCOL APPROVAL PAGE 
PROTOCOL TITLE 
A DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING MECHANICAL VENTILATION  
PROTOCOL NUMBER 
APC-VPCOV-CLN-001 
AMENDMENT #1 
APPROVAL DATE 
03 November 2020 
________________________________________________________________________ 
Judy Doto, RN, BSN 
 
 
 
 
 
 
Date 
Head of Clinical Operations 
Aerogen Pharma 
________________________________________________________________________ 
Jim Fink PhD, RRT, FCCP 
 
 
 
 
 
Date 
Chief Scientific Officer  
Aerogen Pharma 
________________________________________________________________________ 
Plamena Entcheva-Dimitrov, PhD, RAC 
 
 
 
 
Date 
Head of Regulatory and Medical Affairs 
Aerogen Pharma 
________________________________________________________________________ 
Andy Clark PhD 
Date 
Vice President and General Manager 
Aerogen Pharma 
04Nov2020
04 NOV 2020
04 NOV 2020
06 Nov 2020


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 3 of 52 
 
INVESTIGATOR’S SIGNATURE PAGE 
PROTOCOL TITLE 
A DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING MECHANICAL VENTILATION  
PROTOCOL NUMBER  
APC-VPCOV-CLN-001 
AMENDMENT #1 
APPROVAL DATE 
03 November2020 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations 
of the protocol and in accordance with ICH-GCPs and all applicable local guidelines. 
 
________________________________________________________________________ 
Principal Investigator (printed/typed) 
 
 
 
 
 
 
 
 
 
 
________________________________________________________________________ 
Principal Investigator Signature 
 
 
 
 
 
Date 
 
 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 4 of 52 
1. 
CLINICAL PROTOCOL SYNOPSIS 
Sponsor 
Aerogen Pharma 
Protocol No. 
APC-VPCOV-CLN-001 
Title of Study 
Double-blind, placebo controlled study to assess the efficacy and safety of VentaProst 
(Inhaled epoprostenol delivered via dedicated delivery system) in subjects with COVID-19 
requiring mechanical ventilation.  
Study Centers 
One clinical site in the US 
Phase 
Phase 2a 
Objectives 
 
Primary Objective: 
The primary objective of this study is the reduction of respiratory, cardiac or circulatory 
failure in patients with confirmed COVID-19. 
Secondary Objectives: 
The secondary objective in this study is to evaluate the effects of VentaProst on improvement 
in oxygenation and improvement in clinical outcomes.  
 
The study will also evaluate the effects of VentaProst on inflammatory parameters in subjects 
with confirmed COVID-19. 
Study Design 
 
This is a double-blind, placebo controlled study of VentaProst (Active) as compared to 
placebo (Control).  Active is inhaled epoprostenol administered via the VentaProst delivery 
system in 10 COVID-19 positive patients. Control is inhaled 0.9% sodium chloride solution 
administered via the VentaProst delivery system in 10 COVID-19 positive patients.  
Throughout the remainder of the protocol both Active and Control will be referred to as 
“study drug”.  This study will evaluate the potential therapeutic benefit of VentaProst  in 
treating patients with COVID-19 who require mechanical ventilation and are at risk for the 
progression of respiratory and/ or cardiac/circulatory failure.  This study will assess the 
efficacy and safety of VentaProst at an initial dose of 13.6 ng/kg/min (A range from 3.4-30.6 
ng/kg/min may be administered as clinically required for a maximum of 10 days at the 
discretion of the Investigator.  Patients will be followed through Day 28 to assess clinical 
outcomes.   
Patients will be consented and randomized to either the Active or Control group within 48 
hours of being placed on a mechanical ventilator.  Patients will be administered study drug 
using the VentaProst delivery system which allows up and down titration of study drug to 
achieve hemodynamic and oxygenation stability.  The starting dose of study drug will be 
initiated at 13.6 ng/kg/min.  Based on hemodynamic and oxygenation parameters, the dose of 
study drug can be increased in 3.4 ng/kg/min increments up to a maximum of 30.6 ng/kg/min 
or down to a minimum of 3.4 ng/kg/min.  Study drug will be administered based on the pump 
rate calculated for active treatment in mL/hr.  The titration table below (Table 1) shows the 
typical up and down titration steps for study drug.    
 
 
 
 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 5 of 52 
Table 1: Overview of Titration and Weaning Guidelines 
 
Up titration Guideline*  
 
Downward Titration / 
Weaning Guideline** 
Start Dose: 13.6 ng/kg/min 
1st Step Up Dose (17.0) 
2nd Step Up Dose (20.4) 
3rd Step Up Dose (23.8) 
4th Step Up Dose (27.2) 
5th Step Up Dose (30.6) 
Start Dose: 13.6 ng/kg/min 
1st Step Down dose (10.2) 
2nd Step Down Dose (6.8) 
3rd Step Down dose (3.4) 
 
* The study drug will be administered based on the pump rate calculated for active treatment in 
mL/hr.**If the patient has been up-titrated weaning should occur from that level in 3.4 ng/kg/min 
decrements.  
Patients will be weaned from study drug slowly to avoid rebound vasoconstriction.    During 
weaning, doses will be decreased in steps of 3.4 ng/kg/min increments, with a minimum of 15 
minutes between changes. The weaning process should occur in isolation to other treatment 
changes (no changes in inotropes, vasopressors, or vasodilators) whenever possible. Patients 
will be observed closely before, during, and after dose changes. In the event patients 
demonstrate signs of hemodynamic instability  or a decrease in oxygenation indicated by 
pulse oximetry during downward titration, the dose will be returned to its previous level. 
Once patients have been stable for at least 15 minutes, repeat attempts at dose reduction may 
be undertaken.  The process will continue until patients are fully weaned.  Patients will be 
monitored for safety and efficacy throughout study drug administration. 
Number/Type 
of Patients 
Approximately 20 COVID-19 positive patients requiring mechanical ventilation will be 
enrolled in this study. 
Patients will be randomized to either VentaProst Active (aerosolized epoprostenol 
administered via the VentaProst delivery system) or VentaProst Control (aerosolized 0.9% 
sodium chloride solution administered via the VentaProst delivery system). 
 
Inclusion 
Criteria 
 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men Age ≥18 years old (no upper limit)  
2. Confirmed COVID-19 positive by RT-PCR test 
3. Patients who require invasive mechanical ventilation.  
4. Enrolled into study within 48 hours of being placed on mechanical ventilation  
5. Consent or professional consent obtained 
6. Duration of shortness of breath must be within the previous 14 days.   
7. Female subjects of childbearing potential must have a negative pre-treatment 
pregnancy test (serum or urine). 
8. Received or currently receiving dexamethasone for the treatment of COVID. 
9. Willing and able to comply with treatment schedule and follow-up. 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 6 of 52 
 
Exclusion 
Criteria 
 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. 
Patients on ECMO support. 
2. 
Patients receiving another inhalation research medication or inhaled nitric oxide.  
3. 
 Not expected to survive for 48 hours. 
4. 
Pregnant (positive pregnancy test in a pre-dose examination) or breastfeeding  
5. 
Open tracheostomy. 
6. 
Clinical contra-indication, as deemed by the attending physician. 
7. 
Allergy to Epoprostenol and its diluent 
8. 
Using inhaled vasodilators  at baseline.  
9. 
Patients who are hemodynamically unstable as determined by investigator  
10. Patients with  significant hemoptysis as determined by investigator 
Study 
Treatment(s) 
Patients will receive study drug via mechanical ventilator, starting at 13.6 ng/kg/min.  If 
determined by the treating physician, study drug can be up titrated in 3.4 ng/kg/min 
increments to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.  At the 
Investigator’s discretion, the patient will be weaned off the drug in 3.4 ng/kg/min increments. 
Study drug will be administered based on the pump rate calculated for active treatment in 
mL/hr.  Study drug  can be administered up to 10 days.   
Duration of 
Treatment 
The duration of study participation for each patient is as follows:  
• 
Screening: up to 14 days 
• 
Treatment: up to 10 days 
• 
Follow up: 28 days 
Criteria for 
Evaluation 
 
Primary Endpoint  
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• 
Requires VV ECMO   
• 
Inability to extubate patient within 10 days or reintubation within < 24 
hours 
• 
Change in S/F, oxygenation index and P/F ratio (≥15%) from baseline to 12 
hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• 
Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 
• 
Worsening hemodynamic parameters  
• 
Cardiac troponin > 20% from baseline   
• 
BNP ≥ 15% of baseline 
• 
Need for temporary mechanical circulatory support (IABP, Impella) 
• 
Requires VA ECMO 
Secondary Endpoints: 
1. Improvement in oxygenation defined as any one of the following: 
• 
Stabilization of PaO2/FIO2 >250 
• 
Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 7 of 52 
2. Improved clinical outcomes defined as one of more of the following:  
• 
Shorter time to extubation following the site’s extubation protocol 
• 
Free from reintubation 
• 
Reduction in ICU days 
• 
Reduction in the number of re-admissions to the ICU due to COVID-19 
within 28 days. 
• 
Reduction in hospital days Mortality (28 Days) defined as Cardiopulmonary 
mortality or mortality from all causes. 
 
3. Safety and tolerability: 
• 
Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory and oxygenation parameters, 
and laboratory tests. 
Exploratory endpoints will include (where available): 
1. 
Change in LDH 
2. 
Change in fibrinogen 
3. 
Change in WBC count including lymphocytes and neutrophil subsets 
4. 
Change in triglycerides 
5. 
Change in ferritin 
6. 
Change in CRP / ESR 
7. 
Change in IL-6 
8. 
Change in D-Dimer 
Changes in these parameters will be assessed for each patient from baseline to end of 
study as well as changes between the active and control groups. 
Ventilatory 
Parameters 
OSU SOC: 
Ventilator Type (GE) 
Parameters to monitor are:  
1. Ventilator Mode 
2. FiO2 
3. Inspiratory Time 
4. Mean Airway Pressure 
5. Peak Inspiratory Pressure 
6. Positive End Expiratory Pressure 
7. Respiratory Rate 
8. Tidal Volume 
Criteria for 
Stopping 
VentaProst 
Treatment 
Individual patients stopping criteria: At any time during study drug administration, patients 
may be removed from study treatment and placed on standard of care (SoC) therapy if they 
meet one or more of the following pre-defined criteria leading to a deterioration in their 
condition: 
• 
Severe hypotension as evidenced by a systolic BP < 90 mmHg  or MAP < 60 mmHG 
for >2 hours from the start of VentaProst 
• 
Need for VV ECMO 
• 
Need to increase existing vasopressor therapy by more than 25% 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 8 of 52 
• 
Worsening in oxygenation, ventilatory, or hemodynamic parameters that in the 
opinion of the investigator the patient should be removed from study treatment 
• 
Massive hemoptysis thought to be clinically significant and not related to 
endotracheal tube trauma 
• 
Pulmonary edema 
• 
If a clinically inadequate response to treatment is observed 
 
Study stopping criteria: If 3 patients are removed from the study for any of the above 
conditions, the study will stop further enrollment and an investigation will be conducted to 
determine the cause of the events.  An independent safety evaluation will also be conducted.  
If it is suspected that the investigational product has caused the events, the study will be 
terminated. 
Independent Safety Evaluation: Independent safety evaluation will be conducted by a 
licensed physician who is not involved in the VentaProst COVID-19 clinical study or the 
sponsoring organization.   
Statistical 
Methods 
All patients who are enrolled in the study and who receive at least one dose of study drug will 
be included in the intent-to-treat (ITT) analyses of pharmacodynamic and safety data.  All 
available data will be used and missing data will not be estimated or carried forward in any 
statistical summary or analyses. 
Descriptive summary statistics include the number of patients, mean, median, percent 
coefficient of variation (% CV) (if required), standard deviation, and minimum and maximum 
values (quantitative variables) or the number of patients and percentages by category 
(qualitative variables). Changes will be assessed as the difference between baseline 
measurements and the appropriate post-dose measurements unless otherwise specified.  Mean 
differences between active and historical control groups will be assessed and significance will 
be determined on the basis of a 95% CI.   
No formal estimate of the sample size has been made. This is an exploratory study and the 
number of patients was selected to enable an adequate clinical assessment of 
pharmacodynamic, safety, and tolerability parameters without presenting undue risk to a large 
number of patients. 
Efficacy 
Analysis 
Efficacy will be secondarily determined by summarizing success or failure to meet any of the 
primary or secondary endpoints as compared to Control treatment.   
Safety 
Analyses 
Safety data will be summarized for both treatment groups including frequencies and incidence 
rates.  Safety will be assessed through monitoring of adverse events (AEs), serious adverse 
events (SAEs), chest CTs or chest X-rays, laboratory tests, oxygenation and ventilatory 
parameters,  and vital signs.   


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 9 of 52 
Table 2: Schedule of Assessments and Procedures 
 
 
 
Screening 
VentaProst -
Day 1 
 
VentaProst Days 2-10 
 
End of 
Study 
 
 
 
Study Procedures 
Within 14 
Days 
Prior to 
Baseline 
 
 
 
Baseline
- 0 Hr 
 
 
 
12 
hrs 
 
 
 
D-2 
 
 
 
D-3 
 
 
 
D-4 
 
 
 
D-5 
 
 
 
D-6 
 
 
 
D-7 
 
 
 
D-8  
 
 
 
D-9 
 
 
 
D-10 
 
Day 28 
(+/- 
2 
days) 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication History/ 
Prior Meds 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Height1 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Chest CT Scan or 
CXR 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Clinical Laboratory 
Sampling2 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy Test 
(Serum or Urine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RT-PCR + for 
COVID-19 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Administer 
VentaProst 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oxygenation 
Measurements4 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Ventilator 
Parameters5 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
AE/SAE  
Monitoring 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
 
X 
 
X 
 
X 
Concomitant 
Medications 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Prone position 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1  Height only performed at screening 
2 Clinical Labs include: Safety labs: CBC (lymphocyte and neutrophil counts), Full Chemistry Panel (including LFTs) and PT/PTT drawn Screening, Day 1-
12 hours, Days 5 & 10.  Triglycerides, LDH, ferritin, fibrinogen, CRP, ESR, IL-6, D-Dimer, troponin, BNP drawn at Screening, Day 1-12 hours and D-10. 
3 Vital signs: Prior to initiating VentaProst, Days 1-10 twice daily (morning and evening) at the same time to reduce exposure to Health Care Professionals to 
include; temperature, pulse rate, blood pressure. 
4 Continuous SpO2 via pulse oximetry 
5 Ventilator Parameters will be collected twice daily along with vital signs and  include: Ventilator Type, Ventilator Mode, FiO2, Inspiratory Time, Mean 
Airway Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume and Respiratory Rate  
6Time Prone Position – 16 hours per day per OSU protocol 


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 03 Nov 2020 
Confidential 
Page 10 of 52 
TABLE OF CONTENTS 
INVESTIGATOR’S SIGNATURE PAGE ....................................................... 3 
1. 
CLINICAL PROTOCOL SYNOPSIS ............................................... 4 
TABLE OF CONTENTS ......................................................................... 10 
LIST OF ACRONYMS, ABBREVIATIONS AND 
DEFINITION OF TERMS ...................................................................... 13 
2. 
BACKGROUND AND RATIONALE ............................................. 16 
2.1 
Introduction ................................................................................. 16 
2.2 
VentaProst .................................................................................... 17 
2.2.1 Nonclinical Experience ..................................................... 17 
2.2.2 Clinical Experience ........................................................... 17 
2.2.3 Summary of Pharmacokinetic Results ............................ 17 
2.2.4 Summary of Clinical Results ........................................... 18 
2.2.5 Summary of Known and Potential Risks of 
Inhaled Epoprostenol Administration ........................................ 19 
2.2.6 Dosing Rationale for VentaProst...................................... 20 
3. 
STUDY OBJECTIVES.................................................................... 21 
3.1 
Primary Objective ........................................................................ 21 
3.2 
Secondary Objectives ................................................................... 21 
3.3 
Study Design ................................................................................ 21 
3.4 
Duration of Participation ............................................................ 21 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..................... 22 
4.1 
Inclusion Criteria ......................................................................... 22 
4.2 
Exclusion Criteria ........................................................................ 22 
4.3 
Re-Screening of Patients ............................................................. 23 
4.4 
Removal of Patients from Therapy or Assessment ..................... 23 
4.4.1 Criteria for Stopping VentaProst Treatment ................... 23 
5. 
STUDY TREATMENTS ................................................................. 24 
5.1 
Identity of Medication Component of the 
Investigational Product .......................................................................... 24 
5.1.1 Storage Condition ............................................................. 24 
5.2 
Treatments Administered ............................................................ 24 
5.3 
Study Medication Supply, Preparation, and 
Administration ....................................................................................... 24 
5.3.1 Study Medication Supply ................................................. 24 
5.3.2 Study Medication Preparation ......................................... 25 
5.3.3 Study Medication Administration.................................... 25 
5.3.4 Study Medication Weaning .............................................. 26 
5.4 
Identity of the Device Component of the 
Investigational Product .......................................................................... 26 


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5.4.1 Identity of Device .............................................................. 26 
5.4.2 Ventilator Settings ............................................................ 31 
5.4.3 Device Supply ................................................................... 31 
5.4.4 Device Replacement ......................................................... 31 
5.4.5 Device Malfunction or Failure ......................................... 31 
5.5 
Blinding ........................................................................................ 32 
5.6 
Prior and Concomitant Therapy ................................................. 32 
5.6.1 Prohibited Concomitant Therapy .................................... 32 
5.7 
Investigational Product (IP) Supplies and 
Accountability ......................................................................................... 32 
6. 
CRITERIA FOR EVALUATION ..................................................... 33 
6.1 
Primary Endpoint ........................................................................ 33 
6.2 
Secondary Endpoints ................................................................... 33 
6.3 
Exploratory endpoints will include (where available): .............. 34 
6.4 
Appropriateness of Measurements ............................................. 34 
7. 
SAFETY ASSESSMENTS .............................................................. 34 
7.1 
General Safety Procedures .......................................................... 35 
7.1.1 Vital Signs and Weight Measurements ........................... 35 
7.1.2 Physical Examination ...................................................... 35 
7.1.3 Laboratory Measurements ............................................... 35 
7.1.4 Chest Assessments ........................................................... 35 
7.1.5 Time Prone Protocol ......................................................... 35 
7.2 
Adverse Events ............................................................................ 35 
7.2.1 Definitions......................................................................... 35 
7.2.2 Adverse Events of Special Interest (AESI) ...................... 36 
7.2.3 Grading of Adverse Events ............................................... 36 
7.2.4 Relationship to Study Medication/Study 
Device/Procedure ......................................................................... 36 
7.2.5 AE Outcomes .................................................................... 36 
7.2.6 Laboratory Test and other Test Abnormalities 
as Adverse Events ........................................................................ 37 
7.2.7 Serious Adverse Events .................................................... 37 
7.2.8 Reporting for SAEs (24 Hours) ........................................ 38 
7.3 
Reporting of Pregnancy ............................................................... 39 
8. 
PHARMACOKINETIC ASSESSMENTS ...................................... 39 
9. 
SCHEDULE OF ASSESSMENTS AND 
PROCEDURES ....................................................................................... 39 
9.1 
Study Evaluation Timepoints ..................................................... 39 
9.1.1 Screening (within 14 days prior to Baseline 
Day 1) 39 
9.1.2 Days 1-10 Treatment ........................................................ 40 
9.1.3 Day 28/End of Study (EOS) .............................................. 42 


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9.2 
Data Collection ............................................................................ 42 
9.3 
Clinical Data Management ......................................................... 42 
9.4 
Database Quality Assurance ....................................................... 42 
10. 
STATISTICAL CONSIDERATIONS .................................... 42 
10.1 
Statistical Methods ...................................................................... 42 
10.2 
Determination of Sample Size ..................................................... 42 
10.3 
Analyses Sets ............................................................................... 42 
10.4 
Randomization ............................................................................. 43 
10.5 
Demographic and Other Baseline Characteristics ..................... 43 
10.6 
Criteria for Evaluation ................................................................ 43 
10.6.1 Primary Efficacy Endpoint ............................................. 43 
10.6.2 Secondary Efficacy Endpoints ........................................ 44 
1. 
Improvement in oxygenation defined as any one of 
the following: .......................................................................................... 44 
10.6.3 Key Exploratory Endpoints include: .............................. 44 
10.7 
Extent of Exposure ...................................................................... 44 
10.8 
Safety Analyses ............................................................................ 45 
10.8.1 Adverse Events ............................................................... 45 
10.8.2 Laboratory Values........................................................... 45 
10.8.3 Vital Signs ....................................................................... 46 
10.9 
The Procedure for Revising the Statistical Analysis 
Plan 46 
11. ADMINISTRATIVE PROCEDURES AND 
INSTRUCTIONS .................................................................................... 46 
11.1 
Ethics ............................................................................................ 46 
11.1.1 Institutional Review Boards/Independent 
Ethics Committees ....................................................................... 46 
11.1.2 Ethical Conduct of the Study ......................................... 46 
11.1.3 Patient Information and Informed Consent .................. 47 
11.2 
Administrative Procedures .......................................................... 47 
11.2.1 Changes to the Protocol .................................................. 47 
11.2.2 Adherence to the Protocol ............................................... 48 
11.2.3 Monitoring Procedures ................................................... 48 
11.2.4 Recording of Data ........................................................... 49 
11.2.5 Data Storage and Retention of Records ......................... 49 
11.2.6 Handling of Investigational Product .............................. 49 
11.2.7 Publication of Results ..................................................... 50 
11.2.8 Disclosure and Confidentiality ....................................... 50 
11.2.9 Discontinuation of Study ................................................ 50 
11.2.10 Patient Insurance and Indemnity ................................ 50 
12. 
REFERENCES ...................................................................... 51 
 


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List of Figures and Tables 
Table 1: 
Overview of Titration and Weaning Guidelines 
4 
Table 2: 
Schedule of Assessments and Procedures 
9 
Table 3: 
Administration Titration Guidelines 
26 
Table 4:  
Example of Up Titration for male with Ideal Body Weight of 70 kg  
26 
Figure 1: 
Drug Delivery System 
28 
Figure 2: 
Aerogen Pharma Controllers 
29 
Figure 3: 
VentaProst Device Placement in the Gas Pathway 
30 
 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
Active  
Inhaled epoprostenol administered via the VentaProst delivery system 
AE 
Adverse |Event 
ALI 
Acute Lung Injury 
ALT (SGPT) 
Alanine Aminotransferase (serum glutamic pyruvic transaminase) 
AP 
Alkaline Phosphatase 
ARDS 
Acute Respiratory Distress Syndrome 
AST (SGOT) 
Aspartate Aminotransferase (serum glutamic oxaloacetic transaminase)   
bpm 
Beats Per Minute 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
cAMP 
Cyclic Adenosine Monophosphate 
CI 
Cardiac Index (L/min/m2) 
CO 
Cardiac Output (L/min) 
Control  
Inhaled 0.9% sodium chloride solution, USP administered via the VentaProst delivery 
system 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Concentration 
CPB 
Cardiopulmonary Bypass 
CRA 
Clinical Research Associate 
CRF 
Case Report Form   
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CNTS 
Continuous Nebulization Tube Set 
CVP 
Central Venous Pressure (mm Hg) 
DCF 
Data Collection Form 


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Abbreviation 
Term 
DNR 
Do Not Resuscitate  
dPAP 
Diastolic Pulmonary Arterial  Pressure (mm Hg) 
dSAP 
Diastolic Systemic Arterial Pressure (mm Hg) 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
ESR 
Erythrocyte Sedimentation Rate 
ETT 
Endotracheal Tube 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCP 
Good Clinical Practice 
HME 
Heat-Moisture Exchanger 
HR 
Heart Rate (bpm) 
IABP 
Intra-aortic Balloon Pump 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ICU 
Intensive Care Unit 
IL-6 
Interleukin 6 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LAR 
Legally Authorized Representative  
LDR 
Lung Dosing Rate 
LFT 
Liver Function Test 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mPAP 
Mean Pulmonary Arterial Pressure (mm Hg) 
mSAP 
Mean Systemic Arterial Pressure (mm Hg) 
NC 
Nasal Cannula 
ng 
Nanogram 
OR 
Operating Room 
OTC 
Over-the-Counter 
PAH 
Pulmonary Arterial Hypertension 
PaO2 
Partial Pressure of Oxygen in Arterial Blood 
PAP 
Pulmonary Arterial Pressure (mm Hg) 
PCWP 
Pulmonary Capillary Wedge Pressure 
PD 
Pharmacodynamic 
PEEP 
Positive End Expiratory Pressure 
PH 
Pulmonary Hypertension 
PIP 
Peak Inspiratory Pressure 
PK 
Pharmacokinetic 
 
PP 
Per Protocol 


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Abbreviation 
Term 
PGI2 
Prostaglandin I2 (epoprostenol) 
PVR 
Pulmonary Vascular Resistance (dyn/sec/cm5) 
RBC 
Red Blood Cell (count) 
RH 
Right Heart 
RHF 
Right Heart Failure 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
RVSWI 
Right Ventricular Stroke Work Index 
SAE 
Serious Adverse Event 
SaO2 
Arterial Oxygen Saturation 
sPAP 
Systolic Pulmonary Arterial Pressure (mm Hg) 
sSAP 
Systolic Systemic Arterial Pressure (mm Hg) 
SE 
Standard Error 
SOP 
Standard Operating Procedures 
SOC 
Standard of Care 
SpO2 
Oxygen Saturation by Pulse Oximetry 
Study Drug 
Active or Control Treatment 
SVR 
Systemic Vascular Resistance 
TEAE 
Treatment-Emergent Adverse Event 
TEE 
Transesophageal Echocardiogram 
TPG 
Transpulmonary Gradient 
t1/2 
Half-Life 
TLD 
Total Lung Dose 
ULN 
Upper Limit of Normal 
VA-ECMO 
Veno-arterial Extracorporeal Membrane Oxygenation 
VentaProst 
VentaProst™ – Drug/device combination product consisting of aerosolized epoprostenol 
delivered via dedicated drug delivery system 
VentaProst 
Nebulizer 
The nebulizer assembly that is part of the VentaProst delivery system  
VTE 
Venous Thromboemobolism 
VV ECMO 
Venovenous Extracorporeal Membrane Oxygenation 
WBC 
White Blood Cell (count) 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 


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BACKGROUND AND RATIONALE 
2.1 
Introduction 
COVID-19 is a rapidly emerging pathogen that has recently been declared a pandemic by 
the World Health Organization (WHO). No targeted therapeutic treatments for 
coronavirus (COVID-19) have been identified.  Symptoms range from mild upper 
respiratory tract infection to profound hypoxia, severe pneumonia, ARDS and death. 
Progression of end stage disease is unpredictable with high fatality rates in mechanically 
ventilated patients as a result of multi-organ failure.   Among patients who require 
hospitalization, mortality may be 5% to 15%, and for those who become critically ill, 
reported mortality ranges from 22% to 62%.     
 
Prostacyclin therapy—available in oral, inhaled, and intravenous forms—is an analogue 
which mimics endogenous prostacyclin (PGI2). Prostacyclin binds to its receptor (a G-
protein coupled receptor) found on the surface of vascular smooth muscle and platelets, 
activates cyclic adenosine monophosphate (cAMP), and results in inhibition of platelet 
aggregation, vascular smooth muscle relaxation and vasodilation of the pulmonary 
arteries (Mitchell, Ali et al. 2008). Prostacyclins are most commonly used in the 
treatment of PAH due to their potent vasodilatory effects. In addition, prostacyclin 
analogs also inhibit platelet aggregation and may reduce prothrombotic effects of 
endothelin. 
The rationale for use of vasodilators in COVID-19 patients rests on their rapid local 
effect on the pulmonary vasculature, which has shown to lead to increased oxygenation in 
other diseases, such as PAH (Higenbottam, Wheeldon et al. 1984) and post-surgical PH 
(De Wet, Affleck et al. 2004).  Epoprostenol has the additional advantage over inhaled 
nitric oxide in that it may be directly administered through a standard ventilator (closed-
circuit). 
 
The rationale for aerosolized prostacyclin use in COVID-19 patients experiencing 
hypoxia leading to cardiac failure is two-fold:  
 
(1) inhaled prostacyclin therapy has been used in the treatment of ARDS and has been 
shown to improve oxygenation and ventilation-perfusion mismatch (see Section 9).  
Prostacyclins, such as epoprostenol, promote pulmonary vasodilation via a cyclic 
adenosine monophosphate-mediated decrease in intracellular calcium (Figure 4).  While 
it has not been associated with improved outcomes, such as mortality, and it’s use in 
ARDS is off-label, it may be used in severe life-threatening hypoxemia refractory to 
conventional ARDS management, such as has been seen in COVID-19. 
 
(2) The second potential benefit of prostacyclin therapy in the management of COVID-19 
is to mitigate direct SARS-CoV-2-associated coagulopathy.  Prostacyclins have anti-
inflammatory (Dewachter 2012) and antiplatelet aggregation properties1.  Microvascular 
thrombosis and large vessel venous thromboembolism have been described anecdotally 
and in case reports of corona virus infected patients and abnormal coagulation parameters 
are associated with increased mortality (Giannis, Ziogas et al. 2020). Inhibition of platelet 
aggregation occurs with prostacyclin therapy and may mitigate thrombosis in situ seen in 
PAH itself, and potentially in patients with COVID-19 associated respiratory illness. 


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Literature data with both inhaled NO and inhaled epoprostenol in ARDS, acute lung 
injury and severe hypoxemia show improvement of oxygenation (Afshari, Bastholm Bille 
et al. 2017), (Dzierba, Abel et al. 2014), decrease of pulmonary arterial pressure (Fuller, 
Mohr et al. 2015) and in some cases improvement in clinical outcomes such as shorter 
time on mechanical ventilation and shorter time in ICU (Ammar, Bauer et al. 2015).  
However, due to the heterogeneity of the population and the severity of the disease, not 
all studies agree on the effectiveness of inhaled epoprostenol, particularly to reduce 
mortality in ARDS (Adhikari, Dellinger et al. 2014), (Afshari, Bastholm Bille et al. 2017).  
Meta-analyses have concluded that the quality of the currently published data for the use 
of inhaled vasodilators in ARDS, ALI and refractory hypoxemia is insufficient to 
definitely conclude for or against their use (Afshari, Bastholm Bille et al. 2017), (Fuller, 
Mohr et al. 2015). 
 
This study will evaluate the potential therapeutic benefit of VentaProst in treating patients 
with COVID-19 at risk for the progression of respiratory and/or cardiac/circulatory 
failure. This double-blind, placebo controlled study will assess the efficacy and safety of 
VentaProst at a range of 3.4-30.6 ng/kg/min for a maximum of 10 days at the discretion 
of the Investigator.  The patient will be followed through Day 28 to assess their clinical 
status.   
 
2.2 
VentaProst 
2.2.1 
Nonclinical Experience 
Refer to the current Investigator’s Brochure (IB) for details of nonclinical pharmacology 
and toxicology studies with VentaProst. 
2.2.2 
Clinical Experience 
There have been no clinical trials to date with VentaProst in COVID-19 patients (see 
Section 2.2.4 below for summary of clinical data with VentaProst in cardiac surgery 
patients). 
2.2.3 
Summary of Pharmacokinetic Results  
Epoprostenol undergoes rapid chemical hydrolysis under physiological conditions to 
yield 6-keto-PGF1α and is also subject to enzymatic degradation.  As such, it is only 
possible to evaluate the PK using radioactively labeled drug. Studies using 3H-
epoprostenol sodium indicate half-life is generally less than 3 minutes with an I.V. bolus, 
and with I.V. infusion, plasma steady-state concentrations were achieved within 15 
minutes of initiation of the infusions, and steady-state concentrations increased linearly 
with increasing infusion rate.  Tissue distribution studies indicate the highest levels of 
radioactivity were observed in the kidney, liver, and small intestine and the lowest levels 
were observed in brain and adipose tissue.  Epoprostenol-derived material is rapidly 
excreted into urine and feces after dosing with epoprostenol sodium. 
 
There is only one study in the literature that reports the PK of inhaled epoprostenol.  The 
study by Haraldsson (Haraldsson, Kieler-Jensen et al. 2000) was designed to evaluate the 
effects of inhaled epoprostenol on platelet aggregation after surgery.  No differences were 
seen in 6-keto-PGF1α levels with two dose levels of epoprostenol compared to placebo 


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over six hours of administration in the ICU.  Epoprostenol deposition in the lungs was not 
quantified, but the aerosol was administered only during the inspiratory phase of 
mechanical ventilation.  The blood levels of 6-keto-PGF1α by enzyme immunoassay in 
this study were reported to be several times higher than other levels reported in the 
literature.   
 
In 2017, Stanford University’s Department of Cardiac Surgery conducted an 
observational study (IND129777, Report# APC-VP-CLN-004) investigating the levels of 
6-keto-PGF1α in cardiac surgery patient requiring CPB.  Sixteen patients were enrolled; 
eight did not received inhaled epoprostenol, eight received aerosolized epoprostenol at a 
nominal starting dose of 50 ng/kg/min.   
 
Plasma levels determined in aerosol epoprostenol naïve patients indicates that cardiac 
surgery procedures, including CPB, result in elevated endogenous levels of both 6-keto-
PGF1α and thromboxane B2.  Delivery of aerosol epoprostenol in patients resulted in a 
further elevation of 6-keto-PGF1α levels, but not thromboxane B2. 
 
While it proved difficult to delineate the endogenous and exogenous contributions of 
aerosol delivery during surgery, 6-keto-PGF1α levels declined rapidly in aerosol naïve 
patients during ICU stay.  Examination of the 6-keto-PGF1α levels during weaning, after 
this endogenous decline, indicate that the overall aerosol delivery efficiency, nebulized to 
absorbed (deposited lung dose), is less than 8%.  That is, out of a nominal dosing rate of 
50 ng/kg/min only 4 ng/kg/min actually reaches the lungs and gets absorbed. 
Comparison to recently published data (Nicolas, Krause et al. 2012) investigating 6-keto-
PGF1α levels during steady state I.V. administration of Flolan indicates that the systemic 
exposure from aerosol delivery in cardiac surgery is similar to, or lower, than that 
experienced from intravenous administration of the approved Flolan product. 
 
The findings of this observational PK study with inhaled epoprostenol are sufficient to 
make a correlation to historical systemic exposure levels with intravenous administered 
Flolan (the reference listed drug) and show levels of exposure similar to, or lower than, 
the currently approved intravenous product.   
  
2.2.4 
Summary of Clinical Results 
The safety and tolerability of VentaProst were evaluated in a Phase 2a Clinical Study in 
cardiac surgery patients “A Two-Part Pharmacodynamic Study to Compare VentaProstTM 
(Epoprostenol Solution for Inhalation via Custom Drug Delivery System) Dosing to 
Conventionally Administered Aerosolized Epoprostenol Dosing in Cardiac Surgery 
Patients” (NCT03122730).  
 
Overall, 15 patients were exposed to doses of VP from 3.4 to 20.4 ng/kg/min in this study.  
Administration of VP in this dose range was well-tolerated.  Overall, there were 2 
patients (28.6%) in Part I and 1 patient (12.5%) in Part II who experienced a total of 7 
TEAEs.  All 7 TEAEs were assessed by the investigator as related to the surgical 
procedure and as unrelated to the study drug and unrelated to the device.  No deaths 
occurred during the study.  A total of 3 patients had 1 SAE each.  All 3 SAEs were 
considered to be unrelated to the study drug or the study device.   


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Seven patients were evaluated in Part I to determine the effective dose equivalence 
between VP delivered at 17 ng/kg/min and off-label aerosolized Veletri administered at 
50 ng/kg/min during mechanical ventilation.  In all patients, VP 17 ng/kg/min was found 
to be equivalent either by calculation of effect compared with aerosolized Veletri 50 
ng/kg/min or the investigators’ judgement.  In most patients, no differences were 
observed in oxygen saturation ranges between VP and aerosolized Veletri treatments at 
the same FiO2 while on the ventilator. The investigator determined that oxygenation, 
assessed by oxygen saturation measurements, did not change disproportionately with 
ventilator operating parameters on VP compared with aerosolized Veletri. 
 
Eight patients were evaluated in Part II of the study to identify the optimal dose of VP.  In 
the investigator’s judgement, the optimal VP dose was determined to be 6.8 ng/kg/min in 
2 patients, 10.2 ng/kg/min in 3 patients, and 13.6 ng/kg/min in 3 patients, which is the 
minimal dose that reliably produced a maximum hemodynamic response in all patients. 
   
There have been no clinical trials to date with VentaProst in COVID-19 patients. 
See IB for additional clinical information regarding inhaled epoprostenol. 
2.2.5 
Summary of Known and Potential Risks of Inhaled Epoprostenol 
Administration 
Safety of inhaled epoprostenol in cardiothoracic surgery patients is remarkable.  In the 
reported literature to date, there were no reports of serious or life-threatening drug-related 
safety events.  Due to its mechanism of action, inhaled epoprostenol may theoretically 
cause increased bleeding (anti-platelet mechanism) or systemic vasodilation consequent 
to spill over into the central circulatory system, but no such events have been reported.  
Some accounts of the use of inhaled prostacyclin in the chronic setting (e.g. iloprost for 
PAH) report transient events as listed on the approved product labeling.  These include 
cough, headache, flushing, and an influenza-like syndrome.  However, these types of 
events are unlikely to be reported due to sedation in the ICU setting. 
VentaProst may result in hypotension, which will be monitored via frequent   assessments 
of oxygenation, ventilatory and hemodynamic parameters and vital signs. Pulmonary 
edema and pulmonary bleeding are potential risks due to the drug’s mode of action (refer 
to Section 7.2.2).  Worsening oxygenation is a theoretic concern through worsened 
ventilation/ perfusion matching. This will be monitored through continuous pulse 
oximetry throughout the administration of the inhaled epoprostenol.  
 
Risks to subjects in this study are related to common procedures performed (e.g., 
venipuncture) and the documented adverse events (AEs) listed in the current 
Investigator’s Brochure. These risks are communicated to the subjects in the consent 
forms. There may be additional risks that are currently unknown.  
 
The benefits of the study may include targeted lung vasodilation and improved 
oxygenation, potential anti-platelet effects on the lung vasculature, reduction in disease 
progression, avoidance of greater oxygen needs and early weaning off mechanical 
ventilation. If the drug does have such properties, then this may aid recovery, improve 


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outcomes and enable an earlier discharge from the hospital.  
There is no funding awarded to the patients participating in this study. 
2.2.6 
Dosing Rationale for VentaProst 
Literature on the current use of aerosolized epoprostenol in cardiac surgery and in ARDS 
shows a wide range and technically variable dosing for lowering PVR (Rao, Ghadimi et 
al. 2018), (Kallet, Burns et al. 2017), (Fuller, Mohr et al. 2015).  Most of the experience 
is with continuous nebulization by commercially available nebulizers in various positions 
in mechanical ventilator circuits at doses of 50 ng/kg/min.  Unlike the commercially 
available nebulizer systems, the VentaProst delivery platform aerosolizes epoprostenol 
only during the inspiratory cycle of the ventilator and administers respirable sized aerosol 
droplets (3-5 µm) in close proximity to the ETT of mechanically ventilated patients.  
 
The assumed effect of the current continuous dosing regimen of 50 ng/kg/min is that the 
hemodynamic response is maximized and that no further improvements would be seen by 
increasing the dose.  The initial in vitro estimate of the equivalent VentaProst (VP) dose 
to a 50 ng/kg/min conventional dose of continuously aerosolized Veletri was 17 
ng/kg/min, which was the starting dose in Part I of the APC-VP-CLN-001 Phase 2a study 
conducted by Aerogen Pharma.  During Part I of the study, it was determined that this 
dose is equivalent to 50 ng/kg/min epoprostenol delivered off-label via a generic 
nebulizer and continuous delivery.  In Part II of the APC-VP-CLN-001 Phase 2a study, 
the VP dose escalation started from an initial dose of 3.4 ng/kg/min (20% of the 
equivalent dose).  The dose was then increased in 3.4 ng/kg/min increments.  Part II of 
the study was designed to demonstrate that the dose-response plateau could be achieved 
using lower VP doses than the initial estimated equivalent dose in Part I.  Doses up to 
30.6 ng/kg/min were approved for use in the study. In Part I of the study one patient, per 
the investigator discretion, received a 20.4 ng/kg/min dose.  In Part II of the study it was 
determined that the optimal VP dose of 6.8 ng/kg/min in 2 patients, 10.2 ng/kg/min in 3 
patients, and 13.6 ng/kg/min in 3 patients provided stable hemodynamic response.  Based 
on these data,  the recommended starting dose of VP, will be 13.6 ng/kg/min, as this dose 
is anticipated to produce the maximum hemodynamic response. 
The proposed nominal dosing regimen for this COVID-19 trial is for up to 10 days of 
breath-synchronized aerosol delivery with a starting dose of study drug 13.6 ng/kg/min. 
Based on hemodynamic and oxygenation parameters, the dose can be titrated in 3.4 
ng/kg/min steps up to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 
ng/kg/min while patients are on mechanical ventilation.  Of this nominal dosing rate 
approximately 30% will reach and deposit in the lung.  Thus, the maximum Lung Dosing 
Rate (LDR) is ~10 ng/kg/min and the maximum Total Lung Dose (TLD) is ~ 144 µg/kg 
(Refer to VP IB Edition 6 dated 17-Jun-2020).  
The inhalation toxicology program for VentaProst, originally designed for the cardiac 
surgery indication, covered a maximum LDR of 320 ng/kg/min and 60 ng/kg/min and a 
maximum TLD of 1091.4 µg/kg and 172.8 µg/kg in rats and dogs respectively.  The LDR 
and TLD margins over the proposed maximum clinical exposure are thus 32 and 6, and 
7.6 and 1.2, in rats and dogs respectively.   


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3. 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is the reduction of respiratory, cardiac or circulatory 
failure in patients with confirmed COVID-19. 
3.2 
Secondary Objectives 
The secondary objective in this study is to evaluate the effects of VentaProst on 
improvement in oxygenation, improvement in clinical outcomes and safety and 
tolerability.  
The study will also evaluate the effects of VentaProst on inflammatory parameters in 
subjects with confirmed COVID-19.  
3.3 
Study Design 
This is a double-blind, placebo controlled study of VentaProst (Active) as compared to 
placebo (Control).  Active is inhaled epoprostenol administered via the VentaProst 
delivery system in 10 COVID-19 positive patients. Control is inhaled 0.9% sodium 
chloride solution administered via the VentaProst delivery system in 10 COVID-19 
positive patients.  Throughout the remainder of the protocol both Active and Control will 
be referred to as “study drug”.  This study will evaluate the potential therapeutic benefit 
of VentaProst  in treating patients with COVID-19 who require mechanical ventilation 
and are at risk for the progression of respiratory and/ or cardiac/circulatory failure.  This 
study will assess the efficacy and safety of VentaProst at an initial dose of 13.6 ng/kg/min 
(A range from 3.4-30.6 ng/kg/min may be administered as clinically required for a 
maximum of 10 days at the discretion of the Investigator.  Patients will be followed 
through Day 28 to assess clinical outcomes.   
Patients will be consented and randomized to either the Active or Control group within 48 
hours of being placed on mechanical ventilation.  Patients will be administered study 
drug using the VentaProst delivery system which allows up and down titration of study 
drug to achieve hemodynamic and oxygenation stability.  The starting dose of study drug 
will be initiated at 13.6 ng/kg/min.  Based on hemodynamic and oxygenation parameters, 
the dose of study drug can be increased in 3.4 ng/kg/min increments up to a maximum of 
30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.     
All study staff with the exception of the unblinded pharmacist and Sponsor CRA will be 
blinded to which treatment regimen a patient has been assigned.  Titration and weaning 
will be performed the same for all patients.  Study drug will be administered based on the 
pump rate calculated for active treatment in mL/hr. Titration guidelines are provided in 
Section 5.3.3 and Table 3. 
3.4 
Duration of Participation 
Patients who meet entry criteria will be entered into the study and the duration of study 
participation for each patient is listed below. The duration of study participation for each 
patient is as follows:  
• Screening: up to 14 days 
• Treatment: up to 10 days 
• Follow up: 28 days 


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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Approximately 20 COVID-19 positive patients requiring mechanical ventilation will be 
enrolled in this study.  Ten study participants will be randomized to either Active (inhaled 
epoprostenol administered via the VentaProst delivery system) treatment or Control 
(inhaled 0.9% sodium chloride solution administered by the VentaProst delivery system 
at calculated rates (mL/hr) used for the aerosolized epoprostenol). Study drug will 
indicate both Active and Control treatments. 
Patients who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to enroll into the study.   
4.1 
Inclusion Criteria 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men Age ≥18 years old (no upper limit)  
2. Confirmed COVID-19 positive by RT-PCR test 
3. Patients who require invasive mechanical ventilation.  
4. Enrolled into study within 48 hours of being placed on mechanical ventilation  
5. Consent or professional consent obtained 
6. Duration of shortness of breath must be within the previous 14 days.   
7. Female subjects of childbearing potential must have a negative pre-treatment 
pregnancy test (serum or urine).  
8. Received or currently receiving dexamethasone therapy for COVID-19 
9. Willing and able to comply with treatment schedule and follow-up. 
4.2 
Exclusion Criteria 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. Patients on ECMO support. 
2. Patients receiving another inhalation research medication or inhaled nitric oxide.  
3. Not expected to survive for 48 hours. 
4. Pregnant (positive pregnancy test in a pre-dose examination) or breastfeeding  
5. Open tracheostomy. 
6. Clinical contra-indication, as deemed by the attending physician. 
7. Allergy to Epoprostenol and its diluent 
8. Using inhaled vasodilators at baseline.  
9. Patients who are hemodynamically unstable as determined by investigator  
10. Patients with  significant hemoptysis as determined by investigator 


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4.3 
Re-Screening of Patients 
Patients may not be enrolled more than once.   
4.4 
Removal of Patients from Therapy or Assessment 
Aerogen Pharma or the Investigator may discontinue patients from the study at any time 
for safety or administrative reasons.   
The End of Treatment Study procedures (Day 10) are to be completed for all patients 
who discontinue from the study (except Screen Failure patients).  
The Investigator will promptly explain to the patient or their LAR that the study will be 
discontinued for the patient and provide appropriate medical treatment and other 
necessary measures for the patient.   
Patients who discontinue early from the study will be discontinued for one of these 
primary reasons:  Adverse events, patient death, lost to follow-up, patient withdrew 
consent, protocol violation, lack of efficacy, investigator decision, study terminated by 
sponsor, screen failure, or other.  Study disposition information will be collected on the 
Patient Disposition DCF. 
4.4.1 
Criteria for Stopping VentaProst Treatment 
Individual patients stopping criteria: At any time during study drug administration , 
patients may be removed from study treatment and placed on standard of care (SoC) 
therapy if they meet one or more of the following pre-defined criteria leading to a 
deterioration in their condition: 
 
• Severe hypotension as evidenced by a systolic BP < 90 mmHg  or MAP < 60 
mmHG for >2 hours from the start of VentaProst 
• Need for VV ECMO 
• Need to increase existing vasopressor therapy by more than 25% 
• Worsening oxygenation, ventilatory, or hemodynamic parameters that in the 
opinion of the investigator the patient should be removed from study treatment 
• Massive hemoptysis thought to be clinically significant and not due to 
endotracheal tube trauma 
• Pulmonary Edema 
• If a clinically inadequate response is observed 
 
Study stopping criteria: If 3 patients are removed from the study for any of the above 
conditions, the study will stop further enrollment and investigation will be conducted to 
determine the cause of the events.  An independent safety evaluation will also be 
conducted.  If it is suspected that the investigational product has caused the events, the 
study will be terminated. 
Independent Safety Evaluation: Independent safety evaluation will be conducted by a 
licensed physician who is not involved in the VentaProst COVID-19 clinical study or the 
sponsoring organization.   


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5. 
STUDY TREATMENTS 
5.1 
Identity of Medication Component of the Investigational Product 
The study medication  VentaProst, Flolan (epoprostenol sodium), is manufactured by 
GlaxoSmithKline and has been analyzed and released according to their specifications.   
The labelling of Flolan and placebo for this clinical trial will follow the protocols and 
procedures set forth by OSU’s Investigational Drug Services (IDS).   The Control for this 
study is 0.9% sodium chloride solution, USP from the OSU IDS stock and will be labeled 
in a blinded manner per the IDS protocols for maintenance of study blind. 
Drug Substance Name 
Epoprostenol Sodium 
Chemical Name 
5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-
oic acid. 
Molecular Formula 
C20H31NaO5 
Structural Formula 
 
Molecular Weight 
374.45 
 
5.1.1 
Storage Condition 
Both the vials of study medication and sterile diluent buffer should be stored between 20o 
to 25oC (68o to 77oF) with excursions permitted to 15° to 30°C (59° to 86°F) and kept in 
the supplied carton to protect the product from light.  Study medication will be stored in a 
secure, controlled-access location at the study sites. 
The 0.9% sodium chloride solution will be stored according the the product labelling. 
5.2 
Treatments Administered 
Patients will receive study drug via mechanical ventilator, starting at 13.6 ng/kg/min.  If 
determined by the treating physician, study drug can be up titrated in 3.4 ng/kg/min 
increments to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.  At 
the Investigator’s discretion, the patient will be weaned off the drug in 3.4 ng/kg/min 
increments. Study drug will be administered based on the pump rate calculated for the 
active treatment but delivered in mL/hr.  Study drug  can be administered up to 10 days.   
5.3 
Study Medication Supply, Preparation, and Administration 
5.3.1 
Study Medication Supply 
The medicinal component of VentaProst, Flolan, (epoprostenol sodium), is already 
approved for I.V. delivery.  The dosage form is a vial of 1.5 mg epoprostenol as a 


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lyophilizate and the required pH 12 Sterile Flolan diluent per the currently approved 
packet insert (NDA20-444/ Supplement 24 1).  Flolan and its diluent (pH 12 Sterile 
Diluent) are not re-formulated by Aerogen Pharma.  Flolan is used with the same diluent 
system and reconstituted per the approved packet insert.  
  
Flolan and diluent container closure (glass vial and stopper/crimp-pH 12 Sterile Diluent 
for Flolan comes in a plastic bottle for mixing) and secondary packaging (cardboard box) 
are not being altered, including the information on the vial and box label and the 
information in the approved Flolan packet insert.  This preserves the approved drug 
labeling information per NDA 20-444.  
 
Placebo will be a corresponding volume of  0.9% sodium chloride solution from the OSU 
IDS stock. 
5.3.2 
Study Medication Preparation 
Refer to the VentaProst-COVID Pharmacy Manual for preparation of study drug solution.. 
Prior to use, drug solutions  must be protected from light and refrigerated at 2° to 8°C 
(36° to 46°F) if not used immediately.  Do not freeze drug solutions and discard any  
drug solution that has been frozen. Discard any drug solutions if refrigerated for more 
than 8 days.  Control, (0.9% sodium chloride solution) will be placed in identical syringes 
and masked according OSU IDS procedures for blinded studies. 
5.3.3 
Study Medication Administration  
In the ICU, patients will be started on study drug administered via the VentaProst 
delivery system at an initial dose administered at 13.6 ng/kg/min.  Study Drug Study drug 
may be titrated up or down in 3.4 ng/kg/min increments (refer to VentaProst Pharmacy 
Manual) as clinically indicated to a dose range of 3.4-30.6 ng/kg/min.  Study drug will be 
administered based on the pump rate calculated for the active treatment in mL/hr.  Study 
drug  can be administered up to 10 days.   
 
 
 
 
 
 
 
 
 
1 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020444s024lbl.pdf  


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Table 3:  Administration Titration Guidelines 
Up titration Guideline  
Downward Titration / Guideline 
Start Dose: 13.6 ng/kg/min 
1st Step Up Dose (17.0) 
2nd Step Up Dose (20.4) 
3rd Step Up Dose (23.8) 
4th Step Up Dose (27.2) 
5th Step Up Dose (30.6) 
Start Dose: 13.6 ng/kg/min 
1st Step Down dose (10.2) 
2nd Step Down Dose (6.8) 
3rd Step Down dose (3.4) 
 
All study drug will be administered per the calculated pump rate for the active treatment in ml/hr 
 
Table 4-Example of Up Titration for male with Ideal Body Weight of 70 kg  
Initial Dose Rate 
Initial Pump Rate 
New Dose Rate 
New Pump Rate 
13.6 ng/kg/min 
1.89 mL/hr 
13.6 ng/kg/min 
1.89 mL/hr 
17.0 ng/kg/min 
2.39 mL/hr 
20.4 ng/kg/min 
2.86 mL/hr 
23.8 ng/kg/min 
3.33 mL/hr 
27.2 ng/kg/min 
 
3.81 mL/hr 
30.6 ng/kg/min 
4.28 mL/hr 
              Active drug is prepared with 50 mL in each syringe at a concentration of 30,000 ng/mL. 
              All study drug will be administered per the calculated pump rate for the active treatment in ml/hr. 
 
5.3.4 
Study Medication Weaning 
Patients will be weaned from study drug slowly to avoid rebound vasoconstriction.   
During weaning, doses will be decreased in steps of 3.4 ng/kg/min increments, with a 
minimum of 15 minutes between changes. The weaning process should occur in isolation 
to other treatment changes (no changes in inotropes, vasopressors, or vasodilators) 
whenever possible. Patients will be observed closely before, during, and after dose 
changes. In the event patients demonstrate signs of hemodynamic instability  or a 
decrease in oxygenation indicated by pulse oximetry during downward titration, the dose 
will be returned to its previous level. Once patients have been stable for at least 15 
minutes, repeat attempts at dose reduction may be undertaken.  The process will continue 
until patients are fully weaned.  Patients will be monitored for safety and efficacy 
throughout study drug administration. 
5.4 
Identity of the Device Component of the Investigational Product 
5.4.1 
Identity of Device 
The Phase 2a VentaProst drug delivery system is designed to accurately and precisely 
administer aerosol to the lungs of critically ill patients who require support via 
mechanical ventilation.  The aerosol generator’s fundamental operating mechanism and 
materials of construction will be similar to the 510(k)-cleared Aeroneb Solo System 
(K120939, K103635, K070642, Aerogen Ltd) and it is being designed for compatibility 
with the range of ventilators found in the OR and ICU. 


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5.4.1.1 VentaProst Aerosol Delivery to Ventilated Patients 
The VentaProst delivery system (Figure 1) consists of reusable and single-patient use 
disposable elements: 
1. Reusable multi-patient use components consist of two electronic controllers with 
power supplies, Aerogen Solo Nebulizer Cable, and Sensirion Flow Sensor Cable.  
When used together, they synchronize aerosol generation with the patient’s 
inspiratory pattern through a single-patient use, disposable administration kit. 
o Aerogen Pro-X, is a commercially available device (K1209392) cleared 
for use to continuously operate the disposable Aerogen Solo nebulizer. 
(item #1 Figure 1). 
o Aerogen Pharma Controller (AP Controller) is an investigational device, 
which synchronizes aerosol generation with the ventilator inspiratory 
cycle (item #2 on Figure 1).  This controller was tested to demonstrate its 
safety for use under IND129777.  
o Aerogen Solo Nebulizer Cable 
o Sensirion Flow Sensor Cable 
2. Single-patient disposable kit: 
o Aerogen Solo nebulizer (item #3 on Figure 1) is a commercially available, 
low mass and low profile vibrating mesh aerosol generator (K070642) 
cleared for use with the Aerogen Pro-X controller and Aerogen 
Continuous Nebulization Tube Set (CNTS).  
o Aerogen CNTS and syringe (items #4 and 5 on Figure 1) is a 
commercially available device (K103635) cleared for use to connect to the 
Aerogen Solo and deliver medication from the drug reservoir (syringe) to 
the mesh the nebulizer.   
o Flow sensor and cable connected to the Aerogen Pharma Controller (AP 
Controller, item #7 on Figure 1).  This is a new component of the system, 
which was tested to demonstrate safety for use in a clinical study.  
The VentaProst delivery system will be used in conjunction with a commercially 
available and FDA-cleared syringe pump (item #8 on Figure 1).  In general, any available 
syringe pump, which (1) is compatible with the Aerogen Continuous Nebulization Tube 
Set (CNTS syringe and tubing), and (2) is capable of delivering medication to the 
vibrating mesh nebulizer within the range of 0.4 to 12.0 mL/h as required to deliver the 
doses specified in the APC-VPCOV-CLN-001 Pharmacy Manual. For purposes of the 
VPCOV study, Aerogen Pharma will supply  the Perfusor® Space Infusion Syringe Pump 
System from B.Braun (Figure 1).  This particular syringe pump is FDA-cleared 
(K093913), it is compatible with the CNTS syringe (items #4 on Figure 1) and is able to 
 
 
 
2 The product names for the Aerogen commercial products changed from the term “Aeroneb”, to the brand 
name “Aerogen”.  A Note to File was submitted to FDA and receipt was acknowledged by the Branch 
Office 
 


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deliver fluids in the rage of 0.4 to 12.0 mL/h.  It is worth noting that on 11 April 2020, 
this pump received EUA for use in the tracheal delivery of continuous nebulized 
medications into a nebulizer to treat patients of all ages with or suspected of having the 
Coronavirus Disease 2019 (COVID-19)3.   
 
 
 
Figure 1: Drug Delivery System 
 
The Aerogen Pro-X (item #1, Figure 1), Aerogen Solo (item #3, Figure 1) are mounted on 
an I.V. pole at the patient’s bedside.  The two controllers and Aerogen CNTS (items #4 
and 5, Figure 1) are routinely used as a system within their intended use.  The sensor and 
nebulizer are connected into specific locations of the inspiratory limb of the ventilator 
pre- and post the humidifier, respectively (see Figure 2).  The addition of the AP 
Controller and an off-the shelf Sensirion flow sensor enables the VentaProst system to 
synchronize aerosol delivery with the inspiratory cycle of the ventilator (Figures 1 and 2).   
 
Figure 2 illustrates the AP Controller, which is similar to the commercially available 
 
 
 
3 https://www.fda.gov/media/136894/download  
 


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Aerogen Pro-X controller in form, size, weight and materials used for the upper and 
lower shells.  The AP Controller uses the same AC/DC adapter and cable as used in the 
commercial Aerogen Pro-X controller.  The packaging used for the AP Controller is same 
as packaging validated by Aerogen Ltd. for the commercially available Aerogen Pro-X 
system.  Functionality of the AP Controller was tested in design verification studies 
(IND129777).  Two dials (Figure 2) are used to: (1) set the flow threshold for 
nebulization triggering during the inspiratory cycle of the ventilator, accommodating 
initial ventilator baseline bias flows, and (2) set the duration of nebulization during the 
inspiratory cycle (a detailed description of the mechanism of action of the AP Controller 
is presented in IND129777).   
 
 
A. Diagram of Aerogen Pharma Controller 
(left side view) 
 
 
B. Diagram of Aerogen Pharma Controller (right 
side view) 
C. Flow Trigger Dial settings 
D. Aerosol Duration Dial settings 
 
Figure 2: Aerogen Pharma Controllers 
Prior to administration, study drug will be prepared per the VP COVID Pharmacy Manual 
and placed into a 60 mL CNTS syringe.  The syringe will be labeled to maintain the study 
blind.  The user will attach the syringe to the CNTS tubing and prime the tube set so that 
the formulation reaches the Aerogen Solo, producing aerosol generation.  The CNTS 
syringe set will be placed in a B Braun Perfusor Space Infusion syringe pump.  The 15-
mm T-Piece with nebulizer is placed between the ventilator circuit and the ETT (Figure 
2).  The user will select the pump rate (mL/hr) to deliver the recommended dose based on 


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the ideal body weight in kilograms (kg) dispensed to achieve the dose rate in ng/kg/min 
for active treatment.  The control treatment’s corresponding pump flow rate in mL/hour 
will be calculated based on initial dose of Flolan in ng/kg/min. All study drug will be 
administered per the calculated pump rate for active treatment in ml/hr.  The user will be 
able to adjust this recommended dose up or down (per protocol) by changing pump rate 
prior to selecting dose and initiating delivery.  The selected dose will then be dispensed 
by the pump to the receiving surface of the mesh, resulting in generation of an aerosol 
with a volume median diameter in the range of 2 to 5 µm.  The Aerogen Pharma 
Controller monitors the patient’s breathing pattern and user adjusts the knob (on left) to 
initiate aerosol generation at the beginning of the breathing cycle.  The knob on right sets 
the duration of aerosol generation within each breath.   
 
The VentaProst device is designed to be compatible with standard intensive care unit 
(ICU) equipment.  The following site-specific equipment will be needed to deliver the 
therapy: B.Braun syringe pump (provided by Aerogen Pharma), ventilator, endotracheal 
tube (ETT), humidifier, ventilator circuit.  This equipment is standard for critical care 
medicine. 
  
Figure 3 - VentaProst Device Placement in the Gas Pathway 
 


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5.4.2 
Ventilator Settings 
The device is designed for use with standard adult ventilator settings.  An intermittent 
positive pressure ventilatory mode (i.e., not constant positive airway pressure [CPAP] or 
t-piece) is required to activate the device to deliver aerosol during the inspiration phase.  
A Heat-Moisture Exchanger (HME) may be used in the device circuit.   
The site will utilize OSU’s Standard of Care (SOC) mechanical ventilation guidelines for 
care of patients for COVID-19 with ARDS.  The following ventilator parameters will be 
assessed daily while on VentaProst:  Ventilator type, Mode, FiO2, Inspiratory Time, Mean 
Airway Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, 
Respiratory Rate and Tidal Volume. 
5.4.3 
Device Supply 
All device supplies will be provided by Aerogen Pharma Limited (including the B.Braun 
Syringe Pump). The serial numbers for the controllers, flow sensor, and nebulizer will 
also be recorded in an IP accountability dispensing log. 
Used and unused devices will be inventoried and returned to the Sponsor or Sponsor’s 
designee. 
5.4.4 
Device Replacement 
Devices may be replaced at any time if there a suspicion of malfunction, but must be 
replaced if: 
• The investigator suspects that, due to device malfunction, less than 90% of the 
total dose of study drug has been delivered.  Reduced doses must be estimated 
and recorded in the patient’s medical record and source documentation.   
• The investigator suspects the device is not performing optimally for any reason. 
5.4.5 
Device Malfunction or Failure 
One device (Aerogen Pro-X controller, Aerogen Pharma Breath Controller, Flow Sensor, 
Solo nebulizer, CNTS tubing and syringe, and associated components) is expected to 
perform throughout the duration of study treatment.  If the controllers, Flow Sensor, 
CNTS tubing and syringe, or the Solo nebulizer are not functioning optimally for any 
reason, instructions for trouble-shooting provided in the device instruction for use manual 
should be followed.  If one or more devices need to be replaced, the reason should be 
documented in the patient’s medical record, dispensing log, and Device Performance 
Issues Form.  Additional devices are provided for this purpose.  The unique serial 
numbers of the new components will be recorded in the patient’s medical record, 
dispensing log, and the source documentation. 
For device malfunction or complaints, complete the Device Performance Issues Log and 
submit to the Sponsor at Complaints@aerogenpharma.com within 48 hours.  Failed 
devices will be set aside from the general supplies, inventoried and returned to the 
Sponsor or the Sponsor’s designee. 


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5.5 
Blinding 
Clinical and research staff and Sponsor will be blinded to Active or Control dose 
assignments with the exception of the pharmacy staff and an unblinded Sponsor CRA.  
Should unblinding be necessary, the medical monitor for this study will work with the 
unblinded pharmacist or unblinded CRA to unblind the patient.  
Active treatment (Flolan) is clear in color when reconstituted and Control treatment 
(0.9% sodium chloride solution) is also clear in color to maintain the study blind.  The 
Control and Active treatments will be placed in identical 60 mL syringes and labelled in a 
blinded manner prior to leaving the pharmacy. 
5.6 
Prior and Concomitant Therapy 
For patients who receive study drug, any medication (including over-the-counter [OTC] 
medications or other investigational therapies) or therapy administered to the patient 
during the course of the study (starting at Screening and 14  days prior) will be recorded 
on the Prior and Concomitant Therapy data collection forms.  The Investigator will 
record any AE on the AE data collection forms for which a concomitant 
medication/therapy was administered. 
5.6.1 Prohibited Concomitant Therapy 
Other inhaled vasodilators. 
5.7 
Investigational Product (IP) Supplies and Accountability 
Investigational product supplies will not be sent to the Investigator(s) until the following 
documentation has been received by the Sponsor: 
• Written proof of approval of the protocol and its informed consent forms (ICFs) 
by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for 
the institution where the study is to be conducted.  (Due to COVID-19 and the 
availability of the Active study medication, the study medication will be sent to 
the OSU pharmacy and held in quarantine until IRB approval and the completion 
of Study Initiation Visit (SIV), which may be conducted remotely or in person.  A 
NTF will be sent to OSU pharmacy instructing that the study medication not be 
released for use until Sponsor notification.) 
• An Investigator-signed and dated FDA Form 1572. 
• A signed and dated curriculum vitae of the Principal Investigator including a copy 
of the Principal Investigator’s current medical license (required in the US) or 
medical registration number on curriculum vitae. 
The Investigator and study staff will be responsible for the accountability of all IP 
supplies (dispensing, inventory, and record keeping) following Aerogen Pharma 
instructions and adhere to Good Clinical Practice (GCP) guidelines as well as local 
and/or regional requirements. 
Under no circumstances will the Investigator allow the IP to be used other than as 
directed by this protocol.  IP will not be administered to any individual who is not 
enrolled into the study. 


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An accurate and timely record of the receipt of all IP; dispensing of IP to the patient; 
collection of unused IP; and subsequent return of unused IP to Aerogen Pharma must be 
maintained.  This includes, but may not be limited to: (a) documentation of receipt of IP, 
(b) IP dispensing log, (c) IP accountability log, (d) all shipping service receipts, and (e) 
documentation of returned IP to the Sponsor.  All forms will be provided by Aerogen 
Pharma.  Any comparable forms that the investigational site wishes to use must be 
approved by Aerogen Pharma. 
The supplies and inventory records must be made available, upon request, for inspection 
by the designated representative of Aerogen Pharma, a representative of the FDA, or a 
representative of a non-US health authority.  All used and unused IP are to be returned to 
Aerogen Pharma at the conclusion of the study.   
6. 
CRITERIA FOR EVALUATION 
6.1 
Primary Endpoint 
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• Requires VV ECMO   
• Inability to extubate within 10 days or reintubation within < 24 hours 
• Change in S/F, oxygenation index and P/F ratio (>15%) from baseline to 
12 hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
1. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 
• Worsening hemodynamic parameters  
• Cardiac troponin >20% from baseline  
• BNP > 15% of baseline 
• Need for temporary mechanical circulatory support (IABP, Impella) 
• Requires VA ECMO 
6.2 
Secondary Endpoints 
1. Improvement in oxygenation defined as any one of the following: 
• Stabilization of PaO2/FIO2 >250 
• Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
2. Improved clinical outcomes  defined as one of more of the following: 
• Time to extubation following the site’s extubation protocol 


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• Free from re-intubation 
• Reduction in ICU days 
• Reduction in the number of re-admissions to the ICU due to COVID-19   
within 28 days 
• Reduction in total hospital days  
• Mortality [28 days] defined as Cardiopulmonary mortality or mortality 
from all causes  
3. Safety and tolerability 
• Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory/oxygenation parameters,  and 
laboratory tests. 
6.3 
Exploratory endpoints will include (where available): 
• Change in LDH 
• Change in fibrinogen 
• Change in WBC count including lymphocytes and neutrophil subsets 
• Change in triglycerides 
• Change in ferritin 
• Change in CRP / ESR 
• Change in IL-6 
• Change in D-Dimer  
Changes in these parameters will be assessed for each patient from baseline to 
end of study as well as changes between the active and control groups. 
 
6.4 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used and generally 
recognized as reliable, accurate, and relevant in studies of cardiac and respiratory 
function. 
7. 
SAFETY ASSESSMENTS 
Safety will be assessed through monitoring of adverse events (AEs) and serious adverse 
events (SAEs),  laboratory tests, chest assessments (Chest CT or Chest X-ray), 
oxygenation/ventilatory parameters, and vital signs.  Safety assessment frequency is 
shown in the Schedule of Assessments and Procedures. 


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7.1 
General Safety Procedures 
7.1.1 
Vital Signs and Weight Measurements 
Vital sign measurements, including systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR) [beats per minute], respiratory rate (breaths per minute), 
and body temperature (in Celsius) will be obtained twice daily Days 1-10 or  as clinically 
indicated.  Weight (kg) will be obtained at the time of Screening and at Day 10 or end of 
VP treatment.  Height will be obtained at the time of Screening.  If unable to obtain 
height, the study staff will use the best reported historical height from patient or LAR. 
7.1.2 
Physical Examination 
A physical examination will be conducted at the screening visit and will include 
assessments of general appearance; skin and lymphatics; eyes, ears, nose, throat; 
cardiovascular system; respiratory system; abdomen/gastrointestinal system; urological 
system; musculoskeletal and neurological systems.  Other body systems may be 
examined as clinically indicated. 
7.1.3 
Laboratory Measurements 
Clinical laboratory measurements to be performed are listed below.  The Schedule of Assessments 
and Procedures shows the time points at which blood will be collected for clinical laboratory tests and 
pregnancy testing.  The Baseline for laboratory tests is the Screening assessment. 
Category 
Parameters 
Hematology-CBC with diff 
Hemoglobin, hematocrit, RBC, WBC with differential 
(neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, 
basophils), platelets  
Full Chemistry Panel 
 
Electrolytes 
Sodium, potassium, chloride, bicarbonate, calcium 
Liver function tests 
AST, ALT, AP, total bilirubin 
Renal function parameters 
BUN, creatinine 
Coagulation Studies 
PT/PTT 
Other 
Serum or urine pregnancy test, RT-PCR for COVID-19, 
ESR, 
Troponin, 
BNP, 
fibrinogen, 
ferritin, 
LDH, 
Triglycerides, D-Dimer, IL-6, and CRP 
7.1.4 
Chest Assessments 
A Chest CT or Chest X-ray will be obtained at Screening and Day 5. 
7.1.5 
Time Prone Protocol 
The time prone protocol is a standard of care in OSU’s ICU.  This will be in place for all 
days that patients are within the ICU. 
7.2 
Adverse Events 
7.2.1 
Definitions 
Adverse events are any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment.  For the purposes of this study, this will include unanticipated 
medical events in the judgment of the investigator.  A pre-existing condition or symptom 


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is one that is present at the start of the study and is reported as part of the patient’s 
medical history.  A pre-existing condition or symptom should be reported as an AE only 
if its frequency, intensity or character worsens during study treatment. 
All AEs that occur from the time of the first dose of study medication through the End of 
Study (Day 28) will be recorded and reported as Treatment-Emergent Adverse Events 
(TEAE).  All AEs must be appropriately documented in the patient’s medical 
chart/source documentation and on the DCFs.  When known, investigators should report 
syndromes rather than list symptoms associated with the syndrome. 
All AEs that are ongoing at the conclusion of the study should be followed until: a) 
resolution/stable sequelae; b) the Investigator determines that it is no longer clinically 
significant; or, c) the study patient is lost to follow-up.  If no follow-up is provided, the 
Investigator must provide a written justification. 
7.2.2 
Adverse Events of Special Interest (AESI) 
Pulmonary edema and  pulmonary hemorrhage are AEs of special interest due to the 
mode of action of epoprostenol.  If an AE of special interest occurs, the Sponsor will be 
notified of this occurrence within 24 hours. 
7.2.3 
Grading of Adverse Events 
The severity of each AE will be categorized using the following criteria: 
• Grade 1 (Mild):  usually transient; requires no special treatment and does not 
interfere with the patient’s daily activities. 
• Grade 2 (Moderate):  produces a low level of inconvenience to the patient and 
may interfere with daily activities.  These AEs are usually ameliorated by simple 
therapeutic measures. 
• Grade 3 (Severe):  interrupts daily activity and requires systemic drug therapy or 
other medical treatment. 
7.2.4 
Relationship to Study Medication/Study Device/Procedure 
The Investigator must assess the relationship of each reported AE.  The Investigator must 
make an assessment of the relationship of the AE to the study drug/study 
device/procedure using the following scale: 
• Unrelated:  The AE is definitely not or unlikely to be associated with study 
medication/study device/procedure and is judged due to causes other than the 
study medication/study device/procedure. 
• Related:  The AE is possibly or probably related with study medication/study 
device/procedure.    
7.2.5 
AE Outcomes 
The following terms and definitions are used in assessing the final outcome of an AE:  
• Recovered/Resolved - The patient has fully recovered, or by medical or surgical 
treatment, the condition has returned to the level observed at the first trial-related 


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activity. 
• Recovering/Resolving - The condition is improving and the patient is expected to 
recover from the event. 
• Recovered/Resolved with sequelae - The patient has recovered from the 
condition, but with lasting effect due to a disease, injury, treatment or procedure. 
If a sequela meets an SAE criterion, the AE must be reported as an SAE. 
• Not recovered/Not resolved - The condition of the patient has not improved and 
the symptoms are unchanged, or the outcome is not known at the time of 
reporting. 
• Fatal - This term is only applicable if the patient died from a condition related to 
the reported AE. Outcomes of other reported AEs in a patient before he/she died 
should be assessed as “recovered”, “recovering”, “recovered with sequelae” or 
“not recovered”.  An AE with fatal outcome must be reported as an SAE. 
7.2.6 
Laboratory Test and other Test Abnormalities as Adverse Events 
A laboratory or other test (chest assessments, vital signs) abnormality should be reported 
as an AE if the Investigator considers the abnormality an AE or if the abnormality is 
associated with accompanying symptoms, requires medical/surgical intervention, leads to 
a change in study treatment, or results in discontinuation from the trial. When possible, 
syndromes not laboratory values, should be reported as AEs.  For example, elevated 
hepatic transaminases associated with hepatitis should be reported as “hepatitis” and 
decreased hemoglobin and hematocrit requiring iron supplementation should be recorded 
as “anemia.”  Prior to reporting as an AE, abnormal tests should be repeated to verify the 
accuracy of the original result. 
7.2.7 
Serious Adverse Events 
The Investigator is required to determine if each AE is a Serious Adverse Event (SAE).  
An SAE is any AE occurring after randomization and through Day 28 and results in any 
of the following outcomes: 
• Death, or 
• Is life-threatening, or 
• Prolongation of existing hospitalization, or 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
In the event of death, the cause of death should be recorded as the SAE (death is an 
outcome, not the AE itself). 


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Any planned procedures that require admission to hospital as well as any planned elective 
procedures (e.g., angioplasty) are not considered SAEs (unless the underlying condition 
has worsened or the procedure results in a worsening of the patient’s condition).  In 
addition, pregnancy that occurs during the course of the study or absence of a treatment 
effect will also not be considered to be an SAE and will be collected on a separate CRF. 
7.2.8 
Reporting for SAEs (24 Hours) 
Regardless of causality, an SAE must be followed clinically until resolution or 
stabilization.   
All SAEs after randomization and through Day 28 of the study must be reported to the 
Sponsor or the Sponsor’s representative within 24 hours of the investigational site’s 
knowledge of the occurrence.  The investigational site will email a Serious Adverse 
Event Report (SAER) to the Sponsor and the Medical Monitor.    Investigational sites 
will be provided with SAER forms.  The Medical Monitor will work closely with the 
Sponsor to properly assess and report the SAE.  
The SAE information emailed to the Sponsor or the Sponsor’s representative will include 
the following (as available): 
• Patient Number, Investigator name, and Site Number 
• SAE information:  event term, onset date, severity, and causal relationship 
• Basic demographic information (e.g., age, gender, weight) 
• The outcomes attributable to the event (death, a life-threatening adverse drug 
experience, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, other important medical event[s]) 
• A summary of relevant test results, pertinent laboratory data, and any other 
relevant medical history 
• The first and last dates of study drug administration. 
• A statement whether study medication was discontinued or study medication 
administration schedule modified 
• A statement whether event recurred after reintroduction of study medication if 
administration had been discontinued or withheld 
• Supplemental anonymized information may include the following hospital 
records:  laboratory results, radiology reports, progress notes, admission and 
emergency room notes, holding/observation notes, discharge summaries, autopsy 
reports, and death certificates 
Supplemental information may be transmitted using a follow-up report and should not 
delay the initial report. 
For regulatory purposes, initial reports of SAEs should be transmitted within the 
prescribed time frame as long as the following minimum information is available:  patient 
number, suspect study medication, reporting source, and an event or outcome that can be 


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identified as being both serious and unexpected for which the Investigator can make a 
relationship assessment. 
7.3 
Reporting of Pregnancy 
Any pregnancy where the estimated date of conception occurs either prior to the End of 
Study must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, 
this should be reported regardless of the length of time that has passed since the exposure 
to study treatment.  The medical monitor may decide that unblinding of the patient 
treatment assignment may be necessary. 
An induced abortion or a spontaneous abortion is considered to be an SAE and should be 
reported in the same timeframe and in the same format as all other SAEs. 
Pregnancies must be reported as soon as possible but no later than one business day by 
email.  
All pregnancies must be followed to outcome.  The outcome of the pregnancy must be 
reported as soon as possible but not later than 24 hours of the investigational site’s 
knowledge of the outcome. 
8. 
PHARMACOKINETIC ASSESSMENTS 
Not applicable. 
9. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
The assessments and procedures for this study are described in detail below and 
presented in the Schedule of Assessments and Procedures located behind the Synopsis. 
9.1 
Study Evaluation Timepoints 
9.1.1 Screening (within 14 days prior to Baseline Day 1) 
Potential study patients will be recruited by the study staff from patients.  The following 
assessments will occur prior to study enrollment: 
• Informed consent prior to any study procedures or assessments being performed. 
• Demographic Information 
• Medical History  
• Physical Exam 
• Prior Medication History 
• Chest CT or Chest X-ray 
• Inclusion/Exclusion Eligibility Assessment (including assessment of shortness of 
breath within the last 14 days) 


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• Serum/Urine Pregnancy Test (if woman of childbearing potential) 
• Clinical Laboratory Sampling to include: Full Chemistry Panel including LFTs, 
CBC with Diff including neutrophils and lymphocytes, PT/PTT, Triglycerides, 
LDH, ferritin, fibrinogen, CRP, ESR, IL-6, troponin, BNP, D-Dimer, and RT-
PCR for COVID-19 
• Vital Signs  
• Height & Weight (If height can’t be obtained, use the best reported historical 
height) 
9.1.2 Days 1-10 Treatment  
9.1.2.1 Randomization 
• Evaluate that the patient continues to be  eligibile for the study by assessing 
Inclusion/Exclusion Criteria. 
• Once eligibility has been confirmed, a Subject number beginning with 101 and 
rising sequentially will be assigned to the next enrolled subject. 
• A blinded order for the Investigational Drug Services group will be generated by 
EPIC for the next sequential subject to be randomized.  
• The unblinded pharmacist will prepare the treatment assignment (Active or 
Control) for the next assigned Subject number. 
• The reconstituted study drug will be protected from light and labelled in a blinded 
manner to ensure maintenance of the study blind. 
• Subjects will be randomized to receive either Active or Control for a maximum of 
10 days, as clinically indicated and at the discretion of the Investigator. 
9.1.2.2 Baseline-Day 1 (0 Hour) 
 
• Continue evaluation eligibility by assessing Inclusion/Exclusion Criteria. 
•   Study drug treatment will begin at a starting dose of 13.6 ng/kg/min based on the 
concentration used to calculate Active treatment in mL/hr and can be titrated up to 
30.6 ng/kg/min or down to 3.4 ng/kg/min as clinically warranted.  The B.Braun 
syringe pump will be set to the appropriate dose in mL/hr utilizing the subject’s 
sex and height (ideal body weight).  
• Vital signs will be assessed twice daily in AM and PM while on study drug.  
Efforts will be made to obtain vital signs at the same time each day.  Vital signs 
include: temperature, pulse rate, respiration rate and blood pressure.  
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily while on study drug:  Ventilator 
Type, Vent Mode, FiO2, Inspiratory time, Mean Airway Pressure, Peak 
Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume, and 
Respiratory Rate 
• Time Prone Position-16 hours per day per OSU Protocol 


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9.1.2.3 Day 1-12 hours 
• Clinical Laboratory Sampling to include: Full Chemistry Panel including LFTs, 
CBC with Diff including neutrophils and lymphocytes, PT/PTT, Triglycerides, 
LDH, ferritin, fibrinogen, CRP, ESR, IL-6, troponin, BNP, and D-Dimer. 
• Continue to administer study drug if clinically indicated. 
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Oxygenation measurement via continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily while on study drug:  Ventilator 
Type, Vent Mode, FiO2, Inspiratory time, Mean Airway Pressure, Peak 
Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume, and 
Respiratory Rate 
• Vital signs will be assessed twice daily in AM and PM.  Efforts will be made to 
obtain vital signs at the same time each day.  Vital signs include: temperature, 
pulse rate, and blood pressure.  
• Time Prone Position-16 hours per day per OSU Protocol 
9.1.2.4 Days 2-10 (While on study drug) 
• Continue to administer study drug if clinically indicated. 
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Oxygenation measurement via continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily: Ventilator Type, Vent Mode, FiO2, 
Inspiratory time, Mean Airway Pressure, Peak Inspiratory Pressure, Positive End 
Expiratory Pressure, Tidal Volume, and Respiratory Rate 
• Vital signs will be assessed twice daily in AM and PM.  Efforts will be made to 
obtain vital signs at the same time each day.  Vital signs include: temperature, 
pulse rate, and blood pressure.  
• Time Prone Position-16 hours per day per OSU Protocol 
• Full Chemistry Panel including LFTs, CBC with Diff including neutrophils and 
lymphocytes, PT/PTT and RT-PCR for COVID-19. (Day 5 only) 
• Chest CT or Chest X-ray (Day 5 only) 


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• Full Chemistry Panel including LFTs, CBC with Diff including neutrophils and 
lymphocytes, PT/PTT, Triglycerides, LDH, ferritin, fibrinogen, CRP, ESR, IL-6, 
troponin, BNP, D-Dimer, and RT-PCR for COVID-19 (Day 10 only).  
• Obtain weight. (Day 10 only or at end of study drug dosing) 
9.1.2.5 Weaning  
See Section 5.3.4 and Table 3 for weaning guidelines.  
 
9.1.3 
Day 28/End of Study (EOS)  
•    Assess AEs/SAEs  
•    Assess Mortality 
•    Assess concomitant medications 
9.2 
Data Collection 
Investigator or designee will enter the information required by the protocol onto source 
documents and enter data into data collection forms (DCFs) in an excel spreadsheet 
provided by Aerogen Pharma. 
9.3 
Clinical Data Management 
Data from source documents will be verified against the DCF and any discrepancies will 
be clarified and resolved with study staff. 
9.4 
Database Quality Assurance 
All data will be remotely monitored by the Sponsor due to the COVID-19 pandemic. 
Should restrictions be lifted at OSU, an on-site visit may occur if all parties are in 
agreement. 
10. 
 STATISTICAL CONSIDERATIONS 
10.1 
Statistical Methods 
A Statistical Analysis Plan will be not be developed as this is an exploratory trial.  Any 
statistical evaluation will be handled internally by Aerogen Pharma or their designee. 
10.2 
Determination of Sample Size 
The number of patients has been selected to enable an adequate clinical assessment of 
pharmacodynamics, safety, and tolerability parameters without presenting undue risk to a 
large number of patient’s being exposed to this investigational product. 
10.3 
Analyses Sets 
All patients who are enrolled in the study and who receive at least one dose of study drug  
will be included in the intent-to-treat (ITT) analyses of pharmacodynamic and safety data.  
All available data will be used and missing data will not be estimated or carried forward 


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in any statistical summary or analyses. 
Descriptive summary statistics include the number of patients, mean, median, percent 
coefficient of variation (% CV) (if required), standard deviation, and minimum and 
maximum values (quantitative variables) or the number of patients and percentages by 
category (qualitative variables).  Changes will be assessed as the difference between 
baseline measurements and the appropriate post-dose measurements unless otherwise 
specified.  Mean differences between active and control groups (when available) will be 
assessed and significance will be determined on the basis of a 95% CI.  Individual patient 
listings of data will also be provided to allow for review of all pharmacodynamic, safety, 
and tolerability parameters. 
10.4 
Randomization 
Patients will be randomized 1:1. A randomization schedule will be provided to the 
unblinded pharmacist.  Should unblinding be requested due to a medical emergency, the 
unblinded pharmacist will work with the medical monitor or Sponsor unblinded CRA to 
obtain the required information. 
10.5 
Demographic and Other Baseline Characteristics 
Continuous demographic and other baseline characteristics (such as age, weight, and 
height) will be summarized using n, mean, SD, median, minimum, and maximum.  
Qualitative characteristics (such as gender and race) will be summarized by counts and 
percentages.   
10.6 
Criteria for Evaluation 
10.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint:  
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• Requires VV ECMO   
• Inability to extubate patient within 10 days or reintubation within <24 
hours 
• Change in S/F, oxygenation index and P/F ratio (>15%) from baseline to 
12 hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 
• Worsening hemodynamic parameters  
• Cardiac troponin >20 % from baseline   
• BNP > 15% of baseline 


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• Need for temporary mechanical circulatory support (IABP, Impella) 
• Requires VA ECMO 
10.6.2 
Secondary Efficacy Endpoints 
Key secondary endpoints include: 
1. Improvement in oxygenation defined as any one of the following: 
• 
Stabilization of PaO2/FIO2 >250 
• Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
2. Improved clinical outcomes  defined as one of more of the following:  
• Time to extubation following the site’s extubation protocol 
• Free from reintubation 
• Reduction in ICU days 
• Reduction in the number of re-admissions to the ICU due to COVID-19   
within 28 days 
• Reduction in total hospital days  
• Mortality [28 days] defined as Cardiopulmonary mortality or mortality 
from all causes  
3. Safety 
• Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory/oxygenation parameters,  and 
laboratory tests. 
10.6.3 
Key Exploratory Endpoints include: 
• Change in LDH 
• Change in fibrinogen 
• Change in WBC count including lymphocytes and neutrophil subsets 
• Change in triglycerides 
• Change in ferritin 
• Change in CRP / ESR 
• Change in IL-6 
• Change in D-Dimer  
Changes in these parameters will be assessed for each patient from baseline to 
end of study as well as changes between the active and control groups. 
10.7 
Extent of Exposure 
Exposure data will be summarized by using frequencies and percentages. 


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10.8 
Safety Analyses 
Safety measurements include AE/SAEs, vital signs, chest assessments (Chest CT or 
Chest X-ray), laboratory tests, and oxygenation/ventilatory parameters.  Safety data will 
be summarized by using frequencies and incidence rates.   
10.8.1 
Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim 
description (Investigator term) using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be presented by preferred term nested within System Organ Class.  
Verbatim description and all MedDRA level terms, including the lower level terms, for 
all AEs will be contained in the data listings of the clinical study report (CSR).  
AEs will be summarized by presenting the incidence of AEs.  Although a MedDRA term 
may be reported more than once for a patient, that patient will be counted only one time 
in the incidence count for that MedDRA term. 
Treatment-emergent adverse events (TEAEs) will be analyzed.  AEs that are not 
treatment-emergent will be listed.  A TEAE is defined as  
• AEs that emerge during treatment, having been absent at pretreatment, or  
• Reemerge during treatment, having been present at pretreatment but stopped 
prior to treatment, or  
• Worsen in severity or frequency during treatment relative to the pretreatment 
state, when the AE is continuous. 
Adverse events of special interest (AESI) will be analyzed.   An AESI is defined as: 
• Serious or non-serious adverse that is one of scientific and medical    concern 
specific to the sponsor’s product for which ongoing monitoring   and rapid 
communication by the investigator to the sponsor is required 
• Events or symptoms thought to potentially be associated with the investigational 
compound, device, or disease under study, or 
• Can arise with any use of a drug/device (e.g. off-label use, use in combination 
with another approved drug), with any route of administration, formulation, or 
dose, including an overdose. 
 
10.8.2 
Laboratory Values 
Clinical laboratory results post-Baseline will be evaluated for markedly abnormal values.  
For the incidence of markedly abnormal laboratory values, each patient may be counted 
once in the laboratory parameter value high and in the laboratory parameter low 
categories as applicable.  Descriptive summary statistics (e.g. mean, SD, median, 
minimum, maximum) for laboratory values and changes from baseline will be evaluated. 


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10.8.3 
Vital Signs 
Vital sign values will be evaluated on an individual basis by patient.  Abnormal vital sign 
values will be identified as those outside (above or below) the reference range.  
Descriptive summary statistics (e.g., mean, SD, median, minimum, maximum) for vital 
sign parameters and changes from Baseline will be evaluated. 
10.9 
The Procedure for Revising the Statistical Analysis Plan 
Not Applicable. 
11. 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS 
11.1 
Ethics 
11.1.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an IRB or IEC constituted and functioning in accordance with 
International Conference on Harmonization (ICH) E6, Section 3, and any local 
regulations, i.e., Federal Regulations, Title 21 Code of Federal Regulations (CFR) Part 
56.  Any protocol amendment and/or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval (except for changes involving only logistical or 
administrative aspects of the study (e.g., change in CRA[s], change of telephone 
number[s]).  Documentation of IRB/IEC compliance with the ICH and any local 
regulations regarding constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC Chairman must be sent to the 
Principal Investigator with a copy to the Sponsor prior to study start.  If the IRB/IEC 
decides to suspend or terminate the study, the Investigator will immediately send the 
notice of study suspension or termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator 
or Sponsor, depending on local regulatory obligations.  If the Investigator is required to 
report to the IRB/IEC, he/she will forward a copy to the Sponsor at the time of each 
periodic report.  The Investigator or the Sponsor will submit, depending on local 
regulations, periodic reports and inform the IRB/IEC of any reportable AEs per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
Investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required. 
11.1.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating practices of Aerogen 
Pharma (or designee), which are designed to ensure adherence to GCP guidelines as 
required by the following: 
• ICH - E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonization of Pharmaceuticals for Human Use. 


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• US CFR dealing with clinical studies (21 CFR, including parts 50 and 56 
concerning Informed Patient Consent and IRB regulations). 
11.1.3 
Patient Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each patient or their legally authorized representative (LAR), the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, and currently available alternative treatments.  Each 
patient must be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written 
in non-technical language.  The patient or their LAR should understand the statement 
before signing and dating it and will be given a copy of the signed document.  The patient 
or their LAR will be asked to sign an informed consent prior to any study-specific 
procedures being performed.  No patient can enter the study before his/her informed 
consent has been obtained.  Due to the COVID-19 pandemic and restrictions on hospital 
visitors, informed consent may be obtained via telephone or video conference call if the 
patient is incapacitated or sedated due to the severity of their illness.  A witness for the 
study team should be present when a call or video conference is occurring with the 
patient’s LAR.  This process should be carefully documented in the subject’s medical 
records. 
An unsigned copy of an IRB/IEC and Sponsor-approved written informed consent must 
be prepared in accordance with ICH E 6, Section 4, and all applicable local regulations, 
i.e., Federal Regulations, Title 21, CFR Part 50, and provided to the Sponsor.  Each 
patient or their LAR must sign (or give verbal consent with study staff witnessing the 
verbal consent) an approved informed consent prior to study participation.  The form 
must be signed and dated by the appropriate parties.  The original signed ICF for each 
patient will be verified by the Sponsor and kept in the study center’s investigational site 
files. 
The patient should be informed in a timely manner if new information becomes available 
that might be relevant to the patient’s willingness to continue participation in the trial.  
The communication of this information should be documented. 
11.2 
Administrative Procedures 
11.2.1 
Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  
Protocols will be followed as written. 
Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the Sponsor before implementation.  Amendments 
specifically affecting the safety of patients, the scope of the investigation, or the scientific 
quality of the study require additional approval by the applicable IRBs/IECs of all 
investigational sites and, as required, by the regulatory authority.  These requirements 


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should in no way prevent any immediate action from being taken by the Investigator, or 
by the Sponsor, in the interest of preserving the safety of all patients included in the 
study.  If an immediate change to the protocol is felt by the Investigator to be necessary 
for safety reasons, the  Medical Monitor must be notified promptly and the IRB/IEC for 
the site must be informed as soon as possible. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval, but the IRB/IEC must be kept informed of such 
changes.  In these cases, the Sponsor will send a letter to the site for forwarding on to the 
IRB/IEC detailing such changes. 
11.2.2 
Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
11.2.3 
Monitoring Procedures 
The Sponsor or Sponsor’s representative will maintain contact with the Investigator and 
designated staff by telephone, letter, and/or email between study visits.  Monitoring visits 
to each investigational site will be conducted by the sponsor either remotely or in person.  
In accordance with ICH E6, Section 6.10, source documents include, but are not limited 
to the following: 
• Clinic, office, hospital charts. 
• Copies or transcribed health care provider notes which have been certified for 
accuracy after production. 
• Recorded data from automated instruments such as mechanical ventilators, x-
rays, and other imaging reports, e.g., sonograms, computed tomography scans, 
magnetic resonance images, radioactive images, ECGs, rhythm strips, 
electroencephalographs, polysomnography, pulmonary function tests (regardless 
of how these images are stored, including microfiche and photographic 
negatives). 
• Records of telephone contacts. 
• Diaries or evaluation checklists. 
• Investigational product distribution and accountability logs maintained in 
pharmacies or by research personnel. 
• Laboratory results and other laboratory test outputs, e.g., serum pregnancy test 
result documentation. 
• Correspondence regarding a study patient’s treatment between physicians or 
memoranda sent to the IRBs/IECs. 
• CRF components (e.g., questionnaires) that are completed directly by patients 
and serve as their own source. 


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11.2.4 
Recording of Data 
In order to provide the Sponsor with accurate, complete, and legible records following 
criteria are to be maintained.  The Investigator will enter the information required by the 
protocol onto the data collection forms (DCFs)  provided by the sponsor as agreed upon 
with the research staff. 
11.2.5 
Data Storage and Retention of Records 
 
The circumstances of completion or termination of the study notwithstanding, the 
Investigator has the responsibility to retain all study documents, including but not limited 
to the protocol, copies of data collection forms (DCFs) , Investigator's Brochure, 
regulatory agency registration documents, e.g., FDA 1572 form, ICFs, and IRB/IEC 
correspondence.  The investigational site should plan on retaining study documents as 
follows: 
• For at least two years following the date a marketing application is approved for 
the investigational product for the indication for which it is being investigated, or 
• Until two years after the investigation is formally discontinued and no application 
is to be filed or if the application is not approved. 
It is requested that at the completion of the required retention period, or should the 
Investigator retire or relocate, the Investigator contacts the Sponsor, allowing the Sponsor 
the option of permanently retaining the study records. 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Data will be coded (de-identified), stored in a secure electronic database during and after 
the study, and will not be shared with unauthorized persons. The principal investigator 
and co-investigator will have access to the data to review and analyze the data, as 
described in this protocol. For the protection and privacy of the patients, no identifying 
information will be released.  Data will be retained and possibly used in the future for 
further analysis. All identifiers will be removed and not be shared at any time. 
11.2.6 
Handling of Investigational Product 
Investigational study drug (Flolan) will be inventoried and maintained within the site’s 
Investigational Drug Services .  It will be stored according to their protocols and 
procedures.   The study drug should not be dispensed to patients in the VentaProst 
COVID trial (APC-VPCOV-CLN-001) until a favorable IRB approval has been obtained 
by the OSU IRB and a study initiation visit has been conducted by the Sponsor.  
Investigational device  supplies must be kept in an appropriate secure area (e.g., locked 
cabinet) and stored according to the conditions specified on the investigational product 
labels.  The Investigator (or designated pharmacist) must maintain an accurate record of 
the shipment and dispensing of the IP (both device and drug) in an IP accountability log, 
a copy of which must be given to the Sponsor at the end of the study.  An accurate record 
of the date and amount of IP dispensed to each patient must be available for inspection at 
any time.  The assigned sponsor representative will review these documents along with 
all other study conduct documents at an appropriate interval of visit to the investigational 


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site once IP has been received by the investigational site.  Due to COVID-19 a physical 
inventory of IP (drug and device supplies) may not be possible.  If at all possible, an 
inventory of supplies should be conducted via video conferencing.  If video conferencing 
is not possible, study staff will inventory supplies and provide documentation to Aerogen 
Pharma. 
All IP supplies (with the exception of OSU stock 0.9% sodium chloride solution supplies) 
are to be used only for this protocol and not for any other purpose.  The Investigator (or 
designated pharmacist) must not destroy any IP product labels or any partly used or 
unused IP supply without Sponsor authorization.  At the conclusion of the study and as 
appropriate during the course of the study, the Investigator (or designated pharmacist) 
will return or properly dispose of all used IP. Unused investigational device and drug 
components will be returned to Aerogen Pharma at the conclusion of the study. 
11.2.7 
Publication of Results 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each Investigator and Aerogen Pharma, as appropriate. 
11.2.8 
Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the course 
of this study will be kept confidential by the Investigator, the Investigator’s staff, and 
IRB/IEC and will not be disclosed in whole or in part to others or used for any purpose 
other than reviewing or performing the study without the written consent of the Sponsor.  
No data collected as part of this study will be utilized in any written work, including 
publications, without the written consent of Sponsor.  These obligations of confidentiality 
and non-use shall in no way diminish such obligations as set forth in the Confidentiality 
Agreement between the Sponsor and the Investigator.  All persons assisting in the 
performance of this study must be bound by the obligations of confidentiality and non-
use set forth in the Confidentiality Agreement between the Investigator and Sponsor 
(provided by the Sponsor). 
11.2.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.   
The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the Investigator terminates or suspends a trial without prior agreement of the 
Sponsor, the Investigator should inform the Institution where applicable, and the 
Investigator/Institution should promptly inform the Sponsor and the IRB/IEC and should 
provide the Sponsor and the IRB/IEC a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 
11.2.10 Patient Insurance and Indemnity 
The Sponsor will provide the insurance in accordance with local guidelines and 
requirements as a minimum for the patients participating in this study. 


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12. 
REFERENCES 
Adhikari, N. K., R. P. Dellinger, S. Lundin, D. Payen, B. Vallet, H. Gerlach, K. J. Park, S. 
Mehta, A. S. Slutsky and J. O. Friedrich (2014). "Inhaled nitric oxide does not reduce 
mortality in patients with acute respiratory distress syndrome regardless of severity: 
systematic review and meta-analysis." Crit Care Med 42(2): 404-412. 
 
Afshari, A., A. Bastholm Bille and M. Allingstrup (2017). "Aerosolized prostacyclins for 
acute respiratory distress syndrome (ARDS)." Cochrane Database Syst Rev 7: CD007733. 
 
Ammar, M. A., S. R. Bauer, S. N. Bass, M. Sasidhar, R. Mullin and S. W. Lam (2015). 
"Noninferiority of Inhaled Epoprostenol to Inhaled Nitric Oxide for the Treatment of 
ARDS." Ann Pharmacother 49(10): 1105-1112. 
 
De Wet, C. J., D. G. Affleck, E. Jacobsohn, M. S. Avidan, H. Tymkew, L. L. Hill, P. B. 
Zanaboni, N. Moazami and J. R. Smith (2004). "Inhaled prostacyclin is safe, effective, 
and affordable in patients with pulmonary hypertension, right heart dysfunction, and 
refractory hypoxemia after cardiothoracic surgery." J Thorac Cardiovasc Surg 127(4): 
1058-1067. 
 
Dewachter, C., Laurence Dewachter , Marie Vercruyssen , Benoit Rondelet , Dean P. 
Schraufnagel , Serge Brimioulle , Francois Kerbaul , Robert Naeije (2012). 
"Inflammatory Processes In Load-Induced Right Ventricular Failure - Anti-Inflammatory 
Effects Of Epoprostenol." American Journal of Respiratory and Critical Care Medicine 
A3462(185). 
 
Dzierba, A. L., E. E. Abel, M. S. Buckley and I. Lat (2014). "A review of inhaled nitric 
oxide and aerosolized epoprostenol in acute lung injury or acute respiratory distress 
syndrome." Pharmacotherapy 34(3): 279-290. 
 
Fuller, B. M., N. M. Mohr, L. Skrupky, S. Fowler, M. H. Kollef and C. R. Carpenter 
(2015). "The use of inhaled prostaglandins in patients with ARDS: a systematic review 
and meta-analysis." Chest 147(6): 1510-1522. 


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APC-VPCOV-CLN-001 03 Nov 2020 
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Page 52 of 52 
 
Giannis, D., I. A. Ziogas and P. Gianni (2020). "Coagulation disorders in coronavirus 
infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past." J 
Clin Virol 127: 104362. 
 
Haraldsson, A., N. Kieler-Jensen, H. Wadenvik and S. E. Ricksten (2000). "Inhaled 
prostacyclin and platelet function after cardiac surgery and cardiopulmonary bypass." 
Intensive Care Med 26(2): 188-194. 
 
Higenbottam, T., D. Wheeldon, F. Wells and J. Wallwork (1984). "Long-term treatment of 
primary 
pulmonary 
hypertension 
with 
continuous 
intravenous 
epoprostenol 
(prostacyclin)." Lancet 1(8385): 1046-1047. 
 
Kallet, R. H., G. Burns, H. Zhuo, K. Ho, J. S. Phillips, L. P. Pangilinan, V. Yip, A. Gomez 
and M. S. Lipnick (2017). "Severity of Hypoxemia and Other Factors That Influence the 
Response to Aerosolized Prostacyclin in ARDS." Respir Care 62(8): 1014-1022. 
 
Mitchell, J. A., F. Ali, L. Bailey, L. Moreno and L. S. Harrington (2008). "Role of nitric 
oxide and prostacyclin as vasoactive hormones released by the endothelium." Exp 
Physiol 93(1): 141-147. 
 
Nicolas, L. B., A. Krause, M. M. Gutierrez and J. Dingemanse (2012). "Integrated 
pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects." Br J Clin 
Pharmacol 74(6): 978-989. 
 
Rao, V., K. Ghadimi, W. Keeyapaj, C. A. Parsons and A. T. Cheung (2018). "Inhaled 
Nitric Oxide (iNO) and Inhaled Epoprostenol (iPGI2) Use in Cardiothoracic Surgical 
Patients: Is there Sufficient Evidence for Evidence-Based Recommendations?" J 
Cardiothorac Vasc Anesth 32(3): 1452-1457. 
 


 
 
 
PROTOCOL TITLE 
TITLE: DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING MECHANICAL VENTILATION  
PROTOCOL  NUMBER 
APC-VPCOV-CLN-001 
INVESTIGATIONAL 
PRODUCT 
VentaProst™ 
INDICATION 
Reduction of respiratory, cardiac or circulatory failure in patients with 
COVID-19 
PHASE 
Phase 2a 
SPONSOR 
Aerogen Pharma Limited 
1660 S Amphlett Boulevard, Suite 360 
San Mateo, CA 94402 
United States 
MEDICAL MONITOR 
Matthew Exline, MD 
AMENDMENT #3 
APPROVAL DATE 
14 December 2020 
GCP STATEMENT 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) and all applicable local Good 
Clinical Practices (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
CONFIDENTIALITY 
STATEMENT 
This document is confidential as it contains proprietary information 
of Aerogen Pharma.  Any viewing or disclosure of such information 
that is not authorized in writing by the Aerogen Pharma is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 14 Dec 2020 
Confidential 
Page 2 of 54 
 
SPONSOR PROTOCOL APPROVAL PAGE 
 
PROTOCOL TITLE 
A DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING MECHANICAL VENTILATION  
PROTOCOL NUMBER  
APC-VPCOV-CLN-001 
AMENDMENT #3 
APPROVAL DATE 
14 December 2020 
 
 
________________________________________________________________________ 
Judy Doto, RN, BSN 
 
 
 
 
 
 
Date 
Head of Clinical Operations 
Aerogen Pharma 
 
________________________________________________________________________ 
Jim Fink PhD, RRT, FCCP 
 
 
 
 
 
Date 
Chief Scientific Officer  
Aerogen Pharma 
 
________________________________________________________________________ 
Plamena Entcheva-Dimitrov, PhD, RAC 
 
 
 
 
Date 
Head of Regulatory and Medical Affairs 
Aerogen Pharma 
 
 
________________________________________________________________________ 
Andy Clark PhD  
 
 
 
 
 
 
Date 
Vice President and General Manager 
Aerogen Pharma 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 14 Dec 2020 
Confidential 
Page 3 of 54 
 
INVESTIGATOR’S SIGNATURE PAGE 
PROTOCOL TITLE 
A DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF VENTAPROST 
(INHALED EPOPROSTENOL DELIVERED VIA DEDICATED 
DELIVERY 
SYSTEM) 
IN 
SUBJECTS 
WITH 
COVID-19 
REQUIRING MECHANICAL VENTILATION  
PROTOCOL NUMBER  
APC-VPCOV-CLN-001 
AMENDMENT #3 
APPROVAL DATE 
14 December2020 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations 
of the protocol and in accordance with ICH-GCPs and all applicable local guidelines. 
 
________________________________________________________________________ 
Principal Investigator (printed/typed) 
 
 
 
 
 
 
 
 
 
 
________________________________________________________________________ 
Principal Investigator Signature 
 
 
 
 
 
Date 
 
 


Aerogen Pharma 
 
Protocol Number APC-VPCOV-CLN-001  
APC-VPCOV-CLN-001 14 Dec 2020 
Confidential 
Page 4 of 54 
1. 
CLINICAL PROTOCOL SYNOPSIS 
Sponsor 
Aerogen Pharma 
Protocol No. 
APC-VPCOV-CLN-001 
Title of Study 
Double-blind, placebo controlled study to assess the efficacy and safety of VentaProst 
(Inhaled epoprostenol delivered via dedicated delivery system) in subjects with COVID-19 
requiring mechanical ventilation.  
Study Centers 
One clinical site in the US 
Phase 
Phase 2a 
Objectives 
 
Primary Objective: 
The primary objective of this study is the reduction of respiratory, cardiac or circulatory 
failure in patients with confirmed COVID-19. 
Secondary Objectives: 
The secondary objective in this study is to evaluate the effects of VentaProst on improvement 
in oxygenation and improvement in clinical outcomes.  
 
The study will also evaluate the effects of VentaProst on inflammatory parameters in subjects 
with confirmed COVID-19. 
Study Design 
 
This is a double-blind, placebo controlled study of VentaProst (Active) as compared to 
placebo (Control).  Active is inhaled epoprostenol administered via the VentaProst delivery 
system in 10 COVID-19 positive patients. Control is inhaled 0.9% sodium chloride solution 
administered via the VentaProst delivery system in 10 COVID-19 positive patients.  
Throughout the remainder of the protocol both Active and Control will be referred to as 
“study drug”.  This study will evaluate the potential therapeutic benefit of VentaProst  in 
treating patients with COVID-19 who require mechanical ventilation and are at risk for the 
progression of respiratory and/ or cardiac/circulatory failure.  This study will assess the 
efficacy and safety of VentaProst at an initial dose of 13.6 ng/kg/min (A range from 3.4-30.6 
ng/kg/min may be administered as clinically required for a maximum of 10 days at the 
discretion of the Investigator.  Patients will be followed through Day 28 to assess clinical 
outcomes.   
Patients will be consented and randomized to either the Active or Control group within 48 
hours of being placed on a mechanical ventilator.  Patients will be administered study drug 
using the VentaProst delivery system which allows up and down titration of study drug to 
achieve hemodynamic and oxygenation stability.  The starting dose of study drug will be 
initiated at 13.6 ng/kg/min.  Based on hemodynamic and oxygenation parameters, the dose of 
study drug can be increased in 3.4 ng/kg/min increments up to a maximum of 30.6 ng/kg/min 
or down to a minimum of 3.4 ng/kg/min.  Study drug will be administered based on the pump 
rate calculated for active treatment in mL/hr.  The titration table below (Table 1) shows the 
typical up and down titration steps for study drug.    
 
 
 
 


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Table 1: Overview of Titration and Weaning Guidelines 
 
Up titration Guideline*  
 
Downward Titration / 
Weaning Guideline** 
Start Dose: 13.6 ng/kg/min 
1st Step Up Dose (17.0) 
2nd Step Up Dose (20.4) 
3rd Step Up Dose (23.8) 
4th Step Up Dose (27.2) 
5th Step Up Dose (30.6) 
Start Dose: 30.6 ng/kg/min 
1st Step Down dose (23.8) 
2nd Step Down Dose (17.0) 
3rd Step Down dose (10.2) 
4th Step Down dose (3.4) 
 
 
* The study drug will be administered based on the pump rate calculated for active treatment in 
mL/hr.**If the patient has been up-titrated weaning should occur from that level in 6.8 ng/kg/min 
decrements.  
Patients will be weaned from study drug slowly to avoid rebound vasoconstriction.    During 
weaning, doses will be decreased in steps of 6.8 ng/kg/min increments, with a no less than 5 
minutes between changes as clinically appropriate. The weaning process should occur in 
isolation to other treatment changes (no changes in inotropes, vasopressors, or vasodilators) 
whenever possible. Patients will be observed closely before, during, and after dose changes. 
In the event patients demonstrate signs of hemodynamic instability  or a decrease in 
oxygenation indicated by pulse oximetry during downward titration, the dose will be returned 
to its previous level. Once patients have been stable for at least 15 minutes, repeat attempts at 
dose reduction may be undertaken.  The process will continue until patients are fully weaned.  
Patients will be monitored for safety and efficacy throughout study drug administration. 
Number/Type 
of Patients 
Approximately 20 COVID-19 positive patients requiring mechanical ventilation will be 
enrolled in this study. 
Patients will be randomized to either VentaProst Active (aerosolized epoprostenol 
administered via the VentaProst delivery system) or VentaProst Control (aerosolized 0.9% 
sodium chloride solution administered via the VentaProst delivery system). 
 
Inclusion 
Criteria 
 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men Age ≥18 years old (no upper limit)  
2. Confirmed COVID-19 positive by a diagnostic test such as molecular or antigen test 
3. Patients who require invasive mechanical ventilation.  
4. Enrolled into study within 48 hours of being placed on mechanical ventilation  
5. Consent or professional consent obtained 
6. Duration of shortness of breath must be within the previous 14 days.   
7. Female subjects of childbearing potential must have a negative pre-treatment 
pregnancy test (serum or urine). 
8. Received or currently receiving dexamethasone for the treatment of COVID. 


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9. Willing and able to comply with treatment schedule and follow-up. 
 
Exclusion 
Criteria 
 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. 
Patients on ECMO support. 
2. 
Patients receiving another inhalation research medication or inhaled nitric oxide.  
3. 
 Not expected to survive for 48 hours. 
4. 
Pregnant (positive pregnancy test in a pre-dose examination) or breastfeeding  
5. 
Open tracheostomy. 
6. 
Clinical contra-indication, as deemed by the attending physician. 
7. 
Allergy to Epoprostenol and its diluent 
8. 
Using inhaled vasodilators  at baseline.  
9. 
Patients who are hemodynamically unstable as determined by investigator  
10. Patients with  significant hemoptysis as determined by investigator 
Study 
Treatment(s) 
Patients will receive study drug via mechanical ventilator, starting at 13.6 ng/kg/min.  If 
determined by the treating physician, study drug can be up titrated in 3.4 ng/kg/min 
increments to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.  At the 
Investigator’s discretion, the patient will be weaned off the drug in 6.8 ng/kg/min increments. 
Study drug will be administered based on the pump rate calculated for active treatment in 
mL/hr.  Study drug  can be administered up to 10 days.   
Duration of 
Treatment 
The duration of study participation for each patient is as follows:  
• 
Screening: up to 14 days 
• 
Treatment: up to 10 days 
• 
Follow up: 28 days 
Criteria for 
Evaluation 
 
Primary Endpoint  
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• 
Requires VV ECMO   
• 
Inability to extubate patient within 10 days or reintubation within < 24 
hours 
• 
Change in S/F, oxygenation index and P/F ratio (≥15%) from baseline to 12 
hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• 
Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 
• 
Worsening hemodynamic parameters  
• 
Cardiac troponin > 20% from baseline   
• 
BNP ≥ 15% of baseline 
• 
Need for temporary mechanical circulatory support (IABP, Impella) 
• 
Requires VA ECMO 
Secondary Endpoints: 
1. Improvement in oxygenation defined as any one of the following: 
• 
Stabilization of PaO2/FIO2 >250 
• 
Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 


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2. Improved clinical outcomes defined as one of more of the following:  
• 
Shorter time to extubation following the site’s extubation protocol 
• 
Free from reintubation 
• 
Reduction in ICU days 
• 
Reduction in the number of re-admissions to the ICU due to COVID-19 
within 28 days. 
• 
Reduction in hospital days Mortality (28 Days) defined as Cardiopulmonary 
mortality or mortality from all causes. 
3. Safety and tolerability: 
• 
Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory and oxygenation parameters, 
and laboratory tests. 
Exploratory endpoints will include (where available as part of standard of care): 
1. 
Change in LDH 
2. 
Change in fibrinogen 
3. 
Change in WBC count including lymphocytes and neutrophil subsets 
4. 
Change in triglycerides 
5. 
Change in ferritin 
6. 
Change in CRP / ESR 
7. 
Change in IL-6 
8. 
Change in D-Dimer 
Changes in these parameters will be assessed for each patient from baseline to end of 
study as well as changes between the active and control groups. 
Ventilatory 
Parameters 
OSU SOC: 
Ventilator Type (GE) 
Parameters to monitor are:  
1. Ventilator Mode 
2. FiO2 
3. Inspiratory Time 
4. Mean Airway Pressure 
5. Peak Inspiratory Pressure 
6. Positive End Expiratory Pressure 
7. Respiratory Rate 
8. Tidal Volume 
Criteria for 
Stopping 
VentaProst 
Treatment 
Individual patients stopping criteria: At any time during study drug administration, patients 
may be removed from study treatment and placed on standard of care (SoC) therapy if they 
meet one or more of the following pre-defined criteria leading to a deterioration in their 
condition: 
• 
Severe hypotension as evidenced by a systolic BP < 90 mmHg  or MAP < 60 mmHG 
for >2 hours from the start of VentaProst 
• 
Need for VV ECMO 
• 
Need to increase existing vasopressor therapy by more than 25% 


Aerogen Pharma 
 
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• 
Worsening in oxygenation, ventilatory, or hemodynamic parameters that in the 
opinion of the investigator the patient should be removed from study treatment 
• 
Massive hemoptysis thought to be clinically significant and not related to 
endotracheal tube trauma 
• 
Pulmonary edema 
 
Study stopping criteria: If 3 patients are removed from the study for any of the above 
conditions, the study will stop further enrollment and an investigation will be conducted to 
determine the cause of the events.  An independent safety evaluation will also be conducted.  
If it is suspected that the investigational product has caused the events, the study will be 
terminated. 
Independent Safety Evaluation: Independent safety evaluation will be conducted by a 
licensed physician who is not involved in the VentaProst COVID-19 clinical study or the 
sponsoring organization.   
Statistical 
Methods 
All patients who are enrolled in the study and who receive at least one dose of study drug will 
be included in the intent-to-treat (ITT) analyses of pharmacodynamic and safety data.  All 
available data will be used and missing data will not be estimated or carried forward in any 
statistical summary or analyses. 
Descriptive summary statistics include the number of patients, mean, median, percent 
coefficient of variation (% CV) (if required), standard deviation, and minimum and maximum 
values (quantitative variables) or the number of patients and percentages by category 
(qualitative variables). Changes will be assessed as the difference between baseline 
measurements and the appropriate post-dose measurements unless otherwise specified.  Mean 
differences between active and historical control groups will be assessed and significance will 
be determined on the basis of a 95% CI.   
No formal estimate of the sample size has been made. This is an exploratory study and the 
number of patients was selected to enable an adequate clinical assessment of 
pharmacodynamic, safety, and tolerability parameters without presenting undue risk to a large 
number of patients. 
Efficacy 
Analysis 
Efficacy will be secondarily determined by summarizing success or failure to meet any of the 
primary or secondary endpoints as compared to Control treatment.   
Safety 
Analyses 
Safety data will be summarized for both treatment groups including frequencies and incidence 
rates.  Safety will be assessed through monitoring of adverse events (AEs), serious adverse 
events (SAEs), chest CTs or chest X-rays, laboratory tests, oxygenation and ventilatory 
parameters,  and vital signs.   


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Protocol Number APC-VP-COV-CLN-001 
 
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Table 2: Schedule of Assessments and Procedures 
 
Screening 
VentaProst -
Day 1 
 
VentaProst Days 2-10 
End of 
Study 
 
 
Study Procedures 
Within 14 
Days 
Prior 
to 
Baseline 
Baseline  
0 Hr 
 
 
 12 
hrs 
D-2 
D-3 
 
 
D-4 
D-5 
 
 
D-6 
 
 
D-7 
 
 
D-8  
 
 
D-9 
D-10/ 
End 
Study 
Treat
ment 
 
Day 28 
(+/- 
2 
days) 
Written Informed 
Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication History/ Prior 
Meds 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Height2 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Chest CT Scan or CXR 
X 
 
 
 
 
 
X3 
 
 
 
 
 
 
 
Chemistry (including 
AST, ALT, AP, T. Bili) 
CBC , PT/PTT  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Pregnancy Test (Serum or 
Urine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 diagnostic test 
such as molecular or 
antigen test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Troponin, and 
BNP 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Other blood tests: 
fibrinogen, ferritin, LDH, 
Triglycerides, D-Dimer, 
IL-6, ESR,CRP4 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Administer VentaProst 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oxygenation 
Measurements6 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Ventilator Parameters7 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
AE/SAE  Monitoring 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
 
X 
 
X 
 
X 
Concomitant Medications 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Prone position8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 14 Dec 2020 
Confidential 
Page 10 of 54 
1 Informed consent may be obtained after screening study procedures that were conducted as a part of the patient’s standard of care. 
2 Height only performed at screening 
3 Chest CT or CXR may be performed anywhere from 3-8 days as clinically warranted.  
4  These tests are collected only if available as Standard of Care  
5 Vital signs: Prior to initiating VentaProst, Days 1-10 twice daily (morning and evening) at the same time to reduce exposure to Health Care Professionals to 
include; temperature, pulse rate, blood pressure. 
6 Continuous SpO2 via pulse oximetry 
7 Ventilator Parameters will be collected twice daily along with vital signs and  include: Ventilator Type, Ventilator Mode, FiO2, Inspiratory Time, Mean 
Airway Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume and Respiratory Rate  
8Time Prone Position – 16 hours per day per OSU protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Number APC-VP-COV-CLN-001 
 
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Page 11 of 54 
TABLE OF CONTENTS 
INVESTIGATOR’S SIGNATURE PAGE ....................................................... 3 
1. 
CLINICAL PROTOCOL SYNOPSIS ............................................... 4 
TABLE OF CONTENTS ......................................................................... 11 
LIST OF ACRONYMS, ABBREVIATIONS AND 
DEFINITION OF TERMS ...................................................................... 14 
2. 
BACKGROUND AND RATIONALE ............................................. 17 
2.1 
Introduction ................................................................................. 17 
2.2 
VentaProst .................................................................................... 18 
2.2.1 Nonclinical Experience ..................................................... 18 
2.2.2 Clinical Experience ........................................................... 18 
2.2.3 Summary of Pharmacokinetic Results ............................ 18 
2.2.4 Summary of Clinical Results ........................................... 19 
2.2.5 Summary of Known and Potential Risks of 
Inhaled Epoprostenol Administration ........................................ 20 
2.2.6 Dosing Rationale for VentaProst...................................... 21 
3. 
STUDY OBJECTIVES ................................................................... 22 
3.1 
Primary Objective ........................................................................ 22 
3.2 
Secondary Objectives ................................................................... 22 
3.3 
Study Design ................................................................................ 22 
3.4 
Duration of Participation ............................................................ 22 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..................... 23 
4.1 
Inclusion Criteria ......................................................................... 23 
4.2 
Exclusion Criteria ........................................................................ 23 
4.3 
Re-Screening of Patients ............................................................. 24 
4.4 
Removal of Patients from Therapy or Assessment ..................... 24 
4.4.1 Criteria for Stopping VentaProst Treatment ................... 24 
5. 
STUDY TREATMENTS ................................................................. 25 
5.1 
Identity of Medication Component of the 
Investigational Product .......................................................................... 25 
5.1.1 Storage Condition ............................................................. 25 
5.2 
Treatments Administered ............................................................ 25 
5.3 
Study Medication Supply, Preparation, and 
Administration ....................................................................................... 26 
5.3.1 Study Medication Supply ................................................. 26 
5.3.2 Study Medication Preparation ......................................... 26 
5.3.3 Study Medication Administration .................................... 26 
5.3.4 Study Medication Weaning .............................................. 27 
5.4 
Identity of the Device Component of the 
Investigational Product .......................................................................... 27 


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Protocol Number APC-VP-COV-CLN-001 
 
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5.4.1 Identity of Device .............................................................. 27 
5.4.2 Ventilator Settings ............................................................ 32 
5.4.3 Device Supply ................................................................... 32 
5.4.4 Device Replacement ......................................................... 32 
5.4.5 Device Malfunction or Failure ......................................... 32 
5.5 
Blinding ........................................................................................ 33 
5.6 
Prior and Concomitant Therapy ................................................. 33 
5.6.1 Prohibited Concomitant Therapy .................................... 33 
5.7 
Investigational Product (IP) Supplies and 
Accountability ......................................................................................... 33 
6. 
CRITERIA FOR EVALUATION ..................................................... 34 
6.1 
Primary Endpoint ........................................................................ 34 
6.2 
Secondary Endpoints ................................................................... 34 
6.3 
Exploratory endpoints will include (where available 
as part of standard of care): ................................................................... 35 
6.4 
Appropriateness of Measurements ............................................. 35 
7. 
SAFETY ASSESSMENTS .............................................................. 35 
7.1 
General Safety Procedures .......................................................... 36 
7.1.1 Vital Signs and Weight Measurements ........................... 36 
7.1.2 Physical Examination ...................................................... 36 
7.1.3 Laboratory Measurements ............................................... 36 
7.1.4 Chest Assessments ........................................................... 36 
7.1.5 Time Prone Protocol ......................................................... 36 
7.2 
Adverse Events ............................................................................ 36 
7.2.1 Definitions......................................................................... 36 
7.2.2 Adverse Events of Special Interest (AESI) ...................... 37 
7.2.3 Grading of Adverse Events ............................................... 37 
7.2.4 Relationship to Study Medication/Study 
Device/Procedure ......................................................................... 37 
7.2.5 AE Outcomes .................................................................... 37 
7.2.6 Laboratory Test and other Test Abnormalities 
as Adverse Events ........................................................................ 38 
7.2.7 Serious Adverse Events .................................................... 38 
7.2.8 Reporting for SAEs (24 Hours) ........................................ 39 
7.3 
Reporting of Pregnancy ............................................................... 40 
8. 
PHARMACOKINETIC ASSESSMENTS ...................................... 40 
9. 
SCHEDULE OF ASSESSMENTS AND 
PROCEDURES ....................................................................................... 40 
9.1 
Study Evaluation Timepoints ..................................................... 40 
9.1.1 Screening (within 14 days prior to Baseline 
Day 1) 40 
9.1.2 Days 1-10 Treatment ........................................................ 41 


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Protocol Number APC-VP-COV-CLN-001 
 
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9.1.3 Day 28/End of Study (EOS) .............................................. 43 
9.2 
Data Collection ............................................................................ 43 
9.3 
Clinical Data Management ......................................................... 43 
9.4 
Database Quality Assurance ....................................................... 43 
10. 
STATISTICAL CONSIDERATIONS .................................... 43 
10.1 
Statistical Methods ...................................................................... 43 
10.2 
Determination of Sample Size ..................................................... 43 
10.3 
Analyses Sets ............................................................................... 44 
10.4 
Randomization ............................................................................. 44 
10.5 
Demographic and Other Baseline Characteristics ..................... 44 
10.6 
Criteria for Evaluation ................................................................ 44 
10.6.1 Primary Efficacy Endpoint ............................................. 44 
10.6.2 Secondary Efficacy Endpoints ........................................ 45 
1. 
Improvement in oxygenation defined as any one of 
the following: .......................................................................................... 45 
10.6.3 Key Exploratory Endpoints include: .............................. 45 
10.7 
Extent of Exposure ...................................................................... 46 
10.8 
Safety Analyses ............................................................................ 46 
10.8.1 Adverse Events ............................................................... 46 
10.8.2 Laboratory Values .......................................................... 46 
10.8.3 Vital Signs ....................................................................... 47 
10.9 
The Procedure for Revising the Statistical Analysis 
Plan 47 
11. ADMINISTRATIVE PROCEDURES AND 
INSTRUCTIONS .................................................................................... 47 
11.1 
Ethics ............................................................................................ 47 
11.1.1 Institutional Review Boards/Independent 
Ethics Committees ....................................................................... 47 
11.1.2 Ethical Conduct of the Study ......................................... 47 
11.1.3 Patient Information and Informed Consent .................. 48 
11.2 
Administrative Procedures .......................................................... 48 
11.2.1 Changes to the Protocol .................................................. 48 
11.2.2 Adherence to the Protocol ............................................... 49 
11.2.3 Monitoring Procedures ................................................... 49 
11.2.4 Recording of Data ........................................................... 50 
11.2.5 Data Storage and Retention of Records ......................... 50 
11.2.6 Handling of Investigational Product .............................. 50 
11.2.7 Publication of Results ..................................................... 51 
11.2.8 Disclosure and Confidentiality ....................................... 51 
11.2.9 Discontinuation of Study ................................................ 51 
11.2.10 Patient Insurance and Indemnity ................................ 52 
12. 
REFERENCES ...................................................................... 53 


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Protocol Number APC-VP-COV-CLN-001 
 
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Page 14 of 54 
 
List of Figures and Tables 
Table 1: 
Overview of Titration and Weaning Guidelines 
4 
Table 2: 
Schedule of Assessments and Procedures 
9 
Table 3: 
Administration Titration Guidelines 
26 
Table 4:  
Example of Up Titration for male with Ideal Body Weight of 70 kg  
26 
Figure 1: 
Drug Delivery System 
28 
Figure 2: 
Aerogen Pharma Controllers 
29 
Figure 3: 
VentaProst Device Placement in the Gas Pathway 
30 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
Active  
Inhaled epoprostenol administered via the VentaProst delivery system 
AE 
Adverse |Event 
ALI 
Acute Lung Injury 
ALT (SGPT) 
Alanine Aminotransferase (serum glutamic pyruvic transaminase) 
AP 
Alkaline Phosphatase 
ARDS 
Acute Respiratory Distress Syndrome 
AST (SGOT) 
Aspartate Aminotransferase (serum glutamic oxaloacetic transaminase)   
bpm 
Beats Per Minute 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
cAMP 
Cyclic Adenosine Monophosphate 
CI 
Cardiac Index (L/min/m2) 
CO 
Cardiac Output (L/min) 
Control  
Inhaled 0.9% sodium chloride solution, USP administered via the VentaProst delivery 
system 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Concentration 
CPB 
Cardiopulmonary Bypass 
CRA 
Clinical Research Associate 
CRF 
Case Report Form   
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CNTS 
Continuous Nebulization Tube Set 
CVP 
Central Venous Pressure (mm Hg) 
DCF 
Data Collection Form 


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Protocol Number APC-VP-COV-CLN-001 
 
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Abbreviation 
Term 
DNR 
Do Not Resuscitate  
dPAP 
Diastolic Pulmonary Arterial  Pressure (mm Hg) 
dSAP 
Diastolic Systemic Arterial Pressure (mm Hg) 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
ESR 
Erythrocyte Sedimentation Rate 
ETT 
Endotracheal Tube 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCP 
Good Clinical Practice 
HME 
Heat-Moisture Exchanger 
HR 
Heart Rate (bpm) 
IABP 
Intra-aortic Balloon Pump 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ICU 
Intensive Care Unit 
IL-6 
Interleukin 6 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LAR 
Legally Authorized Representative  
LDR 
Lung Dosing Rate 
LFT 
Liver Function Test 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mPAP 
Mean Pulmonary Arterial Pressure (mm Hg) 
mSAP 
Mean Systemic Arterial Pressure (mm Hg) 
NC 
Nasal Cannula 
ng 
Nanogram 
OR 
Operating Room 
OTC 
Over-the-Counter 
PAH 
Pulmonary Arterial Hypertension 
PaO2 
Partial Pressure of Oxygen in Arterial Blood 
PAP 
Pulmonary Arterial Pressure (mm Hg) 
PCWP 
Pulmonary Capillary Wedge Pressure 
PD 
Pharmacodynamic 
PEEP 
Positive End Expiratory Pressure 
PH 
Pulmonary Hypertension 
PIP 
Peak Inspiratory Pressure 
PK 
Pharmacokinetic 
 
PP 
Per Protocol 


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Protocol Number APC-VP-COV-CLN-001 
 
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Page 16 of 54 
Abbreviation 
Term 
PGI2 
Prostaglandin I2 (epoprostenol) 
PVR 
Pulmonary Vascular Resistance (dyn/sec/cm5) 
RBC 
Red Blood Cell (count) 
RH 
Right Heart 
RHF 
Right Heart Failure 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
RVSWI 
Right Ventricular Stroke Work Index 
SAE 
Serious Adverse Event 
SaO2 
Arterial Oxygen Saturation 
sPAP 
Systolic Pulmonary Arterial Pressure (mm Hg) 
sSAP 
Systolic Systemic Arterial Pressure (mm Hg) 
SE 
Standard Error 
SOP 
Standard Operating Procedures 
SOC 
Standard of Care 
SpO2 
Oxygen Saturation by Pulse Oximetry 
Study Drug 
Active or Control Treatment 
SVR 
Systemic Vascular Resistance 
TEAE 
Treatment-Emergent Adverse Event 
TEE 
Transesophageal Echocardiogram 
TPG 
Transpulmonary Gradient 
t1/2 
Half-Life 
TLD 
Total Lung Dose 
ULN 
Upper Limit of Normal 
VA-ECMO 
Veno-arterial Extracorporeal Membrane Oxygenation 
VentaProst 
VentaProst™ – Drug/device combination product consisting of aerosolized epoprostenol 
delivered via dedicated drug delivery system 
VentaProst 
Nebulizer 
The nebulizer assembly that is part of the VentaProst delivery system  
VTE 
Venous Thromboemobolism 
VV ECMO 
Venovenous Extracorporeal Membrane Oxygenation 
WBC 
White Blood Cell (count) 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 


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Protocol Number APC-VP-COV-CLN-001 
 
APC-VPCOV-CLN-001 14 Dec 2020 
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Page 17 of 54 
BACKGROUND AND RATIONALE 
2.1 
Introduction 
COVID-19 is a rapidly emerging pathogen that has recently been declared a pandemic by 
the World Health Organization (WHO). No targeted therapeutic treatments for 
coronavirus (COVID-19) have been identified.  Symptoms range from mild upper 
respiratory tract infection to profound hypoxia, severe pneumonia, ARDS and death. 
Progression of end stage disease is unpredictable with high fatality rates in mechanically 
ventilated patients as a result of multi-organ failure.   Among patients who require 
hospitalization, mortality may be 5% to 15%, and for those who become critically ill, 
reported mortality ranges from 22% to 62%.     
 
Prostacyclin therapy—available in oral, inhaled, and intravenous forms—is an analogue 
which mimics endogenous prostacyclin (PGI2). Prostacyclin binds to its receptor (a G-
protein coupled receptor) found on the surface of vascular smooth muscle and platelets, 
activates cyclic adenosine monophosphate (cAMP), and results in inhibition of platelet 
aggregation, vascular smooth muscle relaxation and vasodilation of the pulmonary 
arteries (Mitchell, Ali et al. 2008). Prostacyclins are most commonly used in the 
treatment of PAH due to their potent vasodilatory effects. In addition, prostacyclin 
analogs also inhibit platelet aggregation and may reduce prothrombotic effects of 
endothelin. 
The rationale for use of vasodilators in COVID-19 patients rests on their rapid local 
effect on the pulmonary vasculature, which has shown to lead to increased oxygenation in 
other diseases, such as PAH (Higenbottam, Wheeldon et al. 1984) and post-surgical PH 
(De Wet, Affleck et al. 2004).  Epoprostenol has the additional advantage over inhaled 
nitric oxide in that it may be directly administered through a standard ventilator (closed-
circuit). 
 
The rationale for aerosolized prostacyclin use in COVID-19 patients experiencing 
hypoxia leading to cardiac failure is two-fold:  
 
(1) inhaled prostacyclin therapy has been used in the treatment of ARDS and has been 
shown to improve oxygenation and ventilation-perfusion mismatch (see Section 9).  
Prostacyclins, such as epoprostenol, promote pulmonary vasodilation via a cyclic 
adenosine monophosphate-mediated decrease in intracellular calcium (Figure 4).  While 
it has not been associated with improved outcomes, such as mortality, and it’s use in 
ARDS is off-label, it may be used in severe life-threatening hypoxemia refractory to 
conventional ARDS management, such as has been seen in COVID-19. 
 
(2) The second potential benefit of prostacyclin therapy in the management of COVID-19 
is to mitigate direct SARS-CoV-2-associated coagulopathy.  Prostacyclins have anti-
inflammatory (Dewachter 2012) and antiplatelet aggregation properties1.  Microvascular 
thrombosis and large vessel venous thromboembolism have been described anecdotally 
and in case reports of corona virus infected patients and abnormal coagulation parameters 
are associated with increased mortality (Giannis, Ziogas et al. 2020). Inhibition of platelet 
aggregation occurs with prostacyclin therapy and may mitigate thrombosis in situ seen in 
PAH itself, and potentially in patients with COVID-19 associated respiratory illness. 


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
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Page 18 of 54 
Literature data with both inhaled NO and inhaled epoprostenol in ARDS, acute lung 
injury and severe hypoxemia show improvement of oxygenation (Afshari, Bastholm Bille 
et al. 2017), (Dzierba, Abel et al. 2014), decrease of pulmonary arterial pressure (Fuller, 
Mohr et al. 2015) and in some cases improvement in clinical outcomes such as shorter 
time on mechanical ventilation and shorter time in ICU (Ammar, Bauer et al. 2015).  
However, due to the heterogeneity of the population and the severity of the disease, not 
all studies agree on the effectiveness of inhaled epoprostenol, particularly to reduce 
mortality in ARDS (Adhikari, Dellinger et al. 2014), (Afshari, Bastholm Bille et al. 2017).  
Meta-analyses have concluded that the quality of the currently published data for the use 
of inhaled vasodilators in ARDS, ALI and refractory hypoxemia is insufficient to 
definitely conclude for or against their use (Afshari, Bastholm Bille et al. 2017), (Fuller, 
Mohr et al. 2015). 
 
This study will evaluate the potential therapeutic benefit of VentaProst in treating patients 
with COVID-19 at risk for the progression of respiratory and/or cardiac/circulatory 
failure. This double-blind, placebo controlled study will assess the efficacy and safety of 
VentaProst at a range of 3.4-30.6 ng/kg/min for a maximum of 10 days at the discretion 
of the Investigator.  The patient will be followed through Day 28 to assess their clinical 
status.   
 
2.2 
VentaProst 
2.2.1 
Nonclinical Experience 
Refer to the current Investigator’s Brochure (IB) for details of nonclinical pharmacology 
and toxicology studies with VentaProst. 
2.2.2 
Clinical Experience 
There have been no clinical trials to date with VentaProst in COVID-19 patients (see 
Section 2.2.4 below for summary of clinical data with VentaProst in cardiac surgery 
patients). 
2.2.3 
Summary of Pharmacokinetic Results  
Epoprostenol undergoes rapid chemical hydrolysis under physiological conditions to 
yield 6-keto-PGF1α and is also subject to enzymatic degradation.  As such, it is only 
possible to evaluate the PK using radioactively labeled drug. Studies using 3H-
epoprostenol sodium indicate half-life is generally less than 3 minutes with an I.V. bolus, 
and with I.V. infusion, plasma steady-state concentrations were achieved within 15 
minutes of initiation of the infusions, and steady-state concentrations increased linearly 
with increasing infusion rate.  Tissue distribution studies indicate the highest levels of 
radioactivity were observed in the kidney, liver, and small intestine and the lowest levels 
were observed in brain and adipose tissue.  Epoprostenol-derived material is rapidly 
excreted into urine and feces after dosing with epoprostenol sodium. 
 
There is only one study in the literature that reports the PK of inhaled epoprostenol.  The 
study by Haraldsson (Haraldsson, Kieler-Jensen et al. 2000) was designed to evaluate the 
effects of inhaled epoprostenol on platelet aggregation after surgery.  No differences were 
seen in 6-keto-PGF1α levels with two dose levels of epoprostenol compared to placebo 


Aerogen Pharma 
 
Protocol Number APC-VP-COV-CLN-001 
 
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Page 19 of 54 
over six hours of administration in the ICU.  Epoprostenol deposition in the lungs was not 
quantified, but the aerosol was administered only during the inspiratory phase of 
mechanical ventilation.  The blood levels of 6-keto-PGF1α by enzyme immunoassay in 
this study were reported to be several times higher than other levels reported in the 
literature.   
 
In 2017, Stanford University’s Department of Cardiac Surgery conducted an 
observational study (IND129777, Report# APC-VP-CLN-004) investigating the levels of 
6-keto-PGF1α in cardiac surgery patient requiring CPB.  Sixteen patients were enrolled; 
eight did not received inhaled epoprostenol, eight received aerosolized epoprostenol at a 
nominal starting dose of 50 ng/kg/min.   
 
Plasma levels determined in aerosol epoprostenol naïve patients indicates that cardiac 
surgery procedures, including CPB, result in elevated endogenous levels of both 6-keto-
PGF1α and thromboxane B2.  Delivery of aerosol epoprostenol in patients resulted in a 
further elevation of 6-keto-PGF1α levels, but not thromboxane B2. 
 
While it proved difficult to delineate the endogenous and exogenous contributions of 
aerosol delivery during surgery, 6-keto-PGF1α levels declined rapidly in aerosol naïve 
patients during ICU stay.  Examination of the 6-keto-PGF1α levels during weaning, after 
this endogenous decline, indicate that the overall aerosol delivery efficiency, nebulized to 
absorbed (deposited lung dose), is less than 8%.  That is, out of a nominal dosing rate of 
50 ng/kg/min only 4 ng/kg/min actually reaches the lungs and gets absorbed. 
Comparison to recently published data (Nicolas, Krause et al. 2012) investigating 6-keto-
PGF1α levels during steady state I.V. administration of Flolan indicates that the systemic 
exposure from aerosol delivery in cardiac surgery is similar to, or lower, than that 
experienced from intravenous administration of the approved Flolan product. 
 
The findings of this observational PK study with inhaled epoprostenol are sufficient to 
make a correlation to historical systemic exposure levels with intravenous administered 
Flolan (the reference listed drug) and show levels of exposure similar to, or lower than, 
the currently approved intravenous product.   
  
2.2.4 
Summary of Clinical Results 
The safety and tolerability of VentaProst were evaluated in a Phase 2a Clinical Study in 
cardiac surgery patients “A Two-Part Pharmacodynamic Study to Compare VentaProstTM 
(Epoprostenol Solution for Inhalation via Custom Drug Delivery System) Dosing to 
Conventionally Administered Aerosolized Epoprostenol Dosing in Cardiac Surgery 
Patients” (NCT03122730).  
 
Overall, 15 patients were exposed to doses of VP from 3.4 to 20.4 ng/kg/min in this study.  
Administration of VP in this dose range was well-tolerated.  Overall, there were 2 
patients (28.6%) in Part I and 1 patient (12.5%) in Part II who experienced a total of 7 
TEAEs.  All 7 TEAEs were assessed by the investigator as related to the surgical 
procedure and as unrelated to the study drug and unrelated to the device.  No deaths 
occurred during the study.  A total of 3 patients had 1 SAE each.  All 3 SAEs were 
considered to be unrelated to the study drug or the study device.   


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Protocol Number APC-VP-COV-CLN-001 
 
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Seven patients were evaluated in Part I to determine the effective dose equivalence 
between VP delivered at 17 ng/kg/min and off-label aerosolized Veletri administered at 
50 ng/kg/min during mechanical ventilation.  In all patients, VP 17 ng/kg/min was found 
to be equivalent either by calculation of effect compared with aerosolized Veletri 50 
ng/kg/min or the investigators’ judgement.  In most patients, no differences were 
observed in oxygen saturation ranges between VP and aerosolized Veletri treatments at 
the same FiO2 while on the ventilator. The investigator determined that oxygenation, 
assessed by oxygen saturation measurements, did not change disproportionately with 
ventilator operating parameters on VP compared with aerosolized Veletri. 
 
Eight patients were evaluated in Part II of the study to identify the optimal dose of VP.  In 
the investigator’s judgement, the optimal VP dose was determined to be 6.8 ng/kg/min in 
2 patients, 10.2 ng/kg/min in 3 patients, and 13.6 ng/kg/min in 3 patients, which is the 
minimal dose that reliably produced a maximum hemodynamic response in all patients. 
   
There have been no clinical trials to date with VentaProst in COVID-19 patients. 
See IB for additional clinical information regarding inhaled epoprostenol. 
2.2.5 
Summary of Known and Potential Risks of Inhaled Epoprostenol 
Administration 
Safety of inhaled epoprostenol in cardiothoracic surgery patients is remarkable.  In the 
reported literature to date, there were no reports of serious or life-threatening drug-related 
safety events.  Due to its mechanism of action, inhaled epoprostenol may theoretically 
cause increased bleeding (anti-platelet mechanism) or systemic vasodilation consequent 
to spill over into the central circulatory system, but no such events have been reported.  
Some accounts of the use of inhaled prostacyclin in the chronic setting (e.g. iloprost for 
PAH) report transient events as listed on the approved product labeling.  These include 
cough, headache, flushing, and an influenza-like syndrome.  However, these types of 
events are unlikely to be reported due to sedation in the ICU setting. 
VentaProst may result in hypotension, which will be monitored via frequent   assessments 
of oxygenation, ventilatory and hemodynamic parameters and vital signs. Pulmonary 
edema and pulmonary bleeding are potential risks due to the drug’s mode of action (refer 
to Section 7.2.2).  Worsening oxygenation is a theoretic concern through worsened 
ventilation/ perfusion matching. This will be monitored through continuous pulse 
oximetry throughout the administration of the inhaled epoprostenol.  
 
Risks to subjects in this study are related to common procedures performed (e.g., 
venipuncture) and the documented adverse events (AEs) listed in the current 
Investigator’s Brochure. These risks are communicated to the subjects in the consent 
forms. There may be additional risks that are currently unknown.  
 
The benefits of the study may include targeted lung vasodilation and improved 
oxygenation, potential anti-platelet effects on the lung vasculature, reduction in disease 
progression, avoidance of greater oxygen needs and early weaning off mechanical 
ventilation. If the drug does have such properties, then this may aid recovery, improve 
outcomes and enable an earlier discharge from the hospital.  


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There is no funding awarded to the patients participating in this study. 
2.2.6 
Dosing Rationale for VentaProst 
Literature on the current use of aerosolized epoprostenol in cardiac surgery and in ARDS 
shows a wide range and technically variable dosing for lowering PVR (Rao, Ghadimi et 
al. 2018), (Kallet, Burns et al. 2017), (Fuller, Mohr et al. 2015).  Most of the experience 
is with continuous nebulization by commercially available nebulizers in various positions 
in mechanical ventilator circuits at doses of 50 ng/kg/min.  Unlike the commercially 
available nebulizer systems, the VentaProst delivery platform aerosolizes epoprostenol 
only during the inspiratory cycle of the ventilator and administers respirable sized aerosol 
droplets (3-5 µm) in close proximity to the ETT of mechanically ventilated patients.  
 
The assumed effect of the current continuous dosing regimen of 50 ng/kg/min is that the 
hemodynamic response is maximized and that no further improvements would be seen by 
increasing the dose.  The initial in vitro estimate of the equivalent VentaProst (VP) dose 
to a 50 ng/kg/min conventional dose of continuously aerosolized Veletri was 17 
ng/kg/min, which was the starting dose in Part I of the APC-VP-CLN-001 Phase 2a study 
conducted by Aerogen Pharma.  During Part I of the study, it was determined that this 
dose is equivalent to 50 ng/kg/min epoprostenol delivered off-label via a generic 
nebulizer and continuous delivery.  In Part II of the APC-VP-CLN-001 Phase 2a study, 
the VP dose escalation started from an initial dose of 3.4 ng/kg/min (20% of the 
equivalent dose).  The dose was then increased in 3.4 ng/kg/min increments.  Part II of 
the study was designed to demonstrate that the dose-response plateau could be achieved 
using lower VP doses than the initial estimated equivalent dose in Part I.  Doses up to 
30.6 ng/kg/min were approved for use in the study. In Part I of the study one patient, per 
the investigator discretion, received a 20.4 ng/kg/min dose.  In Part II of the study it was 
determined that the optimal VP dose of 6.8 ng/kg/min in 2 patients, 10.2 ng/kg/min in 3 
patients, and 13.6 ng/kg/min in 3 patients provided stable hemodynamic response.  Based 
on these data,  the recommended starting dose of VP, will be 13.6 ng/kg/min, as this dose 
is anticipated to produce the maximum hemodynamic response. 
The proposed nominal dosing regimen for this COVID-19 trial is for up to 10 days of 
breath-synchronized aerosol delivery with a starting dose of study drug 13.6 ng/kg/min. 
Based on hemodynamic and oxygenation parameters, the dose can be titrated in 3.4 
ng/kg/min steps up to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 
ng/kg/min while patients are on mechanical ventilation.  Of this nominal dosing rate 
approximately 30% will reach and deposit in the lung.  Thus, the maximum Lung Dosing 
Rate (LDR) is ~10 ng/kg/min and the maximum Total Lung Dose (TLD) is ~ 144 µg/kg 
(Refer to VP IB Edition 6 dated 17-Jun-2020).  
The inhalation toxicology program for VentaProst, originally designed for the cardiac 
surgery indication, covered a maximum LDR of 320 ng/kg/min and 60 ng/kg/min and a 
maximum TLD of 1091.4 µg/kg and 172.8 µg/kg in rats and dogs respectively.  The LDR 
and TLD margins over the proposed maximum clinical exposure are thus 32 and 6, and 
7.6 and 1.2, in rats and dogs respectively.   


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3. 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is the reduction of respiratory, cardiac or circulatory 
failure in patients with confirmed COVID-19. 
3.2 
Secondary Objectives 
The secondary objective in this study is to evaluate the effects of VentaProst on 
improvement in oxygenation, improvement in clinical outcomes and safety and 
tolerability.  
The study will also evaluate the effects of VentaProst on inflammatory parameters in 
subjects with confirmed COVID-19.  
3.3 
Study Design 
This is a double-blind, placebo controlled study of VentaProst (Active) as compared to 
placebo (Control).  Active is inhaled epoprostenol administered via the VentaProst 
delivery system in 10 COVID-19 positive patients. Control is inhaled 0.9% sodium 
chloride solution administered via the VentaProst delivery system in 10 COVID-19 
positive patients.  Throughout the remainder of the protocol both Active and Control will 
be referred to as “study drug”.  This study will evaluate the potential therapeutic benefit 
of VentaProst  in treating patients with COVID-19 who require mechanical ventilation 
and are at risk for the progression of respiratory and/ or cardiac/circulatory failure.  This 
study will assess the efficacy and safety of VentaProst at an initial dose of 13.6 ng/kg/min 
(A range from 3.4-30.6 ng/kg/min may be administered as clinically required for a 
maximum of 10 days at the discretion of the Investigator.  Patients will be followed 
through Day 28 to assess clinical outcomes.   
Patients will be consented and randomized to either the Active or Control group within 48 
hours of being placed on mechanical ventilation.  Informed consent may be obtained after 
some screening study procedures were collected as part of the patient’s standard of care 
treatment. Patients will be administered study drug using the VentaProst delivery system 
which allows up and down titration of study drug to achieve hemodynamic and 
oxygenation stability.  The starting dose of study drug will be initiated at 13.6 ng/kg/min.  
Based on hemodynamic and oxygenation parameters, the dose of study drug can be 
increased in 3.4 ng/kg/min increments up to a maximum of 30.6 ng/kg/min or down to a 
minimum of 3.4 ng/kg/min.     
All study staff with the exception of the unblinded pharmacist and Sponsor CRA will be 
blinded to which treatment regimen a patient has been assigned.  Titration and weaning 
will be performed the same for all patients.  Study drug will be administered based on the 
pump rate calculated for active treatment in mL/hr. Titration guidelines are provided in 
Section 5.3.3 and Table 3. 
3.4 
Duration of Participation 
Patients who meet entry criteria will be entered into the study and the duration of study 
participation for each patient is listed below. The duration of study participation for each 
patient is as follows:  
• Screening: up to 14 days 


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• Treatment: up to 10 days 
• Follow up: 28 days 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Approximately 20 COVID-19 positive patients requiring mechanical ventilation will be 
enrolled in this study.  Ten study participants will be randomized to either Active (inhaled 
epoprostenol administered via the VentaProst delivery system) treatment or Control 
(inhaled 0.9% sodium chloride solution administered by the VentaProst delivery system 
at calculated rates (mL/hr) used for the aerosolized epoprostenol). Study drug will 
indicate both Active and Control treatments. 
Patients who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to enroll into the study.   
4.1 
Inclusion Criteria 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men Age ≥18 years old (no upper limit)  
2. Confirmed COVID-19 positive by a diagnostic test such as molecular or antigen 
test 
3. Patients who require invasive mechanical ventilation.  
4. Enrolled into study within 48 hours of being placed on mechanical ventilation  
5. Consent or professional consent obtained 
6. Duration of shortness of breath must be within the previous 14 days.   
7. Female subjects of childbearing potential must have a negative pre-treatment 
pregnancy test (serum or urine).  
8. Received or currently receiving dexamethasone therapy for COVID-19 
9. Willing and able to comply with treatment schedule and follow-up. 
4.2 
Exclusion Criteria 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. Patients on ECMO support. 
2. Patients receiving another inhalation research medication or inhaled nitric oxide.  
3. Not expected to survive for 48 hours. 
4. Pregnant (positive pregnancy test in a pre-dose examination) or breastfeeding  
5. Open tracheostomy. 
6. Clinical contra-indication, as deemed by the attending physician. 
7. Allergy to Epoprostenol and its diluent 
8. Using inhaled vasodilators at baseline.  
9. Patients who are hemodynamically unstable as determined by investigator  


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10. Patients with  significant hemoptysis as determined by investigator 
4.3 
Re-Screening of Patients 
Patients may not be enrolled more than once.   
4.4 
Removal of Patients from Therapy or Assessment 
Aerogen Pharma or the Investigator may discontinue patients from the study at any time 
for safety or administrative reasons.   
The End of Treatment Study procedures (Day 10) are to be completed for all patients 
who discontinue from the study prior to Day 10 (except Screen Failure patients).  
The Investigator will promptly explain to the patient or their LAR that the study will be 
discontinued for the patient and provide appropriate medical treatment and other 
necessary measures for the patient.   
Patients who discontinue early from the study will be discontinued for one of these 
primary reasons:  Adverse events, patient death, lost to follow-up, patient withdrew 
consent, protocol violation, lack of efficacy, investigator decision, study terminated by 
sponsor, screen failure, or other.  Study disposition information will be collected on the 
Patient Disposition DCF. 
4.4.1 
Criteria for Stopping VentaProst Treatment 
Individual patients stopping criteria: At any time during study drug administration , 
patients may be removed from study treatment and placed on standard of care (SoC) 
therapy if they meet one or more of the following pre-defined criteria leading to a 
deterioration in their condition: 
 
• Severe hypotension as evidenced by a systolic BP < 90 mmHg  or MAP < 60 
mmHG for >2 hours from the start of VentaProst 
• Need for VV ECMO 
• Need to increase existing vasopressor therapy by more than 25% 
• Worsening oxygenation, ventilatory, or hemodynamic parameters that in the 
opinion of the investigator the patient should be removed from study treatment 
• Massive hemoptysis thought to be clinically significant and not due to 
endotracheal tube trauma 
• Pulmonary Edema 
 
 
 
Study stopping criteria: If 3 patients are removed from the study for any of the above 
conditions, the study will stop further enrollment and investigation will be conducted to 
determine the cause of the events.  An independent safety evaluation will also be 
conducted.  If it is suspected that the investigational product has caused the events, the 
study will be terminated. 


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Independent Safety Evaluation: Independent safety evaluation will be conducted by a 
licensed physician who is not involved in the VentaProst COVID-19 clinical study or the 
sponsoring organization.   
5. 
STUDY TREATMENTS 
5.1 
Identity of Medication Component of the Investigational Product 
The study medication  VentaProst, Flolan (epoprostenol sodium), is manufactured by 
GlaxoSmithKline and has been analyzed and released according to their specifications.   
The labelling of Flolan and placebo for this clinical trial will follow the protocols and 
procedures set forth by OSU’s Investigational Drug Services (IDS).   The Control for this 
study is 0.9% sodium chloride solution, USP from the OSU IDS stock and will be labeled 
in a blinded manner per the IDS protocols for maintenance of study blind. 
Drug Substance Name 
Epoprostenol Sodium 
Chemical Name 
5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-
oic acid. 
Molecular Formula 
C20H31NaO5 
Structural Formula 
 
Molecular Weight 
374.45 
 
5.1.1 
Storage Condition 
Both the vials of study medication and sterile diluent buffer should be stored between 20o 
to 25oC (68o to 77oF) with excursions permitted to 15° to 30°C (59° to 86°F) and kept in 
the supplied carton to protect the product from light.  Study medication will be stored in a 
secure, controlled-access location at the study sites. 
The 0.9% sodium chloride solution will be stored according the product labelling. 
5.2 
Treatments Administered 
Patients will receive study drug via mechanical ventilator, starting at 13.6 ng/kg/min.  If 
determined by the treating physician, study drug can be up titrated in 3.4 ng/kg/min 
increments to a maximum of 30.6 ng/kg/min or down to a minimum of 3.4 ng/kg/min.  At 
the Investigator’s discretion, the patient will be weaned off the drug in 3.4 ng/kg/min 
increments. Study drug will be administered based on the pump rate calculated for the 
active treatment but delivered in mL/hr.  Study drug  can be administered up to 10 days.   


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5.3 
Study Medication Supply, Preparation, and Administration 
5.3.1 
Study Medication Supply 
The medicinal component of VentaProst, Flolan, (epoprostenol sodium), is already 
approved for I.V. delivery.  The dosage form is a vial of 1.5 mg epoprostenol as a 
lyophilizate and the required pH 12 Sterile Flolan diluent per the currently approved 
packet insert (NDA20-444/ Supplement 24 1).  Flolan and its diluent (pH 12 Sterile 
Diluent) are not re-formulated by Aerogen Pharma.  Flolan is used with the same diluent 
system and reconstituted per the approved packet insert.  
  
Flolan and diluent container closure (glass vial and stopper/crimp-pH 12 Sterile Diluent 
for Flolan comes in a plastic bottle for mixing) and secondary packaging (cardboard box) 
are not being altered, including the information on the vial and box label and the 
information in the approved Flolan packet insert.  This preserves the approved drug 
labeling information per NDA 20-444.  
 
Placebo will be a corresponding volume of  0.9% sodium chloride solution from the OSU 
IDS stock. 
5.3.2 
Study Medication Preparation 
Refer to the VentaProst-COVID Pharmacy Manual for preparation of study drug solution.. 
Prior to use, drug solutions  must be protected from light and refrigerated at 2° to 8°C 
(36° to 46°F) if not used immediately.  Do not freeze drug solutions and discard any  
drug solution that has been frozen. Discard any drug solutions if refrigerated for more 
than 8 days.  Control, (0.9% sodium chloride solution) will be placed in identical syringes 
and masked according OSU IDS procedures for blinded studies. 
5.3.3 
Study Medication Administration  
In the ICU, patients will be started on study drug administered via the VentaProst 
delivery system at an initial dose administered at 13.6 ng/kg/min.  Study Drug Study drug 
may be titrated up or down in 6.8 ng/kg/min increments (refer to VentaProst Pharmacy 
Manual) as clinically indicated to a dose range of 3.4 - 30.6 ng/kg/min.  Study drug will 
be administered based on the pump rate calculated for the active treatment in mL/hr.  
Study drug  can be administered up to 10 days.   
 
 
 
 
 
 
 
1 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020444s024lbl.pdf  


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Table 3:  Administration Titration Guidelines* 
Up titration Guideline  
Downward Titration / Guideline 
Start Dose: 13.6 ng/kg/min 
1st Step Up Dose (17.0) 
2nd Step Up Dose (20.4) 
3rd Step Up Dose (23.8) 
4th Step Up Dose (27.2) 
5th Step Up Dose (30.6) 
Start Dose: 30.6 ng/kg/min 
1st Step Down dose (23.8) 
2nd Step Down Dose (17.0) 
3rd Step Down dose (10.2) 
4th Step Down dose (3.4) 
 
*All study drug will be administered per the calculated pump rate for the active treatment in ml/hr 
 
Table 4-Example of Up Titration for male with Ideal Body Weight of 70 kg  
Initial Dose Rate 
Initial Pump Rate 
New Dose Rate 
New Pump Rate 
13.6 ng/kg/min 
1.89 mL/hr 
13.6 ng/kg/min 
1.89 mL/hr 
17.0 ng/kg/min 
2.39 mL/hr 
20.4 ng/kg/min 
2.86 mL/hr 
23.8 ng/kg/min 
3.33 mL/hr 
27.2 ng/kg/min 
 
3.81 mL/hr 
30.6 ng/kg/min 
4.28 mL/hr 
              Active drug is prepared with 50 mL in each syringe at a concentration of 30,000 ng/mL. 
              All study drug will be administered per the calculated pump rate for the active treatment in ml/hr. 
 
5.3.4 
Study Medication Weaning 
Patients will be weaned from study drug slowly to avoid rebound vasoconstriction.   
During weaning, doses will be decreased in steps of 6.8 ng/kg/min increments, with a no 
less than 5 minutes between changes as clinically indicated. The weaning process should 
occur in isolation to other treatment changes (no changes in inotropes, vasopressors, or 
vasodilators) whenever possible. Patients will be observed closely before, during, and 
after dose changes. In the event patients demonstrate signs of hemodynamic instability  or 
a decrease in oxygenation indicated by pulse oximetry during downward titration, the 
dose will be returned to its previous level. Once patients have been stable for at least 15 
minutes, repeat attempts at dose reduction may be undertaken.  The process will continue 
until patients are fully weaned.  Patients will be monitored for safety and efficacy 
throughout study drug administration. 
5.4 
Identity of the Device Component of the Investigational Product 
5.4.1 
Identity of Device 
The Phase 2a VentaProst drug delivery system is designed to accurately and precisely 
administer aerosol to the lungs of critically ill patients who require support via 
mechanical ventilation.  The aerosol generator’s fundamental operating mechanism and 
materials of construction will be similar to the 510(k)-cleared Aeroneb Solo System 
(K120939, K103635, K070642, Aerogen Ltd) and it is being designed for compatibility 
with the range of ventilators found in the OR and ICU. 


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5.4.1.1 VentaProst Aerosol Delivery to Ventilated Patients 
The VentaProst delivery system (Figure 1) consists of reusable and single-patient use 
disposable elements: 
1. Reusable multi-patient use components consist of two electronic controllers with 
power supplies, Aerogen Solo Nebulizer Cable, and Sensirion Flow Sensor Cable.  
When used together, they synchronize aerosol generation with the patient’s 
inspiratory pattern through a single-patient use, disposable administration kit. 
o Aerogen Pro-X, is a commercially available device (K1209392) cleared 
for use to continuously operate the disposable Aerogen Solo nebulizer. 
(item #1 Figure 1). 
o Aerogen Pharma Controller (AP Controller) is an investigational device, 
which synchronizes aerosol generation with the ventilator inspiratory 
cycle (item #2 on Figure 1).  This controller was tested to demonstrate its 
safety for use under IND129777.  
o Aerogen Solo Nebulizer Cable 
o Sensirion Flow Sensor Cable 
2. Single-patient disposable kit: 
o Aerogen Solo nebulizer (item #3 on Figure 1) is a commercially available, 
low mass and low profile vibrating mesh aerosol generator (K070642) 
cleared for use with the Aerogen Pro-X controller and Aerogen 
Continuous Nebulization Tube Set (CNTS).  
o Aerogen CNTS and syringe (items #4 and 5 on Figure 1) is a 
commercially available device (K103635) cleared for use to connect to the 
Aerogen Solo and deliver medication from the drug reservoir (syringe) to 
the mesh the nebulizer.   
o Flow sensor and cable connected to the Aerogen Pharma Controller (AP 
Controller, item #7 on Figure 1).  This is a new component of the system, 
which was tested to demonstrate safety for use in a clinical study.  
The VentaProst delivery system will be used in conjunction with a commercially 
available and FDA-cleared syringe pump (item #8 on Figure 1).  In general, any available 
syringe pump, which (1) is compatible with the Aerogen Continuous Nebulization Tube 
Set (CNTS syringe and tubing), and (2) is capable of delivering medication to the 
vibrating mesh nebulizer within the range of 0.4 to 12.0 mL/h as required to deliver the 
doses specified in the APC-VPCOV-CLN-001 Pharmacy Manual. For purposes of the 
VPCOV study, Aerogen Pharma will supply  the Perfusor® Space Infusion Syringe Pump 
System from B.Braun (Figure 1).  This particular syringe pump is FDA-cleared 
(K093913), it is compatible with the CNTS syringe (items #4 on Figure 1) and is able to 
 
 
 
2 The product names for the Aerogen commercial products changed from the term “Aeroneb”, to the brand 
name “Aerogen”.  A Note to File was submitted to FDA and receipt was acknowledged by the Branch 
Office 
 


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deliver fluids in the rage of 0.4 to 12.0 mL/h.  It is worth noting that on 11 April 2020, 
this pump received EUA for use in the tracheal delivery of continuous nebulized 
medications into a nebulizer to treat patients of all ages with or suspected of having the 
Coronavirus Disease 2019 (COVID-19)3.   
 
 
 
Figure 1: Drug Delivery System 
 
The Aerogen Pro-X (item #1, Figure 1), Aerogen Solo (item #3, Figure 1) are mounted on 
an I.V. pole at the patient’s bedside.  The two controllers and Aerogen CNTS (items #4 
and 5, Figure 1) are routinely used as a system within their intended use.  The sensor and 
nebulizer are connected into specific locations of the inspiratory limb of the ventilator 
pre- and post the humidifier, respectively (see Figure 2).  The addition of the AP 
Controller and an off-the shelf Sensirion flow sensor enables the VentaProst system to 
synchronize aerosol delivery with the inspiratory cycle of the ventilator (Figures 1 and 2).   
 
 
 
 
 
3 https://www.fda.gov/media/136894/download  
 


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Figure 2 illustrates the AP Controller, which is similar to the commercially available 
Aerogen Pro-X controller in form, size, weight and materials used for the upper and 
lower shells.  The AP Controller uses the same AC/DC adapter and cable as used in the 
commercial Aerogen Pro-X controller.  The packaging used for the AP Controller is same 
as packaging validated by Aerogen Ltd. for the commercially available Aerogen Pro-X 
system.  Functionality of the AP Controller was tested in design verification studies 
(IND129777).  Two dials (Figure 2) are used to: (1) set the flow threshold for 
nebulization triggering during the inspiratory cycle of the ventilator, accommodating 
initial ventilator baseline bias flows, and (2) set the duration of nebulization during the 
inspiratory cycle (a detailed description of the mechanism of action of the AP Controller 
is presented in IND129777).   
 
 
A. Diagram of Aerogen Pharma Controller 
(left side view) 
 
 
B. Diagram of Aerogen Pharma Controller (right 
side view) 
 
C. Flow Trigger Dial settings 
D. Aerosol Duration Dial settings 
 
Figure 2: Aerogen Pharma Controllers 
Prior to administration, study drug will be prepared per the VP COVID Pharmacy Manual 
and placed into a 60 mL CNTS syringe.  The syringe will be labeled to maintain the study 
blind.  The user will attach the syringe to the CNTS tubing and prime the tube set so that 
the formulation reaches the Aerogen Solo, producing aerosol generation.  The CNTS 
syringe set will be placed in a B Braun Perfusor Space Infusion syringe pump.  The 15-
mm T-Piece with nebulizer is placed between the ventilator circuit and the ETT (Figure 


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2).  The user will select the pump rate (mL/hr) to deliver the recommended dose based on 
the ideal body weight in kilograms (kg) dispensed to achieve the dose rate in ng/kg/min 
for active treatment.  The control treatment’s corresponding pump flow rate in mL/hour 
will be calculated based on initial dose of Flolan in ng/kg/min. All study drug will be 
administered per the calculated pump rate for active treatment in ml/hr.  The user will be 
able to adjust this recommended dose up or down (per protocol) by changing pump rate 
prior to selecting dose and initiating delivery.  The selected dose will then be dispensed 
by the pump to the receiving surface of the mesh, resulting in generation of an aerosol 
with a volume median diameter in the range of 2 to 5 µm.  The Aerogen Pharma 
Controller monitors the patient’s breathing pattern and user adjusts the knob (on left) to 
initiate aerosol generation at the beginning of the breathing cycle.  The knob on right sets 
the duration of aerosol generation within each breath.   
 
The VentaProst device is designed to be compatible with standard intensive care unit 
(ICU) equipment.  The following site-specific equipment will be needed to deliver the 
therapy: B.Braun syringe pump (provided by Aerogen Pharma), ventilator, endotracheal 
tube (ETT), humidifier, ventilator circuit.  This equipment is standard for critical care 
medicine. 
  
Figure 3 - VentaProst Device Placement in the Gas Pathway 
 


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5.4.2 
Ventilator Settings 
The device is designed for use with standard adult ventilator settings.  An intermittent 
positive pressure ventilatory mode (i.e., not constant positive airway pressure [CPAP] or 
t-piece) is required to activate the device to deliver aerosol during the inspiration phase.  
A Heat-Moisture Exchanger (HME) may be used in the device circuit.   
The site will utilize OSU’s Standard of Care (SOC) mechanical ventilation guidelines for 
care of patients for COVID-19 with ARDS.  The following ventilator parameters will be 
assessed daily while on VentaProst:  Ventilator type, Mode, FiO2, Inspiratory Time, Mean 
Airway Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, 
Respiratory Rate and Tidal Volume. 
5.4.3 
Device Supply 
All device supplies will be provided by Aerogen Pharma Limited (including the B.Braun 
Syringe Pump). The serial numbers for the controllers, flow sensor, and nebulizer will 
also be recorded in an IP accountability dispensing log. 
Used and unused devices will be inventoried and returned to the Sponsor or Sponsor’s 
designee. 
5.4.4 
Device Replacement 
Devices may be replaced at any time if there a suspicion of malfunction, but must be 
replaced if: 
• The investigator suspects that, due to device malfunction, less than 90% of the 
total dose of study drug has been delivered.  Reduced doses must be estimated 
and recorded in the patient’s medical record and source documentation.   
• The investigator suspects the device is not performing optimally for any reason. 
5.4.5 
Device Malfunction or Failure 
One device (Aerogen Pro-X controller, Aerogen Pharma Breath Controller, Flow Sensor, 
Solo nebulizer, CNTS tubing and syringe, and associated components) is expected to 
perform throughout the duration of study treatment.  If the controllers, Flow Sensor, 
CNTS tubing and syringe, or the Solo nebulizer are not functioning optimally for any 
reason, instructions for trouble-shooting provided in the device instruction for use manual 
should be followed.  If one or more devices need to be replaced, the reason should be 
documented in the patient’s medical record, dispensing log, and Device Performance 
Issues Form.  Additional devices are provided for this purpose.  The unique serial 
numbers of the new components will be recorded in the patient’s medical record, 
dispensing log, and the source documentation. 
For device malfunction or complaints, complete the Device Performance Issues Log and 
submit to the Sponsor at Complaints@aerogenpharma.com within 48 hours.  Failed 
devices will be set aside from the general supplies, inventoried and returned to the 
Sponsor or the Sponsor’s designee. 


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5.5 
Blinding 
Clinical and research staff and Sponsor will be blinded to Active or Control dose 
assignments with the exception of the pharmacy staff and an unblinded Sponsor CRA.  
Should unblinding be necessary, the medical monitor for this study will work with the 
unblinded pharmacist or unblinded CRA to unblind the patient.  
Active treatment (Flolan) is clear in color when reconstituted and Control treatment 
(0.9% sodium chloride solution) is also clear in color to maintain the study blind.  The 
Control and Active treatments will be placed in identical 60 mL syringes and labelled in a 
blinded manner prior to leaving the pharmacy. 
5.6 
Prior and Concomitant Therapy 
For patients who receive study drug, any medication (including over-the-counter [OTC] 
medications or other investigational therapies) or therapy administered to the patient 
during the course of the study (starting at Screening and 14  days prior) will be recorded 
on the Prior and Concomitant Therapy data collection forms.  The Investigator will 
record any AE on the AE data collection forms for which a concomitant 
medication/therapy was administered. 
5.6.1 Prohibited Concomitant Therapy 
Other inhaled vasodilators. 
5.7 
Investigational Product (IP) Supplies and Accountability 
Investigational product supplies will not be sent to the Investigator(s) until the following 
documentation has been received by the Sponsor: 
• Written proof of approval of the protocol and its informed consent forms (ICFs) 
by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for 
the institution where the study is to be conducted.  (Due to COVID-19 and the 
availability of the Active study medication, the study medication will be sent to 
the OSU pharmacy and held in quarantine until IRB approval and the completion 
of Study Initiation Visit (SIV), which may be conducted remotely or in person.  A 
NTF will be sent to OSU pharmacy instructing that the study medication is not 
released for use until Sponsor notification.) 
• An Investigator-signed and dated FDA Form 1572. 
• A signed and dated curriculum vitae of the Principal Investigator including a copy 
of the Principal Investigator’s current medical license (required in the US) or 
medical registration number on curriculum vitae. 
The Investigator and study staff will be responsible for the accountability of all IP 
supplies (dispensing, inventory, and record keeping) following Aerogen Pharma 
instructions and adhere to Good Clinical Practice (GCP) guidelines as well as local 
and/or regional requirements. 
Under no circumstances will the Investigator allow the IP to be used other than as 
directed by this protocol.  IP will not be administered to any individual who is not 
enrolled into the study. 


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An accurate and timely record of the receipt of all IP; dispensing of IP to the patient; 
collection of unused IP; and subsequent return of unused IP to Aerogen Pharma must be 
maintained.  This includes, but may not be limited to: (a) documentation of receipt of IP, 
(b) IP dispensing log, (c) IP accountability log, (d) all shipping service receipts, and (e) 
documentation of returned IP to the Sponsor.  All forms will be provided by Aerogen 
Pharma.  Any comparable forms that the investigational site wishes to use must be 
approved by Aerogen Pharma. 
The supplies and inventory records must be made available, upon request, for inspection 
by the designated representative of Aerogen Pharma, a representative of the FDA, or a 
representative of a non-US health authority.  All used and unused IP are to be returned to 
Aerogen Pharma at the conclusion of the study.   
6. 
CRITERIA FOR EVALUATION 
6.1 
Primary Endpoint 
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• Requires VV ECMO   
• Inability to extubate within 10 days or reintubation within < 24 hours 
• Change in S/F, oxygenation index and P/F ratio (>15%) from baseline to 
12 hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 
• Worsening hemodynamic parameters  
• Cardiac troponin >20% from baseline  
• BNP > 15% of baseline 
• Need for temporary mechanical circulatory support (IABP, Impella) 
• Requires VA ECMO 
6.2 
Secondary Endpoints 
1. Improvement in oxygenation defined as any one of the following: 
• Stabilization of PaO2/FIO2 >250 
• Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
2. Improved clinical outcomes  defined as one of more of the following: 
• Time to extubation following the site’s extubation protocol 


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• Free from re-intubation 
• Reduction in ICU days 
• Reduction in the number of re-admissions to the ICU due to COVID-19   
within 28 days 
• Reduction in total hospital days  
• Mortality [28 days] defined as Cardiopulmonary mortality or mortality 
from all causes  
3. Safety and tolerability 
• Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory/oxygenation parameters,  and 
laboratory tests. 
6.3 
Exploratory endpoints will include (where available as part of standard of 
care): 
• Change in LDH 
• Change in fibrinogen 
• Change in WBC count including lymphocytes and neutrophil subsets 
• Change in triglycerides 
• Change in ferritin 
• Change in CRP / ESR 
• Change in IL-6 
• Change in D-Dimer  
Changes in these parameters will be assessed for each patient from baseline to 
end of study as well as changes between the active and control groups. 
 
6.4 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used and generally 
recognized as reliable, accurate, and relevant in studies of cardiac and respiratory 
function. 
7. 
SAFETY ASSESSMENTS 
Safety will be assessed through monitoring of adverse events (AEs) and serious adverse 
events (SAEs),  laboratory tests, chest assessments (Chest CT or Chest X-ray), 
oxygenation/ventilatory parameters, and vital signs.  Safety assessment frequency is 
shown in the Schedule of Assessments and Procedures. 


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7.1 
General Safety Procedures 
7.1.1 
Vital Signs and Weight Measurements 
Vital sign measurements, including systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR) [beats per minute], respiratory rate (breaths per minute), 
and body temperature (in Celsius) will be obtained twice daily Days 1-10 or  as clinically 
indicated.  Weight (kg) will be obtained at the time of Screening and at Day 10 or end of 
VP treatment.  Height will be obtained at the time of Screening.  If unable to obtain 
height, the study staff will use the best reported historical height from patient or LAR. 
7.1.2 
Physical Examination 
A physical examination will be conducted at the screening visit and may include 
assessments of general appearance; skin and lymphatics; eyes, ears, nose, throat; 
cardiovascular system; respiratory system; abdomen/gastrointestinal system; urological 
system; musculoskeletal and neurological systems.  Other body systems may be 
examined as clinically indicated. 
7.1.3 
Laboratory Measurements 
Clinical laboratory measurements to be performed are listed below.  The Schedule of Assessments 
and Procedures shows the time points at which blood will be collected for clinical laboratory tests and 
pregnancy testing.  The Baseline for laboratory tests is the Screening assessment. 
Category 
Parameters 
Hematology-CBC with diff 
Hemoglobin, hematocrit, RBC, WBC with differential 
(neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, 
basophils), platelets  
Full Chemistry Panel 
 
Electrolytes 
Sodium, potassium, chloride, bicarbonate, calcium 
Liver function tests 
AST, ALT, AP, total bilirubin 
Renal function parameters 
BUN, creatinine 
Coagulation Studies 
PT/PTT 
Other 
Serum or urine pregnancy test, COVID-19 diagnostic test, 
Troponin, and BNP (fibrinogen, ferritin, LDH, Triglycerides, 
D-Dimer, IL-6, ESR,CRP may be obtained if the patient’s 
standard of care warrants the tests) 
7.1.4 
Chest Assessments 
A Chest CT or Chest X-ray will be obtained at Screening and between days 3 to 8 as 
clinically indicated. 
7.1.5 
Time Prone Protocol 
The time prone protocol is a standard of care in OSU’s ICU.  This will be in place for all 
days that patients are within the ICU. 
7.2 
Adverse Events 
7.2.1 
Definitions 
Adverse events are any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 


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with this treatment.  For the purposes of this study, this will include unanticipated 
medical events in the judgment of the investigator.  A pre-existing condition or symptom 
is one that is present at the start of the study and is reported as part of the patient’s 
medical history.  A pre-existing condition or symptom should be reported as an AE only 
if its frequency, intensity or character worsens during study treatment. 
All AEs that occur from the time of the first dose of study medication through the End of 
Study (Day 28) will be recorded and reported as Treatment-Emergent Adverse Events 
(TEAE).  All AEs must be appropriately documented in the patient’s medical 
chart/source documentation and on the DCFs.  When known, investigators should report 
syndromes rather than list symptoms associated with the syndrome. 
All AEs that are ongoing at the conclusion of the study should be followed until: a) 
resolution/stable sequelae; b) the Investigator determines that it is no longer clinically 
significant; or, c) the study patient is lost to follow-up.  If no follow-up is provided, the 
Investigator must provide a written justification. 
7.2.2 
Adverse Events of Special Interest (AESI) 
Pulmonary edema and  pulmonary hemorrhage are AEs of special interest due to the 
mode of action of epoprostenol.  If an AE of special interest occurs, the Sponsor will be 
notified of this occurrence within 24 hours. 
7.2.3 
Grading of Adverse Events 
The severity of each AE will be categorized using the following criteria: 
• Grade 1 (Mild):  usually transient; requires no special treatment and does not 
interfere with the patient’s daily activities. 
• Grade 2 (Moderate):  produces a low level of inconvenience to the patient and 
may interfere with daily activities.  These AEs are usually ameliorated by simple 
therapeutic measures. 
• Grade 3 (Severe):  interrupts daily activity and requires systemic drug therapy or 
other medical treatment. 
7.2.4 
Relationship to Study Medication/Study Device/Procedure 
The Investigator must assess the relationship of each reported AE.  The Investigator must 
make an assessment of the relationship of the AE to the study drug/study 
device/procedure using the following scale: 
• Unrelated:  The AE is definitely not or unlikely to be associated with study 
medication/study device/procedure and is judged due to causes other than the 
study medication/study device/procedure. 
• Related:  The AE is possibly or probably related with study medication/study 
device/procedure.    
7.2.5 
AE Outcomes 
The following terms and definitions are used in assessing the final outcome of an AE:  


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• Recovered/Resolved - The patient has fully recovered, or by medical or surgical 
treatment, the condition has returned to the level observed at the first trial-related 
activity. 
• Recovering/Resolving - The condition is improving and the patient is expected to 
recover from the event. 
• Recovered/Resolved with sequelae - The patient has recovered from the 
condition, but with lasting effect due to a disease, injury, treatment or procedure. 
If a sequela meets an SAE criterion, the AE must be reported as an SAE. 
• Not recovered/Not resolved - The condition of the patient has not improved and 
the symptoms are unchanged, or the outcome is not known at the time of 
reporting. 
• Fatal - This term is only applicable if the patient died from a condition related to 
the reported AE. Outcomes of other reported AEs in a patient before he/she died 
should be assessed as “recovered”, “recovering”, “recovered with sequelae” or 
“not recovered”.  An AE with fatal outcome must be reported as an SAE. 
7.2.6 
Laboratory Test and other Test Abnormalities as Adverse Events 
A laboratory or other test (chest assessments, vital signs) abnormality should be reported 
as an AE if the Investigator considers the abnormality an AE or if the abnormality is 
associated with accompanying symptoms, requires medical/surgical intervention, leads to 
a change in study treatment, or results in discontinuation from the trial. When possible, 
syndromes not laboratory values, should be reported as AEs.  For example, elevated 
hepatic transaminases associated with hepatitis should be reported as “hepatitis” and 
decreased hemoglobin and hematocrit requiring iron supplementation should be recorded 
as “anemia.”  Prior to reporting as an AE, abnormal tests should be repeated to verify the 
accuracy of the original result. 
7.2.7 
Serious Adverse Events 
The Investigator is required to determine if each AE is a Serious Adverse Event (SAE).  
An SAE is any AE occurring after randomization and through Day 28 and results in any 
of the following outcomes: 
• Death, or 
• Is life-threatening, or 
• Prolongation of existing hospitalization, or 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 


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In the event of death, the cause of death should be recorded as the SAE (death is an 
outcome, not the AE itself). 
Any planned procedures that require admission to hospital as well as any planned elective 
procedures (e.g., angioplasty) are not considered SAEs (unless the underlying condition 
has worsened or the procedure results in a worsening of the patient’s condition).  In 
addition, pregnancy that occurs during the course of the study or absence of a treatment 
effect will also not be considered to be an SAE and will be collected on a separate CRF. 
7.2.8 
Reporting for SAEs (24 Hours) 
Regardless of causality, an SAE must be followed clinically until resolution or 
stabilization.   
All SAEs after randomization and through Day 28 of the study must be reported to the 
Sponsor or the Sponsor’s representative within 24 hours of the investigational site’s 
knowledge of the occurrence.  The investigational site will email a Serious Adverse 
Event Report (SAER) to the Sponsor and the Medical Monitor.    Investigational sites 
will be provided with SAER forms.  The Medical Monitor will work closely with the 
Sponsor to properly assess and report the SAE.  
The SAE information emailed to the Sponsor or the Sponsor’s representative will include 
the following (as available): 
• Patient Number, Investigator name, and Site Number 
• SAE information:  event term, onset date, severity, and causal relationship 
• Basic demographic information (e.g., age, gender, weight) 
• The outcomes attributable to the event (death, a life-threatening adverse drug 
experience, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, other important medical event[s]) 
• A summary of relevant test results, pertinent laboratory data, and any other 
relevant medical history 
• The first and last dates of study drug administration. 
• A statement whether study medication was discontinued or study medication 
administration schedule modified 
• A statement whether event recurred after reintroduction of study medication if 
administration had been discontinued or withheld 
• Supplemental anonymized information may include the following hospital 
records:  laboratory results, radiology reports, progress notes, admission and 
emergency room notes, holding/observation notes, discharge summaries, autopsy 
reports, and death certificates 
Supplemental information may be transmitted using a follow-up report and should not 
delay the initial report. 


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For regulatory purposes, initial reports of SAEs should be transmitted within the 
prescribed time frame as long as the following minimum information is available:  patient 
number, suspect study medication, reporting source, and an event or outcome that can be 
identified as being both serious and unexpected for which the Investigator can make a 
relationship assessment. 
7.3 
Reporting of Pregnancy 
Any pregnancy where the estimated date of conception occurs either prior to the End of 
Study must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, 
this should be reported regardless of the length of time that has passed since the exposure 
to study treatment.  The medical monitor may decide that unblinding of the patient 
treatment assignment may be necessary. 
An induced abortion or a spontaneous abortion is considered to be an SAE and should be 
reported in the same timeframe and in the same format as all other SAEs. 
Pregnancies must be reported as soon as possible but no later than one business day by 
email.  
All pregnancies must be followed to outcome.  The outcome of the pregnancy must be 
reported as soon as possible but not later than 24 hours of the investigational site’s 
knowledge of the outcome. 
8. 
PHARMACOKINETIC ASSESSMENTS 
Not applicable. 
9. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
The assessments and procedures for this study are described in detail below and 
presented in the Schedule of Assessments and Procedures located behind the Synopsis. 
9.1 
Study Evaluation Timepoints 
9.1.1 Screening (within 14 days prior to Baseline Day 1) 
Potential study patients will be recruited by the study staff from patients.  The following 
assessments will occur prior to study enrollment: 
• Informed consent (study procedures or assessments may be  performed prior to 
consent as many screening study procedures were obtained as part of the patient’s 
standard of care treatment). 
• Demographic Information 
• Medical History  
• Physical Exam 


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• Prior Medication History 
• Chest CT or Chest X-ray 
• Inclusion/Exclusion Eligibility Assessment (including assessment of shortness of 
breath within the last 14 days) 
• Serum/Urine Pregnancy Test (if woman of childbearing potential) 
• Clinical Laboratory Sampling to include: Full Chemistry Panel including LFTs, 
CBC with Diff including neutrophils and lymphocytes, PT/PTT,  troponin, and 
BNP (Triglycerides, LDH, ferritin, fibrinogen, CRP, ESR, IL 6 and D-Dimer may 
be collected if the subject’s condition warrants it)  
• COVID-19 diagnostic test such as molecular or antigen test (However the COVID 
test was obtained, documentation of the results must be available prior to study 
entry.  For additional study COVID tests, whenever possible, please use the same 
type of test) 
• Vital Signs  
• Height & Weight (If height can’t be obtained, use the best reported historical 
height) 
9.1.2 Days 1-10 Treatment  
9.1.2.1 Randomization 
• Evaluate that the patient continues to be  eligible for the study by assessing 
Inclusion/Exclusion Criteria. 
• Once eligibility has been confirmed, a Subject number beginning with 101 and 
rising sequentially will be assigned to the next enrolled subject. 
• A blinded order for the Investigational Drug Services group will be generated by 
EPIC for the next sequential subject to be randomized.  
• The unblinded pharmacist will prepare the treatment assignment (Active or 
Control) for the next assigned Subject number. 
• The reconstituted study drug will be protected from light and labelled in a blinded 
manner to ensure maintenance of the study blind. 
• Subjects will be randomized to receive either Active or Control for a maximum of 
10 days, as clinically indicated and at the discretion of the Investigator. 
9.1.2.2 Baseline-Day 1 (0 Hour) 
 
• Continue evaluation eligibility by assessing Inclusion/Exclusion Criteria. 
•   Study drug treatment will begin at a starting dose of 13.6 ng/kg/min based on the 
concentration used to calculate Active treatment in mL/hr and can be titrated up to 
30.6 ng/kg/min or down to 3.4 ng/kg/min as clinically warranted.  The B.Braun 
syringe pump will be set to the appropriate dose in mL/hr utilizing the subject’s 
sex and height (ideal body weight).  
• Vital signs will be assessed twice daily in AM and PM while on study drug.  
Efforts will be made to obtain vital signs at the same time each day.  Vital signs 
include: temperature, pulse rate, respiration rate and blood pressure.  
• Adverse Event/SAE assessment daily 


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• Concomitant medication evaluation daily 
• Continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily while on study drug:  Ventilator 
Type, Vent Mode, FiO2, Inspiratory time, Mean Airway Pressure, Peak 
Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume, and 
Respiratory Rate 
• Time Prone Position-16 hours per day per OSU Protocol 
9.1.2.3 Day 1-12 hours 
• Continue to administer study drug if clinically indicated. 
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Oxygenation measurement via continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily while on study drug:  Ventilator 
Type, Vent Mode, FiO2, Inspiratory time, Mean Airway Pressure, Peak 
Inspiratory Pressure, Positive End Expiratory Pressure, Tidal Volume, and 
Respiratory Rate 
• Vital signs will be assessed twice daily in AM and PM.  Efforts will be made to 
obtain vital signs at the same time each day.  Vital signs include: temperature, 
pulse rate, and blood pressure.  
• Time Prone Position-16 hours per day per OSU Protocol 
9.1.2.4 Days 2-10 (While on study drug) 
• Continue to administer study drug if clinically indicated. 
• Adverse Event/SAE assessment daily 
• Concomitant medication evaluation daily 
• Oxygenation measurement via continuous pulse oximetry (SpO2) 
• Ventilatory parameters assessed twice daily: Ventilator Type, Vent Mode, FiO2, 
Inspiratory time, Mean Airway Pressure, Peak Inspiratory Pressure, Positive End 
Expiratory Pressure, Tidal Volume, and Respiratory Rate 
• Vital signs will be assessed twice daily in AM and PM.  Efforts will be made to 
obtain vital signs at the same time each day.  Vital signs include: temperature, 
pulse rate, and blood pressure.  
• Time Prone Position-16 hours per day per OSU Protocol 


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• Chest X-ray (Days 3-8 as clinically indicated) 
• Full Chemistry Panel including LFTs, CBC with Diff including neutrophils and 
lymphocytes, PT/PTT, troponin, and BNP(Days 5 & 10).  
• Triglycerides, LDH, ferritin, fibrinogen, CRP, ESR, IL 6 and D-Dimer may be 
collected if the subject’s condition warrants it at Days 5 and Day 10. 
• Obtain weight. (Day 10 only or at end of study drug dosing) 
9.1.2.5 Weaning  
See Section 5.3.4 and Table 3 for weaning guidelines.  
 
9.1.3 
Day 28/End of Study (EOS)  
•    Assess AEs/SAEs  
•    Assess Mortality 
•    Assess concomitant medications 
9.2 
Data Collection 
Investigator or designee will enter the information required by the protocol onto source 
documents and enter data into data collection forms (DCFs) in an excel spreadsheet 
provided by Aerogen Pharma. 
9.3 
Clinical Data Management 
Data from source documents will be verified against the DCF and any discrepancies will 
be clarified and resolved with study staff. 
9.4 
Database Quality Assurance 
All data will be remotely monitored by the Sponsor due to the COVID-19 pandemic. 
Should restrictions be lifted at OSU, an on-site visit may occur if all parties are in 
agreement. 
10. 
 STATISTICAL CONSIDERATIONS 
10.1 
Statistical Methods 
A Statistical Analysis Plan will be not be developed as this is an exploratory trial.  Any 
statistical evaluation will be handled internally by Aerogen Pharma or their designee. 
10.2 
Determination of Sample Size 
The number of patients has been selected to enable an adequate clinical assessment of 
pharmacodynamics, safety, and tolerability parameters without presenting undue risk to a 
large number of patient’s being exposed to this investigational product. 


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10.3 
Analyses Sets 
All patients who are enrolled in the study and who receive at least one dose of study drug  
will be included in the intent-to-treat (ITT) analyses of pharmacodynamic and safety data.  
All available data will be used and missing data will not be estimated or carried forward 
in any statistical summary or analyses. 
Descriptive summary statistics include the number of patients, mean, median, percent 
coefficient of variation (% CV) (if required), standard deviation, and minimum and 
maximum values (quantitative variables) or the number of patients and percentages by 
category (qualitative variables).  Changes will be assessed as the difference between 
baseline measurements and the appropriate post-dose measurements unless otherwise 
specified.  Mean differences between active and control groups (when available) will be 
assessed and significance will be determined on the basis of a 95% CI.  Individual patient 
listings of data will also be provided to allow for review of all pharmacodynamic, safety, 
and tolerability parameters. 
10.4 
Randomization 
Patients will be randomized 1:1. A randomization schedule will be provided to the 
unblinded pharmacist.  Should unblinding be requested due to a medical emergency, the 
unblinded pharmacist will work with the medical monitor or Sponsor unblinded CRA to 
obtain the required information. 
10.5 
Demographic and Other Baseline Characteristics 
Continuous demographic and other baseline characteristics (such as age, weight, and 
height) will be summarized using n, mean, SD, median, minimum, and maximum.  
Qualitative characteristics (such as gender and race) will be summarized by counts and 
percentages.   
10.6 
Criteria for Evaluation 
10.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint:  
1. Reduction of respiratory failure. Failure is defined by any one of the following: 
• Requires VV ECMO   
• Inability to extubate patient within 10 days or reintubation within <24 
hours 
• Change in S/F, oxygenation index and P/F ratio (>15%) from baseline to 
12 hours, Days 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 (or end of treatment) 
or 
2. Reduction of cardiac or circulatory failure. Failure is defined by any one of the 
following: 
• Need to begin inotropic therapy or 10% increase in current vasopressor 
therapy 


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• Worsening hemodynamic parameters  
• Cardiac troponin >20 % from baseline   
• BNP > 15% of baseline 
• Need for temporary mechanical circulatory support (IABP, Impella) 
• Requires VA ECMO 
10.6.2 
Secondary Efficacy Endpoints 
Key secondary endpoints include: 
1. Improvement in oxygenation defined as any one of the following: 
• 
Stabilization of PaO2/FIO2 >250 
• Improvement in FIO2 by 50% or improvements >15% in S/F, P/F ratio 
from baseline at 12 hours, Day 5 and Day 10 (or end of treatment) 
2. Improved clinical outcomes  defined as one of more of the following:  
• Time to extubation following the site’s extubation protocol 
• Free from reintubation 
• Reduction in ICU days 
• Reduction in the number of re-admissions to the ICU due to COVID-19   
within 28 days 
• Reduction in total hospital days  
• Mortality [28 days] defined as Cardiopulmonary mortality or mortality 
from all causes  
3. Safety 
• Monitoring of adverse events (AEs), serious adverse events (SAEs), chest 
CT or Chest X-rays, vital signs, ventilatory/oxygenation parameters,  and 
laboratory tests. 
10.6.3 
Key Exploratory Endpoints include: 
• Change in LDH 
• Change in fibrinogen 
• Change in WBC count including lymphocytes and neutrophil subsets 
• Change in triglycerides 
• Change in ferritin 
• Change in CRP / ESR 
• Change in IL-6 
• Change in D-Dimer  
Changes in these parameters will be assessed for each patient from baseline to 
end of study as well as changes between the active and control groups. 


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10.7 
Extent of Exposure 
Exposure data will be summarized by using frequencies and percentages. 
10.8 
Safety Analyses 
Safety measurements include AE/SAEs, vital signs, chest assessments (Chest CT or 
Chest X-ray), laboratory tests, and oxygenation/ventilatory parameters.  Safety data will 
be summarized by using frequencies and incidence rates.   
10.8.1 
Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim 
description (Investigator term) using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be presented by preferred term nested within System Organ Class.  
Verbatim description and all MedDRA level terms, including the lower level terms, for 
all AEs will be contained in the data listings of the clinical study report (CSR).  
AEs will be summarized by presenting the incidence of AEs.  Although a MedDRA term 
may be reported more than once for a patient, that patient will be counted only one time 
in the incidence count for that MedDRA term. 
Treatment-emergent adverse events (TEAEs) will be analyzed.  AEs that are not 
treatment-emergent will be listed.  A TEAE is defined as  
• AEs that emerge during treatment, having been absent at pretreatment, or  
• Reemerge during treatment, having been present at pretreatment but stopped 
prior to treatment, or  
• Worsen in severity or frequency during treatment relative to the pretreatment 
state, when the AE is continuous. 
Adverse events of special interest (AESI) will be analyzed.   An AESI is defined as: 
• Serious or non-serious adverse that is one of scientific and medical    concern 
specific to the sponsor’s product for which ongoing monitoring   and rapid 
communication by the investigator to the sponsor is required 
• Events or symptoms thought to potentially be associated with the investigational 
compound, device, or disease under study, or 
• Can arise with any use of a drug/device (e.g. off-label use, use in combination 
with another approved drug), with any route of administration, formulation, or 
dose, including an overdose. 
 
10.8.2 
Laboratory Values 
Clinical laboratory results post-Baseline will be evaluated for markedly abnormal values.  
For the incidence of markedly abnormal laboratory values, each patient may be counted 
once in the laboratory parameter value high and in the laboratory parameter low 


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categories as applicable.  Descriptive summary statistics (e.g. mean, SD, median, 
minimum, maximum) for laboratory values and changes from baseline will be evaluated. 
10.8.3 
Vital Signs 
Vital sign values will be evaluated on an individual basis by patient.  Abnormal vital sign 
values will be identified as those outside (above or below) the reference range.  
Descriptive summary statistics (e.g., mean, SD, median, minimum, maximum) for vital 
sign parameters and changes from Baseline will be evaluated. 
10.9 
The Procedure for Revising the Statistical Analysis Plan 
Not Applicable. 
11. 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS 
11.1 
Ethics 
11.1.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an IRB or IEC constituted and functioning in accordance with 
International Conference on Harmonization (ICH) E6, Section 3, and any local 
regulations, i.e., Federal Regulations, Title 21 Code of Federal Regulations (CFR) Part 
56.  Any protocol amendment and/or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval (except for changes involving only logistical or 
administrative aspects of the study (e.g., change in CRA[s], change of telephone 
number[s]).  Documentation of IRB/IEC compliance with the ICH and any local 
regulations regarding constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC Chairman must be sent to the 
Principal Investigator with a copy to the Sponsor prior to study start.  If the IRB/IEC 
decides to suspend or terminate the study, the Investigator will immediately send the 
notice of study suspension or termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator 
or Sponsor, depending on local regulatory obligations.  If the Investigator is required to 
report to the IRB/IEC, he/she will forward a copy to the Sponsor at the time of each 
periodic report.  The Investigator or the Sponsor will submit, depending on local 
regulations, periodic reports and inform the IRB/IEC of any reportable AEs per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
Investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required. 
11.1.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating practices of Aerogen 
Pharma (or designee), which are designed to ensure adherence to GCP guidelines as 
required by the following: 


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• ICH - E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonization of Pharmaceuticals for Human Use. 
• US CFR dealing with clinical studies (21 CFR, including parts 50 and 56 
concerning Informed Patient Consent and IRB regulations). 
11.1.3 
Patient Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each patient or their legally authorized representative (LAR), the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, and currently available alternative treatments.  Each 
patient must be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written 
in non-technical language.  The patient or their LAR should understand the statement 
before signing and dating it and will be given a copy of the signed document.  The patient 
or their LAR will be asked to sign an informed consent prior to any study-specific 
procedures being performed (except for study procedures that were conducted as a part of 
the patient’s standard of care).  No patient can enter the study before his/her informed 
consent has been obtained.  Due to the COVID-19 pandemic and restrictions on hospital 
visitors, informed consent may be obtained via telephone or video conference call if the 
patient is incapacitated or sedated due to the severity of their illness.  A witness for the 
study team should be present when a call or video conference is occurring with the 
patient’s LAR.  This process should be carefully documented in the subject’s medical 
records. 
An unsigned copy of an IRB/IEC and Sponsor-approved written informed consent must 
be prepared in accordance with ICH E 6, Section 4, and all applicable local regulations, 
i.e., Federal Regulations, Title 21, CFR Part 50, and provided to the Sponsor.  Each 
patient or their LAR must sign (or give verbal consent with study staff witnessing the 
verbal consent) an approved informed consent prior to study participation.  The form 
must be signed and dated by the appropriate parties.  The original signed ICF for each 
patient will be verified by the Sponsor and kept in the study center’s investigational site 
files. 
The patient should be informed in a timely manner if new information becomes available 
that might be relevant to the patient’s willingness to continue participation in the trial.  
The communication of this information should be documented. 
11.2 
Administrative Procedures 
11.2.1 
Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  
Protocols will be followed as written. 


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Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the Sponsor before implementation.  Amendments 
specifically affecting the safety of patients, the scope of the investigation, or the scientific 
quality of the study require additional approval by the applicable IRBs/IECs of all 
investigational sites and, as required, by the regulatory authority.  These requirements 
should in no way prevent any immediate action from being taken by the Investigator, or 
by the Sponsor, in the interest of preserving the safety of all patients included in the 
study.  If an immediate change to the protocol is felt by the Investigator to be necessary 
for safety reasons, the  Medical Monitor must be notified promptly and the IRB/IEC for 
the site must be informed as soon as possible. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval, but the IRB/IEC must be kept informed of such 
changes.  In these cases, the Sponsor will send a letter to the site for forwarding on to the 
IRB/IEC detailing such changes. 
11.2.2 
Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
11.2.3 
Monitoring Procedures 
The Sponsor or Sponsor’s representative will maintain contact with the Investigator and 
designated staff by telephone, letter, and/or email between study visits.  Monitoring visits 
to each investigational site will be conducted by the sponsor either remotely or in person.  
In accordance with ICH E6, Section 6.10, source documents include, but are not limited 
to the following: 
• Clinic, office, hospital charts. 
• Copies or transcribed health care provider notes which have been certified for 
accuracy after production. 
• Recorded data from automated instruments such as mechanical ventilators, x-
rays, and other imaging reports, e.g., sonograms, computed tomography scans, 
magnetic resonance images, radioactive images, ECGs, rhythm strips, 
electroencephalographs, polysomnography, pulmonary function tests (regardless 
of how these images are stored, including microfiche and photographic 
negatives). 
• Records of telephone contacts. 
• Diaries or evaluation checklists. 
• Investigational product distribution and accountability logs maintained in 
pharmacies or by research personnel. 
• Laboratory results and other laboratory test outputs, e.g., serum pregnancy test 
result documentation. 
• Correspondence regarding a study patient’s treatment between physicians or 
memoranda sent to the IRBs/IECs. 


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• CRF components (e.g., questionnaires) that are completed directly by patients 
and serve as their own source. 
11.2.4 
Recording of Data 
In order to provide the Sponsor with accurate, complete, and legible records following 
criteria are to be maintained.  The Investigator will enter the information required by the 
protocol onto the data collection forms (DCFs)  provided by the sponsor as agreed upon 
with the research staff. 
11.2.5 
Data Storage and Retention of Records 
 
The circumstances of completion or termination of the study notwithstanding, the 
Investigator has the responsibility to retain all study documents, including but not limited 
to the protocol, copies of data collection forms (DCFs) , Investigator's Brochure, 
regulatory agency registration documents, e.g., FDA 1572 form, ICFs, and IRB/IEC 
correspondence.  The investigational site should plan on retaining study documents as 
follows: 
• For at least two years following the date a marketing application is approved for 
the investigational product for the indication for which it is being investigated, or 
• Until two years after the investigation is formally discontinued and no application 
is to be filed or if the application is not approved. 
It is requested that at the completion of the required retention period, or should the 
Investigator retire or relocate, the Investigator contacts the Sponsor, allowing the Sponsor 
the option of permanently retaining the study records. 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Data will be coded (de-identified), stored in a secure electronic database during and after 
the study, and will not be shared with unauthorized persons. The principal investigator 
and co-investigator will have access to the data to review and analyze the data, as 
described in this protocol. For the protection and privacy of the patients, no identifying 
information will be released.  Data will be retained and possibly used in the future for 
further analysis. All identifiers will be removed and not be shared at any time. 
11.2.6 
Handling of Investigational Product 
Investigational study drug (Flolan) will be inventoried and maintained within the site’s 
Investigational Drug Services .  It will be stored according to their protocols and 
procedures.   The study drug should not be dispensed to patients in the VentaProst 
COVID trial (APC-VPCOV-CLN-001) until a favorable IRB approval has been obtained 
by the OSU IRB and a study initiation visit has been conducted by the Sponsor.  
Investigational device  supplies must be kept in an appropriate secure area (e.g., locked 
cabinet) and stored according to the conditions specified on the investigational product 
labels.  The Investigator (or designated pharmacist) must maintain an accurate record of 
the shipment and dispensing of the IP (both device and drug) in an IP accountability log, 
a copy of which must be given to the Sponsor at the end of the study.  An accurate record 


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of the date and amount of IP dispensed to each patient must be available for inspection at 
any time.  The assigned sponsor representative will review these documents along with 
all other study conduct documents at an appropriate interval of visit to the investigational 
site once IP has been received by the investigational site.  Due to COVID-19 a physical 
inventory of IP (drug and device supplies) may not be possible.  If at all possible, an 
inventory of supplies should be conducted via video conferencing.  If video conferencing 
is not possible, study staff will inventory supplies and provide documentation to Aerogen 
Pharma. 
All IP supplies (with the exception of OSU stock 0.9% sodium chloride solution supplies) 
are to be used only for this protocol and not for any other purpose.  The Investigator (or 
designated pharmacist) must not destroy any IP product labels or any partly used or 
unused IP supply without Sponsor authorization.  At the conclusion of the study and as 
appropriate during the course of the study, the Investigator (or designated pharmacist) 
will return or properly dispose of all used IP. Unused investigational device and drug 
components will be returned to Aerogen Pharma at the conclusion of the study. 
11.2.7 
Publication of Results 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each Investigator and Aerogen Pharma, as appropriate. 
11.2.8 
Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the course 
of this study will be kept confidential by the Investigator, the Investigator’s staff, and 
IRB/IEC and will not be disclosed in whole or in part to others or used for any purpose 
other than reviewing or performing the study without the written consent of the Sponsor.  
No data collected as part of this study will be utilized in any written work, including 
publications, without the written consent of Sponsor.  These obligations of confidentiality 
and non-use shall in no way diminish such obligations as set forth in the Confidentiality 
Agreement between the Sponsor and the Investigator.  All persons assisting in the 
performance of this study must be bound by the obligations of confidentiality and non-
use set forth in the Confidentiality Agreement between the Investigator and Sponsor 
(provided by the Sponsor). 
11.2.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.   
The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the Investigator terminates or suspends a trial without prior agreement of the 
Sponsor, the Investigator should inform the Institution where applicable, and the 
Investigator/Institution should promptly inform the Sponsor and the IRB/IEC and should 
provide the Sponsor and the IRB/IEC a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 


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11.2.10 Patient Insurance and Indemnity 
The Sponsor will provide the insurance in accordance with local guidelines and 
requirements as a minimum for the patients participating in this study. 


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12. 
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