An Open-label Extension of BPS-314d-MR-PAH-302 in Pulmonary Arterial Hypertension Patients
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Sponsor: Lung Biotechnology PBC

 
 
 
 
 
NCT# : NCT03657095 

 
 
 
Clinical Trial Protocol: BPS-314d-MR-PAH-303 
Study Title: 
An Open-label Extension of BPS-314d-MR-PAH-302 in Pulmonary 
Arterial Hypertension Patients. 
Study Number: 
BPS-314d-MR-PAH-303 
Study Phase: 
3  
Product Name: 
Esuberaprost Sodium Tablets  
IND Number: 
111,729 
Indication: 
Pulmonary Arterial Hypertension 
Investigators: 
Multicenter 
Sponsor: 
Lung Biotechnology 
Sponsor Contact: 
 
Medical Monitor: 
 
 
 
Date 
Original Protocol: 
13 September 2017 
 
 
GCP Statement:  This study will be conducted in compliance with the protocol, Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
 
Confidentiality Statement 
The concepts and information contained herein are confidential and proprietary and shall not be disclosed in 
whole or part without the express written consent of Lung Biotechnology PBC  
© 2017 Lung Biotechnology PBC. 
 

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Clinical Trial Protocol: BPS-314d-MR-PAH-303 
 
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LIST OF CONTACTS 
Study Sponsor: 
Lung Biotechnology  
1040 Spring Street 
Silver Spring, Maryland 20910 
United States  
Phone:  301-608-9292 
Fax:  
301-589-0855 
 
Sponsor Contact:  
Medical Monitor: 
 
  
 
 
  
 
 
Serious Adverse Event (SAE) 
Reporting: 
 
 
  
  
 
 
Central Laboratory: 
  
  
 
 
 
  
  
  
  
 

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SYNOPSIS 
Sponsor:  Lung Biotechnology 
 
Name of Finished Product:  Esuberaprost Sodium Tablets (Beraprost Sodium 314d Modified 
Release [BPS-314d-MR]) 
 
Name of Active Ingredient:  Esuberaprost (BPS-314d) 
 
Study Title:  An Open-label Extension of BPS-314d-MR-PAH-302 in Pulmonary Arterial 
Hypertension Patients 
 
Study Number:  BPS-314d-MR-PAH-303 
 
Study Phase: 3 
 
Primary Objective:  
The primary objective of this study is to assess the safety and tolerability of long-term treatment 
with esuberaprost in subjects with pulmonary arterial hypertension (PAH). 
 
Secondary Objective: 
The secondary objective of this study will be to assess the efficacy of long-term treatment of 
esuberaprost in subjects with PAH. 
 
Study Design: 
This is a multi-center, open-label study for eligible subjects who were actively participating in 
the BPS-314d-MR-PAH-302 study at the time the study was concluded. Subjects will sign an 
informed consent to continue treatment for PAH with esuberaprost in this open-label extension 
(OLE) study.  At the Enrollment Visit for this study, subjects will begin a blinded transition 
from the BPS-314d-MR-PAH-302 study to the OLE study over a 4-week period.  The first dose 
for all subjects in this OLE study will be 2 tablets.  During this blinded transition period, those 
subjects on active study drug in the BPS-314d-MR-PAH-302 study will continue with blinded 
active study drug 4-times daily (QID); those subjects on placebo study drug will receive one 
active tablet and one placebo tablet QID (blinded) during the first 2 weeks and increase to 
2 active tablets QID (blinded) thereafter.  After the first dose, the investigator may adjust the 
dose as medically warranted.  The maximum dose for this study is 30 µg QID with a minimum 
accepted dose as 15 µg QID. For the first 4 weeks, contact with the subject should occur weekly 
to ensure up-titration to the fixed dose is tolerated and assess adverse events (AEs).   
 
Subjects will return to the clinic at Week 4 to be supplied open-label esuberaprost and complete 
protocol specified procedures.  At the Week 4 Visit, subjects will be dosed with two 
15 µg tablets (30 µg total) of esuberaprost, administered orally QID (provided the target dose is 
tolerated) or follow the Investigator’s (or designee’s) directions if adjustment is needed. 
Following the Week 4 Visit, each subject will return to the clinic at Months 3, 6, 9, and 12, and 
quarterly thereafter for assessment.   
 
At the conclusion of the study or if a subject discontinues the study prematurely, subjects will 
return to the clinic for an End-of-Study (EOS) Visit.  Subjects will be provided instructions 
about down titration off esuberaprost sodium tablets by the investigator.  

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Clinical Trial Protocol: BPS-314d-MR-PAH-303 
 
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Study Population:  
This study will include eligible subjects who were actively participating in the 
BPS-314d-MR-PAH-302 study at the time the study was concluded and who have consented to 
continue treatment for PAH with esuberaprost. 
 
Up to 273 subjects are eligible to enroll.  
 
Test Product, Dose, and Mode of Administration:  
Esuberaprost sodium tablets (BPS-314d-MR), 15 µg.  Subjects will be dosed with two 15 µg 
(30 µg) tablets administered orally 4-times daily (QID). 
 
Duration of Treatment:  
This study is expected to continue until the first of any of the following are reached: the study 
drug is commercially available, the sponsor discontinues the study, or offers enrollment in 
another study. 
 
Safety Assessments: 
Safety will be assessed by AEs, physical examination, vital signs, clinical laboratory parameters 
and electrocardiogram (ECG) findings. 
 
Efficacy Assessments: 
Efficacy will be assessed by six-minute walk distance (6MWD), the Borg Dyspnea Score, World 
Health Organization (WHO) Functional Class (FC), and N-terminal pro-brain natriuretic peptide 
(NT-pro-BNP). 
 
Other Assessments: 
Quality of life will be assessed for all subjects at Enrollment and Month 6 using the patient 
reported outcome (PRO) instrument, emPHasis-10.  
 
For those subjects in the United States (US) who choose to participate and provide a separate 
informed consent, blood samples will be collected at Enrollment and at Month 3 (at any point 
during the site visit) for future biomedical research (e.g., biomarker and genomic analyses). 
 
Statistical Methods:  
The primary safety endpoint of this study is the incidence and severity of AEs associated with 
long-term exposure to esuberaprost in eligible subjects. 
 
Secondary endpoints include: 
- 
Exercise capacity as measured by unencouraged 6MWD 
- 
Borg Dyspnea Score 
- 
WHO FC 
- 
NT-pro-BNP 
 
Pertinent data will be summarized in tables, and all data will be presented in by-subject listings. 
No inferential analyses will be performed. 
 
Date of Original Approved Protocol:  13 September 2017 

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TABLE OF CONTENTS 
List of Contacts ..............................................................................................................................2 
Synopsis ...........................................................................................................................................3 
Table of Contents ...........................................................................................................................5 
List of In-Text Tables ..............................................................................................................7 
List of Abbreviations and Definitions of Terms ..........................................................................8 
1 
Introduction ..........................................................................................................................10 
2 
Study Objectives ...................................................................................................................11 
2.1 
Primary Objective ........................................................................................................11 
2.2 
Secondary Objective ....................................................................................................11 
2.3 
Other Objectives ..........................................................................................................11 
3 
Investigational Plan .............................................................................................................11 
3.1 
Overall Study Design and Plan ....................................................................................11 
3.2 
Rationale for Study Design and Control Group ...........................................................12 
3.3 
Study Duration and Dates ............................................................................................12 
4 
Study Population Selection ..................................................................................................12 
4.1 
Study Population ..........................................................................................................12 
4.2 
Inclusion Criteria .........................................................................................................12 
4.3 
Exclusion Criteria ........................................................................................................13 
5 
Study Treatments .................................................................................................................13 
5.1 
Description of Treatments............................................................................................13 
5.1.1 Study Drug .......................................................................................................13 
5.1.2 Placebo .............................................................................................................13 
5.2 
Treatments Administered .............................................................................................13 
5.2.1 Selection and Timing of Dose for Each Patient ...............................................14 
5.3 
Method of Assigning Patients to Treatment Groups....................................................14 
5.4 
Blinding........................................................................................................................14 
5.5 
Unblinding Procedures.................................................................................................15 
5.6 
Concomitant Therapy...................................................................................................15 
5.6.1 Prohibited Medications ....................................................................................15 
5.7 
Restrictions ..................................................................................................................15 
5.7.1 Prior Therapy ...................................................................................................15 
5.7.2 Fluid and Food Intake ......................................................................................15 
5.7.3 Patient Activity Restrictions ............................................................................16 
5.8 
Treatment Compliance .................................................................................................16 
5.9 
Packaging and Labeling ...............................................................................................16 
5.10 Storage and Accountability ..........................................................................................16 
5.11 Investigational Product Retention at Study Site ..........................................................17 
6 
Study Procedures .................................................................................................................18 
6.1 
Informed Consent.........................................................................................................18 
6.2 
Medical History ...........................................................................................................18 
6.3 
Physical Examination...................................................................................................18 
6.4 
Vital Signs ....................................................................................................................18 
6.5 
Electrocardiogram Assessment ....................................................................................19 

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6.6 
Clinical Laboratory Tests .............................................................................................19 
6.6.1 Laboratory Parameters .....................................................................................19 
6.6.2 Pregnancy Test .................................................................................................20 
6.6.3 Sample Collection, Storage, and Shipping ......................................................20 
6.7 
Dispensing Study Drug ................................................................................................21 
6.8 
Efficacy Assessments...................................................................................................21 
6.8.1 Six-Minute Walk Distance ...............................................................................21 
6.8.2 Borg Dyspnea Score ........................................................................................21 
6.8.3 WHO Functional Class ....................................................................................21 
6.9 
Other Assessments .......................................................................................................22 
6.9.1 Quality of Life Assessment ..............................................................................22 
6.9.2 Future Biomedical Research ............................................................................22 
6.10 Adverse Events Assessments .......................................................................................22 
6.10.1 Performing Adverse Events Assessments ........................................................22 
6.10.2 Timing ..............................................................................................................22 
6.10.3 Severity ............................................................................................................23 
6.10.4 Relationship .....................................................................................................23 
6.10.5 Expectedness ....................................................................................................23 
6.10.6 Clinical Laboratory Adverse Events ................................................................23 
6.10.7 Serious Adverse Events ...................................................................................23 
6.10.7.1 Definition ................................................................................................23 
6.10.7.2 Reporting Serious Adverse Events .........................................................24 
6.10.8 Treatment-Emergent Adverse Events ..............................................................24 
6.11 Concomitant Medication Assessments ........................................................................24 
6.12 Removal of Patients from the Trial or Study Drug ......................................................24 
6.13 Appropriateness of Measurements ...............................................................................25 
7 
Study Activities .....................................................................................................................26 
7.1 
Enrollment Visit (Day 1) .............................................................................................26 
7.2 
Phone Calls ..................................................................................................................26 
7.3 
Week 4 Visit ................................................................................................................27 
7.4 
Quarterly Visits ............................................................................................................27 
7.5 
End-of-Study or Early Termination Visit ....................................................................28 
7.6 
Unscheduled Visit ........................................................................................................28 
8 
Quality Control and Assurance ..........................................................................................29 
9 
Planned Statistical Methods ................................................................................................30 
9.1 
General Considerations ................................................................................................30 
9.2 
Determination of Sample Size .....................................................................................30 
9.3 
Analysis Populations ....................................................................................................30 
9.4 
Demographics and Baseline Characteristics ................................................................30 
9.5 
Primary Endpoint .........................................................................................................30 
9.6 
Secondary Endpoint .....................................................................................................30 
9.7 
Other Assessments or Analyses ...................................................................................31 
9.8 
Interim Analysis ...........................................................................................................31 

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10 Administrative Considerations ...........................................................................................31
10.1 Investigators and Study Administrative Structure .......................................................31 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ......................................................................................................................31 
10.3 Ethical Conduct of the Study .......................................................................................32 
10.4 Patient Information and Consent .................................................................................32 
10.5 Patient Confidentiality .................................................................................................32 
10.6 Study Monitoring .........................................................................................................32 
10.7 Case Report Forms and Study Records .......................................................................32 
10.8 Protocol Deviations ......................................................................................................33 
10.9 Access to Source Documentation ................................................................................33 
10.10 Data Generation and Analysis .....................................................................................33 
10.11 Retention of Data .........................................................................................................34 
10.12 Financial Disclosure.....................................................................................................34 
10.13 Publication and Disclosure Policy ...............................................................................34 
11 Reference List .......................................................................................................................35
Appendix 1
Schedule of Events .........................................................................................36
Appendix 2
6-Minute Walk Test Procedures ...................................................................37
Appendix 3
Borg Dyspnea Scale........................................................................................39
Appendix 4
WHO Functional Classification for PAH ....................................................40
Appendix 5
Adverse Events ...............................................................................................41
Appendix 6
Administration of the Quality of Life Assessment, Emphasis-10 ..............44
Appendix 7
Sponsor Agreement ........................................................................................45
Appendix 8
Investigator’s Agreement ..............................................................................46
LIST OF IN-TEXT TABLES 
Table 1. 
Down-Titration of Esuberaprost ..................................................................................14 
Table 2. 
List of Laboratory Tests ...............................................................................................20 

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Clinical Trial Protocol: BPS-314d-MR-PAH-303 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse Event 
ALB 
Albumin 
ALT 
Alanine Aminotransferase  
ALK-P 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase  
BPS 
Beraprost Sodium 
BPS-314d 
Beraprost Sodium 314d 
BPS-314d-MR 
Beraprost Sodium 314d-Modified Release 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CFR 
Code of Federal Regulations 
Cl 
Chloride 
CO2 
Carbon Dioxide 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
EOS 
End-of-study 
ERA 
Endothelin Receptor Antagonist 
FC 
Functional Class 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IP 
Prostaglandin I2 receptor 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization Technology 
IV 
Intravenous 
K 
Potassium 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Na 
Sodium 
NT-pro-BNP 
N-terminal pro-brain natriuretic peptide  
OLE 
Open-label extension 
PAH 
Pulmonary Arterial Hypertension 
PGI2 
Prostacyclin  
PDE-5i 
Phosphodiesterase Type 5 Inhibitor 
PRO 
Patient reported outcome 
PT 
Prothrombin Time 
PTT 
Activated partial thromboplastin time 
PVR 
Pulmonary Vascular Resistance 
QID 
Four-times daily 
QTc 
QT interval corrected for heart rate 
RBC 
Red Blood Cell (count) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 

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SAS 
Statistical Analysis System 
SGOT 
Serum Glutamic Oxaloacetic Transaminase  
SGPT 
Serum Glutamic Pyruvic Transaminase  
SQ 
Sub-cutaneous 
TEAE 
Treatment-Emergent Adverse Event 
UAE 
Unexpected Adverse Event 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
White Blood Cell (count) 
WHO 
World Health Organization  
 

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1 
INTRODUCTION 
Pulmonary arterial hypertension (PAH), defined as an elevation in pulmonary arterial pressure 
and pulmonary vascular resistance (PVR), is a severe hemodynamic abnormality common to a 
variety of diseases and syndromes.  There are three major factors thought to contribute to the 
increased PVR seen in this disease: vasoconstriction, remodeling of the vessel wall, and 
thrombosis. Treatment of PAH includes three pharmacological classes (prostanoids, endothelin 
receptor antagonists (ERAs), and phosphodiesterase-type 5 inhibitors (PDE-5i), and four 
different routes of administration: oral, inhaled, subcutaneous (SC), and intravenous (IV) 
(Galie 2013).   
Intravenous prostacyclin therapy prolongs survival in patients with PAH (Barst 1996), and it is 
considered by many clinicians as the “gold standard” of care.  Parenteral prostacyclins are 
typically reserved until later in the course of disease, although risks and challenges associated 
with the IV route of administration have led to the emergence of other routes of administration, 
such as inhaled treprostinil solution (Tyvaso® US Package Insert), and an oral formulation of 
treprostinil diethanolamine (Orenitram® US Package Insert).  Inhaled delivery of prostanoids 
permit selective vasodilatory effects to the lung vasculature while minimizing systemic side 
effects.   
Beraprost sodium (BPS) is an orally bioavailable prostacyclin (PGI2) analogue that is comprised 
of a mixture of 4 stereoisomers. Of these, the pharmacologically active single isomer 
esuberaprost, exerts its actions by specifically binding to PGI2 receptors on smooth muscle, 
vascular endothelium, and platelets (Nishio 1997).  This results in vasodilatation, inhibition of 
platelet aggregation, and antiproliferation (Kurumatani 2009; Melian and Goa 2002; 
Demolis 1993).   
Esuberaprost is being evaluated for the treatment of PAH in Study BPS-314d-MR-PAH-302. 
The study was designed to leverage the complementary mechanistic and pharmacokinetic 
differences between locally-acting inhaled treprostinil and the systemic delivery of esuberaprost, 
creating an effect that more closely approximates parenteral therapy compared to using either 
therapy alone, and thus, achieves a more effective and longer-lasting therapeutic effect, delaying 
time to clinical worsening. 
This open-label extension study (OLE) BPS-314d-MR-PAH-303 is designed to evaluate and 
characterize the safety profile of esuberaprost by studying the long-term exposure of PAH 
patients with this drug. In addition, this study will provide observational data on the efficacy of 
long-term treatment of esuberaprost in patients with PAH.  

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this study is to assess the safety and tolerability of long-term treatment 
with esuberaprost in patients with PAH. 
2.2 
Secondary Objective 
The secondary objective of this study will be to assess the efficacy of long-term treatment of 
esuberaprost in patients with PAH. 
2.3 
Other Objectives 
Other study objectives include: 
• To assess quality of life in all subjects at Enrollment and Month 6 using the patient reported 
outcome (PRO) instrument, emPHasis-10. 
• To collect and archive blood samples at Enrollment and Month 3 in an optional assessment 
for future biomedical research (US subjects only). 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multi-center, open-label study for eligible subjects who were actively participating in 
the BPS-314d-MR-PAH-302 study at the time the study was concluded.  Subjects will sign an 
informed consent to continue treatment for PAH with esuberaprost.   
Subjects who provide informed consent for this OLE study on or prior to the End-of-Study 
(EOS) Visit for BPS-314d-MR-PAH-302 may participate in the study, provided all other 
eligibility criteria are met. 
At the Enrollment Visit in this study, subjects will begin a blinded transition from the 
BPS-314d-MR-PAH-302 study to the OLE study over a 4-week period.  The first dose for all 
subjects in this OLE study will be 2 tablets. During this blinded transition period, those subjects 
who are on active study drug in BPS-314d-MR-PAH-302 will continue with blinded active study 
drug 4-times daily (QID); those subjects on placebo in the BPS-314d-MR-PAH-302 study will 
receive one active tablet and one placebo tablet QID (blinded) during the first 2 weeks and 
increase to 2 active tablets QID (blinded) thereafter.  After the first dose, the investigator may 
adjust the dose as medically warranted.  The maximum dose for this study is 30 µg QID with a 
minimum accepted dose as 15 µg QID. For the first 4 weeks, contact with the subject should 
occur weekly to ensure up-titration to the fixed dose is tolerated and assess adverse events (AEs).   
Subjects will return to the clinic at Week 4 to be supplied open-label esuberaprost and complete 
protocol specified procedures.  At the Week 4 Visit, subjects will be dosed with two 15 µg 

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tablets (30 µg total) of esuberaprost, administered orally QID (provided the target dose is 
tolerated) or follow the Investigator’s (or designee’s) directions if adjustment is needed. 
Following the Week 4 Visit, each subject will return to the clinic at Months 3, 6, 9, and 12, and 
quarterly thereafter for assessment.   
At the conclusion of the study (see Section 3.3), or if a subject discontinues the study 
prematurely, subjects will return to the clinic for an EOS Visit.  Subjects will be provided 
instructions about down titration off esuberaprost sodium tablets by the investigator. 
See Appendix 1 Schedule of Events Table for assessments to be performed at each study visit. 
3.2 
Rationale for Study Design and Control Group 
This OLE study continues the evaluation of esuberaprost over a longer duration, as well as 
evaluates the initial administration of esuberaprost in those subjects who previously received 
placebo.  This study will help to better characterize the safety profile of esuberaprost, as well as 
provide a better understanding of longer term efficacy. 
3.3 
Study Duration and Dates 
This study is expected to continue until the first of any of the following are reached: the study 
drug is commercially available, the sponsor discontinues the study, or the sponsor offers 
enrollment in another study. 
 
4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
273 subjects at investigational sites in the United States (US) and Israel were enrolled in Study 
BPS-314d-MR-PAH-302.  This open-label extension (OLE) study will be open to eligible 
subjects who are actively participating in the BPS-314d-MR-PAH-302 study at the time the 
study is concluded.  Subjects who discontinued treatment/participation in 
BPS-314d-MR-PAH-302 study will not be eligible for this study. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study: 
1. Subject must have been actively participating in Study BPS-314d-MR-PAH-302 when the 
sponsor concluded that study.   
2. In the Investigator’s opinion, subject must be competent to understand the information given 
in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved 
informed consent form (ICF) and must sign the form prior to the initiation of any study 
procedures. 
3. Women of child-bearing potential (defined as less than 1 year post-menopausal and not 
surgically sterile) must be practicing abstinence or using two highly-effective methods of 
contraception (defined as a method of birth control that results in a low failure rate, i.e., less 

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than 1% per year, such as approved hormonal contraceptives, barrier methods [such as a 
condom or diaphragm] used with a spermicide, or an intrauterine device). Subject must have 
a negative pregnancy test at the BPS-314d-MR-PAH-302 EOS Visit / 
BPS-314d-MR-PAH-303 Enrollment Visit. 
4. Subject must be willing and able to comply with study requirements and restrictions. 
 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Subject is pregnant or lactating. 
2. Subject is scheduled to receive another investigational drug, device, or therapy during the 
course of the study. 
3. Subject is taking or intends to take any prostacyclin / prostacyclin analog or IP receptor 
agonist (EXCEPT FOR treprostinil, inhaled [Tyvaso®]). 
4. Subject has any other clinically significant illness or other reason that, in the opinion of the 
investigator, might put the subject at risk of harm during the study or might adversely affect 
the interpretation of the study data. 
 
5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Study Drug 
The study drug is esuberaprost sodium tablets, available as 15 μg tablets for oral QID 
administration.  Esuberaprost sodium tablets contain 15 µg of the drug substance, esuberaprost 
sodium (BPS-314d).  
Esuberaprost sodium active and matching placebo tablets will be mounted in child resistant Dose 
Pak® wallet cards.  Following enrollment, each subject will receive a study drug “transition kit” 
containing 4-weekly wallet cards to cover the first 4 weeks of the study, which will be 
subject-specific.  The site staff will instruct the subject on the proper method and sequence of 
taking the tablets.  Starting at the Week 4 Visit, subjects will then receive weekly bulk wallet 
cards for the remainder of the study.  Each subject will be provided appropriate quantities of 
study drug at each study visit. 
5.1.2 
Placebo 
To preserve study blinding for the first 4 weeks of this study, the placebo tablets are identical in 
size, shape, color, and appearance to the esuberaprost sodium tablets.   
5.2 
Treatments Administered 
After informed consent has been provided and at the Enrollment Visit for the OLE study, 
subjects will remain on site and take their scheduled dose of OLE study drug.  The subject 
should remain in the clinic for approximately 2-3 hours for observation by study personnel.   

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5.2.1 
Selection and Timing of Dose for Each Patient 
At the Enrollment Visit in this study, subjects will begin a blinded transition from the 
BPS-314d-MR-PAH-302 study to the OLE study over a 4-week period.  The first dose for all 
subjects in this OLE study will be 2 tablets.  During this blinded transition period, those subjects 
who are on active study drug in the BPS-314d-MR-PAH-302 study will continue with blinded 
active study drug QID; those subjects on placebo in BPS-314d-MR-PAH-302 will receive one 
active tablet and one placebo tablet QID (blinded) during the first 2 weeks and increase to 
2 active tablets QID (blinded) thereafter.  After the first dose, the investigator may adjust the 
dose as medically warranted.  The maximum dose for this study is 30 µg QID with a minimum 
accepted dose as 15 µg QID. 
At the Week 4 Visit, subjects will receive esuberaprost sodium tablets in bulk dosing cards, 
which will be the study drug packaging and configuration provided for the remainder of the 
study (see Section 5.9).   
At the conclusion of the study (see Section 3.3), or if a subject discontinues the study 
prematurely, subjects will return to the clinic for an EOS Visit.  If necessary, the subject should 
be weaned off study drug at a maximum decrement of 1 tablet QID and a minimum decrement of 
1 tablet QID per week (scenarios provided in Table 1). However, the transition strategy off study 
drug is at the Investigator discretion as medically warranted. 
Table 1. Down-Titration of Esuberaprost 
Maximum Scenario 
Minimum Scenario 
Day 1 
2 tablets QID 
Week 1 
2 tablets QID 
Day 2 
1 tablet QID 
Week 2 
1 tablet QID 
Day 3 
No tablets 
Week 3 
No tablets 
 
5.3 
Method of Assigning Patients to Treatment Groups 
There is only one treatment arm in this OLE study.  All subjects will receive active esuberaprost 
sodium tablets. 
5.4 
Blinding 
Treatment during the first 4 weeks of this study is double-blind.  Although all subjects will 
receive active esuberaprost sodium tablets, placebo subjects from the BPS-314d-MR-PAH-302 
study will be up-titrating (1 active esuberaprost sodium tablet for the first 2 weeks and 2 active 
esuberaprost sodium tablets for the next 2 weeks); whereas, subjects who were on active study 
drug during the BPS-314d-MR-PAH-302 study, will continue to receive 2 esuberaprost sodium 
tablets.  After the initial 4 weeks of the OLE study, all subjects will be receiving 2 tablets 
esuberaprost QID, and administering esuberaprost at the maximum dose (30 µg QID), if 
tolerated. 
The investigator and study staff, the subjects, the monitors, and the sponsor will remain blinded 
to the treatment group allocation from BPS-314d-MR-PAH-302 study and to study drug during 

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the first 4 weeks of the OLE study.  Blinding is necessary to minimize the introduction of bias 
during the database lock of the BPS-314d-MR-PAH-302 study.   
The study drug and its matching placebo are indistinguishable and will be packaged in the same 
way to ensure study blinding for the first 4 weeks of the study. 
5.5 
Unblinding Procedures 
An unblinding procedure will only be applicable in the first 4 weeks of the study.  An Interactive 
Randomization Technology (IRT) manual will be provided to the study personnel that outlines 
unblinding procedures. Unblinding of a subject’s treatment assignment may be conducted by 
either the Investigator or the medical monitor using IRT via the web or phone.  Only if a 
subject’s medical condition warrants, such as a medical emergency for which treatment requires 
knowledge of what dose of esuberaprost was given, may the investigator break the blind to 
determine if the subject received 15 µg or 30 µg of esuberaprost per dose.  In most instances of 
medical emergency, the medical monitor must grant prior approval to break the code.  However, 
the code can be broken on the investigator’s request in those cases where the subject’s condition 
is so severe that time would not permit prior approval.  In any case, the medical monitor and the 
study monitor must be informed as soon as possible by telephone following the event and by 
letter explaining the details of the case with accompanying diagnostic reports, where appropriate. 
5.6 
Concomitant Therapy 
Subjects are encouraged to continue co-administration of treprostinil, inhaled.  
Background PAH therapies may be adjusted as medically necessary, with the exception that no 
prohibited medications are added.  Initiation, discontinuation, or dose changes of anticoagulants, 
diuretics and non-PAH medications are allowable. 
5.6.1 
Prohibited Medications 
No other prostacyclin / prostacyclin derivative or IP receptor agonist, with the exception of 
inhaled treprostinil, should be administered for treatment of PAH during this study.  Transient 
use [≤7 days] is allowable. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
Subjects must meet inclusion and exclusion criteria outlined in Sections 4.2 and Section 4.3, 
respectively.   
5.7.2 
Fluid and Food Intake  
In general, subjects should follow their normal diet and fluid intake through the course of the 
study and maintain a consistency regarding when meals and study drug are taken.  

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5.7.3 
Patient Activity Restrictions 
Subjects should continue their normal activities of daily living during the study. 
5.8 
Treatment Compliance 
Subjects should be reminded to return all unused study drug at each study visit, as well as the 
empty packages of study drug used.  The study coordinator or designee will document the 
unused study drug and verify that the quantity is consistent with the intended dosing schedule.  
Based on drug accountability with regard to the subject’s prescribed dosage regimen, throughout 
the study, if non-compliance is suspected, the clinical site personnel will re-educate the subject 
on the importance of proper adherence to the prescribed dosing.  Continued noncompliance may 
lead to termination of the subject from the study after consultation between the investigator and 
the sponsor. 
5.9 
Packaging and Labeling 
The sponsor will supply study drug for the study.  Esuberaprost sodium tablets (15 µg) and 
matching placebo will be mounted in identical child resistant Dose-Pak® wallet cards.  At the 
Enrollment Visit, each subject in the study will be assigned via the IRT, a study drug “transition 
kit”.  The subject-specific “transition kit” will contain 4 weekly wallet cards, one for each of the 
first 4 weeks of the study.  Each designated wallet card will provide the appropriate daily dosing 
for the Weeks 1 through 4; they will contain 8 tablets per day, 2 for each of the 4 doses to be 
taken each day).  The “transition kit” will contain the appropriate blinded treatment of either 
2 tablets of esuberaprost per dose or 1 tablet of placebo and 1 tablet of esuberaprost per dose (for 
the first 2 weeks for former placebo subjects). 
At the Week 4 Visit and at Quarterly Visits thereafter, the subject will be issued via the IRT bulk 
dosing cards of esuberaprost tablets to provide an adequate supply of study drug for continued 
use until the subject’s next scheduled study visit.  
Study drug will be labeled in accordance with all applicable local regulations to include at least 
the following information:  the sponsor’s name and address, protocol number, contents of the 
Dose Pak® wallet cards, lot number, directions for use, storage conditions, and FDA caution 
statement.  
5.10 Storage and Accountability 
Study drug should be stored at approximately 25°C (77°F).  Excursions between 15°C and 30°C 
(59-86 °F) that are experienced in pharmacies, hospitals, and warehouses are acceptable [USP 
Controlled Room Temperature, 2008].  Study drug should be protected from light and moisture 
and should not be frozen or exposed to heat.  At the clinical site, study drug will be stored in a 
securely locked cabinet or enclosure.  Access should be strictly limited to the investigators and 
their designees.   
The sponsor or designee is responsible for assuring that the quantity and quality of the study drug 
is adequate for the duration of the study. 

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Study drug should be used in accordance with the protocol, under the supervision of the 
investigator or designee (e.g., the clinical site pharmacist or other personnel trained to store and 
dispense investigational drugs).  The investigator or designee must agree to supply study drug 
only to subjects enrolled in the study.  Subjects must be given the study drug corresponding to 
their own randomization number.  
The study coordinator, pharmacist or appropriate personnel at the investigational clinical site will 
deliver and retrieve study drug assigned to the subjects at each study visit.  Subjects will be 
instructed to return all study drug, including all empty or partially used packages, to the 
appropriate study personnel on an ongoing basis. 
5.11 Investigational Product Retention at Study Site 
The investigator or designee is responsible for taking an inventory of each shipment of study 
drug received and comparing it with the accompanying packing list.  The investigator or 
designee will verify the accuracy of the information on the packing list, sign and date the 
acknowledgement of receipt, retain a copy in the study file, and acknowledge receipt of the 
shipment to the sponsor via the IRT system.  
The investigator is responsible for study drug accountability and reconciliation overall and on a 
per subject basis.  Drug accountability records are to be maintained during the study and these 
records include:  
• the amount of study drug received from the sponsor,  
• the study drug kit numbers, 
• the amount dispensed to each subject,  
• the dates of drug inventory movement, 
• the initials of the person responsible for each drug inventory entry, 
• the date and amount of unused drug returned from each subject, 
• the amount of unused drug on site, available for future subject assignment 
 
At each study visit, site personnel should assess drug dispensed, drug returned (including all 
empty or partially used wallets), and dosing information to confirm drug accountability and 
compliance.  If any study drug was lost or damaged, its disposition should be documented in the 
subject’s source documents as well as the in the IRT system.  Accurate recording of study drug 
administration (including dispensing and dosing) will also be made in the appropriate section of 
the source documents and IRT system.  Once a representative from the sponsor has confirmed 
drug accountability for each subject, all used and unused study drug will either be returned to the 
sponsor (or designee) per the sponsor’s (or designee’s) written instructions, or be destroyed by 
the site and destruction information entered in the IRT system. 

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6 
STUDY PROCEDURES 
All relevant data captured at the BPS-314d-MR-PAH-302 EOS Visit will be entered in the 
Enrollment Visit CRFs, as required by this protocol. 
6.1 
Informed Consent 
The investigator and/or designee will explain study procedures to potential subjects prior to 
participation in this study.  Those who agree to participate will sign and date the IRB or IEC 
approved ICF after reading the document and after the investigator has answered any questions 
about the study.  The investigator and/or designee will also sign and date the ICF.  Subjects will 
be given a copy of the ICF. 
In the US only, for the optional collection of blood sample for future biomedical research (see 
Section 6.9.2), a separate ICF must be signed by the US subjects agreeing to participate.  A 
subject’s participation in the OLE study will in no way be affected if he/she declines consent for 
the optional future biomedical research. 
In order to provide seamless continuation of esuberaprost sodium tablet treatment, subjects must 
provide informed consent for this OLE study on or prior to the EOS Visit for the 
BPS-314d-MR-PAH-302 study.   
6.2 
Medical History 
Medical and surgical history that was collected from each subject during the randomized, 
controlled, BPS-314d-MR-PAH-302 study will be used for this study. No repeat entry of data 
already entered in BPS-314d-MR-PAH-302 database will be necessary.  
Prescription and/or nonprescription medications at the Enrollment Visit will be assessed and 
entered in the concomitant medications CRF to enable tracking of any changes to medications 
which occur during the study.  Nonprescription medications include vitamins and herbal 
preparations. 
6.3 
Physical Examination 
A physical examination will be conducted by a qualified study clinician as outlined in the 
Schedule of Events (Appendix 1).  Physical findings within the following categories will be 
assessed as relevant:  mental status/mood; neurological; head, eyes, ears, nose, and throat; 
cardiovascular; respiratory; abdomen; gastrointestinal; musculoskeletal; hair and skin; and 
extremities.  Any values judged by the investigator to be clinically significant abnormal changes 
after subject’s first dose of study treatment as part of the OLE study should be recorded on the 
Adverse Event CRF as an AE.   
6.4 
Vital Signs 
Vital signs will be measured at all scheduled study visits.  Subject height will be recorded at the 
Enrollment Visit and weight will be recorded at each study visit.  Systolic and diastolic blood 

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pressure, heart rate, and temperature will be measured after a seated rest per the site’s standard 
procedures.  
Any values judged by the investigator to be clinically significant abnormal changes after 
subject’s first dose of study treatment as part of the OLE study should also be recorded on the 
Adverse Event CRF as an AE. 
6.5 
Electrocardiogram Assessment 
Twelve-lead electrocardiograms (ECGs) will be recorded following rest per the site’s standard 
procedure in the semi-recumbent position at each study visit.   
Recordings will include lead II as a rhythm strip and contain at least 5 QRS complexes.  ECG 
parameters collected include heart rate, as well as PR interval, QT interval, QTc interval, QRS 
duration, and any clinically significant abnormalities.  
Any values judged by the investigator to be clinically significant abnormal changes after the 
subject’s first dose of study treatment as part of the OLE study should also be recorded on the 
Adverse Event CRF as an AE. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
Blood and urine specimens for the measurement and evaluation of serum chemistry, hematology, 
coagulation, urinalysis, and N-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP) will be 
collected at each study visit.  
Subjects will be in a seated or supine position during blood collection.  Clinical laboratory 
parameters will include those presented in Table 2.  Blood samples will be sent by the site to a 
certified central laboratory for analysis.  Results will be forwarded to the sites and electronically 
transferred into the study database.   
Any laboratory test result that the investigator considers clinically significant may be repeated to 
rule out laboratory error.  For tests where a persistent abnormality is considered to be drug 
related, repeat analyses will be performed until the cause is determined and either a return to 
normality occurs or the investigator deems the abnormality to be of no clinical significance.  Any 
values judged by the investigator to be clinically significant abnormal changes after the subject’s 
first dose of study treatment as part of the OLE study should also be recorded on the Adverse 
Event CRF as an AE. 
 

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Table 2. List of Laboratory Tests 
Hematology: 
- 
Hematocrit (Hct) 
- 
Hemoglobin (Hgb) 
- 
Mean corpuscular hemoglobin (MCH) 
- 
Mean corpuscular hemoglobin concentration 
(MCHC) 
- 
Mean corpuscular volume (MCV) 
- 
Platelet count 
- 
Red blood cell (RBC) count  
- 
White blood cell (WBC) count with differential  
- 
Neutrophils (Total %) 
- 
Lymphocytes (Total %) 
- 
Monocytes (Total %) 
- 
Eosinophils (Total %) 
- 
Basophils (Total %) 
 
Urinalysis:  
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Microscopic examination of sediment  
- 
Nitrite  
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Urobilinogen 
Serum Chemistry: 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (ALK-P) 
- 
Alanine aminotransferase (ALT; SGPT) 
- 
Aspartate aminotransferase (AST; SGOT) 
- 
Blood urea nitrogen (BUN) 
- 
Calcium (Ca) 
- 
Carbon dioxide (CO2) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Gamma-glutamyl transferase (GGT) 
- 
Globulin 
- 
Glucose 
- 
Lactate dehydrogenase (LDH) 
- 
Phosphorus 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total bilirubin 
- 
Direct bilirubin 
- 
Total protein 
- 
Uric acid 
- 
NT-pro-BNP 
 
Coagulation:  
- 
Prothrombin time (PT) 
- 
Activated partial thromboplastin time (PTT) 
 
Pregnancy test:  
- 
Urine pregnancy test at Enrollment Visit 
- 
Serum pregnancy test at all post-Enrollment 
study visits 
 
6.6.2 
Pregnancy Test 
A positive pregnancy test will exclude the subject from participation in the study.  For females of 
childbearing potential, a urine pregnancy test will be taken at the Enrollment Visit, and a serum 
test will be performed at all post-Enrollment study visits. 
6.6.3 
Sample Collection, Storage, and Shipping 
Analysis of laboratory specimens listed in Table 2 will be performed by a certified central 
laboratory.  Detailed handling and shipping procedures will be provided in the laboratory manual 
to site personnel.  All laboratory data results will be maintained as source documentation in the 
subject medical record. 

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6.7 
Dispensing Study Drug 
Study site personnel will dispense appropriate supplies of esuberaprost (and placebo during the 
transition period) to subjects at each study visit.  Subjects will be instructed to return all 
esuberaprost, including empty or partially used packages, to the appropriate study personnel at 
post-Enrollment site visits.  
Esuberaprost dosing during the study will be recorded in the appropriate CRF.  Detailed study 
drug disposition records will be maintained as previously described (Section 5.10). 
6.8 
Efficacy Assessments 
Efficacy will be assessed as a secondary objective by continuing to evaluate the efficacy 
parameters from the BPS-314d-MR-PAH-302 study.  The 6-Minute Walk Distance (6MWD), 
the Borg Dyspnea Score, World Health Organization (WHO) Functional Class (FC), and 
NT-pro-BNP, will be assessed at each post-Enrollment study visit.   
6.8.1 
Six-Minute Walk Distance 
The 6-minute walk test (6MWT), which is designed to evaluate exercise capacity associated with 
carrying out activities of daily living, will be performed to evaluate potential treatment effects on 
exercise capacity at each post-Enrollment study visit.   
Appendix 2 presents the standardized procedures for administration of the 6MWT.  
If a subject is assessed for the 6MWT while using oxygen therapy, the use of oxygen should be 
recorded on the CRF.  Oxygen use for all future 6MWTs should be conducted in accordance 
with the Investigator’s clinical judgement. 
6.8.2 
Borg Dyspnea Score 
The modified 0-10 category-ratio Borg scale is one in which the subjects rate the maximum level 
of dyspnea they experienced during the 6MWT.  Scores range from 0 (for the best condition) and 
10 (for the worst condition) with nonlinear spacing of verbal descriptors of severity 
corresponding to specific numbers.  Subjects may choose the number or the verbal descriptor to 
reflect presumed ratio properties of sensation or symptom intensity.  Appendix 3 presents the 
standardized administration details for the Borg Dyspnea Score procedures the clinical site 
personnel should use.  Each subject will provide a rating of dyspnea immediately following the 
6MWT. 
6.8.3 
WHO Functional Class 
At the Enrollment Visit the investigator will classify the subjects for PAH severity using the 
WHO FC.  Assessment for WHO FC for PAH should be made at each post-Enrollment study 
visit.  See Appendix 4 for categories. 

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6.9 
Other Assessments 
6.9.1 
Quality of Life Assessment 
Quality of life will be assessed for all subjects at Enrollment and Month 6 using the PRO 
instrument, emPHasis-10.  Refer to Appendix 6 for details.  
6.9.2 
Future Biomedical Research 
For those subjects in the US who choose to participate and provide a separate informed consent, 
blood samples will be collected at Enrollment (prior to initial esuberaprost dosing in the OLE 
study) and at Month 3 Visits for future biomedical research (e.g., biomarker and genomic 
analysis).  Biomarker and genomic samples will be collected pre-dose at the Enrollment Visit 
and a follow-up biomarker sample at any point during the visit for Month 3. Details about 
sample handling will be provided in Study Procedures Manual. 
6.10 Adverse Events Assessments 
6.10.1 
Performing Adverse Events Assessments 
The clinical site personnel will monitor all AEs throughout the study, from the time of the 
subject’s signed informed consent for this OLE study until the end of the subject’s study 
participation.  At all study site visits and during phone calls to the subject by clinical site 
personnel, reports of AEs will be elicited by a verbal probe (“How are you feeling?”).  Subjects 
will be encouraged to contact the site to report an AE at any time.  Appropriate measures, 
including medical intervention and/or procedures, will be instituted if clinically indicated at the 
discretion of the investigator.  
All AEs occurring during the study, including AEs that are on-going at the EOS Visit from the 
BPS-314d-MR-PAH-302 study, must be documented in the subject’s source documents and in 
the CRFs for AEs.  For each AE, the investigator will evaluate the intensity and seriousness, as 
well as the relationship to esuberaprost.  Information relating to the AE, such as onset and 
cessation date and times, escalation, frequency, action taken, and outcome will also be 
documented (see Appendix 5) in the CRFs for AEs.  Where possible, AEs should be recorded 
using standard medical terminology.  If several signs or symptoms are clearly related to a 
medically defined diagnosis or syndrome, the diagnosis or syndrome should be recorded on the 
CRFs for AEs, not the individual signs and symptoms.   
6.10.2 
Timing 
Subjects with AEs that are ongoing at the subject’s last study visit must be followed until 
resolution or for 30 days after the subject’s last study visit, whichever comes first.  Adverse 
events that are reported during the 7 days following the subject’s last study visit will be recorded 
in the CRFs for AEs and followed until resolution or for up to the 30 days after the subject’s last 
study visit, whichever comes first.  All AEs that are ongoing after follow-up for 30 days will be 
recorded as ongoing in the CRF.  The investigator is expected to provide or arrange appropriate 
supportive care for any subject with ongoing AE(s). 

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Serious adverse events (SAEs) should be followed until they resolve or the event or their 
sequelae stabilize.  Supplemental measurements and/or evaluations may be necessary to 
investigate fully the nature and/or causality of an AE or SAE.  Such supplementary assessments 
may include additional laboratory tests, diagnostic procedures, or consultation with other 
healthcare professionals.  The CRFs for AEs should be updated with any new or additional 
information as appropriate.  
If the subject reports or the investigator learns of any new SAE that occurs up to 30 days after 
the subject’s last study visit, the clinical site personnel will ensure that these data are recorded on 
the AE CRF and the SAE Report Form completed and submitted accordingly.  
6.10.3 
Severity 
For each reported AE the investigator is responsible for grading its severity (or intensity) 
according to the criteria outlined in Appendix 5 and recording these data in the subject’s source 
documents and on the AE page of the CRF. 
6.10.4 
Relationship 
For each AE reported, the investigator is responsible assessing the likelihood that an AE is 
causally related to esuberaprost according to the criteria outlined in Appendix 5.  These data 
must be recorded in the subject’s source documents and on the AE page of the CRF. 
6.10.5 
Expectedness 
The known and expected AEs due to the use of esuberaprost are described in the current 
Investigators’ Brochure. 
6.10.6 
Clinical Laboratory Adverse Events 
The investigator is responsible for reviewing the results of all laboratory tests as they become 
available.  Any values judged by the investigator to be clinically significant abnormal changes 
after subject’s first dose of study treatment as part of the OLE study should also be recorded on 
the Adverse Event CRF as an AE.  The investigator may repeat the laboratory test or request 
additional tests to verify the results of the original laboratory tests.  Assessment of signs or 
symptoms or requirement for therapeutic intervention should be considered when determining 
clinical significance.  Record clinically significant laboratory values on the CRFs for AEs using 
an appropriate diagnostic description. 
6.10.7 
Serious Adverse Events 
6.10.7.1 
Definition 
A SAE is defined by federal regulation as any AE occurring at any dose that results in any of the 
following outcomes: death, life-threatening AE, hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect. 

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Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
6.10.7.2 
Reporting Serious Adverse Events 
All SAEs, as defined in Appendix 5 and regardless of expectedness or causality, must be 
reported via email or fax within 24 hours of the investigator’s knowledge of an SAE occurrence:   
Email: 
drugsafety@unither.com (primary)   
Fax:  
1-919-313-1297 (backup) 
 
The investigator or sponsor (if appropriate) must also notify their IRB, IEC and/or other local 
equivalent body of the SAE, including any follow-up information.  Copies of each report and 
documentation of IEC/IRB/local equivalent body notification and receipt will be kept in the 
Clinical Investigator’s Study File. 
6.10.8 
Treatment-Emergent Adverse Events 
Treatment-emergent AEs will be defined as events that are newly occurring or worsening 
following treatment with esuberaprost at the Enrollment Visit.  
The most frequently reported treatment-emergent adverse events (TEAEs; ≥ 10%) for 
esuberaprost tablets are headache, nausea, dyspnea, dizziness, diarrhea, upper respiratory tract 
infection, cough, fatigue, sinusitis, flushing, worsening PAH, urinary tract infection, and 
vomiting. 
Prostacyclins, as a class, may increase the risk of bleeding and hypotension. 
6.11 Concomitant Medication Assessments 
Concomitant therapy includes any prescription and/or nonprescription medications taken in 
combination with study drug.  All concomitant medications will be followed during the study 
and entered on the appropriate page of the CRF.  Nonprescription medications include vitamins 
and herbal preparations.  See Section 5.6.1 for prohibited concomitant medications. 
6.12 Removal of Patients from the Trial or Study Drug 
A subject may voluntarily withdraw or be withdrawn from study at any time for reasons 
including, but not limited to the following: 
• The subject wishes to withdraw from further participation; 
• A serious or life-threatening adverse event occurs; 

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• The subject is noncompliant with the requirements of the protocol, or; 
• The subject's behavior is likely to undermine the validity of his/her results. 
 
If a subject is discontinued from the study, the investigator must provide an explanation in the 
source documents and record the reason for termination in the appropriate CRF for that subject.  
If necessary, the subject should be weaned off study drug at a maximum decrement of 1 tablet 
QID and a minimum decrement of 1 tablet QID per week (scenarios provided in Table 1).  The 
transition strategy off of study drug is at the investigator discretion as medically warranted.  If 
discontinuation from study drug is within the first 4 weeks of the OLE study, the down-titration 
will occur in a blinded fashion.  The investigator should make every effort to perform all 
scheduled evaluations prior to withdrawal of study drug. A subject who discontinues because of 
an AE will be followed until the investigator determines the AE has resolved, is no longer 
considered clinically significant, has been determined to be stable and unlikely to further evolve, 
or for 30 days, whichever comes first.   
If a subject fails to return to the clinical site, the clinical site staff must document at least two 
phone calls were made to the subject, and a registered letter was sent to them requesting return of 
study drug and contacting study personnel before considering them lost to follow-up.  
The study may be stopped at any time if continuation of the study represents a serious medical 
risk to the subjects.  Such risk may include, but is not limited to, the presence of serious, 
life-threatening, or fatal AEs or AEs that are unacceptable in nature, severity, or frequency.  The 
sponsor reserves the right to discontinue the study for any reason at any time. 
When a subject withdraws from the study, the site should enter the reason for discontinuation 
into the subject’s source documents and in the subject’s CRF. 
6.13 Appropriateness of Measurements 
The primary objective is to assess the safety of long-term treatment with esuberaprost and better 
characterize its safety profile.  Evaluation of AEs, clinical laboratory tests, vitals, ECGs, and 
physical examinations are standard assessments of PAH drug safety and tolerability for patients 
with this disease. 
The secondary objective of this study will be to describe the long-term efficacy of esuberaprost.  
Efficacy endpoints of 6MWD, Borg Dyspnea Score, WHO FC, NT-pro-BNP level, are standard 
evaluations of PAH. 

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7 
STUDY ACTIVITIES 
Please refer to Appendix 1 for Study Time and Events table. 
7.1 
Enrollment Visit (Day 1) 
Subjects who provide informed consent for this OLE study on or prior to the EOS Visit for 
BPS-314d-MR-PAH-302 may participate in the study, provided all other eligibility criteria are 
met.  
The following procedures will be completed for enrollment into this OLE Study:  
• Verify that the subject meets all inclusion/exclusion criteria (See Section 4.2 and Section 4.3) 
• Enter any ongoing AEs from the BPS-314d-MR-PAH-302 study  
• Record concomitant medications  
• Perform a urine pregnancy test for women of child-bearing potential 
• Enroll subject in IRT to receive the study drug kit number for the 4-week, blinded transition 
period 
• OPTIONAL / US SUBJECTS ONLY:  For subjects who consent to provide samples for 
future biomedical research, collect blood sample(s) prior to initial esuberaprost dose in this 
study 
• Quality of life assessment using emPHasis-10 
• Dispense study drug “transition kits” for the first 4 weeks of the study 
• Observe and record study drug administration.  Subjects should remain in the clinic for a 
2-3 hour observation period following dosing to assess for any AEs. 
• Record first study drug administration 
• Subjects will be directed to call the clinical site coordinator or Investigator immediately if 
they experience a worsening of the disease-related symptoms or at any time to discuss 
study-related issues  
 
7.2 
Phone Calls 
Subject should be contacted weekly between the Enrollment Visit and Week 4.  After 2 weeks on 
study drug, the subject should be contacted to assess drug tolerability and instructed to begin 
using the Week 3 and Week 4 wallet cards that will be provided at the Enrollment Visit.  
During phone calls to the subject, the following information should be recorded: 
• Record study drug administration for dose changes, as applicable 
• Record AEs  
• Record concomitant medications 
 

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7.3 
Week 4 Visit 
Subjects will return to the study site at Week 4 (± 3 days) for the following procedures: 
• Perform a physical examination  
• Record vital signs after seated rest  
• Record WHO FC  
• Record a 12-Lead ECG following rest in a semi-recumbent position  
• Conduct an unencouraged 6MWT  
• Record Borg Dyspnea Score  
• Obtain blood and urine samples for clinical laboratory parameters (serum chemistry, 
hematology, coagulation, urinalysis and NT-pro-BNP)  
• Obtain serum pregnancy test for women of childbearing potential 
• Record AEs  
• Record concomitant medications  
• Provide subject with a 2-month supply of esuberaprost.  If applicable, provide additional 
instructions/remind subject on importance of taking esuberaprost and inhaled treprostinil 
together. 
• Record study drug administration for dose changes, as applicable 
• Record study drug accountability  
• Remind subjects to call the clinical site coordinator or investigator immediately if they 
experience a worsening of the disease-related symptoms or at any time to discuss study 
related issues  
 
7.4 
Quarterly Visits 
Subjects will return to the study site at Months 3, 6, 9, and 12 and Quarterly thereafter 
(± 10 days) for the following procedures: 
• Perform a physical examination  
• Record vital signs after seated rest  
• Record WHO FC  
• Record a 12-Lead ECG following rest in a semi-recumbent position  
• Conduct an unencouraged 6MWT  
• Record Borg Dyspnea Score  
• Obtain blood and urine samples for clinical laboratory parameters (serum chemistry, 
hematology, coagulation, urinalysis and NT-pro-BNP)  
• OPTIONAL / US SUBJECTS AT MONTH 3 ONLY:  For subjects who consent to 
provide samples for future biomedical research, collect blood sample(s) at 3 months in this 
study 
• MONTH 6 ONLY:  Quality of life assessment using emPHasis-10 

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• Obtain serum pregnancy test for women of childbearing potential 
• Record AEs  
• Record concomitant medications 
• Provide subject with a 3-month supply of esuberaprost.  If applicable, provide additional 
instructions/remind subject on importance of taking esuberaprost and inhaled treprostinil 
together. 
• Record study drug accountability  
• Record study drug administration for dose changes, as applicable 
• Remind subjects to call the clinical site coordinator or Investigator immediately if they 
experience a worsening of the disease-related symptoms or at any time to discuss study 
related issues  
 
7.5 
End-of-Study or Early Termination Visit 
At the conclusion of the study (see Section 3.3) or if a subject discontinues the study 
prematurely, subjects will return to the clinic an EOS Visit for the following procedures: 
• Perform a physical examination  
• Record vital signs after seated rest  
• Record WHO FC  
• Record a 12-Lead ECG following rest in a semi-recumbent position  
• Conduct an unencouraged 6MWT  
• Record Borg Dyspnea Score  
• Obtain blood and urine samples for clinical laboratory parameters (serum chemistry, 
hematology, coagulation, urinalysis and NT-pro-BNP)  
• Obtain serum pregnancy test for women of childbearing potential 
• Record AEs  
• Record concomitant medications 
• Record study drug accountability 
• Record study drug administration and/or dose changes, as applicable 
 
7.6 
Unscheduled Visit 
At the investigator's discretion, subjects may visit the study site at any time.  Unscheduled visits 
may involve, at the investigator's discretion, the following procedures:  
• Perform a physical examination  
• Record vital signs after seated rest  
• Record a 12-Lead ECG following rest in a semi-recumbent position.  
• Record WHO FC  

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• Conduct an unencouraged 6MWT  
• Record Borg Dyspnea Score  
• Obtain blood and urine samples for clinical laboratory parameters (serum chemistry, 
hematology, coagulation, urinalysis and NT-pro-BNP)  
• Obtain serum pregnancy test (for women of childbearing potential) 
• Record AEs  
• Record concomitant medications  
• Supply of study drug as applicable 
• Record study drug accountability  
• Record study drug administration for dose changes, as applicable 
• Remind subjects to call the clinical site coordinator or Investigator immediately if they 
experience a worsening of the disease-related symptoms or at any time to discuss study 
related issues 
 
8 
QUALITY CONTROL AND ASSURANCE 
The sponsor is responsible for ensuring that the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, Good Clinical Practice (GCP) 
guidelines, and applicable regulatory requirements.  To this end, the clinical monitor will make 
periodic study site visits to assess compliance with the protocol, verify the data collected, and 
identify and resolve problems that may arise.  The investigator agrees to allow the monitor direct 
access to all relevant study documents and to allocate time to discuss findings and any relevant 
issues. 
The sponsor may conduct a quality assurance audit of this study.  If such an audit occurs, the 
investigator agrees to allow the auditor direct access to all relevant study documents and to 
allocate time to discuss findings and any relevant issues.  In addition, this study is subject to 
audit by the relevant Regulatory Authorities.  If such a regulatory inspection occurs, the 
investigator agrees to allow the inspector direct access to all relevant study documents. 

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9 
PLANNED STATISTICAL METHODS 
This section briefly describes the planned statistical analyses. A complete description of the 
methodology will be specified in a statistical analysis plan (SAP), which will be finalized prior to 
database lock. Any changes in the statistical methods described in this protocol that occur prior 
to database lock will be documented in the statistical analysis plan and will not require a protocol 
amendment.  
9.1 
General Considerations 
The data collected in this study is observational and will be presented in listings and tables.  No 
inferential statistical analyses are planned. All statistical analyses will be performed by the 
Sponsor’s biostatistics department personnel (or appropriate designees) using SAS®, Version 9.4 
or higher or other validated software.  
Concomitant medications will be coded using the WHO-drug dictionary and AEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Coding dictionary versions 
will be specified in the statistical analysis plan and/or the study database. 
9.2 
Determination of Sample Size 
This is an open-label study for all subjects who completed the BPS-314d-MR-PAH-302 study 
and were eligible to continue in this study, therefore no sample size calculation was performed. 
9.3 
Analysis Populations  
All patients who receive at least one dose of esuberaprost will be included in the analyses. 
9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects.  
For continuous variables (e.g., age, weight), the number of non-missing and missing values and 
the median, mean, standard deviation, minimum, maximum, and appropriate percentiles will be 
displayed. For categorical variables (e.g., race, gender), the counts and proportions of each value 
will be tabulated. 
9.5 
Primary Endpoint 
The primary objective of this study is to assess the safety and tolerability of long-term treatment 
with esuberaprost in patients with PAH. Descriptive analysis for safety assessments, including 
AEs, vital signs, clinical laboratory parameters and ECG findings, will be presented. 
9.6 
Secondary Endpoint 
The secondary objective of this study will be to assess the efficacy of long-term treatment of 
esuberaprost in patients with PAH. Descriptive analysis for efficacy assessments, including 
6MWD, the Borg Dyspnea Score, WHO FC, and NT-pro-BNP, will be presented. 

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9.7 
Other Assessments or Analyses 
Other study endpoint include the change in the PRO instrument, emPHasis-10, from Enrollment 
to Month 6. 
9.8 
Interim Analysis 
No interim analysis is planned.  However, given the open-label nature of the study, the sponsor 
may tabulate study data and present or publish such data during the course of the study.  
 
10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
The term “investigator” as used in this protocol and in the CRFs refers to the Principal 
Investigator at each study site, or another staff member listed as a sub-investigator on the study 
site Food and Drug Administration (FDA) Form 1572.  The site Principal Investigator is 
ultimately responsible for the conduct of all aspects of the study at that site.  The site Principal 
Investigator is also responsible for ensuring that all site staff working on the study are 
appropriately trained and supervised; staff training and delegation of responsibilities should be 
documented in the files.   
Prior to shipment of study drug to the site, the investigator must read, understand, and sign the 
Investigator Agreement in the protocol.  The Investigator Agreement documents agreement to 
conduct the study according to the protocol, International Conference on Harmonization / Good 
Clinical Practice (ICH/GCP), and Code of Federal Regulations (CFR).  Additional requirements 
must be met by the investigator and institution, as described below. 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
Prior to study initiation at each site, the investigator will obtain approvals for the study from their 
IRB, IEC, and/or other local equivalent body and provide the sponsor with a copy of approval 
documentation.  The relevant bodies must also review and approve the site’s ICF and any other 
written information provided to the subject prior to enrollment, as well as any advertising 
materials used for subject recruitment.  Copies of the ICF and advertising materials must be 
forwarded to the sponsor for review before submission to relevant bodies prior to the start of the 
study.  If, during the study, it is necessary to amend either the protocol or the ICF, the 
investigator is responsible for obtaining required approvals of these amended documents prior to 
implementation.  Copies of the approval correspondence and approval letters must be sent to the 
sponsor.  
During the study, the sponsor will compile an annual progress report for submission to their IRB, 
IEC and/or equivalent body as required.  The investigator will also provide a written summary of 
the study following study updates, completion or termination as appropriate. 

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10.3 Ethical Conduct of the Study 
This study will be conducted according to ICH and GCP guidelines, and all applicable 
government regulations and Institutional research policies and procedures. 
10.4 Patient Information and Consent 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  The formal consent of a subject, using the IRB/IEC-approved consent form, must be 
obtained before any study procedure is undertaken.  This ICF must be signed by the subject or 
legally acceptable surrogate, and the Investigator or designated research professional obtaining 
the consent.  
The consent form and explanation will include; detailed information about esuberaprost, the 
rationale for why it is being studied, frequency of dosing, and length of treatment, potential side 
effects and risks, safeguards and emergency procedures.  Information will also be provided about 
the frequency and length of visits.  The collection of all laboratory specimens will be described 
in detail.  Subjects will be assured that their participation is voluntary and that withdrawal from 
the study would not jeopardize current or future treatment.  All subjects will be informed of 
potential risks and benefits involved in the study, including side effects of esuberaprost. 
There will be a separate informed consent form for the optional future biomedical research (see 
Section 6.9.2).  A subject’s participation in the OLE study will in no way be affected if he/she 
declines consent for the optional assessment. 
10.5 Patient Confidentiality 
Every effort will be made to keep medical information confidential.  The sponsor, appropriate 
regulatory authorities, and the IRB/IEC governing this study may inspect the medical records of 
any subject involved in this study.  The investigator may release the subject’s medical records to 
employees or agents of the sponsor, the IRB/IEC or appropriate regulatory agencies for purposes 
of checking the accuracy of the data.  A number will be assigned to all subjects, and any 
published study reports will not identify subjects. 
10.6 Study Monitoring 
In accordance with US federal and other national regulations, ICH, and GCP guidelines, 
monitors for sponsor or its designee will periodically contact the site and conduct on-site visits.  
During these visits, the monitor will at a minimum: confirm ethical treatment of subjects, assess 
study progress, review data collected, conduct source document verification, verify drug 
accountability periodically, and identify any issues requiring resolution. 
10.7 Case Report Forms and Study Records 
The study CRF is the primary data collection instrument for the study.  For this study, the CRF 
will be completed electronically.  All data requested on the CRF must be recorded following the 
CRF completion guidelines to be provided to site personnel.  Subject data will be entered in the 

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CRF by appropriately trained site staff.  Data recorded in the CRF should be consistent with 
source documents. All relevant data captured at the BPS-314d-MR-PAH-302 EOS Visit will be 
entered in the Enrollment Visit CRFs, as required by this protocol. 
10.8 Protocol Deviations 
A protocol deviation is defined as an unplanned excursion from the approved protocol where the 
investigator or site personnel did not conduct the study according to the study protocol, 
applicable laws or regulations. 
All study deviations will be documented for the clinical site, along with corrective actions where 
required.  Study deviations may be discovered through a variety of sources, such as during the 
CRF review, telephone conversations, and site monitoring.  Study deviations should be reported 
to the applicable IRB in accordance with IRB policies and/or local laws.  When relevant, ethics 
committees, competent authorities or the appropriate regulatory bodies should be informed.  The 
sponsor will review all deviations from the study protocol.  Corrective action and preventative 
action will be performed after protocol deviations are discovered during monitoring visits. 
Deviations will be reported to the sponsor or designee regardless of whether medically justifiable 
or taken to protect the subject in an emergency.  Study deviations should be reported as soon as 
possible upon notification of the deviation.  Examples of deviations from the study protocol may 
include: 
• No informed consent prior to starting any study procedure. 
• Incorrect version of consent provided to subject. 
• Enrollment of subject prior to IRB/IEC approval. 
• Enrollment of subject during an IRB/IEC approval lapse. 
• Subject did not meet inclusion/exclusion criteria. 
• Required testing and/or measurements not performed or performed outside the allotted 
window of time. 
• Incorrect dose or incorrect drug administered. 
• Source data permanently missing. 
• Adverse event not reported by investigator in the required regulatory time frame. 
• Unauthorized physician performed study procedures 
 
10.9 Access to Source Documentation 
The investigators agree to allow the monitors direct access to all relevant documents, including 
electronic records, and the investigators will allocate their time and staff to discuss any findings 
or any relevant issues. 
10.10 Data Generation and Analysis 
All data are submitted into a quality assured database and will be reviewed by the sponsor.  Data 
clarifications will be generated and the database will be edited as appropriate.  The database will 

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be final when all queries have been resolved and all data management quality assurance 
procedures are complete.  A full audit trail of all entries and changes to CRFs will be maintained 
in the database structure. 
10.11 Retention of Data 
In accordance with US federal and other national regulations, ICH, and GCP guidelines, the 
investigator must retain study records for at least 2 years, or as local regulations apply, after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  The investigator 
must notify the sponsor before any disposal or change in location of study records.  The 
investigator should ensure that the location considered for archiving study records is an 
appropriate facility for the secure storage of study documents and records. 
10.12 Financial Disclosure 
Per 21 CFR 54, all investigators are required to complete a Financial Disclosure form prior to 
site activation, attesting to the fact that they are unaware of any financial conflicts of interest, or 
disclosing potential conflicts, including payments, proprietary interests and/or equity interests.  
Completed forms will be maintained in the Trial Master File. 
10.13 Publication and Disclosure Policy 
Manuscripts or abstracts for written or oral presentation by investigators associated with this 
study must be submitted to the sponsor at least 30 working days for approval before submission 
to any journal or meeting.  Scientific comments by the sponsor should be taken into 
consideration before submission.  The sponsor reserves the right to request revision of written or 
oral presentations or to deny such presentations if, in the opinion of the sponsor, such activity 
would adversely affect the drug development program. 

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11 REFERENCE LIST 
Barst RJ, Rubin LJ, Long WA, et al. (1996). A comparison of continuous intravenous 
epoprostenol with conventional therapy for primary pulmonary hypertension.  The Primary 
Pulmonary Hypertension Study Group.  N Engl J Med 334:296-302. 
Demolis, J. L., Robert, A., Mouren, M., Funck-Brentano, C., & Jaillon, P. (1993). 
Pharmacokinetics and platelet antiaggregating effects of beraprost, an oral stable prostacyclin 
analogue, in healthy volunteers. J.Cardiovasc.Pharmacol., 22, 711-716. 
Galie N. and Simonneau G. (2013). The Fifth World Symposium on Pulmonary Hypertension. 
JACC62: Suppl. D. 
Kurumatani, H. (2009). [Pharmacological profiles and clinical effects of oral sustained release 
beraprost sodium (Careload LA tablets 60 microg, Berasus LA tablets 60 microg)]. Nippon 
Yakurigaku Zasshi, 133, 101-111.  
Melian, E. B. & Goa, K. L. (2002). Beraprost: a review of its pharmacology and therapeutic 
efficacy in the treatment of peripheral arterial disease and pulmonary arterial hypertension. 
Drugs, 62, 107-133.  
Nishio, S., Nagase, H., Kanou, K., Aoki, S., & Kanbayashi, Y. (1997). [Research and 
development of beraprost sodium, a new stable PGI2 analogue]. Yakugaku Zasshi, 117, 509-521.  
Orenitram® U.S. Package Insert. United Therapeutics Corporation, 2017; Research Triangle 
Park, N.C. https://www.orenitram.com/pdf/Orenitram_Full_Prescribing_Information.pdf 
Tyvaso® U.S. Package Insert. United Therapeutics Corporation, 2016; Research Triangle Park, 
N.C. https://www.tyvaso.com/pdf/Tyvaso-PI.pdf 
 

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Appendix 1 
Schedule of Events 
STUDY PROCEDURES 
Study Visit Weeka 
Enrollmentb 
(Day 1) 
Phone calls 
Week 4 
(± 3 days) 
Quarterly Visits 
(± 10 days) 
End of Study or 
Early Termination Visitc 
Unscheduled Visit(s)d 
Clinic Site Visit 
X 
 
X 
X 
X 
X 
Phone Callse 
 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
Physical Examination 
 
 
X 
X 
X 
X 
Vital Signs 
 
 
X 
X 
X 
X 
6-Minute Walk Test / 
Borg Dyspnea Scalef 
 
 
X 
X 
X 
X 
WHO Functional Class 
 
 
X 
X 
X 
X 
Laboratory Parameters 
 
 
X 
X 
X 
X 
Pregnancy Testg 
X 
 
X 
X 
X 
X 
12-Lead ECG 
 
 
X 
X 
X 
X 
Enrollment 
X 
 
 
 
 
 
Study drugh 
X 
X 
X 
X 
X 
X 
Drug Accountability 
 
 
X 
X 
X 
X 
AE Assessmenti 
X 
X 
X 
X 
X 
X 
Conmed Assessment 
X 
X 
X 
X 
X 
X 
Quality of life assessment 
X 
 
 
Xj 
 
 
Sample collection for future research 
X 
 
 
Xk 
 
 
a Study Visits will take place at Week 4 and quarterly thereafter (i.e., Months 3, 6, 9, and 12).   
b All subjects who provide informed consent for the study and meet the eligibility criteria (Section 4.2) will be enrolled. Eligibility will be determined at the EOS Visit in the 
BPS-314d-MR-PAH-302 study and subjects will be enrolled in this OLE study on the same day. Data captured at the BPS-314d-MR-PAH-302 EOS Visit will be entered in the 
Enrollment Visit CRFs, as required by this protocol.  
c When the sponsor concludes the study or the subject withdraws consent or is terminated from the study, the subject will be required, as applicable, to return to the study site for 
an EOS Visit and the Study Termination CRF will be completed. 
d An Unscheduled Visit may occur at any time and involve any of the procedures listed as deemed appropriate by the investigator. 
e Phone calls: Contact with the subject should occur weekly for the first 3 weeks to ensure up-titration to the fixed dose is tolerated and assess AEs. 
f 6MWTs and Borg should be conducted each post-Enrollment Visit.  
g  Pregnancy testing for females of childbearing potential. Urine test at the Enrollment Visit and serum test at all other clinic visits. 
h The initial dose in this study will be administered after enrollment.  All doses administered at the study site, all dose changes, and the final dose should be recorded in subject 
dose administration log. 
i If the subject reports or the investigator learns of any new SAE that occurs up to 30 days after the subject’s last study visit, the clinical site personnel will ensure that these data 
are recorded on the AE CRF and the SAE Report Form completed and submitted accordingly. 
j Enrollment and Month 6 only.  Patient-reported outcome of emPHasis-10 will be performed at any time during the visit. 
k At Enrollment and Month 3 in the US only.  For subjects who consent, samples for future biomedical research will be collected at Enrollment (prior to initial esuberaprost dose 
in this study) and at Month 3 (at any point during the visit). 

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Appendix 2 
6-Minute Walk Test Procedures 
General Procedures  
The administration of the 6-Minute Walk Test and specifications of the testing area should be 
generally consistent with the American Thoracic Society (ATS, 2002) guidelines and the usual 
practice of the clinical site.  
To the extent possible and to lessen the opportunity for bias, test administrators should not 
review the subject’s prior 6MWT results before conducting the test.  When the 6MWT is 
completed the test administrator will not tell the subject the distance walked.  Results of the 
6MWT should not be provided to the subject during the course of the study. 
The area used for the 6MWT should be pre-measured at approximately 30 meters (100 feet) in 
length and approximately 2 to 3 meters (7 to 10 feet) in width.  There should be no turns or 
significant curves to the 6-minute walk area.  The length should be marked with gradations to 
ensure the accurate measurement of the distance walked.  The tester may be at the starting end of 
the corridor or at the midpoint of the corridor with a stop-watch.  Intermittent rest periods are 
allowed if the subject can no longer continue.  If the subject needs to rest briefly, he/she may 
stand or sit and then begin again when he/she is sufficiently rested but the clock will continue to 
run.  At the end of 6 minutes, the tester will call “stop” while simultaneously stopping the watch 
and then measure the distance walked.  At any point in the trial, if a subject is assessed for the 
6MWT while using oxygen therapy, the use of oxygen should be recorded on the CRF.  Oxygen 
use for all future 6MWTs should be conducted in accordance with the Investigator’s clinical 
judgement. 
Instructions to the Subject  
Subjects should be told to wear comfortable clothing and sneakers or comfortable walking shoes.  
The person administering the test will use the following exact dialogue with the subject:  
“The purpose of this test is to find out how far you can walk in six minutes.  You will start from 
this point and follow the hallway to the marker (e.g., chair) at the end, turn around and walk 
back.  When you arrive back at the starting point you will go back and forth again.  You will go 
back and forth as many times as you can in the 6-minute period.  You may stop and rest if you 
need to.  Just remain where you are until you can go on again.  However, the most important 
thing about the test is that you cover as much ground as you possibly can during the six minutes.  
I will tell you the time, and I will let you know when the 6 minutes are up.  When I say STOP, 
please stand right where you are.”  
After these instructions are given to the subject, the person administering the test will then ask:  
“Do you have any questions about the test?” 
“Please explain to me what you are going to do.”  

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The person administering the test will then start the test by saying the following to the subject:  
“Are you ready?”  
“Start when I say “GO.”  
The person administering the test will tell the subject the time at 2 and 4 minutes by saying:  
“You have completed 2 minutes.”  
And then by saying:  
“You have completed 4 minutes.”  
No other instruction or encouragement will be given during the test.  Eye contact with the subject 
should be avoided during the test. 

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Appendix 3 
Borg Dyspnea Scale 
Immediately following the 6MWT, the person administering the test will obtain a rating of 
dyspnea using the Borg Scale.  The person will use the following dialogue:  
“I would like to use the following scale to indicate the maximal shortness of breath you had 
during the walk test (indicate the Borg Scale).  If there was no shortness of breath at all you 
would point to 0; if the shortness of breath was not very great you would choose from 0.5 to 2; if 
you were somewhat more short of breath you would select 3; and if the breathing was getting 
very difficult, you would choose 4 to 9, depending on just how hard it was; 10 represent the 
greatest shortness of breath you have ever experienced in your life.  If one of the numbers does 
not exactly represent how short of breath you are, then you can choose a fraction between.  For 
example, if you had shortness of breath somewhere between 4 and 5, you could choose 4 ½.”  
Perceived Breathlessness (Borg Scale)  
0  NOTHING AT ALL  
0.5 VERY VERY SLIGHT (just noticeable)  
1  VERY SLIGHT  
2  SLIGHT  
3  MODERATE  
4  SOMEWHAT SEVERE  
5  SEVERE  
6  
7  VERY SEVERE  
8  
9  VERY VERY SEVERE (almost maximum)  
10 MAXIMUM 

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Appendix 4 
WHO Functional Classification for PAH 
Class I - Patients with pulmonary hypertension but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near 
syncope.  
Class II - Patients with pulmonary hypertension resulting in slight limitation of physical activity. 
These patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or 
fatigue, chest pain or near syncope.  
Class III - Patients with pulmonary hypertension resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or 
fatigue, chest pain, or near syncope.  
Class IV - Patients with pulmonary hypertension with inability to carry out any physical activity 
without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue 
may be present even at rest. Discomfort is increase by any physical activity. 

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Appendix 5 
Adverse Events 
The investigator or designee will probe each subject for any adverse events that may have 
occurred.  When possible, always ask the same question when conducting the verbal probe in 
order to ensure uniformity between subjects.  The subject should be asked:  
“How have you been doing (feeling) since your last visit?”  
“How are you doing (feeling) now?”  
Based on the subject’s response to these questions, the subject should be asked additional 
questions relevant to any specific complaint such as:  
“Have you had this symptom in the past?”  
“How severe is/was the symptom?”  
“How often did the symptom occur?”  
“How long did the symptom last?”  
“Did you take any medication to treat the symptom?”  
“Did you see a physician or go to the hospital because of this symptom?” 
All adverse events should be fully documented on the CRFs. 
DEFINITIONS  
An adverse event (AE) is defined as any untoward medical experience/occurrence associated 
with the use of a drug in humans, whether or not it is considered drug related.  An AE may 
include an intercurrent illness, injury, or any other concomitant impairment of the subject’s 
health, as well as abnormal laboratory findings if deemed to have clinical significance.  AEs may 
also include worsening of an existing symptom or condition or post-treatment events that occur 
as a result of protocol-mandated procedures.  
A serious adverse event (SAE) is an AE occurring that has results in any of the following 
outcomes: 
• Results in death  
• Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate risk 
of death from the event as it occurred; it does not include an event that, had it occurred in a 
more severe form, might have caused death)  
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity (i.e., substantial disruption of a 
person’s ability to conduct normal life functions).  
• Results in a congenital anomaly/birth defect in an offspring of a study subject 

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• Other medically significant event that, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above, e.g., allergic bronchospasm requiring intensive treatment in an 
emergency room or home, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.  
 
An unexpected adverse event (UAE) is any AE not yet identified in nature, severity, or 
frequency in the current Clinical Investigators’ Brochure or in the clinical safety updates. 
Clinical Laboratory Changes:  It is the investigator’s responsibility to review the results of all 
laboratory tests as they become available.  For each abnormal laboratory test result, the 
investigator needs to ascertain if this is a clinically significant change for that individual subject.  
The investigator may repeat the laboratory test or request additional tests to verify the results of 
the original laboratory tests.  If a laboratory value is determined to be clinically significant for 
that subject, this is considered an AE. 
INTENSITY  
Adverse events will be graded on a 3-point scale and reported as indicated on the CRFs.  The 
intensity of an AE is defined as follows:  
• Mild: Discomfort noticed, but no disruption to daily activity  
• Moderate: Discomfort sufficient to disrupt normal daily activity and/or requires symptomatic 
treatment  
• Severe: Inability to work or perform normal daily activity and requires treatment 
 
STUDY DRUG CAUSALITY  
Relationship of an AE to treatment will be assessed as follows:  
• NOT RELATED: The AE is not related if exposure to the investigational product has not 
occurred, OR the occurrence of the adverse event is not reasonably related in time, OR the 
AE is considered unlikely to be related to use of the investigational product.  
• POSSIBLE: The AE is reasonably related in time to the administration of the investigational 
product AND the AE could be explained by causes other than exposure to the investigational 
product. 
• PROBABLE: The AE has a plausible time relationship to the investigational product 
administration or use AND the investigational product is more likely than other causes to be 
responsible for the AE, OR is the most likely cause of the individual AE. 
 

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ACTION TAKEN  
Action taken for an AE to treatment will be assessed as follows:  
• Study drug dose withdrawn:  Study drug administration was stopped permanently as a result 
of the AE.  
• Study drug temporarily discontinued:  Study drug administration was temporarily 
discontinued as a result of the AE. 
• Study drug dose reduced:  Study drug administration was reduced as a result of the AE.  
• Study drug dose increased:  Study drug administration was increased as a result of the AE.  
• Study drug dose not changed:  There was no alteration in either the dose or regimen of the 
study drug.  
• Unknown:  Not known what occurred with study drug administration because information is 
insufficient or contradictory.  
• Not applicable:  The subject was not on study drug at the start of the AE 
 
OUTCOME  
The outcome of an AE should be recorded based on the status of the AE at study completion or 
premature discontinuation from the study.  The AE outcome would be recorded as fatal, not 
recovered/not resolved, recovered/resolved, recovered/resolved with sequelae, recovering/ 
resolving or unknown.  If an AE is ongoing, the AE should be followed until resolution. 

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Appendix 6 
Administration of the Quality of Life Assessment, Emphasis-10 
 

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Appendix 8 
Investigator’s Agreement 
Study Title: 
An Open-label Extension of BPS-314d-MR-PAH-302 in Pulmonary 
Arterial Hypertension Patients 
Study Number: 
BPS-314d-MR-PAH-303 
Final Date: 
13 September 2017 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
I agree to comply with the International Conference on Harmonization Guideline for Good 
Clinical Practice and applicable Food and Drug Administration regulations/guidelines set forth in 
21 Code of Federal Regulations Parts 50, 54, 56 and 312 and any local regulations per country.  
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the conduct of the clinical investigation without the prior written consent 
of Lung Biotechnology. 
I also have read the current Clinical Investigators’ Brochure for BPS-314d-MR and acknowledge 
that review of the information contained in the Clinical Investigators’ Brochure is a requirement 
for Investigators before using BPS-314d-MR in a clinical trial. 
 
Signed: 
 
Date:  
 
 
 
  
 
 
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