A Two-Part Pharmacodynamic Study to Compare VentaProst (Epoprostenol Solution for Inhalation Via Custom Drug Delivery System) Dosing to Conventionally Administered Aerosolized Epoprostenol Dosing in Cardiac Surgery Patients
Phase: PHASE2
Conditions: Pulmonary Hypertension
Sponsor: Aerogen Pharma Limited

 
 
PROTOCOL TITLE 
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 
PROTOCOL  
NUMBER 
APC-VP-CLN-001 
INVESTIGATIONAL 
PRODUCT 
VentaProst 
INDICATION 
Pulmonary Vascular Resistance in Cardiac Surgery Patients 
PHASE 
Phase 2a 
SPONSOR 
Aerogen Pharma Limited 
1660 S Amphlett Boulevard, Suite 360 
San Mateo, CA 94402 
United States 
MEDICAL MONITOR 
Pia Mikkelsen Lynch, MD 
Aerogen Pharma 
Mobile Telephone: +1 404 963 9090 (US) /+45 5381 2607 (DK) 
Facsimile: +1-678-828-5549 
Email: plynch@pmlmedical.com 
APPROVAL DATE 
 28 November 2017 
 
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. 

28 Nov 2017

Aerogen Pharma 
 
Protocol Number APC-VP-CLN-001  
Amendment 3 28 November 2017 
Confidential 
Page 3 of 60 
 
INVESTIGATOR’S SIGNATURE PAGE 
PROTOCOL 
TITLE: 
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 
 
 
PROTOCOL 
NUMBER: 
APC-VP-CLN-001 
 
 
 
 
 
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-VP-CLN-001  
Amendment 3 28 November 2017 
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Page 4 of 60 
1. 
CLINICAL PROTOCOL SYNOPSIS 
Sponsor 
Aerogen Pharma 
Protocol No. 
APC-VP-CLN-001 
Title of Study 
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 
Study Centers 
Approximately three clinical sites in the US 
Phase 
Phase 2a 
Objectives 
 
Primary Objective 
• 
To identify the relative dose equivalency between effective conventionally 
administered aerosolized Veletri® and VentaProst doses 
Secondary Objectives 
• 
To evaluate the safety and tolerability of VentaProst doses in a patient population 
post cardiac surgery with cardiopulmonary bypass (CPB) 
• 
To demonstrate that VentaProst dose titration to achieve at least a 15% improvement 
in one or more hemodynamic parameters (as defined by the clinical team) is safe and 
effective 
• 
To demonstrate the pharmacodynamic (PD) equivalence (based on cardiovascular 
parameters, indices of oxygenation, and ventilator support) of VentaProst doses to 
aerosolized Veletri doses 
• 
To identify cardiovascular medications administered concomitantly with VentaProst 
• 
To monitor ventilator support needed 
Study Design 
 
Part I (see Appendix 1 for Study Design Schematic) 
The first part of this study will be conducted in approximately 10 consented post-operative 
cardiothoracic surgery patients on cardiopulmonary bypass (CPB) who are receiving 
aerosolized Veletri (in accordance with each site’s standard of care guidelines) and who 
demonstrate at least a 15% improvement in one or more hemodynamic parameters (as defined 
by the clinical team) when treated with aerosolized Veletri.  This part of the study is designed 
to demonstrate the dose equivalence between aerosolized Veletri and VentaProst using a 
patient’s hemodynamic parameters, with the goal to determine the VentaProst dose necessary 
to achieve a hemodynamic response that is not less than 90% of the effect observed with 50 
ng/kg/min aerosolized Veletri.  Arterial oxygen saturation (SaO2) must be maintained at or 
above the level obtained with aerosolized Veletri administration.  
Qualifying patients will: 
• 
Receive aerosolized Veletri 50 ng/kg/min in the OR/ICU 
• 
Have hemodynamic parameters measured before and after aerosolized Veletri 
administration to determine changes 
o 
IF AT LEAST A 15% IMPROVEMENT IN ONE OR MORE HEMODYNAMIC 
PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) IS SEEN WITH 
AEROSOLIZED VELETRI AFTER STABILIZATION IN THE ICU: 

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 
Be administered VentaProst as follows:  Setup VentaProst inline to the 
ventilator circuit, start nebulization, then stop conventional Veletri pump 
flow and nebulizer while still inline.  Do not remove Veletri administration 
system until VentaProst administration is confirmed 
o 
IF LESS THAN A 15% IMPROVEMENT IN ONE OR MORE HEMODYNAMIC 
PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) IS SEEN WITH 
AEROSOLIZED VELETRI AFTER STABLIZATION IN THE ICU: 
 
Not be administered VentaProst 
• 
Receive a calculated equivalent starting dose of 17 ng/kg/min of VentaProst while 
still on mechanical ventilation 
• 
Receive increases in the VentaProst dose in 20% increments (refer to the VentaProst 
Pharmacy Manual) every 15 minutes until at least 90% of the hemodynamic effect 
observed with 50 ng/kg/min aerosolized Veletri is achieved while still on mechanical 
ventilation 
Once a VentaProst dose equivalence has been achieved, patients will be weaned from 
VentaProst.  VentaProst weaning will occur from mechanical ventilation only.  If the patient 
has been extubated and is on institution’s standard of care delivery system for administering 
aerosolized Veletri, weaning will occur in accordance with each site’s standard of care 
guidelines for weaning of aerosolized Veletri.  The table below shows the typical weaning 
steps for aerosolized Veletri from mechanical ventilation.  If weaning from VentaProst occurs 
while on mechanical ventilation, doses will be decreased in 20% increments of the VentaProst 
equivalent dose. 
Weaning Guideline 
Aerosolized 
Veletri 
(from Ventilator) 
VentaProst 
(from Ventilator) 
50 ng/kg/min 
Dose Equivalence to aerosolized Veletri 50 ng/kg/min 
40 ng/kg/min 
80% of Dose Equivalence 
30 ng/kg/min 
60% of Dose Equivalence 
20 ng/kg/min 
40% of Dose Equivalence 
10 ng/kg/min 
20% of Dose Equivalence 
Patients on mechanical ventilation 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 decreased in increments of 20% of the VentaProst equivalent dose, with a minimum of 30 
minutes between changes, down to 20% of the dose before discontinuation. 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 (changes in combined hemodynamic parameters) or a decrease in 
oxygenation indicated by either arterial or central blood oxygenation saturation 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.  Final 
hemodynamic measurements will be collected 15 to 30 minutes after discontinuation of 
VentaProst. 
Patients will be monitored for safety and PD efficacy throughout the initial aerosolized Veletri 
and VentaProst administrations. 

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Protocol Number APC-VP-CLN-001  
Amendment 3 28 November 2017 
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Part II (see Appendix 2 for Study Design Schematic) 
The second part of the study will be conducted in approximately 10 consented cardiothoracic 
surgical patients requiring CPB with perioperative pulmonary hypertension (pulmonary 
arterial mean pressure [mPAP] ≥ 25 mm Hg).   This part of the study is designed to establish a 
dose response relationship of VentaProst to PD effect by dose escalation in these 
patients.  The goal will be to determine the VentaProst dose necessary to achieve at least a 
15% improvement in one or more hemodynamic parameters (as defined by the clinical team).   
Hemodynamic measurements will be taken prior to cardiac surgery (after induction) with 
CPB, prior to dosing with VentaProst, and after each dose titration step.    
Qualifying patients will: 
• 
Receive a starting dose of 3.4 ng/kg/min of  VentaProst 
• 
Have hemodynamic parameters monitored and recorded 
• 
Receive increase in the VentaProst dose in 3.4 ng/kg/min increments  (refer to 
VentaProst Pharmacy Manual) 
o 
IF GREATER THAN A 15% IMPROVEMENT IN ONE OR MORE 
HEMODYNAMIC PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) IS 
SEEN WITH THE INITIAL VENTAPROST DOSE, but NO additional clinically 
meaningful change is seen with this first dose escalation: 
 
Have the VentaProst dose reduced to the initial dose level 
o 
IF GREATER THAN A 15% IMPROVEMENT IN ONE OR MORE 
HEMODYNAMIC PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) IS 
SEEN WITH THE INITIAL VENTAPROST DOSE, but AN additional clinically 
meaningful change is seen with the first dose escalation: 
 
Continue to receive VentaProst in increasing steps of 3.4 ng/kg/min  every 5 
to 15 minutes as clinically indicated until no further improvements in one or 
more hemodynamic parameters are achieved or until dose-limiting 
pharmacological effects are elicited or a tolerance limit to VentaProst is 
established. 
o 
IF LESS THAN A 15% IMPROVEMENT IN ONE OR MORE  HEMODYNAMIC 
PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) IS SEEN WITH 
FIRST DOSE INCREASE: 
 
Continue to receive VentaProst in increasing steps of 3.4 ng/kg/min  every 5 
to 15 minutes as clinically indicated until no further improvements in one or 
more hemodynamic parameters are achieved or until dose-limiting 
pharmacological effects are elicited or a tolerance limit to VentaProst is 
established.   
 
Have the VentaProst dose reduced to the previous dose level (after the 
VentaProst dose has stabilized) at which one or more hemodynamic 
parameter showed maximum improvement.  The VentaProst dose level will 
remain at this setting until clinical conditions determine the need for 
changing the dose. 
Arterial and central venous blood oxygenation parameters will also be considered in the 
titration process. 
Patients requiring post-operative support with epoprostenol will be allowed to continue on 
VentaProst treatment in the ICU as long as they are still on mechanical ventilation.  For 
weaning, doses will be decreased in increments of 20% of the VentaProst equivalent dose, 
with a minimum of 30 minutes between changes, down to 20% of the dose before 
discontinuation (see Weaning Guideline from Part I above).   

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VentaProst weaning will occur from mechanical ventilation only.  If the patient is extubated 
and placed on institution’s standard of care delivery system for administering aerosolized 
Veletri, weaning from aerosolized Veletri will follow each institution’s guideline. 
Hemodynamic, oxygenation, and ventilator parameters will be obtained before and at 15 to 30 
minutes after each VentaProst dose change to demonstrate the effect of the changes.  Final 
measurements will be collected 15 to 30 minutes after discontinuation of VentaProst. 
Number/Type 
of Patients 
Approximately 10 patients will be enrolled in each part of this study.  A minimum of three 
patients at an individual site will be enrolled in Part I of the study before the site can continue 
to Part II. 
Inclusion 
Criteria 
 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men 18 to 80 years of age 
2. Provide written informed consent 
3. Willing and able to comply with all aspects of the protocol 
4. For patients in Part I: 
a. 
Undergo cardiac surgery on CPB (including planned cardiac transplantation) 
b. Clinically require treatment with and receive aerosolized Veletri 
c. 
Demonstrate a clinically meaningful hemodynamic response to aerosolized Veletri 
(defined as at least a 15% improvement in one or more hemodynamic parameters [as 
defined by the clinical team]) 
5.    For patients in Part II: 
a.   Undergo cardiac surgery with CPB (including planned cardiac transplantation) 
b.   Have perioperative pulmonary hypertension  (mPAP ≥ 25 mm Hg) 
c.   Clinically require treatment with inhaled epoprostenol  
Exclusion 
Criteria 
 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. Current smoker (i.e., within the last 30 days) 
2. Emergency operative status 
3. Upper and/or lower respiratory tract infection within four weeks of screening 
4. Contraindication to transesophageal echocardiogram (TEE) including esophageal disease 
or unstable cervical spine 
5. Renal (creatinine > 2.0 mg/dL) or severe hepatic impairment 
6. Thromboembolic disease treated with anticoagulant therapy 
7. Bleeding disorders 
8. Presence or history of significant restrictive or obstructive lung disease (FEV1 and/or 
FVC < 60% of predicted normal lung function) 
9. History of concurrent malignancy or recurrence of malignancy within two years prior to 
Screening (not including patients with < 3 excised basal or squamous cell carcinomas) 
10. History of a diagnosis of drug or alcohol dependency or abuse within one year 
11. Recent history of stroke or transient ischemic attack (within six months prior to 
Screening) not due to trauma, repaired vascular malformation, or aneurysm 
12. Significantly abnormal laboratory tests at Screening, including: 
a. 
Alkaline phosphatase (AP), alanine aminotransferase (ALT, SGPT), aspartate 
aminotransferase (AST, SGOT), or total bilirubin >2.5X of the upper limit of normal 
(ULN) 

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b. Hemoglobin < 9 gm/dL, white blood count (WBC) count < 2500 mm3, neutrophil 
count < 1500 mm3, platelet count < 100 × 103/ mm3 
c. 
Evidence of hemoglobinopathy (including but not limited to sickle cell disease, 
thalassemia, hemoglobin M and variants with high oxygen affinity).   
13. Pregnant or breastfeeding  
14. Treatment with an investigational drug, biologic, or investigational cardiac implant 
within 30 days preceding the first dose of study medication or plans to take another 
investigational drug or biologic within 30 days of study completion 
15. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with trial participation or investigational product 
administration or may interfere with the interpretation of trial results and, in the judgment 
of the Investigator or Sponsor, would make the patient inappropriate for entry into this 
trial 
16. Any condition where aerosolized epoprostenol is contraindicated 
17. Known allergy or sensitivity to epoprostenol, any of its ingredients, or the diluent 
(glycine) 
 Study 
Treatment(s) 
Part I 
Study treatments are:  
• 
Aerosolized Veletri 50 ng/kg/min administered in accordance with each site’s 
standard of care guidelines 
• 
VentaProst  
Patients who demonstrate at least a 15% improvement in one or more hemodynamic 
parameters (as defined by the clinical team) with aerosolized Veletri will be crossed 
over to a calculated VentaProst equivalent dose of 17 ng/kg/min with subsequent 
dose titration increases of 20% increments (refer to VentaProst  Pharmacy Manual) 
every 15 minutes until a hemodynamic response that is not less than 90% of the 
effect observed with 50 ng/kg/min aerosolized Veletri is achieved. 
Part II 
Study treatment is VentaProst at a starting dose of 3.4 ng/kg/min of  VentaProst, followed by 
3.4 ng/kg/min dose titration increases  (refer to VentaProst Pharmacy Manual) every 5 to 15 
minutes as clinically indicated until no further improvements in one or more hemodynamic 
parameters are achieved.  VentaProst doses will be decreased to the prior level once a dose 
response plateau is observed. 
Duration of 
Treatment 
Part I 
Individual patient participation is expected to be approximately 5 weeks including Screening, 
Intra-Operative, Aerosolized Veletri Treatment, VentaProst Treatment, and End of Study. 
The duration of study participation for each patient is as follows:  
• 
Screening: up to 30 days 
• 
Intra-Operative: 3 – 8 hours 
• 
Aerosolized Veletri Treatment administered in accordance with each site’s standard 
of care guidelines (OR/ICU):  24+ hours (dependent on multiple factors) 
• 
VentaProst Treatment (ICU): 24+ hours (dependent on multiple factors) 
• 
End of Study: 4+ hours (dependent on multiple factors) 
 
Part II 
Individual patient participation is expected to be approximately 5 weeks including Screening, 
Intra-Operative, VentaProst Treatment (OR/ICU), and End of Study. 
The duration of study participation for each patient is as follows:  

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• 
Screening: up to 30 days 
• 
Intra-Operative: 3 – 8 hours 
• 
VentaProst Treatment (OR/ICU): 24+ hours (dependent on multiple factors) 
• 
End of Study: 4+ hours (dependent on multiple factors) 
Criteria for 
Evaluation 
 
Primary Endpoint 
Determination of the equivalent dose of VentaProst necessary to achieve a hemodynamic 
response that is not less than 90% of the effect observed with 50 ng/kg/min aerosolized Veletri 
Secondary Endpoints 
• 
Safety of VentaProst dosing regimen 
o 
Monitoring of adverse events (AEs), physical examinations, laboratory tests, and 
electrocardiograms 
• 
Effect of VentaProst dosing regimen on: 
o 
Cardiovascular Parameters 
 
Pulmonary Vascular Resistance (PVR) 
 
Pulmonary Arterial Pressure (PAP) 
 
Systemic Arterial Pressure 
 
Central Venous Pressure (CVP) 
 
Pulmonary Capillary Wedge Pressure (PCWP) 
 
Cardiac Output (CO) 
o 
Oxygenation 
 
Arterial Oxygen Saturation (SaO2) or Oxygen Saturation by Pulse Oximetry 
(SpO2) 
 
Partial Pressure of Oxygen in Arterial Blood (PaO2) 
o 
Ventilator Support 
 
Fraction of Inspired Oxygen (FiO2) 
 
Ventilator pressures 
 
Ventilator volumes 
 
Duration of intubation 
• 
Number and type of cardiovascular medications required through end of study 
Criteria for 
Conversion to 
Conventional 
Therapy 
At any time during VentaProst administration, patients will be crossed over to standard 
therapy of aerosolized Veletri if they meet one or more of the following pre-defined criteria 
for a deterioration in their condition: 
• 
Severe postoperative mediastinal bleeding (> 500 mL/hr) 
• 
Hemoptysis 
• 
If a clinically inadequate response to VentaProst is observed, the patient may be 
converted back to aerosolized Veletri administered in accordance with each site’s 
standard of care guidelines at the investigator’s discretion 
Additionally, patients will be crossed over to standard of care therapy with aerosolized Veletri 
after extubation. 
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 
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.  
Individual patient listings of data will also be provided to allow for review of all 

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pharmacodynamic, safety, and tolerability parameters. 
The number of patients has been selected to enable an adequate clinical assessment of 
pharmacodynamic, safety, and tolerability parameters without presenting undue risk to a large 
number of patient’s exposure to this investigational product. 
Further details will be included in the Statistical Analysis Plan. 
Efficacy 
Analysis 
Efficacy will be secondarily determined by summarizing success or failure to meet the 
pharmacodynamics goals of the study. 
Safety 
Analyses 
Safety data will be summarized using frequencies and incidence rates.  

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Table 1 – Schedule of Assessments and Procedures – Part I  
Study Procedures 
Screening 
Intra-
Operative 
Aerosolized 
Veletri 
Treatment 
Period 
(OR/ICU) 
VentaProst 
Treatment 
Period (ICU) 
End of Study 
Written Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Assign Patient ID 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Medication History 
X 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
Vital Signs/Weight/Height 
X 
 
 
 
X12 
12-Lead ECG 
X 
 
 
 
X 
Spirometry 
X11 
 
 
 
 
Clinical Laboratory Sampling 
X 
 
 
 
X 
Serum Pregnancy Test 
X 
 
 
 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
Cardiac Surgery with CPB 
 
X 
 
 
 
Administer Aerosolized Veletri 
 
 
X6 
 
 
Administer VentaProst 
 
 
 
X9 
 
Hemodynamic Parameters1 
 
X5 
X7,8 
X10 
 
Oxygenation Measurements2 
 
 
X7 
X10 
 
Ventilator Parameters3 
 
 
X7 
X10 
 
AE Monitoring4 
 
X 
 
 
X 
Concomitant Medications 
X 
X 
 
 
X 
1  Hemodynamic parameters include, but not limited to, Cardiac Index (CI), Cardiac Output (CO), Central Venous Pressure 
(CVP), Diastolic Pulmonary Arterial Pressure (dPAP), Diastolic Systemic Arterial Pressure (dSAP), Heart Rate (HR), 
Mean Pulmonary Arterial Pressure (mPAP), Mean Systemic Arterial Pressure(mSAP), Pulmonary Capillary Wedge 
Pressure (PCWP), Pulmonary Vascular Resistance (PVR), Rhythm, Systolic Pulmonary Arterial Pressure (sPAP), and 
Systolic Systemic Arterial Pressure (sSAP) 
2   Oxygenation measurements include SaO2 or SpO2 and PaO2 
3  Ventilator parameters include Ventilator Type, Ventilator Mode, FiO2, Inspiratory Time, Mean Airway Pressure, Peak 
Inspiratory Pressure, Positive End Expiratory Pressure, and Respiratory Rate 
4   To include unanticipated medical events in the judgment of the investigator 
5  Measure hemodynamic parameters prior to cardiac surgery with CPB and prior to dosing with aerosolized Veletri 
6 Initiate aerosolized Veletri dose at 50 ng/kg/min in accordance with each site’s standard of care guidelines and 
stabilize the patient on aerosolized Veletri for at least 15 minutes  
7  Measure hemodynamic, oxygenation, and ventilator parameters after stabilization of aerosolized Veletri 
8 Determination of hemodynamic response from baseline for study inclusion, study continuation, and transition to 
VentaProst 
9  Initiate VentaProst dose at the calculated equivalent dose of 17 ng/kg/min; titrate up in 20% increments every 15 minutes 
(refer to VentaProst Pharmacy Manual); continue until dose is achieved that matches the hemodynamic measurements 
obtained with aerosolized Veletri dosing; stabilize patient on VentaProst for at least 15 minutes 
10 Measure hemodynamic, oxygenation, and ventilator parameters before and at 15 to 30 minutes after each VentaProst 
dose (during dosing, stabilization, and weaning [if still intubated]) and at 15 to 30 minutes after discontinuation of 
VentaProst 
11 For those patients with presence or history of significant restrictive or obstructive lung disease 
12 Vital signs and weight only 

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Table 2 – Schedule of Assessments and Procedures – Part II 
Study Procedures 
Screening 
Intra-
Operative 
VentaProst 
Treatment 
Period 
(OR/ICU) 
End of Study 
Written Informed Consent 
X 
 
 
 
Demographics 
X 
 
 
 
Assign Patient ID 
X 
 
 
 
Medical History 
X 
 
 
 
Medication History 
X 
 
 
 
Physical Examination 
X 
 
 
X 
Vital Signs/Weight/Height 
X 
 
 
X9 
12-Lead ECG 
X 
 
 
X 
Spirometry 
X8 
 
 
 
Clinical Laboratory Sampling 
X 
 
 
X 
Serum Pregnancy Test 
X 
 
 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
Cardiac Surgery with CPB 
 
X 
 
 
Administer VentaProst 
 
 
X6 
 
Hemodynamic Parameters1 
 
X5 
X7 
 
Oxygenation Measurements2 
 
 
X7 
 
Ventilator Parameters3 
 
 
X7 
 
AE Monitoring4 
 
X 
 
X 
Concomitant Medications 
X 
X 
 
X 
1  Hemodynamic parameters include, but not limited to, Cardiac Index (CI), Cardiac Output (CO), Central 
Venous Pressure (CVP), Diastolic Pulmonary Arterial Pressure (dPAP), Diastolic Systemic Arterial 
Pressure (dSAP), Heart Rate (HR), Mean Pulmonary Arterial Pressure (mPAP), Mean Systemic Arterial 
Pressure(mSAP), Pulmonary Capillary Wedge Pressure (PCWP), Pulmonary Vascular Resistance (PVR), 
Rhythm, Systolic Pulmonary Arterial Pressure (sPAP), and Systolic Systemic Arterial Pressure (sSAP) 
2   Oxygenation measurements include SaO2 or SpO2 and PaO2 
3  Ventilator parameters include Ventilator Type, Ventilator Mode, FiO2, Inspiratory Time, Mean Airway 
Pressure, Peak Inspiratory Pressure, Positive End Expiratory Pressure, and Respiratory Rate 
4   To include unanticipated medical events in the judgment of the investigator 
5  Measure hemodynamic parameters prior cardiac surgery with CPB.  Prior to dosing with VentaProst, 
measure hemodynamic, oxygenation, and ventilator parameters 
6 Initiate VentaProst at a starting dose of 3.4 ng/kg/min of VentaProst and titrate VentaProst dose up in 3.4 
ng/kg/min  increments as clinically indicated (refer to VentaProst Pharmacy Manual); stabilize the patient 
on final dose of VentaProst 
7  Measure hemodynamic, oxygenation, and ventilator parameters before and after each VentaProstdose 
change (during dosing, stabilization, and weaning [if still intubated) and at 15 to 30 minutes after 
discontinuation of VentaProst 
8  For those patients with presence or history significant restrictive or obstructive lung disease 
9  Vital signs and weight only 

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TABLE OF CONTENTS 
 
 
INVESTIGATOR’S SIGNATURE PAGE ............................................................. 3 
1. 
CLINICAL PROTOCOL SYNOPSIS ........................................................... 4 
TABLE OF CONTENTS...................................................................................... 13 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITION OF 
TERMS ................................................................................................................. 17 
2. 
BACKGROUND AND RATIONALE ........................................................ 19 
2.1 
Introduction ............................................................................................... 19 
2.2 
VentaProst .................................................................................................. 21 
2.2.1 Nonclinical Experience ................................................................. 21 
2.2.2 Clinical Experience ....................................................................... 21 
2.2.3 Summary of Pharmacokinetic Results .......................................... 21 
2.2.4 Summary of Clinical Results ......................................................... 21 
2.2.5 Summary of Known and Potential Risks of Inhaled 
Epoprostenol Administration..................................................................... 21 
2.2.6 Dosing Rationale for VentaProst ................................................... 21 
3. 
STUDY OBJECTIVES ............................................................................... 22 
3.1 
Primary Objective ..................................................................................... 22 
3.2 
Secondary Objectives ................................................................................ 22 
4. 
OVERALL STUDY DESIGN AND PLAN ................................................ 22 
4.1 
Part I .......................................................................................................... 22 
4.2 
Part II ......................................................................................................... 24 
4.3 
Duration of Participation ........................................................................... 25 
4.3.1 Part I .............................................................................................. 25 
4.3.2 Part II ............................................................................................. 26 
4.4 
Screening ................................................................................................... 26 
4.5 
Intra-Operative/ICU .................................................................................. 26 
4.6 
End of Treatment ....................................................................................... 26 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ................................. 26 
5.1 
Inclusion Criteria ....................................................................................... 27 
5.2 
Exclusion Criteria ...................................................................................... 27 
5.3 
Re-Screening of Patients ........................................................................... 28 
5.4 
Removal of Patients from Therapy or Assessment ................................... 28 
5.4.1 Criteria for Patient Conversion to Conventional 
Therapy ...................................................................................................... 28 
6. 
STUDY TREATMENTS ............................................................................. 29 
6.1 
Identity of Medication Component of the Investigational 

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Product .................................................................................................................. 29 
6.1.1 Storage Condition .......................................................................... 29 
6.2 
Treatments Administered .......................................................................... 29 
6.2.1 Part I .............................................................................................. 29 
6.2.2 Part II ............................................................................................. 29 
6.3 
Study Medication Supply, Preparation, and Administration ..................... 29 
6.3.1 Study Medication Supply .............................................................. 29 
6.3.2 Study Medication Preparation ....................................................... 30 
6.3.3 Study Medication Administration ................................................. 30 
6.3.4 Study Medication Titration ............................................................ 31 
6.3.5 Study Medication Weaning ........................................................... 31 
6.4 
Identity of the Device Component of the Investigational 
Product .................................................................................................................. 31 
6.4.1 Identity of Device .......................................................................... 31 
6.4.2 Ventilator Settings ......................................................................... 34 
6.4.3 Device Supply ............................................................................... 34 
6.4.4 Device Replacement ...................................................................... 34 
6.4.5 Device Malfunction or Failure ...................................................... 35 
6.5 
Blinding ..................................................................................................... 35 
6.6 
Prior and Concomitant Therapy ................................................................ 35 
6.6.1 Prohibited Concomitant Therapy .................................................. 35 
6.7 
Investigational Product (IP) Supplies and Accountability ........................ 35 
7. 
PHARMACODYNAMIC ASSESSMENTS ............................................... 36 
7.1 
Primary Endpoint ...................................................................................... 36 
7.2 
Secondary Endpoints ................................................................................. 36 
7.3 
Appropriateness of Measurements ............................................................ 37 
8. 
SAFETY ASSESSMENTS .......................................................................... 37 
8.1 
General Safety Procedures ........................................................................ 37 
8.1.1 Vital Signs and Weight Measurements .......................................... 37 
8.1.2 Physical Examination .................................................................... 37 
8.1.3 Laboratory Measurements ............................................................. 38 
8.1.4 Electrocardiograms ........................................................................ 38 
8.2 
Adverse Events .......................................................................................... 38 
8.2.1 Definitions ..................................................................................... 38 
8.2.2 Grading of Adverse Events ........................................................... 39 
8.2.3 Relationship to Study Medication/Study 
Device/Procedure ...................................................................................... 39 
8.2.4 AE Outocomes .............................................................................. 39 
8.2.5 Laboratory Test and other Test Abnormalities as 
Adverse Events .......................................................................................... 40 
8.2.6 Serious Adverse Events ................................................................. 40 
8.2.7 Reporting for SAEs (24 Hours) ..................................................... 40 
8.3 
Reporting of Pregnancy ............................................................................. 41 
9. 
PHARMACOKINETIC ASSESSMENTS .................................................. 42 

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10. SCHEDULE OF ASSESSMENTS AND PROCEDURES ......................... 42 
10.1 
Part I .......................................................................................................... 42 
10.1.1 Screening ..................................................................................... 42 
10.1.2 Intra-Operative (OR) ................................................................... 43 
10.1.3 Aerosolized Epoprostenol Treatment (OR/ICU) ......................... 43 
10.1.4 VentaProst Treatment (ICU) ........................................................ 44 
10.1.5 End of Study (ICU) ...................................................................... 45 
10.2 
Part II ......................................................................................................... 45 
10.2.1 Screening ..................................................................................... 45 
10.2.2 Intra-Operative (OR) ................................................................... 46 
10.2.3 VentaProst Treatment (OR/ICU) ................................................. 46 
10.2.4 End of Study (ICU) ...................................................................... 48 
11. 
DATA QUALITY ASSURANCE ................................................................ 48 
11.1 
Data Collection .......................................................................................... 48 
11.2 
Clinical Data Management ........................................................................ 49 
11.3 
Database Quality Assurance ...................................................................... 49 
12. STATISTICAL CONSIDERATIONS ......................................................... 49 
12.1 
Statistical Methods .................................................................................... 49 
12.2 
Determination of Sample Size ................................................................... 49 
12.3 
Analyses Sets ............................................................................................. 49 
12.4 
Demographic and Other Baseline Characteristics ..................................... 49 
12.5 
Pharmacodynamic Analyses ...................................................................... 50 
12.5.1 Primary Endpoint ......................................................................... 50 
12.5.2 Secondary Endpoints ................................................................... 50 
12.6 
Extent of Exposure .................................................................................... 50 
12.7 
Safety Analyses ......................................................................................... 50 
12.7.1 Adverse Events ............................................................................ 51 
12.7.2 Laboratory Values ........................................................................ 51 
12.7.3 Vital Signs .................................................................................... 51 
12.8 
The Procedure for Revising the Statistical Analysis Plan ......................... 51 
13. ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS ................. 51 
13.1 
Ethics ......................................................................................................... 51 
13.1.1 Institutional Review Boards/Independent Ethics 
Committees ................................................................................................ 51 
13.1.2 Ethical Conduct of the Study ....................................................... 52 
13.1.3 Patient Information and Informed Consent ................................. 52 
13.2 
Administrative Procedures ........................................................................ 53 
13.2.1 Changes to the Protocol ............................................................... 53 
13.2.2 Adherence to the Protocol ........................................................... 53 
13.2.3 Monitoring Procedures ................................................................ 53 
13.2.4 Recording of Data ........................................................................ 54 
13.2.5 Retention of Records ................................................................... 54 
13.2.6 Auditing Procedures and Inspection ............................................ 55 

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13.2.7 Handling of Investigational Product ............................................ 55 
13.2.8 Publication of Results .................................................................. 55 
13.2.9 Disclosure and Confidentiality .................................................... 55 
13.2.10 Discontinuation of Study ........................................................... 56 
13.2.11 Patient Insurance and Indemnity ............................................... 56 
14. REFERENCES ............................................................................................ 57 
15. APPENDICES ............................................................................................. 58 
Appendix 1 
Part I Study Design Schematic ...................................................... 59 
Appendix 2 
Part II Study Design Schematic .................................................... 60 
 

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LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
AE 
Adverse |Event 
ALT (SGPT) 
Alanine Aminotransferase (serum glutamic pyruvic transaminase) 
AP 
Alkaline Phosphatase 
AST (SGOT) 
Aspartate Aminotransferase (serum glutamic oxaloacetic transaminase)   
bpm 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
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 
CSR 
Clinical Study Report 
CVP 
Central Venous Pressure (mm Hg) 
dPAP 
Diastolic Pulmonary Arterial  Pressure (mm Hg) 
dSAP 
Diastolic Systemic Arterial Pressure (mm Hg) 
ECG 
Electrocardiogram 
ETT 
Endotracheal Tube 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCP 
Good Clinical Practice 
HFNC 
High Flow Nasal Cannula 
HME 
Heat-Moisture Exchanger 
HPLC-MS/MS 
High-Pressure Liquid Chromatography Coupled to Mass Spectrometry 
HR 
Heart Rate (bpm) 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ICU 
Intensive Care Unit 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mPAP 
Mean Pulmonary Arterial Pressure (mm Hg) 

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Abbreviation 
Term 
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 
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 
SpO2 
Oxygen Saturation by Pulse Oximetry 
SVR 
Systemic Vascular Resistance 
TEAE 
Treatment-Emergent Adverse Event 
TEE 
Transesophageal Echocardiogram 
TPG 
Transpulmonary Gradient 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell (count) 
WHO 
World Health Organization 

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2. 
BACKGROUND AND RATIONALE 
2.1 
Introduction 
Aerogen Pharma is developing VentaProst, an inhaled epoprostenol, as an integrated 
medication/device combination product consisting of a FDA-approved and commercially 
available epoprostenol sodium intravenous (IV) solution (Flolan®) administered by a 
precision single-patient use custom nebulizer compatible with ventilator support 
equipment used in operating rooms (ORs) and intensive care units (ICUs).  VentaProst is 
being investigated as a perioperative pulmonary vasodilator for patients undergoing 
cardiac surgery with cardiopulmonary bypass (CPB). VentaProst therapy will be 
transferable from anesthesia ventilator to patient transport to ICU ventilator and on to 
nasal cannula post-extubation, thus maintaining vasodilation and preventing rebound 
pulmonary hypertension (PH) during patient transition from surgery.   
Flolan (epoprostenol sodium), also known as prostacyclin, PGI2 or PGX, a metabolite of 
arachidonic acid, is a naturally occurring prostaglandin. Epoprostenol has two major 
pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial 
vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory 
effects of epoprostenol reduce right and left ventricular afterload and increase cardiac 
output (CO) and stroke volume. 
Epoprostenol is rapidly hydrolyzed at neutral blood pH and is also subject to enzymatic 
degradation. No available chemical assay is sufficiently sensitive and specific to assess 
the in vivo human pharmacokinetics (PK) of epoprostenol. Animal studies using tritium-
labelled epoprostenol have indicated a high clearance (93 mL/min/kg), small volume of 
distribution (357 mL/kg), and a short half-life (2.7 minutes). During infusions in animals, 
steady-state plasma concentrations of tritium-labelled epoprostenol were reached within 
15 minutes and were proportional to infusion rates. 
Epoprostenol is metabolized to 6-keto-PGF1α (formed by spontaneous degradation) and 
6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have 
pharmacological activity at orders of magnitude less than epoprostenol in animal test 
systems.  6-keto-PGF1α has been used as a surrogate PK metabolite for epoprostenol, but 
does not accurately represent the local active concentration of epoprostenol in the lungs 
with an elimination half-life of approximately 20-30 minutes.  Additionally, large and 
rapid fluctuations in endogenous epoprostenol as indicated by 6-keto-PGF1α levels 
perioperatively in cardiac surgery confound the exogenous epoprostenol contribution for 
PK determinations (Ylikorkala 1981). 
Inhalation delivery of epoprostenol in cardiothoracic surgery patients offers an attractive 
alternative to IV delivery because it minimizes systemic exposure associated with 
clinically hazardous effects such as hypotension and exacerbation of pulmonary and 
cardiac shunts. The rationale for administering epoprostenol continuously as an aerosol 
through ventilator support equipment stems from its extremely short half-life of 
approximately three minutes in vivo.  This enables delivery of high local concentrations 
of vasodilator into the lung vasculature, reducing PVR (pulmonary vascular resistance) 

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and RH (right heart) afterload.  As a result, the use and effectiveness of inhaled 
epoprostenol is widely reported [Buckley and Feldman, 2010; De Wet, 2004; Fattouch, 
2005; Fattouch, 2006; Hache, 2003; Haraldsson, 2001; Khan, 2009; Ocal, 2005] in a 
variety of applications including mitral valve surgery.  Nonetheless, such practices 
remain off-label, as inhaled epoprostenol is not FDA-approved for this indication or route 
of administration.   
Clinical centers have independently developed protocols to deliver the IV formulation as 
aerosol by mechanical ventilation and nasal cannula using commercially available 
nebulizers.  The nominally prescribed dose of 50 ng/kg/min is administered without 
regard for system efficiencies with these protocols.  This results in dose delivery to the 
lungs that is assumed to be within the flat portion of the hemodynamic dose response 
curve to inhaled epoprostenol. 
A review of published literature demonstrates that the use of inhaled epoprostenol in 
patients undergoing cardiothoracic surgery is safe and well tolerated.  Doses of 10 – 100 
ng/kg/min administered through a wide variety of conventional aerosol delivery methods 
led to improved hemodynamics (such as lowering of pulmonary arterial pressure [PAP] 
and pulmonary vascular resistance [PVR]), improved cardiac index (CI) and right 
ventricular ejection fraction (RVEF), easier separation from CPB, reduced intubation 
times, and shorter stays in the ICU. 
The VentaProst nebulizer delivery platform is designed to accurately and precisely 
administer aerosol to the lungs of critically ill patients requiring support via mechanical 
ventilation and/or supplemental oxygen by nasal cannula.  The intent is to standardize the 
critical components for consistent and quantifiable aerosolized epoprostenol delivery by 
mechanical ventilator and nasal cannula systems.  Aerogen Pharma has evaluated various 
delivery systems used for conventional aerosol administration of epoprostenol to the 
lungs (in accordance with each site’s standard of care practice guideline) and has 
estimated the equivalent dose by VentaProst.   
The intent of Part I of the Phase 2a study is to demonstrate that the estimated VentaProst 
dose has the same hemodynamic effect as aerosolized Veletri at 50 ng/kg/min (in 
accordance with each site’s standard of care guidelines).  The assumption is that the 
hemodynamic response from the aerosolized Veletri dose will not change significantly 
with minor changes in dose (flat portion of the dose response curve).  When patients are 
converted to VentaProst, a determination is made whether or not the hemodynamic 
response is similar by being at least as much as the response with the aerosolized 
epoprostenol dose.  If the hemodynamic response with VentaProst is less than that of the 
aerosolized Veletri dose, the dose will be increased until a similar response is observed.  
VentaProst dosing will not be titrated downward to match the aerosolized Veletri 
hemodynamic response because of the possibility that the patients’ requirements for 
pulmonary vasodilation may have improved since the start of aerosolized Veletri. 
Part II of the study is intended to start VentaProst dosing at a dose that will show an 
improved hemodynamic response by increasing the dose (steep portion of the dose 
response curve).  The intent is to demonstrate that simple dose adjustments to the 
VentaProst delivery device flow of epoprostenol to the nebulizer can rapidly optimize 

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VentaProst dose administration.   
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. 
2.2.3 
Summary of Pharmacokinetic Results  
Refer to the current IB for pharmacokinetic results with inhaled epoprostenol. 
2.2.4 
Summary of Clinical Results 
There have been no clinical trials to date with VentaProst. 
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. 
2.2.6 
Dosing Rationale for VentaProst 
Literature on the current use of aerosolized epoprostenol shows a wide range and 
technically variable dosing for lowering PVR.  Most of the experience is with continuous 
nebulization by commercially available nebulizers in various positions in mechanical 
ventilator circuits. 
Unlike the commercially available nebulizer systems, VentaProst aerosolizes 
epoprostenol only during the inspiratory cycle of the ventilator, and administers very 
consistently sized aerosol droplets in close proximity to the endotracheal tube (ETT) of 
mechanically ventilated patients.   

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3. 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to identify the relative dose equivalency between 
effective conventionally administered aerosolized Veletri and VentaProst doses. 
3.2 
Secondary Objectives 
The secondary objectives are: 
• To evaluate the safety and tolerability of VentaProst doses in a patient population 
post cardiac surgery with cardiopulmonary bypass (CPB) 
• To demonstrate that VentaProst dose titration to achieve at least a 15% 
improvement in one or more hemodynamic parameters (as defined by the clinical 
team) is safe and effective 
• To demonstrate the PD equivalence (based on cardiovascular parameters, indices 
of oxygenation, and ventilator support) of VentaProst doses to aerosolized Veletri 
doses 
• To identify cardiovascular medications administered concomitantly with 
VentaProst 
• To monitor ventilator support needed 
4. 
OVERALL STUDY DESIGN AND PLAN 
4.1 
Part I 
The first part of this study will be conducted in approximately 10 consented post-
operative cardiothoracic surgery patients on CPB who are receiving aerosolized Veletri 
(in accordance with each site’s standard of care guidelines) and who demonstrate at least 
a 15% improvement in one or more hemodynamic parameters (as defined by the clinical 
team) when treated with aerosolized Veletri.  This part of the study is designed to 
demonstrate the dose equivalence between aerosolized Veletri and VentaProst using a 
patient’s hemodynamic  parameters, with the goal to determine the VentaProst dose 
necessary to achieve a hemodynamic response that is not less than 90% of the effect 
observed with 50 ng/kg/min aerosolized Veletri.  Arterial oxygen saturation (SaO2) must 
be maintained at or above the level obtained with aerosolized epoprostenol 
administration. 
 Qualifying patients will: 
• Receive aerosolized Veletri 50 ng/kg/min in the OR/ICU 
• Have hemodynamic parameters measured before and after aerosolized Veletri 
administration to determine changes 

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o IF AT LEAST A 15% IMPROVEMENT IN ONE OR MORE HEMODYNAMIC 
PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) IS SEEN WITH 
AEROSOLIZED VELETRIAFTER STABILIZATION IN THE ICU: 
 Be administered VentaProst as follows:  Setup VentaProst inline to the 
ventilator circuit, start nebulization, then stop conventional Veletri pump 
flow and nebulizer while still inline.  Do not remove Veletri administration 
system until VentaProst administration is confirmed 
o IF LESS THAN A 15% IMPROVEMENT IN ONE OR MORE 
HEMODYNAMIC PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) 
IS SEEN WITH AEROSOLIZED VELETRI AFTER STABLIZATION IN THE 
ICU: 
 Not be administered VentaProst 
• Receive a calculated equivalent starting dose of 17 ng/kg/min of VentaProst while 
still on mechanical ventilation 
• Receive increases in the VentaProst dose in 20% increments (refer to the 
VentaProst Pharmacy Manual) every 15 minutes until at least 90% of the 
hemodynamic effect observed with 50 ng/kg/min aerosolized Veletri is achieved 
Once a VentaProst dose equivalence has been achieved, patients will be weaned from 
VentaProst.  VentaProst weaning will occur from mechanical ventilation only.  If the 
patient has been extubated and is on institution’s standard of care delivery system for 
administering aerosolized Veletri, weaning will occur in accordance with each site’s 
standard of care guidelines for weaning of aerosolized Veletri.  The table below shows 
the typical weaning steps for aerosolized Veletri from mechanical ventilation.  If weaning 
from VentaProst occurs while on mechanical ventilation, doses will be decreased in 20% 
increments of the VentaProst equivalent dose.   
Weaning Guideline 
Aerosolized Veletri 
(from Ventilator) 
VentaProst 
(from Ventilator) 
50 ng/kg/min 
Dose Equivalence to aerosolized Veletri 50 ng/kg/min 
40 ng/kg/min 
80% of Dose Equivalence 
30 ng/kg/min 
60% of Dose Equivalence 
20 ng/kg/min 
40% of Dose Equivalence 
10 ng/kg/min 
20% of Dose Equivalence 
Patients on mechanical ventilation 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 decreased in increments of 20% of the VentaProst equivalent dose, with a 
minimum of 30 minutes between changes, down to 20% of the dose before 
discontinuation. The VentaProst weaning process should occur in isolation to other 

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treatment changes (no changes in inotropes, pressors or vasodilators). Patients will be 
observed closely before, during, and after dosing changes. In the event patients 
demonstrate signs of hemodynamic instability (changes in combined hemodynamic 
parameters) or a decrease in oxygenation indicated by either arterial or central blood 
oxygenation saturation 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.  A final PD measurement will be collected 15 to 30 minutes 
after discontinuation of VentaProst. 
Patients will be monitored for safety and PD efficacy throughout the aerosolized Veletri 
and VentaProst administrations. 
4.2 
Part II 
The second part of the study will be conducted in approximately 10 consented 
cardiothoracic surgical patients on CPB with perioperative pulmonary hypertension 
(mPAP > 25 mm Hg).  This part of the study is designed to establish a dose response 
relationship of VentaProst to PD effect by dose escalation in  these patients.  The goal 
will be to determine the VentaProst dose necessary to achieve at least a 15% 
improvement in one or more hemodynamic parameters (as defined by the clinical team). 
Hemodynamic measurements will be taken prior cardiac surgery (after induction) with 
CPB, prior to dosing with VentaProst, and after each dose titration step.    
Qualifying patients will: 
• Receive a starting dose of 3.4 ng/kg/min of VentaProst 
• Have hemodynamic parameters monitored and recorded 
• Receive increase in the VentaProst dose  in 3.4 ng/kg/min increments (refer to 
VentaProst Pharmacy Manual) 
o IF A GREATER THAN A 15% IMPROVEMENT IN ONE OR MORE 
HEMODYNAMIC PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) 
IS SEEN WITH THE INITIAL VENTAPROST DOSE, but NO additional 
clinically meaningful change is seen with this first dose escalation: 
 Have the VentaProst dose reduced to the initial dose level 
o IF A GREATER THAN A 15% IMPROVEMENT IN ONE OR MORE 
HEMODYNAMIC PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) 
IS SEEN WITH THE INITIAL VENTAPROST DOSE, but AN additional 
clinically meaningful change is seen with the first dose escalation: 
 Continue to receive VentaProst in increasing steps of 3.4 ng/kg/min every 
5 to 15 minutes as clinically indicated until no further improvements in 
one or more hemodynamic parameters are achieved or until dose-limiting 
pharmacological effects are elicited or a tolerance limit to VentaProst is 
established. 

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o IF A LESS THAN A 15% IMPROVEMENT IN ONE OR MORE 
HEMODYNAMIC PARAMETERS (AS DEFINED BY THE CLINICAL TEAM) 
IS SEEN WITH FIRST DOSE INCREASE: 
 Continue to receive VentaProst in increasing steps of 3.4 ng/kg/min every 
5 to 15 minutes as clinically indicaged until no further improvements in 
one or more hemodynamic parameters are achieved or until dose-limiting 
pharmacological effects are elicited or a tolerance limit to VentaProst is 
established.   
 Reduce the VentaProst dose to the previous dose level (after the 
VentaProst dose has stabilized) at which the one or more hemodynamic 
parameters showed maximum improvement.  The VentaProst dose level 
will remain at this setting until clinical conditions determine the need for 
changing the dose. 
Arterial and central venous blood oxygenation parameters will also be considered in the 
titration process. 
Hemodynamic, oxygenation, and ventilator parameters will be obtained at the time of 
each VentaProst dose adjustment in the ICU.   
Patients requiring post-operative support with epoprostenol will be allowed to continue 
on VentaProst treatment in the ICU as long as they are still on mechanical ventilation.  
For weaning, doses will be decreased in increments of 20% of the VentaProst equivalent 
dose, with a minimum of 30 minutes between changes, down to 20% of the dose before 
discontinuation (see Section 4.1, Weaning Guideline in Part I above).  If the patient is 
extubated and placed on institution’s standard of care delivery system for administering 
aerosolized Veletri, weaning from aerosolized Veletri will follow each institution’s 
guideline.   
4.3 
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. 
4.3.1 
Part I 
Individual patient participation is expected to be approximately 5 weeks including: 
• Screening: up to 30 days 
• Intra-Operative: 3-8 hours 
• Aerosolized Veletri Treatment administered in accordance with each site’s 
standard of care guidelines (OR/ICU):  24+ hours (dependent on multiple factors) 
• VentaProst Treatment (ICU):  24+ hours (dependent on multiple factors) 
• End of Study:  4+ hours (dependent on multiple factors) 

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4.3.2 
Part II 
Individual patient participation is expected to be approximately 5 weeks including: 
• Screening: up to 30 days 
• Intra-Operative: 3-8 hours 
• VentaProst Treatment (OR/ICU):  24+ hours (dependent on multiple factors) 
• End of Study: 4+ hours (dependent on multiple factors) 
4.4 
Screening 
The purpose of Screening is to ensure that each patient meets all the specified inclusion 
and none of the exclusion criteria.    
4.5 
Intra-Operative/ICU 
In Part I, approximately 10 cardiac surgery patients on CPB who meet entry criteria will 
be entered into the study and will receive conventionally-administered aerosolized Veletri 
(in accordance with each site’s standard of care guidelines) in the OR or ICU.  Once 
clinically defined hemodynamic effects are achieved in the ICU, the aerosolized 
epoprostenol will be stopped and patients will be crossed-over to a calculated VentaProst 
equivalent dose of 17 ng/kg/min.  The VentaProst dose will then be increased in 20% 
increments (refer to VentaProst Pharmacy Manual) every 15 minutes to match the PD 
measures achieved with the aerosolized Veletri dose. 
In Part II, approximately 10 cardiac surgery patients on CPB who meet study entry 
criteria will be entered into the study and will be assigned to receive a starting dose of 3.4 
ng/kg/min of VentaProst in the OR or ICU.  The VentaProst dose will then be increased in 
3.4 ng/kg/min increments (refer to VentaProst Pharmacy Manual) every 5 to 15 minutes 
as clinically indicated until no further improvements in one or more hemodynamic 
parameters are achieved. 
4.6 
End of Treatment 
In both Part I and Part II, final PD measurements (based on hemodynamic parameters, 
indices of oxygenation, and venilator support) will be collected 15 to 30 minutes after 
discontinuation of VentaProst.  End of study physical examination, vital signs/weight, 12-
lead ECG, clinical laboratory testing, serum pregnancy testing, hemodynamic parameters, 
oxygenation measurements, ventilator parameters, adverse events monitoring, and 
concomitant medications will also be obtained at the end of treatment. 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Approximately 10 patients will be enrolled in each part of this study at approximately 
three clinical sites in the United States.  A minimum of three patients at an individual site 
will be enrolled in Part I of the study before the site can continue to Part II.  
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.  

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5.1 
Inclusion Criteria 
Patients are eligible for this study if they meet all of the following criteria: 
1. Women and Men 18 to 80 years of age 
2. Provide written informed consent 
3. Willing and able to comply with all aspects of the protocol 
4. For patients in Part I: 
a. Undergo 
cardiac 
surgery 
on 
CPB 
(including 
planned 
cardiac 
transplantation) 
b. Clinically require treatment with and receive aerosolized Veletri 
c. Demonstrate a clinically meaningful hemodynamic 
response to 
aerosolized Veletri (defined as at least a 15% improvement in one or more 
hemodynamic parameters [as defined by the clinical team]) 
5.    For patients in Part II: 
a. Undergo cardiac surgery with CPB (including planned cardiac 
transplantation) 
b.   Have perioperative pulmonary hypertension  (mPAP > 25 mm Hg ) 
c.   Clinically require treatment with inhaled epoprostenol 
5.2 
Exclusion Criteria 
Patients are NOT eligible for this study if they meet any of the following criteria: 
1. Current smoker (i.e., within the last 30 days) 
2. Emergency operative status 
3. Upper and/or lower respiratory tract infection within four weeks of screening 
4. Contraindication to transesophageal echocardiogram (TEE) including esophageal 
disease or unstable cervical spine 
5. Renal (creatinine > 2.0 mg/dL) or severe hepatic impairment 
6. Thromboembolic disease treated with anticoagulant therapy 
7. Bleeding disorders 
8. Presence or history of significant restrictive or obstructive lung disease (FEV1 
and/or FVC < 60% of predicted normal lung function) 
9. History of current malignancy or recurrence of malignancy within two years prior 
to Screening (not including patients with  < 3 excised basal or squamous cell 
carcinomas) 
10. History of a diagnosis of drug or alcohol dependency or abuse within one year 
11. Recent history of stroke or transient ischemic attack (within six months prior to 
Screening) not due to trauma, repaired vascular malformation, or aneurysm 
12. Signficantly abnormal laboratory tests at Screening, including: 
a. Alkaline phosphatase (AP), alanine aminotransferase (ALT, SGPT), 
aspartate aminotransferas (AST, SGOT), or total bilirubin > 2.5X of the 

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upper limit of normal (ULN) 
b. Hemoglobin <9 gm/dL, white blood count (WBC) count <2500 mm3, 
neutrophil count <1500 mm3, platelet count <100 x 103/mm3 
c. Evidence of hemoglobinopathy (including but not limited to sickle cell 
disease, thalassemia (all variants), hemoglobin M and variants with high 
oxygen affinity)   
13. Pregnant or breastfeeding 
14. Participation in an investigational drug, biologic, or investigational cardiac 
implant study within 30 days preceding the first dose of study medication or plans 
to take part in another investigational study within 30 days of study completion 
15. Other severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with trial participation or 
investigational product administration or may interfere with the interpretation of 
trial results and, in the judgment of the Investigator or Sponsor, would make the 
patient inappropriate for entry into this trial 
16. Any condition where aerosolized epoprostenol is contraindicated 
17. Known allergy or sensitivity to epoprostenol, any of its ingredients, or the diluent 
(glycine) 
5.3 
Re-Screening of Patients 
Patients may not be enrolled more than once.   
5.4 
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.   
All patients who discontinue from the study are to complete the End of Study procedures 
(except Screen Failure patients).  
The Investigator will promptly explain to the patient involved 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 CRF. 
5.4.1 
Criteria for Patient Conversion to Conventional Therapy 
At any time during VentaProst administration, patients will be crossed-over to standard 
of care therapy with aerosolized Veletri if they meet one or more of the following pre-
defined criteria for a deterioration in their condition: 
• Severe postoperative mediastinal bleeding (> 500 mL/hr) 

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• Hemoptysis 
• If a clinically inadequate response to VentaProst is observed, the patient may be 
converted back to aerosolized Veletri administered in accordance with each site’s 
standard of care guidelines at the investigator’s discretion 
Additionally, patients will be crossed-over to standard of care therapy with aerosolized 
Veletri after extubation. 
6. 
STUDY TREATMENTS 
6.1 
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 clinical label will identify the product by name, lot number, Sponsor, storage 
conditions, and indicate that it is limited to investigational use only. 
6.1.1 
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. 
6.2 
Treatments Administered 
6.2.1 
Part I 
Post-cardiac surgical patients will initially receive treatment with aerosolized Veletri 50 
ng/kg/min in either the OR or the ICU in accordance with each site’s standard of care 
guidelines on administration of aerosolized Veletri.  In the ICU, patients who demonstrate 
at least a 15% improvement in one or more hemodynamic parameters with aerosolized 
Veletri will be crossed over  to a calculated VentaProst equivalent dose of 17 ng/kg/min.  
The VentaProst dose will then be increased in 20% increments (refer to VentaProst 
Pharmacy Manual) every 15 minutes to match the clinically meaningful PD measures 
achieved (i.e., not less than 90% of the effect observed) with the aerosolized Veletri dose. 
6.2.2 
Part II 
In the OR or the ICU, post-cardiac surgical patients will receive VentaProst at a starting 
dose of 3.4 ng/kg/min ofVentaProst, followed by dose titration up in 3.4 
ng/kg/minincrements (refer to VentaProst Pharmacy Manual) every 5 to 15 minutes as 
clinically indicated until clinically meaningful hemodynamic effects are achieved (i.e., at 
least a 15% improvement in one or more hemodynamic parameters). 
6.3 
Study Medication Supply, Preparation, and Administration 
6.3.1 
Study Medication Supply 
The medicinal component of VentaProst, Flolan, will be supplied as a lyophilized 

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formulation of 1.5 mg of epoprostenol sodium in single-use 17 mL glass vials with gray 
butyl rubber closures, along with the required sterile diluent buffer for reconstitution in 
glass vials containing 50 mL of 94 mg glycine, 73.3 mg sodium chloride, sodium 
hydroxide (added to adjust pH), and Water for Injection, USP. 
The patient number and dose number will be recorded on the study medication carton and 
vial.  The patient number, dose number, date and time of dose administration will be 
recorded in the study medication dispensing logs. 
6.3.2 
Study Medication Preparation 
Refer to the VentaProst 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 48 hours. 
During use, a single reservoir of reconstituted solution of epoprostenol sodium can be 
administered at room temperature for a total duration of eight hours and protect the 
reconstituted product from temperatures greater than 25oC (77oF) and less than 0oC 
(32oF) and do not expose to direct sunlight. 
6.3.3 
Study Medication Administration 
6.3.3.1 Part I 
Aerosolized Veletri 50 ng/kg/min will be administered to study patients in the OR or the 
ICU in accordance with each site’s standard of care guidelines on administration of 
aerosolized Veletri.  In the ICU, patients who demonstrate a clinically meaningful 
hemodynamic response (i.e., at least a 15% improvement in one or more hemodynamic 
parameters) to aerosolized Veletri will be crossed over to a calculated VentaProst 
equivalent dose of 17 ng/kg/min to be administered through a custom nebulizer delivery 
system.   The VentaProst dose will then be increased in 20% increments (refer to 
VentaProst Pharmacy Manual) every 15 minutes to match the clinically meaningful PD 
measures achieved (i.e., not less than 90% of the effect observed) with the aerosolized 
Veletri dose. 
6.3.3.2 Part II 
In the OR or ICU, patients will receive a starting dose of 3.4 ng/kg/min of VentaProst.  
The VentaProst dose will be titrated up or down in 3.4 ng/kg/min increments (refer to 
VentaProst Pharmacy Manual) every 5 to 15 minutes as clinically indicated until 
clinically meaningful hemodynamic effects are achieved (i.e., at least a 15% 
improvement in one or more hemodynamic parameters). 

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6.3.4 
Study Medication Titration 
6.3.4.1 Part I 
In the ICU, the VentaProst dose will be increased in 20% increments (refer to VentaProst 
Pharmacy Manual) every 15 minutes to match the clinically meaningful hemodynamic 
effects achieved with the conventionally administered aerosolized Veletri.  Once 
clinically meaningful hemodynamic effects are achieved (i.e., not less than 90% of the 
effect observed), the VentaProst dose will be maintained for at least 15 minutes. 
6.3.4.2 Part II 
In the OR or ICU, the patient will have their VentaProst dose titrated up in 3.4 ng/kg/min 
increments (refer to VentaProst Pharmacy Manual) every 5 to 15 minutes as clinically 
indicated until clinically meaningful PD endpoints are achieved (i.e., at least a 15% 
improvement in one or more hemodynamic parameters) and the dose stabilized.  If the 
patient fails to achieve clinically meaningful PD endpoints, VentaProst dose escalation 
will continue until dose-limiting pharmacological effects are elicited or a tolerance limit 
to VentaProst is established. 
6.3.5 
Study Medication Weaning 
After VentaProst dose stabilization, patients will be weaned from VentaProst.  
VentaProst weaning will occur from mechanical ventilation only.  If the patient has been 
extubated and is on institution’s standard of care delivery for administering aerosolized 
Veletri, weaning will occur in accordance with each site’s standard of care guideline for 
weaning of aerosolized Veletri. 
Patients on mechanical ventilation 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 decreased in increments of 20% of the VentaProst equivalent dose, with a 
minimum of 30 minutes between changes, down to 20% of the dose before 
discontinuation. The VentaProst weaning process should occur in isolation to other 
treatment changes (no changes in inotropes, vasopressors or vasodilators). Patients will 
be observed closely before, during, and after dosing changes. In the event patients 
demonstrate signs of hemodynamic instability (changes in combined hemodynamic 
parameters) or a decrease in oxygenation indicated by either arterial or central blood 
oxygenation saturation 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. 
6.4 
Identity of the Device Component of the Investigational Product 
6.4.1 
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 

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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. 
6.4.1.1 Aerosol Delivery to Ventilated Patients 
The Phase 2a VentaProst drug delivery system (Figure 1) consists of reusable and single-
patient disposable elements: 
• 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, a device to continuously operate the disposable Aerogen Solo 
nebulizer.  
o Aerogen Pharma Controller,  which synchronizes aerosol generation with the 
ventilator breathing pattern.   
o Aerogen Solo Nebulizer Cable 
o Sensirion Flow Sensor Cable 
• Single-patient disposable kit: 
o Aerogen Solo Nebulizer - a low mass and low profile vibrating mesh aerosol 
generator. 
o Aerogen Continuous Nebulization Tube Set (CNTS) and syringe connected to 
the nebulizer.  
o Sensirion Flow Sensor. 

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Figure 1 – Drug Delivery System 
Prior to VentaProst administration, the study medication will be reconstituted in the 
recommended diluent buffer and placed into the CNTS syringe.  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 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.   
 

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Figure 2 - VentaProst Device Placement in the Gas Pathway 
 
6.4.2 
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. 
6.4.3 
Device Supply 
Prior to the first dose of VentaProst for each patient, one delivery device setup will be 
dispensed.  The serial numbers for the controllers, flow sensor, and nebulizer will also be 
recorded in the dispensing log 
Used and unused devices will be inventoried and returned to the Sponsor or Sponsor’s 
designee. 
6.4.4 
Device Replacement 
Devices may be replaced at any time if there a suspicion of malfunction, but must be 
replaced if: 

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• 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 on the appropriate page 
of the case report form (CRF). 
• The investigator suspects the device is not performing optimally for any reason. 
6.4.5 
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 of more devices need to be replaced, the reason should be documented in the 
patient’s medical record, dispensing log, and eCRF.  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 eCRF. 
For device malfunction or complaints, the Sponsor or the Sponsor’s designee should be 
contacted within 48 hours.  Failed devices will be inventoried and returned to the Sponsor 
or the Sponsor’s designee. 
6.5 
Blinding 
Since this is an open-label study, there will be no blinding of the study medication. 
6.6 
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 30 days prior) will be recorded on the Prior and Concomitant 
Therapy eCRF.  The Investigator will record any AE on the AE eCRF for which a 
concomitant medication/therapy was administered. 
6.6.1 Prohibited Concomitant Therapy 
Not applicable. 
6.7 
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. 
• 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. 

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• A signed and dated clinical trial agreement. 
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, including empty 
containers, are to be returned to Aerogen Pharma at the conclusion of the study, unless 
provision is made by Aerogen Pharma for destruction of supplies and containers at the 
investigational site.  Upon completion of IP accountability and reconciliation procedures 
by investigational site personnel and documentation procedures by Aerogen Pharma 
personnel, IP that is to be returned to Aerogen Pharma, if necessary, must be boxed, 
sealed and shipped back to Aerogen Pharma following all local regulatory requirements.   
A Clinical Research Associate (CRA) will review IP accountability during investigational 
site visits and at the completion of the study. 
7. 
PHARMACODYNAMIC ASSESSMENTS 
7.1 
Primary Endpoint 
Determination of the equivalent dose of VentaProst necessary to achieve a hemodynamic 
response that is not less than 90% of the effect observed with 50 ng/kg/min aerosolized 
Veletri. 
7.2 
Secondary Endpoints 
The secondary endpoints that will be assessed include: 
• Safety of VentaProst dosing regimen 
o Monitoring of adverse events (AEs), physical examinations, laboratory tests, 
and electrocardiograms 
• Effect of VentaProst dosing regimen on: 
o Cardiovascular Parameters 
 Pulmonary Vascular Resistance (PVR) 

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 Pulmonary Arterial Pressure (PAP) 
 Systemic Arterial Pressure 
 Central Venous Pressure (CVP) 
 Pulmonary Capillary Wedge Pressure (PCWP) 
 Cardiac Output (CO) 
o Oxygenation 
 Arterial Oxygen Saturation (SaO2) or Oxygen Saturation by Pulse Oximetry 
(SpO2)  
 Partial Pressure of Oxygen in Arterial Blood (PaO2) 
o Ventilator Support 
 FiO2 
 Ventilator pressures 
 Ventilator volumes 
 Duration of intubation 
• Number and type of cardiovascular medications required through end of study 
7.3 
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. 
8. 
SAFETY ASSESSMENTS 
Safety will be assessed through monitoring of adverse events (AEs), physical 
examinations, laboratory tests, and electrocardiograms.  Safety assessment frequency is 
shown in the Schedule of Assessments and Procedures. 
8.1 
General Safety Procedures 
8.1.1 
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 as clinically indicated.  Weight (kg) 
will be obtained at the time of Screening and at End of Study.  Height will be obtained at 
the time of Screening. 
8.1.2 
Physical Examination 
Complete physical examination 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.  Clinically significant changes from Screening 
will be recorded as AEs.   

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8.1.3 
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 
Hemoglobin, hematocrit, RBC, WBC with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, 
basophils), platelets  
Chemistry 
Electrolytes 
Sodium, potassium, chloride, bicarbonate, calcium 
Liver function tests 
AST, ALT, AP, total bilirubin 
Renal function parameters 
BUN, creatinine, eGFR calculation 
Other 
Glucose, albumin, total protein, uric acid, creatine 
kinase, serum pregnancy test 
 
 
 
8.1.4 
Electrocardiograms 
Twelve-lead electrocardiograms (ECGs) will be obtained at the visits designated on the 
Schedule of Assessments and Procedures.  The Baseline for 12-lead ECGs is Screening. 
8.2 
Adverse Events 
8.2.1 
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.  Expected medical events are 
untoward clinical occurrences that are perceived by the investigator to occur with 
reasonable frequency in the day-to-day care of patients who have undergone cardiac 
surgery with CPB and who are treated in the ICU with mechanical ventilation.  Such 
events will not be considered adverse events unless the investigator considers the event to 
be associated with study medication, study device, or to be unexpectedly severe or 
frequent for a patient. 
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 will be recorded and reported as Treatment-Emergent Adverse Events (TEAE).  
All AEs must be appropriately documented in the patient’s medical chart and on the 
CRFs.  When known, investigators should report syndromes rather than list symptoms 
associated with the syndrome. 

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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. 
8.2.2 
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. 
8.2.3 
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.    
8.2.4 
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 

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should be assessed as “recovered”, “recovering”, “recovered with sequelae” or 
“not recovered”.  An AE with fatal outcome must be reported as an SAE. 
8.2.5 
Laboratory Test and other Test Abnormalities as Adverse Events 
A laboratory or other test (ECG, 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.” 
8.2.6 
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 
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. 
8.2.7 
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 must be reported to the Sponsor or the 
Sponsor’s representative within 24 hours of the investigational site’s knowledge of the 

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occurrence.  The investigational site will either telephone the report to the Sponsor’s 
Medical Monitor (contact information found on the Protocol Title Page) or transmit by 
email a Serious Adverse Event Report (SAER) to the Sponsor’s Medical Monitor or the 
Sponsor’s representative.  If the initial report is made via telephone, a completed SAER 
must be emailed within 24 hours of the site’s knowledge of the event.  Investigational 
sites will be provided with SAER forms. 
The SAE information phoned or 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 
The SAER should be emailed within 24 hours with as much of the above information as 
available at the time.  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. 
8.3 
Reporting of Pregnancy 
Any pregnancy where the estimated date of conception occurs either prior to the End of 
Study must be reported. 

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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 
fax or 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. 
9. 
PHARMACOKINETIC ASSESSMENTS 
Not applicable. 
10. 
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. 
10.1 
Part I 
10.1.1 Screening 
Potential study patients will be recruited by the study staff from patients who will 
undergo cardiac surgery with CPB.  Prior to performing any study procedures or 
assessments, the nature of the study and the potential risks associated with the trial will 
be explained to the potential study patient and written informed consent obtained.  Once 
informed consent has been obtained, the potential study patient will undergo the 
following study-related procedures and evaluations: 
• Review inclusion and exclusion criteria 
• Obtain medical history (including history of any medications within 30 days prior 
to Screening) and demographics (including date of birth, gender, race, and 
ethnicity)  
• Obtain vital signs (SBP, DBP, HR, respiration rate, and body temperature), height, 
and weight 
• Perform comprehensive physical examination 
• Perform 12-lead ECG 
• Spirometry – only for those patients with presence or history of significant 
restrictive or obstructive lung disease 
• Collect blood for clinical laboratory tests, including serum pregnancy test for 
women of childbearing potential. 

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If the patient satisfies all the eligibility criteria, the patient may be enrolled into the study.  
If the patient is not eligible for the study, the patient will be considered a screen failure. 
Note:  Before patients may be switched over to VentaProst, patients must meet Inclusion 
Criteria 4c, that is, demonstrate a clinically defined response to aerosolized Veletri, 
defined as at least a 15% improvement in one or more hemodynamic parameters (as 
defined by the clinical team). 
10.1.2 Intra-Operative (OR) 
The patient will undergo cardiac surgery with CPB in the OR and the following study-
related procedures and evaluations: 
• Measure hemodynamic parameters prior to cardiac surgery with CPB.  These 
measurements will represent the baseline for hemodynamic parameters. 
• Record all cardiovascular procedures and concomitant medications 
• Investigator assessment of any unanticipated medical events 
10.1.3 Aerosolized Veletri Treatment (OR/ICU) 
If there is a need for administration of aerosolized Veletri, the patient will begin dosing at 
50 ng/kg/min (in accordance with each site’s standard of care guidelines) and will 
undergo the following study-related procedures and evaluations: 
• Measure hemodynamic, oxygenation, and ventilator parameters before 
aerosolized Veletri administration and after stabilization of aerosolized Veletri 
• If at least a 15% improvement in one or more hemodynamic parameters (as 
defined by the clinical team) is seen with aerosolized Veletri after stabilization in 
the ICU, the VentaProst will be set-up inline to the ventilator circuit, VentaProst 
nebulization will be started, and then the Veletri pump flow will be stopped once 
VentaProst administration is confirmed.  Do not remove Veletri administration 
system until VentaProst administration is confirmed 
• If less than a 15% improvement is seen in one or more hemodynamic parameters 
(as defined by the clinical team) with aerosolized Veletri after stabilization in the 
ICU, the patient will not be administered VentaProst 
• Record all concomitant medications 
• Investigator assessment of any unanticipated medical events 
If the patient does not require aerosolized Veletri, or if the patient fails to achieve at least 
a 15% improvement in one or more hemodynamic parameters with aerosolized Veletri, 
the patient will be withdrawn from the study as a screen failure. 

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10.1.4 VentaProst Treatment (ICU) 
10.1.4.1 Dosing 
Patients who demonstrate at least a 15% improvement in one or more hemodynamic 
parameters with aerosolized Veletri will be eligible to receive VentaProst.  Patients will 
undergo the following study-related procedures and evaluations: 
• Patients will be switched from aerosolized Veletri to receive a calculated 
equivalent starting dose of 17 ng/kg/min VentaProst while still on mechanical 
ventilation 
• Patients will receive increases in the VentaProst dose in 20% increments (refer to 
VentaProst Pharmacy Manual) every 15 minutes until at least 90% of the 
hemodynamic effect observed with 50 ng/kg/min aerosolized Veletri is achieved.  
Once this has been achieved, the patient will remain on a stable dose of 
VentaProst for at least15 minutes   
• Measure hemodynamic, oxygenation, and ventilator parameters before and after 
each VentaProst dose  
• Record all concomitant medications 
• Record AEs 
10.1.4.2 Weaning 
After the stabilization period, VentaProst weaning procedures will be initiated when the 
clinical team determines the patient is hemodynamically stable enough to begin the 
weaning process.  VentaProst weaning will occur from mechanical ventilation only.  The 
table below shows the typical weaning steps for aerosolized Veletri from mechanical 
ventilation.  If weaning from VentaProst occurs while on mechanical ventilation, doses 
will be decreased in 20% increments of the VentaProst equivalent dose.  If the patient has 
been extubated and is on institution’ standard of care delivery system for administering 
aerosolized Veletri, weaning will occur in accordance with each site’s standard of care 
guidelines for weaning of aerosolized Veletri. 
Weaning Guideline 
Aerosolized Veletri 
(from Ventilator) 
VentaProst 
(from Ventilator) 
50 ng/kg/min 
Dose Equivalence to aerosolized Veletri 50 ng/kg/min 
40 ng/kg/min 
80% of Dose Equivalence 
30 ng/kg/min 
60% of Dose Equivalence 
20 ng/kg/min 
40% of Dose Equivalence 
10 ng/kg/min 
20% of Dose Equivalence 
Patients on mechanical ventilation will be weaned from VentaProst slowly due to concern 
that VentaProst is providing significant clinical benefit and to avoid a rebound effect.  

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VentaProst weaning will be performed as per institutional guidelines for weaning of 
inhaled Veletri, except that VentaProst doses will be decreased in increments of 20% of 
the VentaProst equivalent dose, with a minimum of 30 minutes between changes, down 
to 20% of the dose before discontinuation.  The VentaProst weaning process should occur 
in isolation to other treatment changes (no changes in inotropes, pressors, or vasodilators). 
Patients will be observed closely before, during and after dosing changes. In the event the 
patient demonstrates signs of hemodynamic instability (changes in combined 
hemodynamic parameters) or a decrease in oxygenation indicated by either arterial or 
central blood oxygenation saturation during downward titration, the VentaProst dose will 
be returned to its previous level. Once the patient has been stable for 15 minutes, repeat 
attempts at dose reduction may be undertaken.  The process will continue until the patient 
is fully weaned from VentaProst. The patient will undergo the following study-related 
procedures and evaluations during VentaProst weaning: 
• Stabilize the patient at each dose adjustment for at least 15 minutes 
• Measure hemodynamic, oxygenation, and ventilator parameters before and at 15 
to 30 minutes after each VentaProst dose adjustment and at 15 to 30 minutes after 
discontinuation of VentaProst 
• Record all concomitant medications 
• Record AEs 
10.1.5 End of Study (ICU) 
Once VentaProst dosing has been discontinued, the patient will undergo the following 
study-related procedures and evaluations within 24 hours of VentaProst discontinuation: 
• Record all concomitant medications 
• Record AEs 
• Perform comprehensive physical examination 
• Obtain vital signs and weight 
• Perform 12-lead ECG 
• Collect blood for clinical laboratory tests, including serum pregnancy test for 
women of childbearing potential 
10.2 
Part II 
10.2.1 Screening 
Potential study patients will be recruited by the study staff from patients who will 
undergo cardiac surgery with CPB.  Prior to performing any study procedures or 
assessments, the nature of the study and the potential risks associated with the trial will 
be explained to the potential study patient and written informed consent obtained.  Once 
informed consent has been obtained, the potential study patient will undergo the 
following study-related procedures and evaluations: 
• Review inclusion and exclusion criteria 

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• Obtain medical history (including history of any medications within 30 days prior 
to Screening) and demographics (including date of birth, gender, race, and 
ethnicity)   
• Obtain vital signs, height, and weight 
• Perform comprehensive physical examination 
• Spirometry – only for those patients with presence or history of significant 
restrictive or obstructive lung disease 
• Perform 12-lead ECG 
• Collect blood for clinical laboratory tests, including serum pregnancy test for 
women of childbearing potential 
If the patient meets all the eligibility criteria, the patient may be enrolled into the study.  
If the patient is not eligible for the study, the patient will be considered a screen failure. 
10.2.2 Intra-Operative (OR) 
The patient will undergo cardiac surgery with CPB in the OR and the following study-
related procedures and evaluations: 
• Measure hemodynamic parameters prior to cardiac surgery (after induction) with 
CPB.  These measurements will represent the baseline for hemodynamic 
parameters 
• Record all cardiovascular procedures and concomitant medications 
• Investigator assessment of any unanticipated medical events 
10.2.3 VentaProst Treatment (OR/ICU) 
10.2.3.1 Dosing 
 The patient will undergo the following study-related procedures and evaluations: 
• Patients will receive a starting dose of 3.4 ng/kg/min of VentaProst 
• Patients will receive increases in VentaProst dose by 3.4 ng/kg/min (refer to 
VentaProst Pharmacy Manual)  
o If greater than a 15% improvement in one or more hemodynamic 
parameters (as defined by the clinical team) is seen with the initial 
VentaProst dose, but NO additional clinically meaningful change is seen 
with the first dose escalation, the VentaProst dose will be reduced to the 
initial dose level 
o If greater than a 15% improvement in one or more hemodynamic 
parameters (as defined by the clinical team) is seen with the initial 
VentaProst dose, but AN additional clinically meaningful change is seen 
with the first dose escalation, continue to dose with VentaProst in 
increasing steps of 3.4 ng/kg/min every 5 to 15 minutes as clinically 
indicated until no further improvements in one or more hemodynamic 

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parameters are achieved or until dose-limiting pharmacological effects are 
elicited or a tolerance limit to VentaProst is established 
o If less than a 15% improvement in one or more hemodynamic parameters 
(as defined by the clinical team) is seen with first dose increase, continue 
to dose with VentaProst in increasing steps of 3.4 ng/kg/min every 5 to 15 
minutes as clinically indicated until no further improvements in one or 
more hemodynamic parameters are achieved or until dose-limiting 
pharmacological effects are elicited or a tolerance limit to VentaProst is 
established.  After the VentaProst has been stabilized, reduce the 
VentaProst dose to the previous dose level at which a hemodynamic 
parameter showed maximum improvement.  The VentaProst dose level 
will remain at this setting until clinical conditions determine the need for 
changing the dose 
• Measure hemodynamic, oxygenation, and ventilator parameters at each dose 
adjustment 
• Record all concomitant medications 
• Record AEs 
10.2.3.2 Weaning (ICU) 
After the stabilization period, VentaProst weaning procedures will be initiated when the 
clinical team determines the patient is hemodynamically stable enough to begin the 
weaning process.  VentaProst weaning will occur from mechanical ventilation only.  The 
table below shows the typical weaning steps for aerosolized Veletri from mechanical 
ventilation.  If weaning from VentaProst occurs while on mechanical ventilation, doses 
will be decreased in 20% increments of the VentaProst equivalent dose.  If the patient has 
been extubated and is on institution’s standard of care delivery system for administering 
aerosolized Veletri, weaning will occur in accordance with each site’s standard of care 
practice guidelines for weaning of aerosolized Veletri.  
Weaning Guideline 
Aerosolized Veletri 
(from Ventilator) 
VentaProst 
(from Ventilator) 
50 ng/kg/min 
Dose Equivalence to aerosolized Veletri 50 ng/kg/min 
40 ng/kg/min 
80% of Dose Equivalence 
30 ng/kg/min 
60% of Dose Equivalence 
20 ng/kg/min 
40% of Dose Equivalence 
10 ng/kg/min 
20% of Dose Equivalence 
Patients on mechanical ventilation will be weaned from VentaProst slowly due to concern 
that VentaProst is providing significant clinical benefit and to avoid a rebound effect.  
VentaProst weaning will be performed as per institutional guidelines for weaning of 

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inhaled Veletri, except that VentaProst doses will be decreased in increments of 20% of 
the VentaProst equivalent dose, with a minimum of 30 minutes between changes, down 
to 20% of the dose before discontinuation.  The VentaProst weaning process should occur 
in isolation to other treatment changes (no changes in inotropes, pressors, or vasodilators). 
Patients will be observed closely before, during and after dosing changes. In the event the 
patient demonstrates signs of hemodynamic instability (changes in combined 
hemodynamic parameters) or a decrease in oxygenation indicated by either arterial or 
central blood oxygenation saturation during downward titration, the VentaProst dose will 
be returned to its previous level. Once the patient has been stable for 15 minutes, repeat 
attempts at dose reduction may be undertaken.  The process will continue until the patient 
is fully weaned from VentaProst. The patient will undergo the following study-related 
procedures and evaluations during VentaProst weaning: 
• Stabilize the patient at each dose adjustment for at least 15 minutes 
• Measure hemodynamic, oxygenation, and ventilator parameters before and at 15 
to 30 minutes after each VentaProst dose adjustment and at 15 to 30 minutes after 
discontinuation of VentaProst 
• Record all concomitant medications 
• Record AEs 
10.2.4 End of Study (ICU) 
Once VentaProst dosing has been discontinued, the patient will undergo the following 
study-related procedures and evaluations within 24 hours of VentaProst discontinuation: 
• Record all concomitant medications 
• Record AEs 
• Perform comprehensive physical examination 
• Obtain vital signs and weight 
• Perform 12-lead ECG 
• Collect blood for clinical laboratory tests, including serum pregnancy test for 
women of childbearing potential 
11. 
DATA QUALITY ASSURANCE 
11.1 
Data Collection 
Investigator or designee will enter the information required by the protocol onto the 
eCRFs in accordance with the eCRF Completion Guidelines that are provided with the 
eCRFs.  CRAs will visit each investigational site as frequently as documented in the 
monitoring plan to review the eCRFs for completeness and accuracy against the source 
documents.  CRAs will highlight any discrepancies found in the documentation of study 
conduct and ensure that appropriate site personnel address the discrepancies. 

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11.2 
Clinical Data Management 
Data from eCRFs will be entered into a clinical database as specified in the data 
management plan.  Quality control and data validation procedures will be applied to 
ensure the validity and accuracy of the clinical database. 
11.3 
Database Quality Assurance 
All databases will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be documented and returned to the investigational site for 
resolution.  Only authorized personnel will make corrections to the clinical database, and 
all corrections will be documented in an audit trail. 
12. 
 STATISTICAL CONSIDERATIONS 
12.1 
Statistical Methods 
A Statistical Analysis Plan will be developed that describes in detail the statistical 
methods to be used for analysis of this study and will be finalized prior to database lock. 
12.2 
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 exposure to this investigational product. 
12.3 
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 
specified.  Individual patient listings of data will also be provided to allow for review of 
all pharmacodynamic, safety, and tolerability parameters. 
12.4 
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.  Baseline hemodynamic parameters will be obtained prior to cardiac surgery 
with CPB. 

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12.5 
Pharmacodynamic Analyses 
12.5.1 
Primary Endpoint 
The primary efficacy endpoint of this study is to determine the equivalent dose of 
VentaProst necessary to achieve a hemodynamic parameter measurement that is not less 
than 90% of the effect observed with 50 ng/kg/min aerosolized Veletri. 
Further details will be included in the Statistical Analysis Plan. 
12.5.2 
Secondary Endpoints 
Key secondary endpoints include: 
• Safety of VentaProst dosing regimen 
o Monitoring 
of 
AEs, 
physical 
examinations, 
laboratory 
tests, 
and 
electrocardiograms 
• Effect of VentaProst dosing regimen on: 
o Cardiovascular Parameters  
 Pulmonary Vascular Resistance (PVR) 
 Pulmonary Arterial Pressure (PAP) 
 Systemic Arterial Pressure 
 Central Venous Pressure (CVP) 
 Pulmonary Capillary Wedge Pressure (PCWP) 
 Cardiac Output (CO) 
o Oxygenation 
 Arterial Oxygen Saturation (SaO2) or Oxygen Saturation by Pulse Oximetry 
(SpO2) 
 Partial Pressure of Oxygen in Arterial Blood (PaO2) 
o Ventilator Support 
 FiO2 
 Ventilator pressures 
 Ventilator volumes 
 Duration of intubation 
o Number and type of cardiovascular medications required through end of study 
Similar analyses for the primary endpoint will be applied to the key secondary efficacy 
endpoints. 
12.6 
Extent of Exposure 
Exposure data will be summarized by treatment group using frequencies and percentages. 
12.7 
Safety Analyses 
Safety measurements include AEs, physical examination, vital signs, laboratory tests, and 
electrocardiograms.  Safety data will be summarized by treatment group using 
frequencies and incidence rates.   

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12.7.1 
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 CSR.  
AEs will be summarized by presenting, for each treatment group, 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. 
12.7.2 
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. 
12.7.3 
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 by treatment group. 
12.8 
The Procedure for Revising the Statistical Analysis Plan 
Any changes to the statistical analysis plan will be formalized and dated in an amendment 
and documented in the CSR. 
13. 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS 
13.1 
Ethics 
13.1.1 
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 

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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 
any study medication 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. 
13.1.2 
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). 
13.1.3 
Patient Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each patient 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 should understand the statement before signing 
and dating it and will be given a copy of the signed document.  The patient 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. 

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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 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. 
13.2 
Administrative Procedures 
13.2.1 
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 Sponsor’s 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. 
13.2.2 
Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
13.2.3 
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 assigned CRA.  The Investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCPs and local regulatory requirements.  The CRFs and patient’s 
corresponding original medical records (source documents) are to be fully available for 
review by the Sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with federal regulations and 

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local regulations.  All records at the investigational site are subject to inspection by the 
FDA. 
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, polysomnographs, 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. 
13.2.4 
Recording of Data 
In order to provide the Sponsor with accurate, complete, and legible case reports, the 
following criteria are to be maintained.  The Investigator will enter the information 
required by the protocol onto the eCRFs in accordance with the eCRF Completion 
Guidelines provided by the Sponsor. 
13.2.5 
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 eCRFs, Investigator's Brochure, regulatory agency registration 
documents, e.g., FDA 1572 form, ICFs, and IRB/IEC correspondence.  In addition, the 
Sponsor will send a list of treatment codes by study patient to the Investigator after the 
clinical database for this study has been secured.   
The investigational site should plan on retaining study documents as follows: 

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• 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. 
13.2.6 
Auditing Procedures and Inspection 
In addition to the routine monitoring procedures, the Sponsor’s Quality Assurance 
department or representative conducts audits of clinical research activities in accordance 
with the Sponsor’s or representative’s SOPs to evaluate compliance with the principles of 
ICH GCPs and all applicable local regulations.  A government regulatory authority may 
also wish to conduct an inspection (during the study or after its completion).  If an 
inspection is requested by a regulatory authority, the Investigator must inform the 
Sponsor immediately that this request has been made. 
13.2.7 
Handling of Investigational Product 
All IP will be supplied to the Principal Investigator (or designated pharmacist) by the 
Sponsor or Sponsor representative.  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 CRA 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. 
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 product and provide 
a copy of the completed IP accountability logs to the Sponsor or Sponsor’s Designee. 
13.2.8 
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. 
13.2.9 
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 

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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). 
13.2.10 Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a trial is prematurely terminated or suspended, the Sponsor should 
promptly inform the Investigator/Institution and the regulatory authority(ies) of the 
termination or suspension, and the reason(s) for the termination or suspension.  The 
IRB/IEC should also be informed promptly and provided the reason(s) for the termination 
or suspension by the Sponsor or by the Investigator/Institution, as specified by the 
applicable regulatory requirement(s). 
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. 
13.2.11 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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14. 
REFERENCES 
1. Buckley MS and Feldman JP.  Inhaled epoprostenol for the treatment of pulmonary 
arterial hypertension in critically ill adults.  Pharmacotherapy 2010; 30(7):728-740. 
2. De Wet CJ, Affleck DG, Jacobsohn E, Avidan MS, Tymkew H, Hill LL, Zanaboni 
PB, Moazami N, and Smith JR.  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 2004; 
127(4):1058-1067. 
3. Fattouch K, Sbraga F, Bianco G, Speziale G, Gucciardo M, Sampognaro R, and 
Ruvolo G.  Inhaled prostacyclin, nitric oxide and nitroprusside in pulmonary 
hypertension after mitral valve replacement.  J Card Surg 2005; 20(2):171-176. 
4. Fattouch K, Sbraga F, Sampognaro R, Bianco G, Gucciardo M, Lavalle C, Vizza CD, 
Fedele F, and Ruvolo G.  Treatment of pulmonary hypertension in patients 
undergoing cardiac surgery with cardiopulmonary bypass: a randomized, prospective, 
double-blind study.  J Cardiovasc Med (Hagerstown) 2006; 7(2):119-123. 
5. Hache M, Denault A, Belisle S, Robitaille D, Couture P, Sheridan P, Pellerin M, 
Babin D, Noel N, Guertin MC, Martineau R, and Dupuis J.  Inhaled epoprostenol 
(prostacyclin) and pulmonary hypertension before cardiac surgery.  J Thorac 
Cardiovasc Surg 2003; 125(3):642-649. 
6. Haraldsson SA, Kieler-Jensen N, and Ricksten SE.  The additive pulmonary 
vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac 
surgical patients with pulmonary hypertension.  Anesth Analg 2001; 93(6):1439-
1445.  
7. Khan TA, Schnickel G, Ross D, Bastani S, Laks H, Esmailian F, Marelli D, Beygui 
R, Shemin R, Watson L, Vartapetian I, and Ardehali A.  A prospective, randomized, 
crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart 
transplant and lung transplant recipients.  J Thorac Cardiovasc Surg 2009; 
138(6):1417-1424. 
8. Ocal, A, Kiris I, Erdinc M, Peker O, Yavuz T, and Ibrisim E.  Efficiency of 
prostacyclin in the treatment of protamine-mediated right ventricular heart failure and 
acute pulmonary hypertension.  Tohoku J Exp Med 2005; 2007(1):51-58. 
9. Ylikorkala O and Viinikka L.  Measurement of 6-keto-prostaglandin F1α in human 
plasma with radioimmunoassay: Effect of prostacyclin infusion.  Prostaglandins and 
Medicine 1981; 6:427-436. 
10. Ylikorkala O, Saarela MD, and Viinikka L.  Increased prostacyclin and thromboxane 
production in man during cardiopulmonary bypass.  J Thorac Cardiovasc Surg 1981; 
82:245-247. 

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15. 
APPENDICES 
 

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Appendix 1 
Part I Study Design Schematic 
 
 

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Appendix 2 
Part II Study Design Schematic 
 
 
 
 
 
 
 
 
 
 
SCREENING 
Patients assessed for eligibility and informed consent obtained 
ENROLLMENT 
Patients excluded;  
Screen Fail from Study 
OR 
Cardiac surgery with CPB 
OR/ICU 
Measure hemodynamic parameters before starting VentaProst; initiate 
starting dose of VentaProst at 3.4 ng/kg/min 
ICU 
Extubate and convert to institution’s SOC 
administration of inhaled Veletri; wean patient 
from inhaled Veletri 
ICU 
Intubation continues; wean patient from 
VentaProst 
OR/ICU 
Titrate VentaProst dose up in 3.4 ng/kg/min increments as clinically 
indicated 
OR/ICU 
1. If greater than a 15% improvement in a hemodynamic parameter is seen with the initial VentaProst dose, 
but NO additional clinically meaningful change is seen with the first dose escalation, reduce the 
VentaProst dose back to the initial dose level 
2. If greater than a 15% improvement in a hemodynamic parameter is seen with the initial VentaProst dose, 
but AN additional clinically meaningful change is seen with the first dose escalation, continue VentaProst 
in increasing steps of 3.4 ng/kg/min every 5 to 15 minutes as clinically indicated until no further 
improvements in a hemodynamic parameter are achieved 
3. If less than a 15% improvement in a hemodynamic parameter is seen with first dose increase, continue to 
dose with VentaProst in increasing steps of 3.4 ng/kg/min every 5 to 15 minutes as clinically indicated 
until no further improvements in hemodynamic parameter measurements are achieved.  After the 
VentaProst dose has been stabilized, reduce the VentaProst dose to the previous dose level at which a 
hemodynamic parameter showed maximum improvement