Conditions: Pulmonary Arterial Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 273
Healthy volunteers: no

Brief summary:
This is a multicenter, double-blind, randomized, placebo-controlled Phase 3 study, to assess the efficacy and safety of BPS-314d-MR when added-on to inhaled treprostinil (Tyvaso®)in patients with pulmonary arterial hypertension.

Patients new to Tyvaso, will enter a run-in period on inhaled treprostinil until 90 days of experience is achieved to ensure drug tolerability before enrolling in the study.

Treatment groups consist of one active and one placebo group. Subjects will be randomly allocated in a 1:1 ratio to one of the two treatment groups.

Detailed description:

Arms:
arm 1: Available as 15 μg tablets for oral, 1 or 2 tablets four times daily (QID) administration. arm 2: Placebo tablets, which are identical in size and appearance to those containing BPS-314d-MR.

Interventions: intervention 1: Beraprost Sodium 314d Modified Release Tablets intervention 2: Placebo
Intervention descriptions: intervention 1: Available as 15 μg tablets for oral, 1 or 2 tablets four times daily (QID) administration intervention 2: Placebo tablets, which are identical in size and appearance to those containing BPS-314d-MR

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol: BPS-314d-MR-PAH-302
Study Title:
A multicenter, double-blind, randomized, placebo-controlled, Phase 3 
study to assess the efficacy and safety of oral BPS-314d-MR added-on to 
treprostinil, inhaled (Tyvaso®) in subjects with pulmonary arterial 
hypertension
Study Number:
BPS-314d-MR-PAH-302
Study Phase:
3
Product Name:
Beraprost Sodium 314d Modified Release
IND Number:
111,729
Indication:
Treatment of Pulmonary Arterial Hypertension
Investigators:
Multicenter
Sponsor:
Lung Biotechnology Inc.
Sponsor Contact:
Medical Monitor:
Date
Original Protocol:
16 April 2013
Amendment 1:
17 December 2013
Amendment 2
15 October 2014
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 Inc.
© 2014 Lung Biotechnology Inc.


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LIST OF CONTACTS
Study Sponsor:
Lung Biotechnology Inc.
1040 Spring Street
Silver Spring, Maryland 20910
United States 
Phone: 301-608-9292
Fax: 
301-589-0855
Sponsor Contact:
Medical Monitor:
 
   
SAE Reporting:
 


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SYNOPSIS
Sponsor: Lung Biotechnology Inc.
Name of Investigational Product: Beraprost Sodium 314d Modified Release
Name of Active Ingredient: Beraprost Sodium 314d (BPS-314d) 
Study Title:
A multicenter, double-blind, randomized, placebo-controlled, Phase 3 study to assess the 
efficacy and safety of oral BPS-314d-MR added-on to treprostinil, inhaled (Tyvaso®) in subjects 
with pulmonary arterial hypertension
Study Number: BPS-314d-MR-PAH-302
Study Phase: 3
Primary Objective:
The primary objective of this study is to compare the effect of BPS-314d-MR versus placebo 
added to treprostinil, inhaled (Tyvaso®) on the composite endpoint of time-to-clinical-worsening 
(TtCW), defined as the time from randomization to the first of any of the following clinical 
worsening events: 
•
Death (all causes)
•
Hospitalization due to worsening PAH defined as:
-
Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure and requiring intensification 
of treatment; or
-
Lung or heart / lung transplantation; or
-
Atrial septostomy
•
Initiation of a parenteral (infusion or sub-cutaneous)  prostacyclin, directly related to 
worsening PAH (transient use [≤7 days] for non-PAH related illness allowable)
•
Disease progression (all criteria required):
-
A decrease in six minute walk distance (6MWD) of at least 15% from Baseline (defined 
as the average of the two 6MWTs performed on sequential days of the Baseline Visit), or 
being too ill to walk as a consequence of PAH progression, confirmed by six-minute 
walk tests (6MWT) performed at 2 consecutive visits
-
Worsening of PAH symptoms, which must include either:
◦
An increase in WHO Functional Class or
◦
Worsening symptoms of right heart failure
•
Unsatisfactory long-term clinical response (all criteria below required):
-
Receiving randomized treatment for at least 24 weeks
-
A decrease of at least 15% from Baseline (defined as the average of the two Baseline 
Visit 6MWTs) in 6MWD, or too ill to walk, directly related to PAH progression, at Week 
24 and beyond; at 2 consecutive visits, and 
-
Sustained WHO Functional Class III or IV symptoms for at least 24 weeks.


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Secondary Objectives:
•
To compare the effect of BPS-314d-MR versus placebo added to treprostinil, inhaled 
(Tyvaso®) on the composite endpoint of time-to-clinical-failure (TtCF), defined as the time 
from randomization to the first of any of the following events:
-
Meets primary endpoint definition of clinical worsening, as confirmed by EAC; or   
-
Receiving randomized treatment for at least 24 weeks and has:

Lack of sustained improvement from Baseline WHO Functional Class: defined by 
two consecutive visits of no sustained improvement from Baseline WHO FC, visits 
may be scheduled or unscheduled; and   

Lack of sustained improvement from Baseline 6MWD (average at Baseline): defined 
by two consecutive visits of no sustained improvement from Baseline 6MWD 
(≤0 meters or too ill to walk, directly related to PAH), visits may be scheduled or 
unscheduled.  
•
To compare the effects of BPS-314d-MR to placebo on changes from baseline to each 
scheduled study visit, as applicable, for the following measures:
-
6MWD
-
Borg Dyspnea Score
-
WHO Functional Class 
-
NT-pro-BNP levels 
•
To evaluate the safety of BPS-314d-MR based on adverse events, clinical laboratory 
parameters, electrocardiogram (ECG) findings, physical examination and vital signs.
Exploratory Objectives:
•
 
 
 
Study Design:
A multicenter, double-blind, randomized, placebo-controlled, Phase 3 study to assess the 
efficacy and safety of oral BPS-314d-MR added-on to treprostinil, inhaled (Tyvaso®) in subjects 
with pulmonary arterial hypertension.
Patients who consent to the study will be assessed at the Screening and Baseline Visits to 
determine eligibility for the study. After the Screening Visit, subjects who consent to the study 
and are determined to be eligible but are not currently taking inhaled treprostinil will enter a 
run-in period on inhaled treprostinil to achieve 90 days of experience to ensure drug tolerability 
before being randomized. During the run-in period, subjects will be prescribed inhaled 
treprostinil by the Investigator and will receive the Tyvaso® inhalation device and inhaled 
treprostinil, and training in accordance with specialty pharmacy and the standard procedures of 
the clinical site. Subjects who consent to the study and are currently taking inhaled treprostinil at 
the Screening Visit should be randomized into the study as soon as eligibility criteria have been 
met. Subjects who meet eligibility criteria and who have been treated with inhaled treprostinil for 
at least 90 days, with 30 or more of the 90 days at a stable dose, at the time of the Baseline Visit 


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will be randomized into the study using a centralized randomization system, stratified by use of
inhaled treprostinil, to either active or placebo study drug. Subjects who are initially ineligible 
for this study may be reassessed for eligibility following consultation with the Sponsor.
Following randomization, the subject, study site staff, the Sponsor and the Event Adjudication 
Committee (EAC) will all be blinded to the treatment group assignment. 
Following the Baseline Visit, subjects will return to the study site at Week 4, Week 8, Week 12
(first Quarterly Visit) and for Quarterly Visits thereafter.  During these study visits, subjects will 
undergo all scheduled efficacy and safety assessments as defined by the protocol and the 
Schedule of Events (Appendix 1). Between scheduled study visits, the subject will be contacted 
by phone to assess for possible clinical worsening events and to record any newly occurring or 
changes to adverse events or concomitant medications. Phone contact should be made weekly 
(except during study visit weeks) between Baseline and Week 12 (first Quarterly Visit), then
monthly between Quarterly Visits through the end of study participation. 
An optional hemodynamic assessment will be offered to subjects at selected study sites
providing those sites agree to participate in the hemodynamic study and are approved by the 
Sponsor. Hemodynamic measurements which will be measured/calculated are heart rate, 
pulmonary arterial pressure (systolic, diastolic and mean), systemic arterial pressure (systolic, 
diastolic and mean), right atrial pressure, pulmonary capillary wedge pressure, mixed venous 
oxygen saturation, system arterial oxygen saturation, cardiac output via the Fick or 
thermodilution methods, will be assessed by Right Heart Catheterization (RHC). For those 
subjects who consent to this assessment, the RHC procedure will be performed at the Baseline 
Visit (or within 0-21 days prior) and at the Month 6 Quarterly Visit (or within 7 days before or 
after). 
An optional plasma concentration assessment will also be offered to subjects at study sites that 
are capable of collecting, processing and storing samples, are approved by the Sponsor and agree 
to participate. For subjects electing to participate, a trough (15 minutes pre-dose, ± 5 minutes) 
blood sample will be collected at the Week 4 Visit and four blood samples will be collected 
during Week 12 (first Quarterly Visit) around the second daily dose of study drug (15 minutes 
pre-dose, and 15 minutes, 1 hour and 2.5 hours post-dose; ± 5 minutes). If feasible, a sample 
should be collected for SAEs. Unwillingness to participate in the hemodynamic and/or the 
plasma concentration assessment sub-studies will not affect the subject’s or site’s participation in 
the main study.
Subjects will continue participation in the study until it is formally concluded by the Sponsor. 
When the Sponsor concludes the study the subjects will return to the study site for an End of 
Study visit to undergo all scheduled assessments. Subjects who are participating in the study at 
its conclusion may be offered the opportunity to enroll in a long-term open-label extension study. 
In the event that a subject withdraws consent for participation in the study or the Investigator 
terminates the subject prior to formal study conclusion, the subject will be weaned from study 
drug and return to the study site for an End of Study Visit to undergo all scheduled assessments. 


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Study Population: 240 subjects are planned across sites in the U.S. and Israel.
Test Product, Dose, and Mode of Administration:
Beraprost sodium 314d Modified Release (BPS-314d-MR) tablets, 15 µg for oral, four times 
daily (QID) administration. Subjects will begin treatment at a dose of 15 µg QID. The dose will 
be increased by 15 µg QID for a maximum dose of 30 µg QID, 120 µg total daily dose (TDD) as 
tolerated. 
Duration of Treatment:
The maximum duration of treatment for an individual subject is expected to be 3 years.  The 
anticipated date for last subject, last study visit in mid-2016.
Efficacy Assessments:
Efficacy parameters for this study include: clinical worsening, clinical failure, exercise capacity 
measured by a 6MWT, Borg Dyspnea Score, WHO Functional Class and NT-pro-BNP.
Safety Assessments:
Safety assessments will include the recording of adverse events (AE), clinical laboratory 
evaluations, ECG findings, physical examination, and vital signs. 
Statistical Methods:
The primary efficacy endpoint is clinical worsening confirmed by an independent EAC. The 
primary efficacy endpoint analysis will evaluate clinical worsening as the time to first clinical 
worsening (TtCW) event. 
Based on the assumptions specified in Section 10.2, a one-year rate of clinical worsening of 
45% in the placebo (inhaled treprostinil alone) group, 25% in the BPS-314d-MR group (a 
20% reduction from treprostinil, inhaled (Tyvaso®) therapy alone), proportional hazards over 
time, an accrual period of 1.5 years, a 0.01 two-sided significance level, and a total follow-up 
time of 2.5 years, an exponential maximum likelihood test of equality of survival curves would 
require 113 events and 116 subjects per treatment group to detect treatment difference at a power 
of 90% at a 0.01 two-sided significance level (or 97% power at a 0.05 two-sided significance 
level or approximately 90% power at a 0.05 two-sided significance level to detect a 
13% reduction from an inhaled treprostinil rate as low as 30%). Therefore, this study will 
randomize approximately 240 subjects. Sample size calculations were performed using nQuery 
Advisor 7.0 using sample size methods for the log-rank statistic based on Lakatos & Lan (1992).
The Sponsor will continuously monitor the overall (pooled) event and drop-out rates during the 
course of the study. Sample size may be increased during the trial to maintain the planned power 
at between 80% and 90% and the intended trial duration. Only pooled blinded data will be used 
to increase sample size.
Date of Original Approved Protocol: 16 April 2013
Amendment 1: 17 December 2013
Amendment 2: 15 October 2014


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TABLE OF CONTENTS
List of Contacts ..............................................................................................................................2
Synopsis...........................................................................................................................................3
List of In-Text Tables ..................................................................................................................10
List of Appendices........................................................................................................................10
List of Abbreviations and Definitions of Terms........................................................................11
1
Introduction..........................................................................................................................13
1.1
Pulmonary Arterial Hypertension Overview and Treatment....................................13
1.2
Investigational Drug: Beraprost Sodium, BPS-314d-MR and Dosing.....................14
1.2.1
Beraprost Sodium.......................................................................................14
1.2.2
BPS-314d-MR............................................................................................14
1.2.3
Dosing........................................................................................................15
1.3
Study Rationale.........................................................................................................15
1.3.1
Treprostinil, Inhaled (Tyvaso®) Background............................................16
1.4
Clinical Hypothesis...................................................................................................16
2
Study Objectives...................................................................................................................17
2.1
Primary Objective.....................................................................................................17
2.2
Secondary Objectives................................................................................................18
2.3
Exploratory Objectives .............................................................................................18
3
Expected risks/benefits ........................................................................................................19
4
Investigational Plan .............................................................................................................19
4.1
Overall Study Design and Plan.................................................................................19
4.1.1
Initial Dosing and Safety Assessment........................................................20
4.1.2
Optional Plasma Concentration Assessment .............................................20
4.1.3
Optional Hemodynamic Assessment.........................................................21
4.2
Rationale for Study Design and Control Group........................................................21
4.3
Study Duration and Dates.........................................................................................21
5
Study Population Selection..................................................................................................22
5.1
Study Population.......................................................................................................22
5.2
Inclusion Criteria ......................................................................................................22
5.3
Exclusion Criteria .....................................................................................................23
6
Study Treatment ..................................................................................................................24
6.1
Description of Treatment ..........................................................................................24
6.1.1
Study Drug.................................................................................................24
6.1.2
Placebo.......................................................................................................24
6.1.3
Treprostinil, Inhaled (Tyvaso®) ................................................................24
6.2
Treatments Administered..........................................................................................25
6.2.1
Drug Dosage, Administration and Schedule..............................................25
6.3
Method of Assigning Patients to Treatment Groups.................................................25
6.4
Blinding.....................................................................................................................26
6.5
Unblinding Procedures..............................................................................................26
6.6
Concomitant Therapy................................................................................................26
6.7
Restrictions ...............................................................................................................27


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6.7.1
Prior Therapy .............................................................................................27
6.7.2
Fluid and Food Intake................................................................................27
6.7.3
Patient Activity Restrictions ......................................................................27
6.8
Treatment Compliance..............................................................................................27
6.9
Packaging and Labeling............................................................................................27
6.10
Storage and Accountability.......................................................................................28
6.11
Investigational Product Retention at Study Site .......................................................28
7
Study Procedures .................................................................................................................29
7.1
Informed Consent......................................................................................................29
7.2
Medical History ........................................................................................................29
7.3
Physical Examination................................................................................................30
7.4
Vital Signs.................................................................................................................30
7.5
PAH History..............................................................................................................30
7.6
Pregnancy Test..........................................................................................................30
7.7
ECG Assessment.......................................................................................................30
7.8
Clinical Laboratory Tests..........................................................................................31
7.8.1
Laboratory Parameters...............................................................................31
7.8.2
Sample Collection, Storage, and Shipping ................................................32
7.9
Dispensing Study Drug and Tyvaso® ......................................................................33
7.10
Efficacy Assessments................................................................................................33
7.10.1
Clinical Worsening ....................................................................................33
7.10.2
Clinical Failure...........................................................................................34
7.10.3
Six Minute Walk Test................................................................................34
7.10.4
Borg Dyspnea Score ..................................................................................35
7.10.5
WHO Functional Class ..............................................................................35
7.10.6
NT-pro-BNP ..............................................................................................35
7.11
Other Assessments....................................................................................................35
7.11.1
Optional Plasma Concentration Assessment .............................................35
7.11.2
Optional Hemodynamic Measurement Assessment ..................................36
7.12
Adverse Events Assessments....................................................................................36
7.12.1
Performing Adverse Events Assessments..................................................36
7.12.2
Timing........................................................................................................37
7.12.3
Severity ......................................................................................................37
7.12.4
Relationship ...............................................................................................37
7.12.5
Expectedness..............................................................................................37
7.12.6
Clinical Laboratory Adverse Events..........................................................38
7.12.7
Serious Adverse Events .............................................................................38
7.12.7.1
Definition.................................................................................38
7.12.7.2
Reporting Serious Adverse Events ..........................................38
7.12.8
Treatment-Emergent Adverse Events........................................................38
7.12.9
Overdose ....................................................................................................39
7.12.10 Pregnancy...................................................................................................39
7.13
Concomitant Medication Assessments .....................................................................39
7.14
Removal of Patients from the Trial or Study Drug...................................................40
7.15
Access to Open-Label Extension Study....................................................................40
8
Study Activities.....................................................................................................................41
8.1
Screening Visit..........................................................................................................41


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8.2
(2-Day) Baseline Visit Procedures............................................................................41
8.2.1
Study Drug Administration........................................................................43
8.2.2
Phone Calls ................................................................................................43
8.3
Week 4 Procedures ...................................................................................................43
8.4
Week 8 Procedures ...................................................................................................44
8.5
Week 12 (first Quarterly Visit) Procedures ..............................................................45
8.6
Quarterly Visit Procedures........................................................................................46
8.7
End of Study (or Early Termination) Procedures .....................................................46
8.8
Unscheduled Visit(s).................................................................................................47
9
Quality Control and Assurance ..........................................................................................48
10
Planned Statistical Methods................................................................................................48
10.1
General Considerations.............................................................................................48
10.2
Determination of Sample Size ..................................................................................49
10.3
Analysis Populations.................................................................................................50
10.3.1
Intent to Treat Population ..........................................................................50
10.3.2
Per Protocol Population .............................................................................50
10.3.3
Safety Population.......................................................................................51
10.4
Demographics and Baseline Characteristics.............................................................51
10.5
Study Drug................................................................................................................51
10.6
Concomitant Therapy................................................................................................51
10.7
Study Disposition......................................................................................................51
10.8
Primary Efficacy Endpoint .......................................................................................51
10.9
Secondary Efficacy Endpoints..................................................................................52
10.10
Exploratory Efficacy Endpoints................................................................................52
10.10.1 Plasma Concentration Data........................................................................52
10.10.2 Hemodynamic Data ...................................................................................53
10.10.3 Exposure Response....................................................................................53
10.11
Safety Endpoints.......................................................................................................53
10.11.1 Adverse Events ..........................................................................................53
10.11.2 Vital Signs..................................................................................................53
10.11.3 Laboratory Data .........................................................................................53
10.11.4 Electrocardiogram......................................................................................54
10.11.5 Physical Examination.................................................................................54
10.12
Pooling of Clinical Sites ...........................................................................................54
10.13
Interim Analysis........................................................................................................54
11
Administrative Considerations...........................................................................................54
11.1
Investigators and Study Administrative Structure....................................................54
11.2
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ...................................................................................................................55
11.3
Ethical Conduct of the Study....................................................................................55
11.4
Patient Information and Consent ..............................................................................55
11.5
Patient Confidentiality..............................................................................................55
11.6
Study Monitoring......................................................................................................56
11.7
Case Report Forms and Study Records ....................................................................56
11.8
Oversight Committees ..............................................................................................56
11.8.1
Data Safety Monitoring Board...................................................................56


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11.8.2
Endpoint Adjudication Committee ............................................................56
11.9
Access to Source Documentation .............................................................................56
11.10
Data Generation and Analysis ..................................................................................57
11.11
Retention of Data......................................................................................................57
11.12
Publication and Disclosure Policy ............................................................................57
12
Reference List.......................................................................................................................58
LIST OF IN-TEXT TABLES
Table 1 
List of Laboratory Tests.........................................................................................32
LIST OF APPENDICES
Appendix 1
Schedule of Events.................................................................................................60
Appendix 2
Schematic of Study Entry Based on Tyvaso Use...................................................62
Appendix 3
6-Minute Walk Test Procedures ............................................................................63
Appendix 4
Borg Dyspnea Scale...............................................................................................65
Appendix 5
WHO Functional Classification for PAH ..............................................................66
Appendix 6
Plasma Concentration Samples:  Handling and Shipping......................................67
Appendix 7
Adverse Events ......................................................................................................69
Appendix 8
Optional Hemodynamic Assessment.....................................................................72
Appendix 9
Sponsor Guidance for Comorbid Conditions.........................................................73
Appendix 10
Sponsor Signatures.................................................................................................74
Appendix 11
Investigator’s Signature .........................................................................................75


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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 
BID
Twice Daily
BPS
Beraprost Sodium
BPS-IR
Beraprost Sodium-Immediate Release
BPS-MR
Beraprost Sodium-Modified Release
BPS-314d
Beraprost Sodium 314d
BPS-314d-MR
Beraprost Sodium 314d-Modified Release
BUN
Blood Urea Nitrogen
Ca
Calcium
CD4
Cluster of Differentiation 4
CFR
Code of Federal Regulations
CI
Cardiac Index 
CL
Chloride
CO2
Carbon Dioxide
CRF
Case Report Form
DSMB
Data Safety Monitoring Board
EAC
Endpoint Adjudication Committee
ECG
Electocardiogram
ERA
Endothelin Receptor Antagonist
FC
FDA
Functional Class
Food and Drug Administration
FEV1
Forced Expiratory Volume at one second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GGT
Gamma Glutamyl Transferase
HCG
Human Chorionic Gonadotropin
Hct
Hematocrit
Hgb
Hemoglobin
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IPAH
Idiopathic Pulmonary Arterial Hypertension 
IR
Immediate Release
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
ITT
Intent To Treat
IV
Intravenous
LDH
Lactate Dehydrogenase
LVEDP
Left Ventricular End-Diastolic Pressure
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MR
Modified Release
Na
Sodium
NT-pro-BNP
N-terminal pro-Brain Natriuretic Peptide 


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OTC
PAH
Over the Counter
Pulmonary Arterial Hypertension
PAPm
Mean Pulmonary Artery Pressure
PP
Per Protocol
PCWP
Pulmonary Capillary Wedge Pressure 
PGI2
Prostacyclin 
PDE-5i
Phosphodiesterase Type 5 Inhibitor
PK
Pharmacokinetics
PPH
Primary Pulmonary Hypertension
PT
Prothrombin Time
PTT
Activated partial thromboplastin time
PVR
Pulmonary Vascular Resistance
QID
Four Times Daily
RBC
Red Blood Cell (count)
RHC
Right Heart Catheterization 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SGOT
Serum Glutamic Oxaloacetic Transaminase 
SGPT
Serum Glutamic Pyruvic Transaminase 
SQ
Sub-cutaneous
TEAE
Treatment-Emergent Adverse Event
TDD
Total Daily Dose
TLC
Total Lung Capacity
TtCF
Time to Clinical Failure
TtCW
Time to Clinical Worsening
UAE
Unexpected Adverse Event
UPI
Unique Patient Identification
US
United States
USP
United States Pharmacopeia
WBC
White Blood Cell (count)
WHO
World Health Organization


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1
INTRODUCTION
1.1
Pulmonary Arterial Hypertension Overview and Treatment 
Pulmonary arterial hypertension (PAH), defined as an elevation in pulmonary arterial pressure 
and pulmonary vascular resistance, is a severe hemodynamic abnormality common to a variety 
of diseases and syndromes.  Elevation in pulmonary arterial pressure causes an increase in right 
ventricular afterload, impairing right ventricular function and ultimately leading to heart failure 
and death.
The diagnosis of PAH requires confirmation with a right heart catheterization (RHC). The 
current hemodynamic definition of PAH is mean pulmonary artery pressure (PAPm) greater than 
25 mmHg; a pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular 
end-diastolic pressure (LVEDP) less than or equal to 15 mmHg; and a pulmonary vascular 
resistance (PVR) greater than 3 Wood units (McLaughlin et al, 2009). 
Subjects most commonly present in their third and fourth decade; however, PAH may occur at 
any age. Women are more likely than men to be diagnosed with idiopathic PAH (McLaughin et 
al, 2009) (Rich et al, 2001). The prognosis of PAH is poor, with an approximately 15% mortality 
in the first year after diagnosis when treated with modern therapies (Thenappan et al, 2007). 
The typical etiologies of PAH include idiopathic, heritable or associated with collagen 
vascular/connective tissue disease, portal hypertension, infection with the human 
immunodeficiency virus (HIV), history of cocaine inhalation and exposure to appetite 
suppressant drugs.  An estimated annual incidence of approximately 2 cases per million has been 
reported for idiopathic PAH (Rich, 1987; Rubin 1997).
There are three major factors thought to contribute to the increased pulmonary vascular 
resistance seen in this disease: vasoconstriction, remodeling of the vessel wall, and thrombosis.  
There are a number of metabolic pathways which contribute to these changes that involve 
vasoactive mediators such as the vasodilators nitric oxide and prostacyclin, and the 
vasoconstrictor endothelin-1.  These substances affect both vascular tone and remodeling leading 
to their use as pharmacologic targets (Farber, 2004).
Approval of current PAH-specific pharmacotherapies has traditionally been based upon the 
6 minute walk test (6MWT). The 6MWT is an assessment of exercise capacity and remains a 
standard measure of efficacy for trials of investigational medicines in subjects with PAH. 
However, recent literature has challenged the continued use of 6MWT as a primary endpoint to 
assess the efficacy of treatments for PAH. Although the 6MWT is still viewed as a valuable tool 
for measuring clinical efficacy of PAH therapies, a composite endpoint to evaluate the ‘time to 
clinical worsening’ is emerging as an alternative, to allow better assessment of long-term 
efficacy (McLaughlin, 2009).


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1.2
Investigational Drug: Beraprost Sodium, BPS-314d-MR and Dosing
1.2.1
Beraprost Sodium 
Beraprost sodium (BPS) is an orally bioavailable prostacyclin (PGI2) analogue that was 
synthesized at the Basic Research Laboratories, Toray Industries, Inc. in 1979.  BPS consists of 
equal amounts of four optical isomers: two diastereomers, each containing a racemic mixture of 
two optical isomers (BPS-314d and BPS-314l, and BPS-315d and BPS-315l).  Of these isomers, 
nonclinical studies have identified BPS-314d as the primary pharmacologically active isomer in
BPS. 
Two formulations of BPS have been developed and studied prior to BPS-314d-MR: an 
immediate release (BPS-IR) formulation and a modified release (BPS-MR) formulation.  
Marketing approval for BPS-IR was obtained in Japan in 1992 with an indication for 
improvement of ulcer, pain, and feeling cold accompanying chronic arterial occlusion.  In 1999, 
marketing approval was obtained in Japan to treat primary pulmonary hypertension (PPH).  
BPS-MR contains the same active substance as BPS-IR (i.e., the racemic mixture of four optical 
isomers) and obtained marketing approval for the treatment of PAH in Japan in 2007.  
The safety and efficacy of BPS has been evaluated in multiple Phase 2 and Phase 3 studies, 
including a Japanese study of patients with primary pulmonary hypertension or pulmonary 
hypertension related to collagen vascular disease (Kurumatani, 2009; Kunieda et al, 1997). In 
this study, the mean change from baseline 6 minute walk distance (6MWD) at Week-12 was 
33.4 meters. In addition to this statistically significant improvement in 6MWD, improvements 
were also noted in several hemodynamic parameters.  In a randomized, placebo-controlled 
European-based study (ALPHABET), the primary endpoint of 6MWD was significantly 
improved at Week 12 (+25.1 meters) in the BPS treatment group (Galie et al, 2002). However, in 
a US-based randomized, controlled study, the primary (composite) endpoint of disease 
progression was not significantly improved at month 12 (Barst et al, 2003).  While this study did 
not achieve statistical significance for the primary analysis, there were strong trends favoring 
BPS treatment in disease progression as well as 6MWD across all study time points. 
1.2.2
BPS-314d-MR
As previously noted, BPS consists of four optical isomers, one of which (BPS-314d) is primarily 
responsible for the pharmacologic properties.  BPS-314d exerts its pharmacologic actions by 
specifically binding to PGI2 receptors on smooth muscle, vascular endothelium, and platelets 
(Nishio, et.al, 1997).  This results in vasodilatation, inhibition of platelet aggregation, and 
antiproliferation (Kurumatani, 2009; Melian & Goa, 2002; Demolis, Robert, Mouren, Funck-
Brentano, & Jaillon, 1993).   The presence of three optical isomers that carry little or no desired 
pharmacologic activity is not a requisite feature of BPS drug substance.  For this reason, a 
modified release product containing only the physiologically active BPS-314d stereoisomer has 
been developed.


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1.2.3
Dosing
Earlier multiple-dose studies with BPS demonstrated steady state pharmacokinetics (PK) with
twice daily (BID) administration, though with considerable fluctuation in the peak and trough 
plasma concentrations of BPS-314d.  PK modeling of BPS simulating four times daily (QID) 
dosing suggests reduction in peak-to-trough fluctuation and more consistent plasma 
concentrations maintained over a 24-hour period compared to BID dosing. Accordingly, it is
postulated that four times daily dosing may enhance daily BPS-314d exposure, improving 
tolerability and potentially therapeutic benefit through mimicking continuous dosing, compared 
to twice daily dosing. 
BPS-314d four times daily (QID) dosing has been evaluated in study BPS-314d-PAH-MR-101 in 
healthy volunteers. Consistent peak values were seen between 1.5 to 2 hours after dosing along 
with an increase in overall BPS-314d exposure time. 
1.3
Study Rationale 
Intravenous prostacyclin therapy prolongs survival in patients with PAH (Barst 1996), and it is 
considered by many clinicians as the “gold standard” of care. As more therapies have emerged
for PAH treatment, prostacyclin therapy has evolved, now with inhaled formulations available
and oral formulations under development.  
Parenteral prostacyclins are typically reserved until later in the course of disease due to risks and
challenges associated with this route of administration.  
The rationale for the use of BPS-314d-MR as an add-on oral therapy to inhaled treprostinil in 
subjects with PAH is based upon the quantitative differences observed in their mechanism of 
action and more specifically their complementary pharmacokinetic profiles. 
Inhaled treprostinil and oral BPS exhibit independent pharmacokinetics. Inhaled treprostinil is
characterized by rapid absorption and a relatively short half-life, whereas BPS-314d-MR 
demonstrates lower peak plasma concentrations, slower absorption, and a more protracted 
elimination from the circulation.
Pharmacokinetic modeling of their respective profiles, suggested that the proposed combination 
of inhaled treprostinil and BPS-314d-MR given together, might provide a less invasive, tolerable 
and clinically beneficial approach to achieving sustained prostacyclin exposure, approximating 
the desired profile observed with continuous intravenous delivery. Pharmacokinetic modeling 
used actual PK data for BPS-314d from Study BPS-314d-MR-PAH-101, evaluating 15 µg and 
30 µg dose, QID along with predicted PK data for combination administration with inhaled 
treprostinil to gain an understanding of the concentration-time profiles and how they might 
influence the safety and efficacy of both drugs. 


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1.3.1
Treprostinil, Inhaled (Tyvaso®) Background
Inhaled delivery of treprostinil for the treatment of pulmonary arterial hypertension was 
developed to deliver selective vasodilatory effects to the lung vasculature while minimizing 
systemic side effects.  Inhaled treprostinil was FDA approved (Tyvaso®) in July 2009 (Tyvaso® 
US Package Insert) and approved in Israel in 2010.
During the development of inhaled treprostinil, a series of acute and chronic Investigator
initiated clinical studies were conducted with inhaled treprostinil sodium to optimize the 
formulation for inhalation, determine dose response, tolerability, and safety and also to evaluate 
safety and tolerability when combined with other PAH therapies (Voswinckel 2006; Channick 
2006).  In the acute dosing studies, administration of inhaled treprostinil sodium resulted in 
pulmonary vasodilation with excellent tolerability at relatively low doses inhaled in a few 
breaths.  In the chronic studies, administration of inhaled treprostinil sodium resulted in 
sustained improvement of exercise capacity.
A randomized, double blind, placebo controlled, Phase 3 pivotal study (TRIUMPH-I) was 
conducted to assess the safety and efficacy of inhaled treprostinil. Two hundred thirty-five 
subjects who were clinically stable on approved background oral PAH therapy (either bosentan 
or sildenafil) were randomly allocated to receive either placebo or inhaled treprostinil for 
12 weeks. The primary efficacy endpoint was change in exercise capacity at Week 12 as 
measured by 6 minute walk distance (6MWD). At Week 12, patients receiving inhaled 
treprostinil had a median improvement of +21.6 meters in 6MWD and patients in the placebo 
group had a median improvement of +3.0 meters.  The Hodges-Lehmann placebo corrected 
median change from baseline in peak 6MWD was +20.0 meters (p=0.00044). This result was 
supported by secondary measures related to 6MWD, including similar Week 6 results and 
maintenance of effect on 6MWD improvement at Week 12 trough, which was measured at least 
4 hours after the last dose. The most common adverse events in the treprostinil group were cough 
(54%), headache (41%), and nausea (19%).  There were no remarkable treatment related changes 
in vital signs, physical examination findings, chest x-rays, pulmonary function tests, or clinical 
laboratory parameters (McLaughlin 2010).
1.4
Clinical Hypothesis
Treprostinil, inhaled (Tyvaso®) is a registered treatment for PAH with an acceptable safety 
profile. Oral BPS-314d-MR is under development as a prostacyclin for the treatment of PAH. 
This study is designed to leverage the complimentary mechanistic and pharmacokinetic 
differences between locally acting inhaled treprostinil and the systemic delivery of 
BPS-314d-MR, creating an effect that more closely approximates parenteral therapy than using 
either therapy alone. This study will test the hypothesis that combining these therapies will 
achieve a more effective and longer lasting therapeutic effect, delaying time to clinical 
worsening. 


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2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is to compare the effect of BPS-314d-MR versus placebo 
added to treprostinil, inhaled (Tyvaso®) on the composite endpoint of time-to-clinical-worsening 
(TtCW), defined as the time from randomization to the first of any of the following clinical 
worsening events: 
•
Death (all causes)
•
Hospitalization due to worsening PAH defined as:
-
Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure and requiring intensification 
of treatment; or
-
Lung or heart / lung transplantation; or
-
Atrial septostomy
•
Initiation of a parenteral (infusion or sub-cutaneous)  prostacyclin, directly related to 
worsening PAH (transient use [≤7 days] for non-PAH related illness allowable)
•
Disease progression (all criteria required):
-
A decrease in six minute walk distance (6MWD) of at least 15% from Baseline (defined 
as the average of the two 6MWTs performed on sequential days of the Baseline Visit), or 
being too ill to walk as a consequence of PAH progression, confirmed by six-minute 
walk tests (6MWT) performed at 2 consecutive visits
-
Worsening of PAH symptoms, which must include either:
◦
An increase in WHO Functional Class or
◦
Worsening symptoms of right heart failure
•
Unsatisfactory long-term clinical response (all criteria below required):
-
Receiving randomized treatment for at least 24 weeks
-
A decrease of at least 15% from Baseline (defined as the average of the two Baseline 
Visit 6MWTs) in 6MWD, or too ill to walk, directly related to PAH progression, at Week 
24 and beyond; at 2 consecutive visits, and 
-
Sustained WHO Functional Class III or IV symptoms for at least 24 weeks.
The Investigator will initially judge whether a suspected clinical worsening event has occurred 
based on the definition provided above. An Event Adjudication Committee (EAC) will review all 
suspected clinical worsening events and make a final determination. The EAC will be composed 
of medical experts in the PAH field, will be independent from the Sponsor, and will assess each 
event in a blinded fashion. Specific details regarding the Committee’s membership, processes 
and procedures will be outlined in the EAC charter. 
Subjects will continue participation in the study until it is formally concluded by the Sponsor. 
Subjects are expected to remain on study drug throughout their participation in the study 
unless/until IV or SQ prostanoid therapy is added or in the event of lung transplantation. If a 
subject discontinues the study for any reason prior to the formal conclusion of the study by the 
Sponsor, the subject will be asked to return to the clinical for an End of Study (Early 
Termination) Visit.


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Vital status will be assessed for all randomized subjects at the formal conclusion of the study. 
For randomized subjects who terminate early, vital status will be assessed three months 
following discontinuation unless the formal conclusion of the study occurs within the three 
month time period.
2.2
Secondary Objectives
The secondary objectives of this study are:
•
To compare the effect of BPS-314d-MR versus placebo added to treprostinil, inhaled 
(Tyvaso®) on the composite endpoint of time-to-clinical-failure (TtCF), defined as the time 
from randomization to the first of any of the following events:
-
Meets primary endpoint definition of clinical worsening, as confirmed by EAC, or
-
Receiving randomized treatment for at least 24 weeks and has:

Lack of sustained improvement from Baseline WHO Functional Class: defined by 
two consecutive visits of no sustained improvement from Baseline WHO FC, visits 
may be scheduled or unscheduled; and   

Lack of sustained improvement from Baseline 6MWD (average at Baseline): defined 
by two consecutive visits of no sustained improvement from Baseline 6MWD 
(≤0 meters or too ill to walk, directly related to PAH), visits may be scheduled or 
unscheduled.  
•
To compare the effects of BPS-314d-MR to placebo added to inhaled treprostinil on changes 
from baseline to each scheduled study visit, as applicable, for the following measures:
-
6MWD
-
Borg Dyspnea Score
-
WHO Functional Class 
-
NT-pro-BNP levels 
•
To evaluate the safety of BPS-314d-MR based on adverse events, clinical laboratory 
parameters, electrocardiogram (ECG) findings, physical examination and vital signs.
2.3
Exploratory Objectives
 
 
 


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3
EXPECTED RISKS/BENEFITS
The risks of BPS-MR and BPS-314d-MR appear to be associated with the known risks of the 
prostanoid class of medication and no new or unique safety concerns have been identified. 
BPS-MR and BPS-314d-MR has been administered to approximately 100 healthy volunteers and 
to over 50 patients with PAH through Lung Biotechnology Inc. sponsored studies. Total daily 
doses of BPS 314d (calculated as one fourth of the racemic BPS MR dose) ranged from 30 to 
570 µg with more than two years of clinical observations in most patients. Data from these 
studies indicate that BPS is well tolerated and has an acceptable safety profile in the treatment of 
PAH via the oral route. The most frequently reported treatment emergent adverse reactions      
(≥10%) are headache, nausea, diarrhea, flushing, jaw pain, dizziness, pain in extremity, 
palpitations, pain, fatigue, vomiting, and hot flush. For more information please refer to the 
Investigators’ Brochure. 
The theoretical benefits of BPS-314d-MR are based on several factors, including the current 
understanding of the pathophysiology of the disease, the established pharmacodynamic activities 
of beraprost (e.g. vasodilation, anti-proliferation, and anti-platelet activity) and the beneficial 
effects that have been established for other members of the prostanoid class (epoprostenol, 
treprostinil, and iloprost). Notably, these other routes of administration are associated with 
certain inherent risks, such as bloodstream infections and local site reactions, which have not 
been observed and would not be expected with oral administration of BPS-314d-MR. In addition 
to these factors, prior clinical studies conducted by Lung Biotechnology Inc, Toray Industries 
and others have suggested beneficial effects of BPS-IR and BPS-MR in the treatment of patients 
with PAH, Section 1.0. In addition, as described in Section 1.3, it is hypothesized that the 
proposed combination of BPS-314d-MR with inhaled treprostinil might provide a less invasive, 
more tolerable and clinically beneficial approach to achieving sustained prostacyclin exposure, 
approximating the desired profile observed with continuous intravenous delivery.
4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This study is designed to evaluate the efficacy and safety of BPS-314d-MR in subjects with PAH 
who are also treated with treprostinil, inhaled (Tyvaso®). 
Patients who consent to the study will be assessed at the Screening and Baseline Visits to 
determine eligibility for the study. After the Screening Visit, subjects who consent to the study 
and are determined to be eligible but are not currently taking inhaled treprostinil will enter a 
run-in period on inhaled treprostinil to achieve 90 days of experience to ensure drug tolerability 
before being randomized. During the run-in period, subjects will be prescribed inhaled 
treprostinil by the Investigator and will receive the Tyvaso® inhalation device and inhaled 
treprostinil, and training in accordance with specialty pharmacy and the standard procedures of 
the clinical site. Subjects who consent to the study and are currently taking inhaled treprostinil at 
the Screening Visit should be randomized into the study as soon as eligibility criteria have been 
met. Subjects who meet eligibility criteria and who have been treated with inhaled treprostinil for 
at least 90 days, with 30 or more days at a stable dose, at the time of the Baseline Visit will be 


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randomized into the study using a centralized randomization system, stratified by use of inhaled 
treprostinil, to either active or placebo study drug. See Appendix 2. Two baseline 6MW 
assessments will be done, one each on consecutive days after randomization has been 
completed. The mean value of these two assessments will establish the baseline value for later 
comparisons. Subjects, study site personnel, the Sponsor and the EAC will be blinded to the 
treatment group assignment. 
Following the Baseline Visit, subjects will return to the study site for scheduled study visits at 
Week 4, Week 8, and Week 12 (first Quarterly Visit) and for scheduled Quarterly Visits 
thereafter. Subjects will undergo all scheduled efficacy and safety assessments as defined by the 
protocol and the Schedule of Events (Appendix 1). Between scheduled study visits, the subject 
will be contacted to assess for possible clinical worsening events and to record any newly 
occurring or changes to adverse events or concomitant medications. Subject contact should occur 
weekly for the first twelve weeks (except for study visit weeks) when subjects are becoming 
familiar with the study drug dosing (including up-titration to the fixed dose, as tolerated) and 
study procedures. Subjects should be contacted monthly between scheduled Quarterly Visits 
through the end of study participation. 
Subjects will continue the study until it is formally concluded by the Sponsor. Following study 
conclusion the subject will return to the clinical site for an End of Study Visit to undergo all 
scheduled assessments. Subjects who are participating in the study at its conclusion may be 
offered the opportunity to enroll in a long-term open-label extension study. 
In the event that a subject withdraws consent for participation in the study or the Investigator 
terminates the subject from the study the subject will be weaned from study drug and will return 
to the clinical site for an End of Study (Early Termination) Visit to undergo all scheduled 
assessments.  
4.1.1
Initial Dosing and Safety Assessment
As this study is novel in the use of combined prostanoid therapy, the Sponsor intends to limit
study site start-up and subject recruitment activities during the first six months. Study site 
selection during this period will be based on site experience with prostanoid therapy and the 
conduct of clinical studies. As such, a minimum number of subjects will initially be exposed to 
combined prostanoid therapy. 
The independent Data Safety Monitoring Board (DSMB), in accordance with the charter, 
reviews unblinded study data during scheduled review meetings to ensure adequate subject 
safety to the combined exposure of BPS-314d-MR and inhaled treprostinil.  No new safety 
signals have been detected thus far.
4.1.2
Optional Plasma Concentration Assessment
An optional plasma concentration assessment will be offered at study sites that are capable of 
collecting, processing and storing samples, are approved by the Sponsor and agree to participate. 
Subjects within those sites will decide if they wish to participate in the optional plasma 
concentration assessment. Subjects electing to participate will have blood drawn at the following 
time points: A trough sample (15 minutes pre-dose, ± 5 minutes) at the Week 4 Visit, and four 


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blood samples (around the second daily dose of study drug) during Week 12 (first Quarterly 
Visit) at 15 minutes pre-dose, and 15 minutes, 1 hour and 2.5 hours post-dose (± 5 minutes), and, 
if feasible, for SAEs for measurement of BPS-314d and treprostinil plasma concentrations. 
Dosing times should be documented in the subject’s source documentation. Unwillingness to 
participate in the optional plasma concentration assessment will not affect the subject’s or the 
site’s participation in the study.
See Appendix 1 Study Events Table.
4.1.3
Optional Hemodynamic Assessment
An optional hemodynamic assessment will be offered at study sites capable of conducting 
hemodynamic procedures, are approved by the Sponsor and agree to participate. Subjects at 
selected research centers may elect to volunteer in the sub-study until the Sponsor closes 
enrollment. Hemodynamic measurements, such as mean pulmonary arterial pressure, cardiac 
index, and pulmonary vascular resistance, will be assessed by right heart catheterization (RHC). 
For those subjects consenting to the RHC, the procedure will be performed at the Baseline Visit 
(within 0-21 days prior to the scheduled Baseline Visit) and at the Month 6 Quarterly Visit (or 
within 7 days before or after). During the Baseline assessment the RHC should be performed 
prior to study drug dosing. At the Month 6 Quarterly Visit the RHC should be performed at peak 
study drug blood levels (1-2 hours, ± 15 minutes, after the study drug is administered).
4.2
Rationale for Study Design and Control Group
This is a randomized, double-blind, placebo-controlled study with a parallel group design. 
Randomization will avoid potential bias in the assignment of subjects to treatment arms and will 
increase the likelihood that unknown and known subject characteristics (e.g., demographics and 
disease characteristics) are evenly balanced across the two arms.  Double-blind treatment is used 
to reduce potential bias in dosing, therapeutic decisions, and data handling. The placebo control 
group allows all subjects to receive similar treatment paradigms and serves as a direct reference 
group for assessing the effect of study drug. The parallel (control)-group design allows the direct 
comparison of the two treatment groups with minimal confounding of time and reduces the 
potential that improvements in measures of efficacy from baseline are merely due to the fact that 
subjects are involved in a clinical intervention during the course of the study.
4.3
Study Duration and Dates
As the trial is intended to continue until the specified number of Clinical Worsening Events 
(113) has occurred, the duration of treatment for individual subjects will vary. The maximum 
duration of treatment for any individual subject is expected to be 3 years, with the anticipated 
date for last subject last study visit in Q2 2016.


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5
STUDY POPULATION SELECTION
5.1
Study Population
The study population is comprised of males and females with PAH, age 18 to 80 years, inclusive, 
presently on a stable regimen of inhaled treprostinil.
5.2
Inclusion Criteria
The following are inclusion criteria to be enrolled in this study:
1.
Male or female, age 18 to 80 years (inclusive).
2.
Established diagnosis of pulmonary arterial hypertension that is either idiopathic or familial 
PAH, collagen vascular disease associated PAH, PAH associated with HIV infection, PAH 
induced by anorexigens/toxins, or PAH associated with repaired congenital systemic-to-
pulmonary shunts (repaired ≥1 years).
3.
If HIV positive, has a CD4 lymphocyte count ≥200 cells/mm3 within 30 days of Baseline 
Visit and is receiving current standard of care anti-retroviral or other effective medication.
4.
At the Screening Visit, WHO functional class III or IV and who have declining or 
unsatisfactory clinical response to current PAH therapy.
5.
At the Baseline Visit, WHO functional class III or IV and who have declining or 
unsatisfactory clinical response to inhaled treprostinil therapy.
6.
Able to walk unassisted (oxygen use allowed).
7.
A 6-Minute Walk distance (6MWD) of ≥ 100 meters at the Screening Visit.
8.
Previous (within five years prior to the Baseline Visit) right heart cardiac catheterization 
(RHC) with findings consistent with PAH, specifically mean Pulmonary Arterial Pressure 
(PAPm) ≥25 mmHg (at rest), Pulmonary Capillary Wedge Pressure (PCWP) (or left 
ventricular end diastolic pressure) ≤15 mmHg, and Pulmonary Vascular Resistance (PVR) 
>3 mmHg/L/min.1
9.
Echocardiography excluding any clinically significant left heart disease (e.g. left sided 
valve disease, wall motion abnormality suggesting of myocardial infarction, left ventricular 
hypertrophy, etc.). 
10.
Pulmonary function tests conducted within 12 months before or during the Screening 
period to confirm the following:
a.
Total lung capacity (TLC) is at least 60% (predicted value); and
b. Forced expiratory volume at one second (FEV1) of at least 50% (predicted value).
11.
Subjects receiving additional FDA approved PAH therapies must be stable on their current 
dose for at least 30 days prior to the Baseline Visit, apart from modification of 
anticoagulant or diuretic dosages. 
12.
Must have completed 90 days of uninterrupted inhaled treprostinil treatment and received 
a stable dose of inhaled treprostinil for at least 30 days prior to Baseline to be eligible for 
randomization into the study. 
13.
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 result in a low failure rate, i.e., less 
                                                
1 For conflicting RHCs, the most recent assessment is preferred if relevant in Investigator’s judgment.


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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 Screening and Baseline Visits.
14.
Willing and able to comply with study requirements and restrictions.
5.3
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from the study:
1.
Pregnant or lactating.
2.
Has previous experience with beraprost or BPS-314d (i.e., BPS-IR, BPS-MR or 
BPS-314d-MR).
3.
PAH related to any condition not covered under inclusion criteria, including but not limited 
to pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary capillary 
hemangiomatosis, or chronic thromboembolic pulmonary hypertension.
4.
History of interstitial lung disease, unless subject has collagen vascular disease and has had 
pulmonary function testing conducted within 12 months of the Baseline Visit
demonstrating a total lung capacity ≥60% of predicted.
5.
Has active hemorrhagic condition (e.g., upper digestive tract hemorrhage, hemoptysis, 
etc.), or has a pre-existing condition that, in the Investigator’s judgment, may increase the 
risk for developing hemorrhage during the study (e.g., hemophilia). Transient hemorrhage 
(e.g., epistaxis, normal menstrual bleeding, gingival bleeding, hemorrhoidal bleeding, etc.) 
will not preclude enrollment.
6.
Has received any investigational drug, device or therapy within 30 days prior to the 
Baseline Visit or is scheduled to receive another investigational drug, device or therapy 
during the course of the study.
7.
Has any musculoskeletal disease or any other disease that would significantly limit 
ambulation.
8.
Has any form of unrepaired or recently repaired (< 1 year) congenital systemic-to-
pulmonary shunt other than patent foramen ovale.
9.
Evidence of significant coronary arterial disease with symptoms, such as angina.
10.
Left sided myocardial disease as evidenced by left ventricular ejection fraction < 40%, or 
shortening fraction <22%.2
11.
Has creatinine clearance <30 (using the Crockroft-Gault formula) or requires hemodialysis.
12.
Has Childs-Pugh class C liver cirrhosis.
13.
Has had previous atrial septostomy.
14.
Any other clinically significant illness or abnormal laboratory values (measured during the 
Screening period) 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.3
15.
Anticipated survival less than 1 year due to concomitant disease.
                                                
2 Note that subjects in whom abnormal left ventricular function is attributed entirely to impaired left ventricular 
filling due to the effects of right ventricular overload (i.e., right ventricular hypertrophy and/or dilatation) will not be 
excluded.
3 Please see Appendix 9 for non-binding Sponsor guidance to be considered when determining a subject’s 
appropriateness for this study. 


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The Sponsor recognizes that the pulmonary hypertension population is complex and diverse. In 
order to facilitate enrollment of appropriate subjects to this pivotal trial, Investigators are 
strongly encouraged to contact the medical director or study team to discuss potential study 
subjects who have comorbid conditions before enrollment into this study. See Appendix 9 for 
additional details.    
No waivers to entry criteria are allowable in this study. Subjects who are initially ineligible for 
this study may be reassessed for eligibility after consultation with the Sponsor.
6
STUDY TREATMENT
6.1
Description of Treatment
6.1.1
Study Drug
The study drug is BPS-314d-MR, available as 15 μg tablets for oral, four times daily (QID) 
administration. BPS-314d-MR 15 µg tablets contain 15 µg of the drug substance BPS-314d. 
BPS-314d-MR active and matching placebo tablets will be mounted in child resistant Dose Pak® 
wallet cards. Following randomization, each subject will receive a “starter kit” containing four 
weekly wallet cards to cover the first 4 weeks of the study. 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.
6.1.2
Placebo
To preserve study blinding, the placebo tablets are identical in size, shape, color, and appearance 
to the BPS-314d-MR tablets.  The tablet packaging and configuration for placebo tablets are also 
identical to active tablets.
6.1.3
Treprostinil, Inhaled (Tyvaso®)
For subjects who are currently taking inhaled treprostinil at the Screening Visit and who meet 
study eligibility criteria, Tyvaso starter kits will be provided by the clinical site during the 
Baseline Visit. For subjects who are not currently taking inhaled treprostinil at the Screening 
Visit and continue to remain study eligible, these subjects will be contacted by the specialty 
pharmacy to schedule device training, supply the Tyvaso® inhalation device and inhaled 
treprostinil and initiate of Tyvaso® treatment. The specialty pharmacy will maintain regular 
contact with the study subject until the subject achieves 90 days of experience on inhaled 
treprostinil. These subjects, when study eligibility criteria are met, will be randomized into the 
study. Re-supply of Tyvaso will be managed through a specialty pharmacy throughout the 
duration of the study.


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6.2
Treatments Administered
6.2.1
Drug Dosage, Administration and Schedule
After all Baseline assessments are completed and randomization occurs, subjects will be 
provided a study drug “starter kit” and will take the first dose (one tablet) of study drug. Study 
drug dosing should occur in conjunction with the treprostinil inhalation dose. All doses of study 
drug are to be administered in conjunction with inhaled treprostinil. The dosage for Tyvaso®, 
inhaled treprostinil, according to label, is a maximum of 9 breaths per treatment session QID. 
The number of breaths per treatment session should remain consistent throughout the subject’s 
participation in the trial. Following the first dose of study drug, the subject should remain in the 
clinic for approximately 2 - 3 hours for periodic observation by study personnel. 
The study drug “starter kit” will supply the subject with study drug for the first four weeks of the 
study to allow subject to become familiar with the study drug tablets, configuration, packaging, 
and dosing frequency. 
For the first two weeks after randomization, the study drug dose will be one tablet QID. After 
two weeks on study drug, site personnel will contact the subject to monitor adverse events and, 
as appropriate, instruct the subject to increase the study drug dose to two tablets QID. At the 
Week 4 Visit, subjects will receive study drug in bulk dosing cards which will be the study drug 
packaging and configuration provided for the remainder of the study (see Section 6.9). Study 
drug will continue to be administered in conjunction with inhaled treprostinil throughout the 
study. If a subject is unable to tolerate the targeted two tablets QID dosing regimen, it is 
acceptable to continue in the study on one tablet QID dosing. At the Investigator’s discretion, an 
observed re-challenge may be attempted using the target, two tablets QID dosing, at either the 
Week 4 or Week 8 Visit. 
6.3
Method of Assigning Patients to Treatment Groups
Treatment groups consist of one active and one placebo group. Subjects will be randomly 
allocated in a 1:1 ratio to one of the two treatment groups.  All subjects will be randomized using 
a centrally administered randomization stratified by use of inhaled treprostinil (specifically, 
current user at the time of the Screening Visit: yes or no). Randomization codes will be blocked.  
Block sizes will not be disclosed to Investigators to prevent inferences about possible treatment 
assignments for current or future subjects. Interactive Randomization Technology (IRT) will be 
utilized for the central randomization procedure. Once all entry criteria have been met at the 
Baseline Visit, the Investigator or designee will access the IRT (by phone or by web) to assign 
the subject a randomization number and the study drug corresponding to the assigned treatment 
group.
An independent biostatistician, designated by the Sponsor, will review and approve the 
randomization scheme. 
Each screened subject will receive a Unique Patient Identification (UPI) number (a unique 
7 character alpha-numeric identifier) consisting of a 3-digit clinical site number, a 3-digit patient 
number (i.e., subject number), and a hyphen separating these two numbers. The Sponsor will 
assign site numbers to each clinical site. The patient number will be assigned by the IRT system 


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as a 3-digit number to each subject in sequential order by clinical site at the time of the Screening 
Visit. For example: The first subject who is screened at Site 301 will be assigned the UPI of 
301-001, the second, 301-002, etc. 
The UPI will remain the same throughout the study to identify uniquely the subject’s Case 
Report Forms (CRFs) and other documentation. The UPI of a subject who discontinues from the 
study for any reason after having been assigned a UPI will not be reassigned.
6.4
Blinding
The study is double-blind. The Investigator and study staff, the subjects, the monitors, the 
sponsor staff and the EAC will remain blinded to the treatment group allocation until study 
closure.  The investigational drug and its matching placebo are indistinguishable and will be 
packaged in the same way to ensure study blinding.
At regular intervals an independent Data Safety Monitoring Board (DSMB) will review 
unblinded data to ensure subject safety and assess study conduct, as defined in the Charter. To 
ensure proper blinding of study personnel, an independent statistician will prepare data tables for 
the DSMB.
6.5
Unblinding Procedures
Study subjects, site medical staff, the Sponsor and the EAC will be blinded to which treatment is 
being administered to the subject.  
Subjects who complete the study may be offered the opportunity to continue taking study drug in 
a separate open-label continuation protocol. Data will remain blinded until fully reviewed, 
cleaned and the database locked, at which time the randomization schedule may be formally 
unblinded by the Sponsor.
Only if a subject’s medical condition warrants, such as a medical emergency for which treatment 
requires knowledge of what study drug was given, may the Investigator break the blind to 
determine if the subject received active drug or placebo.  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 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. 
6.6
Concomitant Therapy
All subjects randomized into this study and receiving study drug will be treated with inhaled 
treprostinil. Subjects must have received a stable dose of inhaled treprostinil for at least 30 days 
prior to the Baseline Visit. All subjects must have been stabilized on an optimal dosing regimen 
of conventional PAH therapies (e.g., oral vasodilator, digoxin, oxygen) for at least 30 days prior 
to the Baseline Visit. 


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No PAH therapies may be added, removed or dose adjusted during the study, unless a change is 
required by medical necessity. Initiation, discontinuation or dose changes of anticoagulants, 
diuretics and non-PAH medications are allowable.
6.7
Restrictions
6.7.1
Prior Therapy
Subjects must meet inclusion and exclusion criteria outlined in Sections 5.2 and 5.3. Prior 
experience with BPS is exclusionary. No further restrictions on prior or concomitant therapies 
are required. 
6.7.2
Fluid and Food Intake 
In general, subjects should follow their normal diet and fluid intake through the course of the 
study. 
For subjects participating in the plasma concentration assessment portion of the study, caffeine 
or alcohol-containing beverages may not be consumed during the day of the scheduled study
visit until the assessment is completed. There are no other restrictions during the day of the
assessment.
6.7.3
Patient Activity Restrictions
Subjects should continue their normal activities of daily living during the study.
6.8
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 non-compliance may lead to 
termination of the subject from the study after consultation between the Investigator and the 
Sponsor.
6.9
Packaging and Labeling
The Sponsor will supply study drug for the study. BPS-314d-MR (15 µg) tablets and matching 
placebo will be mounted in identical child resistant Dose-Pak® wallet cards. At the Baseline 
Visit following randomization, each subject in the study will be assigned a study drug “starter 
kit”. The subject’s “starter kit” will contain 4 weekly wallet cards, one for each of the first four
weeks of the study. Each designated wallet card will provide the appropriate daily dosing for the 
assigned week based on weekly dose escalation (Weeks 1 and 2 dosing card will contain 
4 tablets to be taken each day; Weeks 3 and 4 wallet card will contain 8 tablets per day, two for 
each of the four doses to be taken that day).  The “starter kit” will allow the subject time to 


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become familiar and comfortable with the study drug (tablets, configuration, and packaging), 
dosing frequency, etc. 
At the Week 4, Week 8, Week 12 (first Quarterly Visit) and at Quarterly Visits thereafter, the 
subject will be issued bulk dosing cards of study drug tablets to provide an adequate supply of 
study drug for continued use until the subject’s next scheduled study visit. 
Subjects will be trained by the site personnel on how to open the study drug packages and collect 
the proper quantity of tablets to make up the prescribed dose.  The subject will be instructed on 
the importance of not damaging the tablets and educated on the importance of compliance with 
taking the study drug and attending study visits.
Study drug will be labeled in accordance with all applicable U.S. federal 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. Each “starter kit” and bulk wallet card label will have a tear-off panel that will be 
placed into the subject’s record.
6.10
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.
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.
6.11
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. 


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In addition to study drug, study-specific Starter kits (devices and drug) will be dispensed by the 
study site. Re-supply of inhaled treprostinil will be managed through the specialty pharmacy 
through the duration of the study.
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 batch 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, the Sponsor or its designee will instruct the Investigator on 
the return of all used and unused study drug. 
7
STUDY PROCEDURES
7.1
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 Institutional 
Review Board (IRB) approved Informed Consent Form (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.
7.2
Medical History
Medical and surgical history will be collected from each subject during the Screening Visit and 
updated at the Baseline Visit, as applicable. The medical and surgical history will focus on 
relevant and significant past or present illnesses. The history will cover relevant areas such as
head, eyes, ears, nose, and throat, cardiovascular; respiratory; abdomen; gastrointestinal/liver; 
kidney/urinary, genitalia/reproductive, musculoskeletal; endocrine, history of allergies or 
idiosyncratic responses to drugs, psychiatric, neurological; dermatologic, and extremities. This 
information will be used for assessing whether subject meets inclusion/exclusion criteria.


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Current prescription and/or nonprescription medications will be assessed and entered in the 
concomitant medications CRF to enable tracking of any changes to prior medications which 
occur during the study. Nonprescription medications include vitamins and herbal preparations.
7.3
Physical Examination
A physical examination will be conducted by a qualified study clinician at Screening, Baseline, 
Study Visit Week 4, Week 8, Week 12 (first Quarterly Visit), at Quarterly Visits and at the End 
of Study Visit. 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 consent to the study 
should be recorded on the Adverse Event CRF as an AE.
7.4
Vital Signs
Vital signs will be measured at all scheduled study visits. Subject height will be recorded at 
Screening and weight will be recorded at each study visit. Systolic and diastolic blood pressure, 
heart rate, respiratory rate and temperature will be measured after at least 5 minutes of seated 
rest. 
Any values judged by the Investigator to be clinically significant abnormal changes after 
subject’s consent to the study should also be recorded on the Adverse Event CRF as an AE.
7.5
PAH History
Based on the subject’s medical records, the PAH etiology and date of diagnosis will be entered 
into the CRF. Types of PAH allowed into the study are: idiopathic or familial, collagen vascular 
disease associated PAH, PAH associated with HIV infection, PAH induced by anorexigens/
toxins, or PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired 
≥1 years). This information will be used for assessing inclusion and exclusion criteria.
7.6
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 performed at the Baseline Visit and a serum 
test at all other study visits.
7.7
ECG Assessment
Twelve-lead ECGs will be recorded following at least a 5-minute rest in the semi-recumbent 
position at the following visits: Screening, Baseline, Week 4, Week 8 (optional), Week 
12, Quarterly and End of Study. At the Screening (as applicable) and Baseline Visits, ECGs 
should be measured within 1-2 hours, ± 15 minutes, after second or third dose of inhaled 
treprostinil. At all subsequent visits, e.g. Week 4 and beyond, ECGs should be measured within 
1-2 hours, ± 15 minutes, after second or third dose of inhaled treprostinil and study drug 
combined.


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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 
subject’s consent to the study should also be recorded on the Adverse Event CRF as an AE.
7.8
Clinical Laboratory Tests
7.8.1
Laboratory Parameters
Blood and urine specimens for the measurement and evaluation of serum chemistry, hematology, 
coagulation, urinalysis and NT-pro-BNP will be collected at Screening, Baseline, Week 4, 
Week 8, Week 12, at Quarterly Visits and at the End of Study Visit. 
Subjects will be in a seated or supine position during blood collection. Clinical laboratory 
parameters will include those presented in Table 1. Results will be forwarded to the sites and 
electronically transferred into the study database. Eligibility for the study will be based upon 
laboratory parameters collected during the Screening phase of the study.
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 subject’s 
consent to the study should also be recorded on the Adverse Event CRF as an AE.


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Table 1
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
Pregnancy test:
-
Urine human chorionic gonadotropin (hCG) 
for females  of childbearing potential –
Baseline Visit only;  Serum pregnancy test at 
all other scheduled visits
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 (not required to determine study 
eligibility)
Coagulation: 
-
Prothrombin time (PT)
-
Activated partial thromboplastin time (PTT)
7.8.2
Sample Collection, Storage, and Shipping
Analysis of laboratory specimens listed in Table 1 will be performed by a certified central 
laboratory. Results will be forwarded to the sites and electronically transferred into the study 
database. 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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7.9
Dispensing Study Drug and Tyvaso®
Study site personnel will dispense appropriate supplies of study drug to subjects at each study
visit. Subjects will be instructed to return all study drug, including empty or partially used 
packages, to the appropriate study personnel on an ongoing basis. 
For subjects who are currently taking inhaled treprostinil at the Screening Visit and who meet 
study eligibility criteria, Tyvaso starter kits will be provided by the clinical site during the 
Baseline Visit. For subjects who are not currently taking inhaled treprostinil at the Screening 
Visit and continue to remain study eligible, these subjects will be contacted by the specialty 
pharmacy to schedule device training, supply the Tyvaso® inhalation device and inhaled 
treprostinil and initiate of Tyvaso® treatment. The specialty pharmacy will maintain regular 
contact with the study subject until the subject achieves 90 days of experience on inhaled 
treprostinil. These subjects, when study eligibility criteria are met, will be randomized into the 
study. Re-supply of Tyvaso will be managed through a specialty pharmacy throughout the 
duration of the study.
Study drug dosing, including missed doses, during the study will be recorded in the appropriate 
CRF.
Detailed study drug disposition records will be maintained as previously described 
(Section 6.11).
7.10
Efficacy Assessments
7.10.1
Clinical Worsening 
Clinical worsening will be assessed from randomization to the first of the following events: 
To compare the effects of BPS-314d-MR to placebo in patients receiving inhaled treprostinil 
(Tyvaso®) on time-to-clinical-worsening (TtCW) defined as the time from randomization to the 
first of any of the following clinical worsening events: 
•
Death (all causes)
•
Hospitalization due to worsening PAH defined as:
-
Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure and requiring intensification 
of treatment; or
-
Lung or heart / lung transplantation; or
-
Atrial septostomy
•
Initiation of a parenteral (infusion or sub-cutaneous)  prostacyclin, directly related to 
worsening PAH (transient use [≤7 days] for non-PAH related illness allowable)
•
Disease progression (all criteria required):
-
A decrease in six minute walk distance (6MWD) of at least 15% from Baseline (defined 
as the average of the two 6MWTs performed on sequential days of the Baseline Visit), or 
being too ill to walk as a consequence of PAH progression, confirmed by six-minute 
walk tests (6MWT) performed at 2 consecutive visits


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-
Worsening of PAH symptoms, which must include either:
◦
An increase in WHO Functional Class or
◦
Worsening symptoms of right heart failure
•
Unsatisfactory long-term clinical response (all criteria below required):
-
Receiving randomized treatment for at least 24 weeks
-
A decrease of at least 15% from Baseline (defined as the average of the two Baseline 
Visit 6MWTs) in 6MWD, or too ill to walk, directly related to PAH progression, at 
Week 24 and beyond; at 2 consecutive visits, and 
-
Sustained WHO Functional Class III or IV symptoms for at least 24 weeks.
The Investigator will initially judge whether a suspected clinical worsening event has occurred 
based on the definition provided above. An EAC will be established by the Sponsor to review all 
suspected clinical worsening events and make a final determination. The Committee will be 
composed of medical experts in the PAH field, will be independent from the Sponsor, and will 
assess each event in a blinded fashion. Specific details regarding the Committee’s membership, 
processes and procedures will be outlined in the EAC charter. 
Subjects will continue their participation in the study until a clinical worsening event is 
confirmed by the EAC or the study is formally concluded by the Sponsor.
7.10.2
Clinical Failure
Clinical failure will be assessed from randomization to the first of the following events: 
•
Meets primary endpoint definition of clinical worsening, as confirmed by EAC, or
•
Receives randomized treatment for at least 24 weeks and has:
-
Lack of sustained improvement from Baseline WHO Functional Class: defined by two 
consecutive visits of no sustained improvement from Baseline WHO FC, visits may be 
scheduled or unscheduled; and
-
Lack of sustained improvement from Baseline 6MWD (average at Baseline): defined by 
two consecutive visits of no sustained improvement from Baseline 6MWD (≤ 0 meters or 
too ill to walk, directly related to PAH), visits may be scheduled or unscheduled. 
The Sponsor will derive the composite measures of clinical failure and TtCF from the data 
collected per the protocol. Unlike clinical worsening, neither a specific Investigator’s assessment 
for clinical failure nor an EAC confirmation of suspected events will occur. 
As above, subjects are expected to continue their participation in the study until a clinical 
worsening event is confirmed by the EAC or the study is formally concluded by the Sponsor.
7.10.3
Six Minute Walk Test
The 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 all scheduled study visits: Screening, Baseline (two 6MWTs, taken on consecutive 
days, before the start of study drug dosing), Weeks 4, 8, 12, Quarterly Visits and at the End of 
Study Visit. At the Screening Visit, the 6MWT should be measured within 1-2 hours, ± 15 


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minutes, after second or third dose of inhaled treprostinil or approximately 4-6 hours, ± 15 
minutes, after waking if the subject has not begun inhaled treprostinil treatment yet. At both days 
of the Baseline Visit (Days 1 and 2), the 6MWT should be measured within 1 hour, ± 15 
minutes, before the second or third dose of inhaled treprostinil. At all subsequent visits, e.g. 
Week 4 and beyond, the 6MWT should be measured within 1-2 hours, ± 15 minutes, after 
second or third dose of inhaled treprostinil and study drug combined. Appendix 3 presents the 
standardized procedures for administration of the 6MWT.
At any point in the trial, if a subject is assessed for the 6MWT while using oxygen therapy then 
all future 6MWTs should be conducted with the same oxygen flow.
7.10.4
Borg Dyspnea Score 
The modified 0–10 category-ratio Borg scale consists of an 11-point scale with 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. Subject may choose the number or the 
verbal descriptor to reflect presumed ratio properties of sensation or symptom intensity. 
Appendix 4 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.
7.10.5
WHO Functional Class
At the Screening Visit the Investigator will classify the subjects for PAH severity using the 
World Health Organization (WHO) Functional Class. Assessment for WHO Functional 
Classification for PAH should be made at Screening, Baseline, Week 4, Week 8, Week 12 (first 
Quarterly Visit), at Quarterly Follow-up Visits and at the End of Study Visit. See Appendix 5 for 
categories.
7.10.6
NT-pro-BNP
Blood samples to be used for Plasma N-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP; a 
biomarker of congestive heart failure) measurement will be collected at Screening, Baseline, 
Week 4, Week 8, Week 12 (first Quarterly Visit), at Quarterly Follow-up Visits, and at the 
End of Study Visit. 
7.11
Other Assessments
7.11.1
Optional Plasma Concentration Assessment
An optional plasma concentration assessment will be offered at study sites that are capable of 
collecting, processing and storing samples, are approved by the Sponsor and agree to participate. 
Subjects electing to participate will have blood drawn at the following time points: A trough
(15 minutes pre-dose, ± 5 minutes) blood sample at the Week 4 Visit, four blood samples 
(around the second daily dose of study drug) during Week 12 Visit at 15 minutes pre-dose, and 
15 minutes, 1 hour and 2.5 hours post-dose (± 5 minutes), and, if feasible, for SAEs for 
measurement of BPS-314d and treprostinil plasma concentrations. Patients electing to participate 


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should be contacted one week (seven days) prior to the Week 4 and Week 12 Visits as a 
reminder to record their Tyvaso® and study drug dosing times during the week leading up to the 
study visit. 
Blood sample collection kits and a laboratory operations manual will be provided to each site.
The blood samples will be handled and shipped according to the procedure outlined in  
Appendix 6. Given the implications for unblinding, the Sponsor will only receive plasma 
concentration results after the study has been officially completed and unblinded.
Unwillingness to volunteer for the optional plasma concentration assessment will not affect the 
subject’s participation in the study.
7.11.2
Optional Hemodynamic Measurement Assessment
The objective of the optional hemodynamic assessment is to assess hemodynamic changes 
corresponding to treatment with BPS-314d. The optional hemodynamic assessment will be 
offered to all study subjects at study sites capable of conducting hemodynamic procedures and to 
those who are approved by the Sponsor and agree to participate. Subjects at the selected research 
centers will be offered the opportunity to volunteer in the assessment until the Sponsor closes 
enrollment. Hemodynamic measurements will be assessed by Right Heart Catheterization (RHC) 
as outlined in Appendix 8. For those subjects who consent to this assessment, the RHC 
procedure will be performed at the Baseline Visit (within 0-21 days prior to the scheduled 
Baseline Visit) and at the Month 6 Quarterly Visit (or within 7 days before or after). During the 
Baseline assessment the RHC should be performed prior to study drug dosing.  At the Month 6 
Quarterly Visit, the RHC should be performed at peak study drug blood levels (1-2 hours, ± 15 
minutes, after the second or third dose of study drug administration).
Unwillingness to volunteer for the hemodynamic assessment will not affect the subject’s or site’s 
participation in the main study.
7.12
Adverse Events Assessments
7.12.1
Performing Adverse Events Assessments
The clinical site personnel will monitor all AEs throughout the study, from the time of the 
subject’s Informed Consent signature until the end of the subject’s study participation (see
Appendix 1). 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 clinic 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 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 study drug and/or background therapies. 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 7) in the CRFs for AEs. Where possible, AEs should be 


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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.
7.12.2
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. AEs 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).
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. 
For each reported AE the Investigator is responsible for grading its severity (or intensity) 
according to the criteria outlined in Appendix 7 and recording these data in the subject’s source 
documents and on the CRF for AEs. 
7.12.3
Severity
For each reported AE the Investigator is responsible for grading its severity (or intensity) 
according to the criteria outlined in Appendix 7 and recording these data in the subject’s source 
documents and on the AE page of the CRF.
7.12.4
Relationship
For each AE reported, the Investigator is responsible assessing the likelihood that an AE is 
causally related to the study drug according to the criteria outlined in Appendix 7. These data 
must be recorded in the subject’s source documents and on the AE page of the CRF.
7.12.5
Expectedness
The known and expected AEs due to the use of BPS-314d-MR are described in the current 
Clinical Investigators’ Brochure.


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7.12.6
Clinical Laboratory Adverse Events
The Investigator is responsible for reviewing the results of all laboratory tests as they become 
available.  Abnormal laboratory values or test results should not generally be considered AEs, 
unless the Investigator deems the values or results a clinically significant abnormal change from 
baseline.  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. 
7.12.7
Serious Adverse Events
7.12.7.1
Definition
A serious adverse event (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.
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.
7.12.7.2
Reporting Serious Adverse Events
All SAEs, as defined in Appendix 7 and regardless of expectedness or causality, must be 
reported to the pharmacovigilance monitor within 24 hours of the Investigator’s knowledge of an 
SAE occurrence through submission of the SAE form in the CRFs. An updated SAE CRF should 
be submitted to the pharmacovigilance monitor upon receipt of the any new or revised 
information. The Investigator or Sponsor (if appropriate) must also notify their Institutional 
Review Board (IRB), Independent Ethics Committee (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.
7.12.8
Treatment-Emergent Adverse Events
Treatment-emergent AEs will be defined as events that are newly occurring or worsening from 
baseline following treatment with study drug. 
BPS-314d is the active component of BPS-MR. The most frequently reported treatment 
emergent adverse reactions (≥10%) are headache, nausea, diarrhea, flushing, jaw pain, dizziness, 
pain in extremity, palpitations, pain, fatigue, vomiting, and hot flush.


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The most common adverse reactions (≥10%) with Tyvaso are cough, headache, nausea, 
dizziness, flushing (blushing of the skin), throat irritation, pharyngolaryngeal (pharynx and the 
larynx) pain and diarrhea.
Prostacyclins, as a class, may increase the risk of bleeding and hypotension.
7.12.9
Overdose 
Any clear or significant overdose, in the Investigator’s judgment, that occurs during study 
participation must be reported to the pharmacovigilance monitor using an SAE form (see 
Section 7.12.7.2) within 24 hours of learning of its occurrence and must be followed to 
determine the outcome. In addition, the data must be entered on the CRFs for AEs and be fully 
retrievable by the Sponsor within 48 hours following the event. A subject who experiences an 
overdose may be withdrawn from the study at the discretion of the Investigator and the Medical 
Monitor. 
7.12.10
Pregnancy 
All subjects must be instructed to contact the Investigator immediately if they suspect they or 
their partner might be pregnant while participating in this study. Any pregnancy that occurs 
during study participation must be reported to the Medical Monitor using the Pregnancy 
Notification form within 24 hours of learning of its occurrence. 
All pregnancies must be followed to determine outcome and must be reported to the 
pharmacovigilance monitor using the Pregnancy Reporting form within 24 hours of learning of 
the outcome. A subject who becomes pregnant will be discontinued from the study and the 
Investigator or designee should make all reasonable efforts to track the outcome of the 
pregnancy. 
If a male subject’s female partner becomes pregnant the Medical Monitor must be notified and 
all efforts should be made to track the outcome of the pregnancy with the same notification made 
to the Medical Monitor as defined above. 
7.13
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.


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7.14
Removal of Patients from the Trial or Study Drug
Subjects should be encouraged to complete the study, remain on study drug (even if only one 
tablet QID dosing is tolerated) until the conclusion of the study and to complete all required 
study assessments. However, 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;
•
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. 
The subject should be weaned from study drug prior to termination from the study. 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.
Vital status will be assessed for all randomized subjects at the formal conclusion of the 
study. For randomized subjects who terminate early, vital status will be assessed three months 
following discontinuation unless the formal conclusion of the study occurs within the three 
month time period. Study site personnel will record vital status information in source documents 
and record relevant information on appropriate CRFs.
7.15
Access to Open-Label Extension Study 
Subjects who successfully complete this BPS-314d-MR-PAH-302 study as scheduled per 
protocol (i.e., treated until unblinding of the study) may be offered the opportunity to enroll in a 
long-term open-label extension study at the conclusion of the study. 
Subjects who will not enroll in an open-label continuation protocol will be weaned off of study 
drug in a blinded manner. The maximum decrement should not exceed one tablet QID per day 
and the minimum decrement should be one tablet QID per week.


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8
STUDY ACTIVITIES
Please refer to Appendix 1 for Study Time and Events table.
8.1
Screening Visit
A Screening Visit will occur from 3 days up to 120 days prior to the scheduled Baseline Visit. 
The following activities, after obtaining voluntary informed consent, will be performed at this 
visit: 
•
Evaluate Inclusion/Exclusion Criteria
•
Record demographic information 
•
Record PAH history 
•
Record medical history 
•
Perform a physical examination
•
Record WHO Functional Class
•
Record vital signs after five minutes of seated rest 
•
Record a 12-Lead ECG following at least a 5-minute rest in a semi-recumbent position (if 
subject is on inhaled treprostinil, conduct ECG within 1-2 hours, ± 15 minutes, after the 
second or third dose of inhaled treprostinil )
•
Conduct an unencouraged 6MWT (if subject is on inhaled treprostinil, between 1-2 hours, ±
15 minutes, after second or third dose of inhaled treprostinil or, if subject is Tyvaso naïve,
approximately 4-6 hours, ± 15 minutes, after waking)
•
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 medications 
•
Record AEs
8.2
(2-Day) Baseline Visit Procedures
A 2-day Baseline Visit will be performed between 3-120 days after the Screening Visit. The 
Baseline Visit should occur when the subject achieves a minimum of 90 days of experience on 
inhaled treprostinil, with at least 30 of the 90 days at a stable dose.
Baseline Visit Day 1
Prior to randomization:
•
Update medical history, as necessary 
•
Perform a physical examination 
•
Record WHO Functional Class 
•
Record vital signs after five minutes of seated rest 


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•
Obtain blood and urine samples for clinical laboratory parameters (serum chemistry, 
hematology, coagulation, urinalysis and NT-pro-BNP); NT-pro-BNP not required to 
determine eligibility
•
Obtain urine pregnancy test for women of childbearing potential
•
Update prior and concomitant medications, as necessary 
•
Confirm Inclusion/Exclusion Criteria
•
For optional RHC assessment: For subjects who consent to participate, RHC should be 
performed within 1-2 hours, ± 15 minutes, after the second or third dose of inhaled 
treprostinil. RHC may be performed within 0-21 days prior to the scheduled Baseline Visit.
Randomization and following:
•
Randomize subject in IRT
•
Conduct an unencouraged 6MWT within 1 hour, ± 15 minutes, before the second or third
dose of inhaled treprostinil
•
Record Borg Dyspnea Score 
•
Administer second dose of inhaled treprostinil
•
Record a 12-lead ECG following at least a 5-minute rest in a semi-recumbent position 
between 1-2 hours, ± 15 minutes, after second or third dose of inhaled treprostinil
•
Record concomitant medications 
•
Record AEs 
Baseline Visit - Day 2
•
Conduct an unencouraged 6MWT within 1 hour, ± 15 minutes, prior to second or third daily 
dose of inhaled treprostinil and study drug
•
Record Borg Dyspnea Score 
•
Provide Tyvaso® starter kits, as appropriate for the subject, and document any training
•
Provide study drug starter kit supply (Provide training/instructions for subject participation in 
the study: study drug (packaging, storage, accountability, etc.), daily QID dosing for study 
drug and inhaled treprostinil, etc.), regular telephone calls, date of next study visit and 
importance of attending all study visits, etc.
•
Observe and record study drug and inhaled treprostinil co-administration. Subjects should 
remain in the clinic for a 2-3 hour observation period following dosing to assess for any AEs
•
Record concomitant medications 
•
Record AEs
•
For subjects electing to participate in the optional plasma concentration assessment, provide 
Week 4 and Week 12 (first Quarterly Visit) drug dosing record.


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8.2.1
Study Drug Administration
Study drug administration will occur after all Baseline assessments, including the second 
6MWT, and randomization are complete. Study drug will be dosed immediately before or after 
the subject administers dosing of inhaled treprostinil. Subjects should remain in the clinic for a 
2-3 hour observation period following dosing to assess for any AEs. Following dosing the 
following procedures should occur:
•
Record time and dose of study drug and inhaled treprostinil administration
•
Provide training/instructions for subject participation in the study: study drug (packaging, 
storage, accountability, etc.), daily QID dosing for study drug and inhaled treprostinil, etc.), 
regular telephone calls, date of next study visit and importance of attending all study visits, 
etc.
•
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 
8.2.2
Phone Calls
Subject should be contacted weekly between the Baseline Visit through Week12 except for 
weeks with study visits, then monthly between Quarterly Visits through the end of study 
participation. After two weeks on study drug, the subject should be contacted to assess drug 
tolerability and instructed to increase the study drug dose by one tablet QID for a fixed dose of 
two tablets QID through the duration of the study. If a subject is unable to tolerate the two tablets 
QID dosing regimen, after appropriate assessment (e.g. OTC use to alleviate headache), and at 
the Investigator’s discretion, the subject may continue in the study on one tablet QID dosing. An 
observed re-challenge may be attempted using the target, two tablets QID dosing, at either the 
Week 4 or Week 8 Visit. 
During phone calls to the subject, the following information should be recorded:
•
Record time and dose of study drug and inhaled treprostinil administration
•
Assess and record AEs 
•
Record concomitant medications
•
Assess clinical worsening
Subjects participating in the plasma concentration assessment should be contacted one week 
(seven days) prior to Week 4 and Week 12 (first Quarterly Visit) as a reminder to record 
their inhaled treprostinil and study drug dosing times during the week leading up to the visit.
8.3
Week 4 Procedures
Subjects will return to the study site at Week 4 (± 3 days) for the following procedures: 
•
Perform a physical examination 
•
Record WHO Functional Class 


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•
Record a 12-Lead ECG following a 5-minute rest in a semi-recumbent position (conduct 
ECG within 1-2 hours, ± 15 minutes, following the second or third daily dose of study drug)
•
Record vital signs after five minutes of seated rest 
•
Conduct an unencouraged 6MWT (1-2 hours, ± 15 minutes, after the second or third dose of 
inhaled treprostinil and study drug)
•
Record Borg Dyspnea Score 
•
Assess clinical worsening 
•
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
•
OPTIONAL Plasma Concentration Assessment: Obtain two 10 mL trough (15 minutes 
pre-dose, ± 5 minutes) blood samples (Section 4.1.2). Subjects should be contacted one week 
(7 days) prior to the visit and reminded to record the timing of study drug and inhaled 
treprostinil dosing for the week leading up to the study visit.
•
Record AEs 
•
Record concomitant medications 
•
Provide subject with a 1 month supply of study drug. Provide additional instructions/remind 
subject on importance of taking study drug and inhaled treprostinil together, 
•
Record study drug and inhaled treprostinil administration and/or 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 
8.4
Week 8 Procedures
Subjects will return to the clinical site at Week 8 after randomization (± 4 days) for the following 
procedures: 
•
Perform a physical examination 
•
Record WHO Functional Class 
•
OPTIONAL assessment at Week 8: Record a 12-Lead ECG following a 5-minute rest in a 
semi-recumbent position (conduct ECG within 1-2 hours, ± 15 minutes, following the second 
or third daily dose of study drug and inhaled treprostinil)
•
Record vital signs after five minutes of seated rest 
•
Conduct an unencouraged 6MWT (1-2 hours, ± 15 minutes, after second or third daily dose
of study drug and inhaled treprostinil)
•
Record Borg Dyspnea Score 
•
Assess clinical worsening 
•
Obtain blood and urine samples for clinical laboratory parameters (serum chemistry, 
hematology, coagulation, urinalysis and NT-pro-BNP) 


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•
Obtain serum pregnancy test for women of childbearing potential
•
Record AEs 
•
Record concomitant medications 
•
Provide subject with a 4 week supply of study drug. Provide additional instructions/remind 
subject on importance of taking study drug and inhaled treprostinil together, review study 
drug dosing, packaging, storage, etc.
•
Record study drug and inhaled treprostinil administration and/or dose changes, as applicable
•
Record study drug accountability 
•
Subjects to be reminded 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 
8.5
Week 12 (first Quarterly Visit) Procedures
Subjects will return to the study site for Week 12 (± 10 days) for the following procedures:
•
Perform a physical examination 
•
Record WHO Functional Class 
•
Record a 12-Lead ECG following a 5-minute rest in a semi-recumbent position (conduct 
ECG within 1-2 hours, ± 15 minutes, following the second or third daily dose of study drug
and inhaled treprostinil)
•
Record vital signs after five minutes of seated rest 
•
Conduct an unencouraged 6MWT (1-2 hours, ± 15 minutes, after the second or third daily 
dose of study drug and inhaled treprostinil)
•
Record Borg Dyspnea Score 
•
Assess clinical worsening 
•
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 3 month supply of study drug. Remind subject of importance of taking 
study drug and inhaled treprostinil together, review study drug dosing, packaging, storage, 
etc.
•
Record study drug accountability 
•
Record study drug and inhaled treprostinil administration and/or 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 
•
OPTIONAL Plasma Concentration Assessment: Obtain two 10 mL blood samples at the 
following four time points around the second daily dose of study drug: 15 minutes pre-dose, 


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and 15 minutes, 1 hour and 2.5 hours post-dose; ± 5 minutes) (Section 4.1.2). Subjects should 
be contacted one week (7 days) prior to the visit and reminded to record the timing of study 
drug and Tyvaso® dosing for the week leading up to the study visit.
8.6
Quarterly Visit Procedures
Subjects will return to the study site for Quarterly Visits (± 10 days) for the following 
procedures:
•
Perform a physical examination 
•
Record WHO Functional Class 
•
Record a 12-Lead ECG following a 5-minute rest in a semi-recumbent position (conduct 
ECG within 1-2 hours, ± 15 minutes, following the second or third daily dose of study drug
and inhaled treprostinil)
•
Record vital signs after five minutes of seated rest 
•
Conduct an unencouraged 6MWT (1-2 hours, ± 15 minutes, after the second or third daily 
dose of study drug and inhaled treprostinil)
•
Record Borg Dyspnea Score 
•
Assess clinical worsening 
•
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 3 month supply of study drug. Remind subject of importance of 
taking study drug and inhaled treprostinil together, review study drug dosing, packaging, 
storage, etc.
•
Record study drug accountability 
•
Record study drug and inhaled treprostinil administration and/or 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 
•
Optional RHC assessment: For subjects who consent to participate in the RHC assessment, 
perform RHC at the Month 6 Quarterly Visit (± 7 days), approximately 1-2 hours after 
dosing of study drug.
8.7
End of Study (or Early Termination) Procedures
All subjects should receive an End of Study Visit, if possible. Prior to this Visit, subjects will be 
contacted to determine whether they will enroll in the Open Label Extension Study. Subjects 
who elect to enroll in the extension study will be transitioned in a blinded fashion. 


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Subjects who do not elect to enroll in the open-label extension or who do not complete the 
current study will be weaned off of study drug at a maximum decrement of one tablet QID and a 
minimum decrement of one tablet QID per week. Following down-titration and discontinuation 
of study drug, the subject should return for an End of Study Visit for the following procedures: 
•
Perform a physical examination
•
Record WHO Functional Class for PAH
•
Record a 12-Lead ECG following a 5-minute rest in a semi-recumbent position (conduct 
ECG within 1-2 hours, ± 15 minutes, following the second or third daily dose of inhaled 
treprostinil, or, if enrolling in the open label extension study, conduct after second or third 
dose of inhaled treprostinil and study drug)
•
Record vital signs after at least five minutes of seated rest 
•
Conduct an unencouraged 6MWT within1-2 hours, ± 15 minutes, after second or third daily 
dose of inhaled treprostinil, or, if enrolling in the open label extension study, conduct after 
second or third dose of inhaled treprostinil and study drug
•
Record Borg Dyspnea Score 
•
Assess clinical worsening 
•
Obtain blood and urine samples for clinical laboratory parameters (serum chemistry, 
hematology, coagulation, urinalysis and NT-pro-BNP) 
•
Perform a serum pregnancy test for women of child-bearing potential
•
Perform drug accountability (and collect remaining unused study drug and packaging for 
uses/partially used study drug)
•
Record AEs
•
Record concomitant medications
•
Complete Study Termination CRF
8.8
Unscheduled Visit(s)
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 WHO Functional Class 
•
Record a 12-Lead ECG following a 5-minute rest in a semi-recumbent position. 
•
Record vital signs after five minutes of seated rest 
•
Conduct an unencouraged 6MWT 
•
Record Borg Dyspnea Score 
•
Assess clinical worsening 
•
Obtain blood and urine samples for clinical laboratory parameters (serum chemistry, 
hematology, coagulation, urinalysis and NT-pro-BNP) 
•
Plasma concentration sample, if feasible, for drug related SAEs (obtain two 10 mL tubes)


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•
Obtain serum pregnancy test (for women of childbearing potential)
•
Record AEs 
•
Record concomitant medications 
•
Supply of study drug as applicable. Remind subject of importance of taking study drug and 
inhaled treprostinil together, review study drug dosing, packaging, storage, etc.
•
Record study drug accountability 
•
Record study drug and inhaled treprostinil administration and/or 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.
9
QUALITY CONTROL AND ASSURANCE
The Sponsor is responsible for ensuring that the trial 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.
10 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.
10.1
General Considerations
The primary efficacy endpoint is independently confirmed clinical worsening. The primary 
endpoint analysis will evaluate clinical worsening as the time from randomization to first clinical 
worsening event. The primary null hypothesis to be tested is that there are no differences in the 
hazard ratio for clinical worsening between BPS-314d-MR and placebo. The primary endpoint 
analysis will test the hypothesis of a reduction in clinical worsening with BPS-314d-MR, 
compared to placebo, as a time to event variable within a log-rank test. Randomized subjects for 
whom an independently confirmed clinical worsening event has not occurred during the study 


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will be censored. Sensitivity analyses to support the primary endpoint analysis will be conducted 
to examine outcomes under more restrictive criteria (e.g., loss to follow-up treated as an event).
Statistical analyses will be performed using two-sided tests.  The strata will be included in all 
statistical analyses as a controlled variable. A 0.05 significance level will be used in all tests of 
treatment differences.  In addition, for labeling purposes only, the experiment-wise Type I error 
will be controlled to a maximum of 5%.  A gatekeeper strategy may be employed such that any 
secondary endpoints or subset analyses will be considered for statistical significance only if the 
primary endpoint is statistically significant. The type I family-wise error rate will be controlled at 
the 0.05 level of significance.
Data will be summarized by treatment group (and by visit when applicable). For parameters 
measured at baseline, the outcome variables of interest are the changes from baseline.
Summary statistics will include the mean, N, standard deviation, median, minimum, maximum, 
and the 25th and 75th percentile values for continuous variables, and frequencies and percentages 
for categorical variables.
The SAP will specify the details of the models to be used for the efficacy, safety and exploratory
analyses.  All statistical analyses will be performed by the Sponsor’s biostatistics department 
personnel (or appropriate designees) using SAS®, Version 9.1 or higher or other validated 
software.
10.2
Determination of Sample Size
The primary efficacy endpoint is clinical worsening confirmed by an independent EAC. The 
primary efficacy endpoint analysis will evaluate clinical worsening as the time to first clinical 
worsening event. 
A review of the literature show that few articles have been published which discuss the observed 
rates of clinical worsening with patients treated with inhaled treprostinil. Benza et al (2011)
reported that, in an open-label extension study of 206 PAH patients involved in inhaled 
treprostinil registration trial, 12-, 18- and 24-month clinical worsening rates were 18%, 26% and 
31%, respectively. Voswinckel et al (2009) investigated the long-term safety and efficacy of 
inhaled treprostinil in 24 PAH patients over approximately 3 years of follow-up in a small, 
open-label study. Reported were 12-, 24- and 36-month clinical worsening rates of 15%, 30% 
and 50%, respectively.
Based the aforementioned published literature, the anticipated one-year rate of clinical worsening 
is approximately 15% for the population treated with inhaled treprostinil. As such, the large 
sample size necessary to show a clinically meaningful difference between the BPS-314d-MR and 
the placebo groups treated with inhaled treprostinil would be prohibitive to the Sponsor to 
conduct this study. The Sponsor intends to restrict subject recruitment to inhaled treprostinil 
subjects where a BPS-314d-MR treatment effect will be more readily discerned. Following 
guidance from the FDA (2012) on clinical study enrichment strategies, the current study specifies in 
the inclusion criteria that the only patients who are showing signs of deterioration after initial 
improvement on inhaled treprostinil treatment or have had a clinically sub-optimal response to 
inhaled treprostinil treatment will be randomized into the trial. The specific exclusion of subjects 


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who are likely at a lower risk of clinical worsening will reduce the proportion of subjects 
available for recruitment but will expectedly increase the event rate among the complement 
sub-population targeted for recruitment and will allow fewer subjects needed to test the 
hypothesized absolute effect size. Thus, in restricting the population of this study to the 
sub-population most likely to benefit with an add-on therapy, it is expected that the observed 
one-year rate of clinical worsening will be approximately 45% for the subset of subjects targeted 
for this study.
Initial start-up activities and recruitment of subjects will be restricted to ensure subject safety. As 
such, the sample size determination calculations will not include the initial 6 months of the study 
to make certain of adequate powering for this study. The accrual period and follow-up period 
used will be 1.5 and 2.5 years, respectively. Thus, assuming a one-year rate of clinical worsening 
of 45% in the placebo (inhaled treprostinil alone) group, 25% in the BPS-314d-MR group 
(a 20% reduction from inhaled treprostinil therapy alone), proportional hazards over time, an 
accrual period of 1.5 years, a 0.01 two-sided significance level, and a total follow-up time of 
2.5 years, an exponential maximum likelihood test of equality of survival curves would require 
113 events and 116 subjects per treatment group to detect treatment difference at a power of 90% 
at a 0.01 two-sided significance level (or 97% power at a 0.05 two-sided significance level or 
approximately 90% power at a 0.05 two-sided significance level to detect a 13% reduction from 
an inhaled treprostinil rate as low as 30%). Therefore, this study will randomize approximately 
240 subjects. Sample size calculations were performed using nQuery Advisor 7.0 using sample
size methods for the log-rank statistic based on Lakatos & Lan (1992). Subjects who discontinue 
from the trial will not be replaced.
The Sponsor will continuously monitor the overall (pooled) event and drop-out rates during the 
course of the study. Sample size may be increased during the trial to maintain the planned power 
at between 80% and 90% and the intended trial duration. Only pooled blinded data will be used 
to increase sample size.
10.3
Analysis Populations 
With the exception of the assessment of vital status until the formal close of the study, the 
statistical analyses or summaries for efficacy and safety parameters will include evaluations 
performed from randomization up to the date of the subject’s last study visit or 30 days after the 
permanent discontinuation of study drug. Any additional evaluations will be included in the data 
listings only.
10.3.1
Intent to Treat Population
The intent to treat (ITT) population will contain all subjects randomized into the study. The 
analyses for the primary, secondary and exploratory efficacy endpoints will be made on the ITT 
population.
10.3.2
Per Protocol Population
The per protocol (PP) population will contain all subjects randomized into the study who are 
compliant with study drug until they either experience an EAC adjudicated event or the study is 
terminated. The specific definition of the PP population will be noted in the SAP. Analyses to 


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support the primary analysis of the primary, secondary and exploratory efficacy endpoints will 
be made on the PP population.
10.3.3
Safety Population
The safety population will contain any subject randomized into the study who receives any 
amount of study drug.  Safety analyses or summaries will include all available data, as 
appropriate.
10.4
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group for all 
randomized subjects. Baseline efficacy assessments will be included in these summaries for 
distance walked on a 6MWT, Borg Dyspnea Score, the WHO functional class and NT-pro-BNP 
levels. Additionally, non-randomized (“screening failures”) may be summarized, as appropriate.
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 each treatment group.  For categorical variables (e.g., race, gender), the counts and 
proportions of each value will be tabulated.
10.5
Study Drug
The duration of exposure to study drug will be summarized for all randomized subjects. 
Compliance with the dosing regimen, based on supplied and returned tablet count information, 
will also be summarized.
10.6
Concomitant Therapy
Concomitant medications (medications present while on study drug) will be recorded throughout 
the study. These medications will be coded using the WHO drug dictionary. The number of 
randomized subjects using prior or concomitant medications will be categorized by the WHO 
drug category and preferred term, and presented for each treatment group. In any given category 
[e.g., drug category] a subject will be counted only once.
10.7
Study Disposition
Subject disposition will be tabulated for all randomized subjects.
10.8
Primary Efficacy Endpoint
The primary objective of the study is to compare the effects of BPS-314d-MR added to inhaled 
treprostinil to placebo on TtCW defined as the time from randomization to the first of any of the 
clinical worsening events as specified in Section 2.1. The occurrence of clinical worsening will 
be independently adjudicated by an EAC. 


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10.9
Secondary Efficacy Endpoints
Secondary efficacy endpoints will include and are defined as:
1. The composite endpoint of time-to-clinical-failure (TtCF), defined as the time from 
randomization to the first of any of the following events:
-
Meets primary endpoint definition of clinical worsening, as confirmed by EAC, or
-
Received randomized treatment for at least 24 weeks and has:
◦
Lack of sustained improvement from Baseline WHO Functional Class: defined by 
two consecutive visits of no sustained improvement from Baseline WHO FC, visits 
may be scheduled or unscheduled; and
◦
Lack of sustained improvement from Baseline 6MWD (average at Baseline): defined 
by two consecutive visits of no sustained improvement from Baseline 6MWD 
(≤0 meters or too ill to walk, directly related to PAH), visits may be scheduled or 
unscheduled.
2. Exercise capacity at each study visit as measured by the change from baseline in distance 
walked on a 6MWT
3. Dyspnea associated with each 6MWT at each study visit, as defined as the change from 
baseline in the Borg Dyspnea Score
4. PAH functional class at each study visit as defined as the change from baseline in the WHO 
functional class
5. Congestive heart failure at each study visit, as defined as the change from baseline in 
NT-pro-BNP levels
The secondary objectives of the study are to compare the effects of BPS-314d-MR to placebo on 
all secondary endpoints. The Sponsor will derive the composite measures of clinical failure and 
TtCF from the data collected per the protocol. Unlike clinical worsening, neither a specific 
Investigator’s assessment for clinical failure nor an EAC confirmation of suspected events will 
occur. The analysis strategy of TtCF will be similar to the analysis strategy used for TtCW. 
Continuous secondary efficacy variables, defined above as the change from baseline at each 
study visit, will be summarized and compared between treatment groups using the Wilcoxon 
rank-sum test, separately for each study visit. The SAP will specify the analysis strategy for all 
secondary efficacy endpoints.
Hypothesis testing of secondary efficacy endpoints may be conducted using a gatekeeper 
strategy such that any secondary endpoints will be considered for statistical significance only if 
the primary endpoint is statistically significant. Under closed testing procedures, the type I 
family-wise error rate will be controlled at the 0.05 level of significance. The SAP will detail the 
order of testing for secondary efficacy endpoints.  
10.10 Exploratory Efficacy Endpoints
 
 
 
 


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Sponsor until the data are formally locked and study is unblinded. The pharmacokinetic data may 
 
 
 
 
10.11 Safety Endpoints
10.11.1
Adverse Events
Adverse events will be recorded throughout the study and at early termination. Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Treatment-emergent adverse events will be defined as those 
events, which are newly occurring or worsening from baseline. In all cases only treatment 
emergent adverse events will be summarized. 
Treatment-emergent adverse events will be summarized by treatment group as the number and 
percentage of subjects having any treatment-emergent AE, having an AE in each body system, 
and having each individual AE. (Note: In any given category [e.g., body system] a subject will 
only be counted once.) Adverse events will further be categorized by severity, relationship to 
study drug, and action taken. Other information collected will be listed, as appropriate. 
Any event starting more than 5 days after the final dose of study drug will be excluded from the 
above described tables and only listed, unless the event caused discontinuation from the study
10.11.2
Vital Signs
Vital sign data will be listed for each subject. Clinically significant values will be flagged. Data 
will be summarized by treatment group using mean change from baseline and proportions of 
subjects with clinically significant values. 
10.11.3
Laboratory Data
Laboratory data will be listed for each subject. Laboratory data will be summarized for each 
treatment group by presenting the proportions of subjects with clinically significant 
abnormalities; shift tables, baseline to most extreme post-baseline value, using normal ranges; 
summary statistics of raw data and change from baseline values (means, medians, standard 
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10.11.4
Electrocardiogram
Results from the electrocardiogram (ECG) will be listed for each subject. These data will also be 
summarized for each treatment group by presenting subjects with newly occurring or worsening 
ECG abnormalities from baseline; shift tables, baseline to most extreme post-baseline value; 
summary statistics of raw data and change from baseline values (means, medians, standard 
deviations, ranges). Whenever multiple ECG readings are done on the same day, the average of 
these readings will be taken for the data summaries.
10.11.5
Physical Examination
Any clinically significant abnormality prior to randomization is to be recorded as medical history 
and tabulation of those events will occur within medical history summaries. Any clinically 
significant abnormal change from baseline post-randomization is to be recorded as an AE and 
tabulation of those events will occur within AE summaries. 
10.12 Pooling of Clinical Sites
Study sizes within the clinical site are expected to be too small to allow stratification by clinical 
site in efficacy analyses. Any change to this approach will be specified in the SAP prior to 
database lock.  
10.13 Interim Analysis
An interim efficacy analysis will be considered. The Sponsor will fully specify any interim 
efficacy analysis plan in the statistical analysis plan, including the personnel involved, the 
stopping rules, an alpha spending strategy, etc. if such an analysis is to be conducted. Interim
safety analyses will be performed by an independent external statistician and reviewed only by 
an independent data safety monitoring committee. Lung Biotechnology Inc. will remain blinded 
throughout the conduct of this study. 
11 ADMINISTRATIVE CONSIDERATIONS
11.1
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 


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Clinical Practice (ICH/GCP), and Code of Federal Regulations (CFR).  Additional requirements 
must be met by the Investigator and institution, as described below. 
11.2
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 Institutional Review Board (IRB), Independent Ethic Committee (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 Informed Consent Form (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.   
11.3
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.
11.4
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 BPS-314d-MR, 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 lab 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 BPS-314d-MR.
11.5
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 


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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. 
11.6
Study Monitoring
In accordance with U.S. 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.  
The first monitoring visit will occur within the first few weeks after the first subject’s Screening 
Visit. 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.
11.7
Case Report Forms and Study Records
The study case report form (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 CRF by appropriate site staff. Data recorded in the CRF should be consistent with 
source documents.  
11.8
Oversight Committees
11.8.1
Data Safety Monitoring Board
A Data Safety Monitoring Board (DSMB), independent of the Sponsor, will be established for 
the study. Operating under a formal charter, the DSMB will be comprised of three members: two 
physicians knowledgeable in the treatment of PAH and one statistician. Throughout the course of 
the study the DSMB will meet regularly to monitor the safety of the subjects in the study.  
11.8.2
Endpoint Adjudication Committee
The study will have an Endpoint Adjudication Committee (EAC) composed of PAH physicians 
not otherwise involved in the conduct of the study. The EAC will operate under a formal charter. 
Throughout the course of the study the EAC will review clinical worsening events (the primary 
study endpoint). The EAC may meet with frequency based on the rate of enrollment and the rate 
of occurrence of clinical worsening events.
11.9
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. 


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11.10 Data Generation and Analysis
All data are submitted into a quality assured database from the site and will be reviewed by the 
Sponsor.  Data clarifications will be generated and the database will be edited as appropriate.  
The database will 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. 
11.11 Retention of Data
In accordance with U.S. federal and other national regulations, ICH, and GCP guidelines, the 
Investigator must retain study records for at least 2 years 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.
11.12 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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16. Demolis, J. L., Robert, A., Mouren, M., Funck-Brentano, C., & Jaillon, P. (1993). 
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Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension. 
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Appendix 1
Schedule of Events
STUDY 
PROCEDURES
Study Visit Week
Screening9
Baseline
Day 1
(3-120
days)
Baseline
Day 2
Phone 
calls
Week 4
(± 3
days)
Week 8
(± 4 
days)
Week 12
First Quarterly 
Visit
(± 10 days)
Quarterly 
Visits
(± 10 days)
End of Study 
or Early 
Termination 
Visit10
Unscheduled 
Visit(s)11
Clinic Site Visit
X
X
X
X
X
X
X
X
X
Phone Calls1
X
Informed Consent
X
I/E Criteria2
X
X
Demographics
X
PAH History
X
Medical History3
X
X
Physical Examination
X
X
X
X
X
X
X
X
Vital Signs (height at 
Screening only)
X
X
X
X
X
X
X
X
Clinical Worsening 
Assessment
X
X
X
X
X
X
X
6-Minute Walk Test
X
X4
X4
X
X
X
X
X
X
Borg Dyspnea Scale
X
X
X
X
X
X
X
X
X
WHO Functional Class
X
X
X
X
X
X
X
X
Laboratory Parameters
X
X
X
X
X
X
X
X
OPTIONAL: Plasma 
Concentration5
X
X
X
OPTIONAL: RHC6
X
X
Pregnancy Test7
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
Optional
X
X
X
X
X
Randomization
X
Study drug & Tyvaso 
Administration 
instructions & record8
X
Tyvaso 
only
X
Tyvaso 
only
X
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
AE Assessment
X
X
X
X
X
X
X
X
X
X
Conmed Assessment
X
X
X
X
X
X
X
X
X
X
1
Phone calls: Between the Baseline Visit and the Week 12 (first Quarterly Visit) subjects should be contacted weekly (except for weeks with study visits), then monthly between 
Quarterly Visits through the end of study participation.
2
Inclusion/Exclusion criteria to be collected at the Screening Visit and updated at the Baseline Visit as needed (Sections 5.2 and 5.3).


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3
Medical history to include relevant and significant past or present illness or surgeries.
4
6MWTs at Baseline (Day 1 and Day 2) should be conducted post-randomization and prior to dosing study drug. 6MWTs at scheduled visits after Baseline should be performed 
between 1-2 hours, ± 15 minutes, after the second or third dose of inhaled treprostinil. During the run-in period, subjects should be guided through proper up-titration, 
monitored for appropriate dosing and offered additional training by phone or in-person as needed.
5
Optional Plasma Concentration Assessment: For the Week 4 Visit collect two 10mL trough (15 minutes pre-dose, ± 5 minutes) samples; for Week 12 (first Quarterly Visit)
collect two 10mL samples around the second daily dosing of study drug: 15 minutes pre-dose, and 15 minutes, 1 hour and 2.5 hours post-dose (± 5 minutes); subjects
participating in the plasma concentration assessment should be contacted one week (7 days) prior to Week 4 and Week 12 (first Quarterly Visit) as a reminder to record their 
Tyvaso and study drug dosing times during the week leading up to the visit. 
6
Optional RHC assessment procedures may be conducted up to 21 days prior to the Baseline Visit and at the Month 6 Quarterly Visit (± 7 days). Baseline RHC should be 
performed prior to study drug dosing. The Month 6 RHC should be performed between 1-2 hours, ± 15 minutes, after the second or third dose of study drug and inhaled 
treprostinil.
7
Pregnancy testing for females of childbearing potential. Urine test at Baseline Visit and serum test at all other clinic visits.
8
All doses of study drug and inhaled treprostinil administered at the study site and all dose changes should be recorded in subject dose administration log.
9
Subjects who consent to the study but are not currently taking inhaled treprostinil and who otherwise meet study eligibility criteria will enter a run-in period on inhaled 
treprostinil to achieve 90 days of experience, with 30 or more days at a stable dose, to ensure drug tolerability before being randomized. Subjects who consent to the study and 
are currently taking inhaled treprostinil at the Screening Visit should be randomized into the study as soon as eligibility criteria have been met. See Appendix 2.
10 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 End of Study Visit and the Study Termination CRF will be completed.
11 An Unscheduled Visit may occur at any time and involve any of the procedures listed as deemed appropriate by the Investigator.


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Appendix 2
Schematic of Study Entry Based on Tyvaso Use
Eligibility for the study is available to PAH patients regardless of their current Tyvaso use status. 
1. Tyvaso Naïve or Inactive patients who meet candidacy criteria for the study protocol will be 
initiated on Tyvaso during the screening period, commencing with training and followed by a 
run-in period. Following completion of the 90 day run-in period, if eligibility is confirmed 
then patients will be randomized into the study. 
2. Patients who are Active Tyvaso Users at the initiation of screening will continue with their 
current therapy. It is anticipated that patients will be promptly enrolled in the study as soon 
as eligibility is confirmed. 
Following randomization, study subjects will receive Tyvaso and study drug for the duration of 
the study with clinical assessments (red diamonds) as identified in the study protocol.


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Appendix 3
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 then all future 6MWTs should be conducted in the same way 
with the same oxygen flow.
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 4
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 5
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 6
Plasma Concentration Samples:  Handling and Shipping
BPS-314d-MR and Tyvaso® (Treprostinil, inhaled)
Blood Sample Collection and Processing 
Detailed instructions for collection and processing will be specified in the Study Reference 
Manual. General instructions are as follows: 
Sample Collection and Processing Instructions
For the Week 4 blood collection time point, collect 2 (two) 10mL blood samples at study drug 
trough(15 minutes pre-dose, ± 5 minutes) in a chilled, lavender-topped evacuated tube containing 
K2EDTA as an anticoagulant and immediately place the sample on ice. 
For Week 12 (first Quarterly Visit), collect 2 (two) 10mL blood samples in chilled, lavender-
topped evacuated tubes containing K2EDTA as an anticoagulant and immediately place the 
sample on ice. Samples should be collected around the second daily dosing of study drug: 
15 minutes pre-dose, and 15 minutes, 1 hour and 2.5 hours post-dose.
The samples should be kept cold throughout all handling procedures. 1 (one) tube is collected for 
BPS-314d-MR analysis and another one for treprostinil analysis.
Within 15min after drawing the blood, centrifuge the sample at 4 °C for 15 minutes at 3000x g. 
There should be approximately 6mL of plasma per each full 10mL blood draw.
Pipette four (4) EQUAL aliquots of plasma into four (4) cryotubes of an appropriate size and 
labeled as A, B, C, D. Keep all cryotubes on ice until frozen. Once frozen place into freezer: 
either -20°C or -70°C.  Samples A and B will be labeled as BPS samples. Samples C and D will 
be labeled as treprostinil samples.
Plasma Sample Shipment 
Plasma samples from each cohort will be sent as two batches on separate days to Intertek 
Pharmaceutical Services. Samples A and C tubes will be packed in dry ice and shipped on a 
Monday; samples B and D tubes will be packed in dry ice and shipped on a Tuesday to Intertek 
for laboratory analysis. Shipping tubes should be individually packaged to prevent breaking and 
contamination of other samples.  Plasma samples will be packed in Styrofoam boxes containing 
a generous supply of dry ice for 2-3 days in-transit.
All shipments must be accompanied by a packing list.
Prior to shipment of samples, the site will contact the sponsor-designated laboratory by fax or 
email.  An advance electronic copy of the packing list will be provided to 


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The shipping address and contact information for 


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Appendix 7
Adverse Events 
The Investigator or designee will probe each subject for any adverse events which 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
-
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. 


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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 from baseline 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 an 
abnormal change from baseline for that subject, this is considered an AE.
INTENSITY 
AEs will be graded on a 3-point scale and reported as indicated on the Case Report Forms. 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: 
•
Certain: The AE is clearly related to the investigational agent(s). 
•
Probably Related: The AE is likely related to the investigational agent(s).
•
Possibly Related: The AE may be related to the investigational agent(s). 
•
Unlikely to be Related: The AE is doubtfully related to the investigational agent(s). 
•
Unrelated: The AE is clearly NOT related to the investigational agent(s). 
•
Unassessable/unclassifiable: The AE is cannot be judged because information is insufficient 
or contradictory. 
BACKGROUND PAH DRUG CAUSALITY 
Relationship of an AE to treatment will be assessed as follows: 
•
Certain: The AE is clearly related to the background PAH agent(s). 
•
Probably Related: The AE is likely related to the background PAH agent(s).
•
Possibly Related: The AE may be related to the background PAH agent(s). 
•
Unlikely to be Related: The AE is doubtfully related to the background PAH agent(s). 
•
Unrelated: The AE is clearly NOT related to the background PAH agent(s). 
•
Unassessable/unclassifiable: The AE is cannot be judged because information is insufficient 
or contradictory. 


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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: Not applicable. 
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 sequalae, 
recovering/resolving or unknown. If an AE is ongoing, the AE should be followed until 
resolution.


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Appendix 8
Optional Hemodynamic Assessment
Hemodynamic measurements, such as mean pulmonary arterial pressure, cardiac index, and 
calculation of pulmonary vascular resistance, will be assessed by right heart cardiac 
catheterization as an optional sub- study for sites and subjects who agree. Measurements will 
include heart rate, pulmonary arterial pressure (systolic, diastolic and mean), systemic arterial 
pressure (systolic, diastolic and mean), right atrial pressure, pulmonary capillary wedge pressure, 
mixed venous oxygen saturation, systemic arterial oxygen saturation, cardiac output via the Fick 
or thermodilution methods. 
Right heart catheterization should be performed under fluoroscopic guidance with a flow-
directed catheter (Swan-Ganz). All procedures will be performed under local anesthesia with 
conscious sedation if clinically indicated. All hemodynamic determinations must be made after 
determining the zero reference level at the midaxillary line with the subject supine. To ensure 
reproducibility of this reference level for subsequent measurements and to avoid zero level drift, 
the transducer must be anchored at the midaxillary line, and before each measurement, this 
juxtaposition should be confirmed. 
The subject may sit up prior to or after hemodynamic assessments, as permitted by the medical 
professional, but must be lying flat for at least 10 minutes prior to and during each hemodynamic 
assessment; hemodynamics must be stable during this time.
Hemodynamic values will be determined by serial measurements of hemodynamic parameters 
(specifically CO and PAPm) to demonstrate stability. Stable hemodynamics are defined by 
changes in CO and PAPm of less than or equal to 20% between two consecutive serial 
measurements. After hemodynamic stability is demonstrated, the hemodynamic and oxygen 
saturation variables from the last assessment used to demonstrate stability will be recorded in the 
CRF.
Systemic blood pressures may be obtained by cuff, and systemic arterial oxygen saturation may 
be obtained by pulse oximetry.


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Appendix 9
Sponsor Guidance for Comorbid Conditions
The Sponsor recognizes that the pulmonary hypertension population is complex and diverse. In 
order to facilitate enrollment of appropriate subjects to this pivotal trial, Investigators are 
strongly encouraged to contact the medical director or study team when at least 2 of the 
following characteristics are present in a potential study subject:
•
Age> 65
•
Hypertension 
•
Diabetes mellitus
•
Coronary artery disease, coronary revascularization, previous myocardial infarction or acute 
coronary syndrome
•
Moderate or severe valvular heart disease
•
Interstitial lung disease with FVC or TLC <70% predicted or HRCT showing moderate, 
diffuse interstitial disease
•
Prior history of deep venous thrombosis or pulmonary embolus
•
Chronic continuous oxygen use (>18 hrs./day)
•
PCWP between 12-15mmHg or PVR < 4 woods units
NB: While most of these do not, by themselves, exclude the subject from enrollment, they may 
indicate a subject whose medical condition is atypical for PAH and further clarification is needed 
prior to a decision of enrollment is made.




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Appendix 11
Investigator’s Signature
Study Title:
A multicenter, double-blind, randomized, placebo-controlled, Phase 3 
study to assess the efficacy and safety of oral BPS-314d-MR added-
on to treprostinil, inhaled (Tyvaso®) in subjects with pulmonary 
arterial hypertension
Study Number:
BPS-314d-MR-PAH-302
Original Protocol Date:
Amendment 1:
Amendment 2:
16 April 2013
17 December 2013
15 October 2014
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 Inc.
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:
Printed:

SAP_001.pdf: 
Statistical Analysis Plan: BPS-314d-MR-PAH-302
Study Title: 
A multicenter, double-blind, randomized, placebo-controlled, Phase 3 
study to assess the efficacy and safety of oral BPS-314d-MR added-on 
to treprostinil, inhalation solution (Tyvaso®) in subjects with 
pulmonary arterial hypertension 
Study Number: 
BPS-314d-MR-PAH-302 
Study Phase: 
3 
Product Name: 
Esuberaprost (Beraprost Sodium 314d Modified Release) 
Indication: 
Treatment of Pulmonary Arterial Hypertension 
IND Number: 
111,729 
Sponsor: 
Lung Biotechnology  
1040 Spring Street 
Silver Spring, MD 20910 
United States 
Author: 
Final Date: 
13 September 2018 
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. 
© 2018 Lung Biotechnology PBC 




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Statistical Analysis Plan: BPS-314d-MR-PAH-302 
 
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TABLE OF CONTENTS 
Signature Page ................................................................................................................................2 
Modification History ......................................................................................................................6 
List of Abbreviations and Definition of Terms ...........................................................................7 
1 
Introduction ............................................................................................................................8 
2 
Study Objectives .....................................................................................................................9 
2.1 
Primary Objective ..........................................................................................................9 
2.2 
Secondary Objectives...................................................................................................10 
2.3 
Exploratory Objectives ................................................................................................10 
3 
Study Design .........................................................................................................................11 
3.1 
General Description .....................................................................................................11 
3.2 
Treatments....................................................................................................................12 
3.2.1 Treatments Administered .................................................................................13 
3.2.1.1 Esuberaprost (Active IMP) ...............................................................13 
3.2.1.2 Placebo (Non-active IMP) ................................................................13 
3.2.2 Treatment Groups ............................................................................................13 
3.2.3 Patient Identification ........................................................................................13 
3.2.4 Method of Assigning Subjects to Treatment Groups .......................................14 
3.2.5 Blinding............................................................................................................14 
4 
Sample Size and Statistical Power ......................................................................................15 
4.1 
Design ..........................................................................................................................15 
4.2 
Study Design Review ...................................................................................................16 
5 
Efficacy and Safety Endpoints ............................................................................................17 
5.1 
Efficacy Endpoints .......................................................................................................17 
5.1.1 Primary Efficacy Endpoint (Stage 1) ...............................................................17 
5.1.2 Key Secondary Endpoints (Stage 2) ................................................................17 
5.1.3 Other Secondary Endpoints (Stage 3) ..............................................................17 
5.1.4 Exploratory Endpoints .....................................................................................18 
5.2 
Safety Variables ...........................................................................................................18 
5.3 
Exploratory Endpoints .................................................................................................18 
6 
Statistical Methods ...............................................................................................................19 
6.1 
Datasets for Analyses ...................................................................................................19 
6.2 
General Methodology ..................................................................................................19 
6.3 
Definition of Analysis Time Points .............................................................................20 
6.3.1 Baseline ............................................................................................................20 
6.3.2 Change from Baseline ......................................................................................20 
6.3.3 Study Day.........................................................................................................20 
6.3.4 Visit Windows .................................................................................................20 
6.4 
Data Handling ..............................................................................................................21 
6.4.1 Stratification Variable ......................................................................................21 
6.4.2 Handling of Missing Data ................................................................................22 
6.5 
Disposition of Subjects ................................................................................................23 
6.6 
Protocol Deviations ......................................................................................................23 
6.7 
Demographic and Other Baseline Characteristics .......................................................23 


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6.7.1 Demographic and Baseline Characteristics .....................................................23 
6.7.2 PAH Disease Characteristics ...........................................................................23 
6.7.3 Medical History ...............................................................................................24 
6.7.4 Medications ......................................................................................................24 
6.7.4.1 Prior Medications ..............................................................................25 
6.7.4.2 Concomitant Medications .................................................................25 
6.8 
Treatment Compliance .................................................................................................25 
6.8.1 Analysis of Pill Count Data .............................................................................25 
6.8.2 IMP Dosing ......................................................................................................26 
6.9 
Analysis of Efficacy .....................................................................................................27 
6.10 Hypothesis Testing.......................................................................................................27 
6.10.1 Stage 1: Testing for Primary Endpoint ............................................................27 
6.10.2 Stage 2: Testing the Key Secondary Endpoints ...............................................27 
6.10.3 Stage 3: Testing for Other Secondary Endpoints .............................................27 
6.11 Blinded Data Review ...................................................................................................28 
6.12 Primary Efficacy Analysis ...........................................................................................28 
6.12.1 Death (All Cause) ............................................................................................29 
6.12.2 Hospitalization due to worsening PAH ............................................................29 
6.12.3 Initiation of a Parenteral (infusion or sub-cutaneous) Prostacyclin .................29 
6.12.4 Disease Progression .........................................................................................30 
6.12.5 Unsatisfactory long-term clinical response ......................................................30 
6.12.6 First Occurrence Derivation and Analysis .......................................................30 
6.12.7 Supportive Analyses for Primary Analyses .....................................................31 
6.12.8 Sensitivity Analyses for the Primary Outcome ................................................31 
6.13 Key Secondary Analyses .............................................................................................32 
6.13.1 Change from Baseline Six Minute Walk Test at Week 24 ..............................32 
6.13.2 Time to Clinical Failure ...................................................................................33 
6.13.3 Worsening from Baseline of WHO Functional Class at Week 24...................33 
6.14 Other Secondary Analyses ...........................................................................................33 
6.14.1 Change from Baseline in 6MWT at Week 12 ..................................................34 
6.14.2 Worsening from Baseline in WHO Functional Class at Week 12 ...................34 
6.14.3 Change in Borg Dyspnea Score at Weeks 12 and 24 .......................................34 
6.14.4 NT-pro-BNP at Weeks 12 and 24 ....................................................................35 
6.14.5 Total Mortality .................................................................................................35 
6.15 Subgroup Analysis .......................................................................................................36 
7 
Analysis of Safety .................................................................................................................36 
7.1 
Extent of Exposure .......................................................................................................36 
7.2 
Adverse Events ............................................................................................................37 
7.2.1 Treatment-Emergent Adverse Events ..............................................................37 
7.2.2 Date of Onset of Adverse Event ......................................................................37 
7.2.3 Intensity Rating ................................................................................................38 
7.2.4 Relationship to Study Drug ..............................................................................38 
7.2.5 Relationship to Background Therapy ..............................................................38 
7.2.6 Action Taken with Study Drug ........................................................................38 
7.2.7 Summary of Treatment-Emergent Adverse Events .........................................38 
7.2.8 Subjects with a TEAE leading to dose modifications of IMP Summaries of 
Adverse Events ................................................................................................39 


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7.2.9 Subgroup Analysis ...........................................................................................40 
7.2.10 Clinical Laboratory Evaluations ......................................................................40 
7.2.11 Vital Signs ........................................................................................................41 
7.2.12 ECG Evaluations ..............................................................................................41 
7.3 
Physical Examinations .................................................................................................41 
7.4 
Interim Analyses and Data Monitoring........................................................................41 
8 
References .............................................................................................................................42 
Event Adjudication ................................................................................................................44 
Event Dossier Checklist .........................................................................................................45 
 
 


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MODIFICATION HISTORY 
Unique Identifier 
for this Version 
Date of the 
Document Version 
Author(s) 
Significant Changes from 
Previous Authorized Version 
1.0 
13 September 2018 
 
 
Initial Version 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
6MWT 
6-Minute Walk Test 
AE 
Adverse Event 
BMI 
Body Mass Index 
BPS 
Beraprost sodium 
BPS-MR 
Beraprost sodium-modified release 
BPS-314d 
Beraprost sodium 314d (esuberaprost) 
BPS-314d-MR 
Beraprost sodium 314d-modified release (esuberaprost tablet) 
CI 
Confidence interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
DSMB 
Data Safety Monitoring Board 
eCRF 
electronic Case Report Form 
EAC 
Endpoint Adjudication Committee 
ECG 
Electrocardiogram 
EoS 
End-of-study 
ERA 
Endothelin receptor antagonist 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug  
IRT 
Interactive Randomization Technology 
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-pro-BNP 
N-terminal pro-brain natriuretic peptide  
PAH 
Pulmonary arterial hypertension 
PDE-5 
Phosphodiesterase Type 5  
QID 
Four times daily 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TFs 
Tables and Figures 
TtCF 
Time to Clinical Failure 
TtCW 
Time to Clinical Worsening 
UPI 
Unique Patient Identification 
US 
United States 
WHO 
World Health Organization  
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes in detail the statistical methodology, as well as the 
rules and conventions, to be employed in the presentation and analyses of efficacy and safety 
data from Study BPS-314d-MR-PAH-302.  The methods described herein conform to the 
recommendations outlined in the International Conference on Harmonisation (ICH) E9 guideline 
entitled, “Guidance for Industry: Statistical Principles for Clinical Trials” (1998) and the ICH E3 
guideline entitled, “Guidance for Industry: Structure and Content of Clinical Study Reports” 
(1995).  
The various sections of this document describe the planned tabulated summaries, graphics and 
and other figures (termed Tables and Figures [TFs]) to be presented in the clinical study report 
(CSR).  A separate document will contain mock-ups of unique TFs. 
All subjects in Israel who consent to participate in BPS-314d-MR-PAH-302 are required to 
co-consent to the companion study, BPS-314d-MR-PAH-302c, in order to receive inhaled 
treprostinil. Although inhaled treprostinil has been registered as a treatment for PAH in Israel, it 
was not commercially available at the time this study was implemented there.  Therefore, Lung 
Biotechnology has implemented a companion study in order to provide initial and continued 
access of inhaled treprostinil to consenting subjects who are eligible to participate in the current 
study (BPS-314d-MR-PAH-302).  Subjects in Israel are required to remain in the companion 
study in order to receive study drug under BPS-314d-MR-PAH-302; however, regardless of 
whether the subjects are randomized in BPS-314d-MR-PAH-302, those who meet eligibility 
criteria are permitted to continue in the companion study and receive inhaled treprostinil. The 
BPS-314d-MR-PAH-302 and BPS-314d-MR-PAH-302c studies are separate trials with distinct 
data collection goals. Data collection for the BPS-314d-MR-PAH-302c study is minimal, 
focusing only on exposure and overall safety for treprostinil, an approved product. Data gathered 
in the BPS-314d-MR-PAH-302 are comprehensive; they include the data gathered in the 
BPS-314d-MR-PAH-302c study for treprostinil exposure in subjects enrolled in both studies. 
Evaluation of the BPS-314d-MR-PAH-302c study data is unnecessary to the goals of this 
analysis plan, thus the companion study and any analyses of it are outside the scope of this SAP. 
This SAP is based on study protocol, United States (US) Amendment 2 (dated 15 October 2014) 
and Israel Amendment 1 (dated 13 April 2015). It supersedes the statistical considerations 
identified in the study protocol. Any major deviations in this SAP from the statistical 
considerations of the protocol will be described and justified within the CSR.  Lung 
Biotechnology (the sponsor) will follow this SAP in analyzing the study data.  If during the 
course of the trial, the protocol or the set of Case Report Forms (CRFs) is modified in a way that 
affects the planned statistical analyses, a revised version of the SAP will be developed.  
Only minor changes in the analyses shall be applied following the final version of the SAP.  The 
CSR shall document minor changes.  
Separate SAPs will be written to address the exploratory objectives of the hemodynamic, the 
plasma concentrations, and the exposure-response analysis for safety and efficacy endpoints.  


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to compare the effect of esuberaprost (BPS-314d-MR) to 
placebo, each added to treprostinil, inhalation solution (Tyvaso®) on the composite endpoint of 
time-to-clinical-worsening (TtCW), defined as the time from randomization to the first of any of 
the following clinical worsening events: 
• Death (all causes) 
• Hospitalization due to worsening pulmonary arterial hypertension (PAH), defined as: 
- 
Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure and requiring intensification 
of treatment; or Lung or heart/lung transplantation; or Atrial septostomy 
• Initiation of a parenteral (infusion or sub-cutaneous) prostacyclin directly related to 
worsening PAH (transient use [≤ 7 days] for non-PAH related illness allowable)  
• Disease progression (all criteria below required):  
- 
A decrease in six minute walk distance (6MWD) of at least 15% from Baseline (defined 
as the average of the two 6MWTs performed on sequential days of the Baseline Visit), or 
being too ill to walk as a consequence of PAH progression, confirmed by six-minute 
walk tests (6MWT) performed at 2 consecutive visits,  
- 
Worsening of PAH symptoms, which must include either: 
◦ 
An increase in WHO Functional Class or 
◦ 
Worsening symptoms of right heart failure 
• Unsatisfactory long-term clinical response (all criteria below required):  
- 
Receiving randomized treatment for at least 24 weeks 
- 
A decrease of at least 15% from Baseline (defined as the average of the two Baseline 
Visit 6MWTs) in 6MWD, or too ill to walk, directly related to PAH progression, at Week 
24 and beyond; at 2 consecutive visits, and 
- 
Sustained WHO Functional Class III or IV symptoms for at least 24 weeks.  
 
The Investigator will use the above criteria to provide an initial judgment of whether a suspected 
clinical worsening event has occurred.  A blinded Event Adjudication Committee (EAC) will 
review all suspected clinical worsening events and make a final determination for each (see 
Appendix 1).  


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2.2 
Secondary Objectives 
The study protocol lists the following secondary objectives: 
• To compare the effect of esuberaprost (BPS-314d-MR) and placebo each added to inhaled 
treprostinil on the composite endpoint of time-to-clinical-failure (TtCF), defined as the time 
from randomization to the first of any of the following events: 
- 
Meets primary endpoint definition of clinical worsening, as confirmed by the EAC; or 
- 
Receiving randomized treatment for at least 24 weeks and has: 
◦ 
Lack of sustained improvement from Baseline WHO Functional Class, defined by 
two consecutive visits of no sustained improvement from Baseline WHO Functional 
Class where visits may be scheduled or unscheduled and 
◦ 
Lack of sustained improvement from the Baseline 6MWT (average at Baseline), 
defined by two consecutive visits of no sustained improvement from Baseline 6MWT 
(≤ 0 meters or too ill to walk, directly related to PAH); visits may be scheduled or 
unscheduled. 
• To compare the effects of BPS-314d-MR to placebo on changes from baseline to each 
scheduled study visit, as applicable, for the following measures: 
- 
6MWT 
- 
Borg Dyspnea Score 
- 
WHO Functional Class 
- 
N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels 
• To evaluate the safety of BPS-314d-MR based on adverse events (AEs), clinical laboratory 
parameters, electrocardiogram (ECG) findings, physical examination, and vital signs.  
 
The section for Efficacy and Safety Endpoints (Section 5) present explicitly-defined secondary 
endpoints (rather than general protocol-specified objectives).   
 
2.3 
Exploratory Objectives 
The study has the following exploratory objectives: 
• 
 
 
 
 
 
 
 
  
 


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3 
STUDY DESIGN 
3.1 
General Description 
This Phase 3, multicenter, double-blind, randomized, placebo-controlled study is designed to 
assess the efficacy and safety of oral esuberaprost in subjects with PAH who are also treated with 
treprostinil, inhalation solution (Tyvaso).  The study, which is initiated and sponsored by Lung 
Biotechnology PBC, formerly known as Lung LLC and Lung Biotechnology Inc. (sponsor), is 
being performed at study centers within the US and Israel. 
The subject population includes males and females 18 to 80 years, inclusive, with a diagnosis of 
PAH that is either idiopathic or familial, collagen vascular disease associated PAH, PAH 
associated with HIV infection, PAH induced by anorexigens/toxins, or PAH associated with 
repaired congenital systemic-to-pulmonary shunts (repaired ≥1 years). For randomization, 
subjects must be WHO Functional Class III or IV and have declining or unsatisfactory clinical 
response to inhaled treprostinil therapy.  The protocol defines unsatisfactory clinical response as 
having at least 90 days of uninterrupted inhaled treprostinil treatment, in which a stable dose of 
inhaled treprostinil has been received for at least 30 days prior to baseline/randomization, and 
still meeting the clinical criteria of a moderately-to severely-ill PAH patient, described in the 
protocol-defined inclusion/exclusion criteria.  Subjects are permitted to receive other approved 
PAH therapies of an optimal, stable dose regimen for at least 30 days prior to the Baseline Visit 
and maintained throughout the study. Patients must sign informed consent prior to participation 
in any study procedure.   
After the Screening Visit, subjects who consent to the study and are determined to be eligible but 
are not currently taking inhaled treprostinil will enter a run-in period on inhaled treprostinil to 
achieve 90 days of experience in order to ensure drug tolerability before being randomized.  
After having had 90 days of experience with inhaled treprostinil, a subject who continues to meet 
the eligibility criteria will be eligible to be randomized.  Subjects who consent to the study and 
are currently taking inhaled treprostinil at the Screening Visit were randomized into the study 
after determination of eligibility criteria.  Subjects are randomized to either esuberaprost or 
placebo through a centralized system, stratified by use of inhaled treprostinil (current user at the 
time of the Screening Visit:  yes or no)).  Following randomization, the subject, study site staff, 
the sponsor and the EAC all remain blinded to the treatment group assignment.  
Baseline assessments are conducted over two consecutive days with Baseline 6MWT performed 
on each day; the mean value will establish the Baseline value.  Subjects return to the study site at 
Weeks 4, 8, 12 (first Quarterly Visit), and for Quarterly Visits thereafter.  During these study 
visits, subjects undergo all scheduled efficacy and safety assessments as defined by Appendix 1 
of the study protocol.  Between scheduled study visits, subjects will be contacted by phone to 
assess for possible clinical worsening events and to record any newly-occurring or changes to 
AEs or concomitant medications.  Phone contact will be made weekly (except during study visit 
weeks) between Baseline and Week 12 (first Quarterly Visit), then monthly between Quarterly 
Visits through the end of study participation. 


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An optional hemodynamic assessment will be offered to subjects at sponsor-approved sites in the 
US only.  Subjects who volunteer to participate in the hemodynamic substudy will undergo a 
right heart catheterization 0 to 21 days prior to the Baseline Visit (prior to the first dose of IMP) 
and at the Month 6 Quarterly Visit (±7 days) at peak study drug blood levels (1 to 2 hours, 
± 15 minutes, after administration of Investigational Medicinal Product [IMP; esuberaprost or 
placebo]).  
An optional plasma concentration assessment will be offered to subjects at sponsor-approved 
sites.  Subjects who participate will have blood drawn at the following time points: trough 
sample at the Week 4 Visit (15 minutes pre-dose, ± 5 minutes) and four blood samples during the 
Week 12 Visit (first Quarterly Visit) at 15 minutes prior to the second daily dose of study drug, 
and 15 minutes, 1 hour and 2.5 hours postdose; ± 5 minutes).  If feasible, blood samples will be 
drawn for measurement of esuberaprost and treprostinil plasma concentrations following any 
serious adverse event (SAE). 
Subjects will continue to participate in the study until the sponsor formally concludes the study 
when the prespecified number of Clinical Worsening Events has occurred (n=113).  Initially, the 
investigator will judge whether a suspected clinical worsening event, the primary endpoint, has 
occurred; however, a blinded EAC, composed of medical experts in the PAH field and 
independent of the sponsor, reviews all suspected clinical worsening events and makes a final 
determination (refer to the study protocol).  Following study conclusion, subjects will return to 
the study site for an End of Study (EOS) Visit to undergo all scheduled assessments.  Subjects 
who are participating in the study at its conclusion may be offered the opportunity to enroll in a 
long-term open-label extension study.  A separate document will describe those analyses.  
Subjects who withdraw consent for participation in the study or those whom the Investigator 
terminates prior to formal study conclusion will be weaned from IMP.  They were asked to 
return to the study site for an EOS Visit to undergo all scheduled assessments.  
3.2 
Treatments 
Eligible subjects are randomized to treatment with double-blind IMP.  
All tablets of esuberaprost and matching placebo are to be taken four times daily (QID) without 
regard to meals.  All subjects receiving other approved PAH therapies must be stabilized on an 
optimal dosing regimen for at least 30 days prior to the Baseline Visit and are required to 
maintain the same dose throughout the study. 
Subjects randomized to esuberaprost are titrated to a target dose of 30 µg QID; 120 µg/day over 
a two-week period. 
For the first two weeks after randomization, one tablet of IMP (esuberaprost or placebo) is 
administered QID.  After two weeks on IMP, site personnel will contact the subject to monitor 
AEs and, as appropriate, instruct the subject to increase the IMP dose to two tablets QID.  At the 
Week 4 Visit, subjects will receive IMP in bulk dosing cards, which will be the IMP packaging 
and configuration provided for the remainder of the study.  


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All doses of IMP are to be administered in conjunction with inhaled treprostinil.  A subject who 
was unable to tolerate the targeted two tablets QID dosing regimen may continue in the study on 
one tablet QID dosing.  At the Investigator’s discretion, an observed rechallenge may be 
attempted using the target, two tablets QID dosing at either the Week 4 or Week 8 Visit. 
The dosage for inhaled treprostinil, according to the package insert, is a maximum of 9 breaths 
per treatment session QID.  The dosage of inhaled treprostinil is based on the subject’s 
≥90-day exposure where a stable dose is established for ≥30 days prior to the Baseline Visit.  
The number of breaths per treatment session should remain consistent throughout the subject’s 
participation in the study. 
3.2.1 
Treatments Administered 
3.2.1.1 
Esuberaprost (Active IMP)  
The active IMP in this study is esuberaprost (BPS-314d-MR), available as 15μg tablets for oral 
administration.  
The target dose of esuberaprost is 30 µg QID (120 µg/day).  Subjects are permitted to remain on 
study if the target dose is not tolerated; de-escalation back to the starting dose (15μg QID) should 
occur, followed by rechallenge to the target dose per the Investigator’s discretion. 
3.2.1.2 
Placebo (Non-active IMP) 
To preserve study blinding, the placebo tablets are identical in size, shape, color, and appearance 
to the esuberaprost tablets.  The tablet packaging and configuration for placebo tablets are also 
identical to active tablets.  
For the first two weeks after randomization, the study drug dose will be one tablet QID.  After 
two weeks on study drug, site personnel will contact the subject to monitor AEs and, as 
appropriate, instruct the subject to increase the study drug dose to two tablets QID. 
3.2.2 
Treatment Groups 
Subjects who are taking a stable dose of inhaled treprostinil for the required duration and who 
met all other eligibility criteria are randomized 1:1 to esuberaprost or placebo as described in 
Section 3.2.4.  
3.2.3 
Patient Identification  
Each screened subject receives a Unique Patient Identification (UPI) number (a unique 
7-character alpha-numeric identifier) consisting of a 3-digit clinical site number and a 3-digit 
subject number, separated by a hyphen.  The sponsor will assign site numbers to each clinical 
site.  The subject number will be assigned by the Interactive Randomization Technology (IRT) 
system as a 3-digit number to each subject in sequential order by clinical site at the time of the 
Screening Visit.  For example, the first subject who is screened at Site 301 is assigned the UPI of 
301-001, the second, 301-002, etc.  


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The UPI remains the same throughout the study to identify uniquely the subject’s CRFs and 
other documentation.  The UPI of a subject who discontinues from the study for any reason after 
having been assigned a UPI will not be reassigned.  Subjects who discontinue from the trial will 
not be replaced. 
3.2.4 
Method of Assigning Subjects to Treatment Groups 
All subjects are randomized using a centrally administered randomization scheme stratified by 
use of inhaled treprostinil (specifically, current use at the time of the Screening Visit: yes or no).  
Randomization is blocked but block sizes will not be disclosed to the investigators or sponsor to 
prevent inferences about possible treatment assignments for current or future subjects.  An IRT 
system is utilized for the central randomization procedure.  Once all entry criteria have been met 
at the Baseline Visit, the investigator or designee accesses the IRT (by phone or by web) to 
assign the subject a randomization number and the IMP corresponding to the assigned treatment 
group. 
An independent biostatistician, designated by the sponsor, reviewed and approved the 
randomization scheme.   
3.2.5 
Blinding 
During the entire study, treatment with inhaled treprostinil is open-label and therefore known to 
the Investigator and the subject. 
Randomization to esuberaprost or placebo is double-blind.  The investigator and study staff, the 
subjects, the monitors, the sponsor staff, the statisticians and programmers analyzing the data, 
and the EAC will remain blinded to treatment group allocation until the study database is locked.  
Esuberaprost and placebo are indistinguishable and are packaged in the same way to ensure 
study blinding. 
Only if a subject’s medical condition warrants, such as the occurrence of a medical emergency 
for which treatment requires knowledge of what study drug was given, may the investigator 
break the blind to determine if the subject received active drug or placebo.  In most medical 
emergencies, the sponsor medical monitor must grant prior approval to break the codes; 
however, the code may be broken on the investigator’s request if the subject’s condition is so 
severe that time would not permit prior approval.  In any case, 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.  
 


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4 
SAMPLE SIZE AND STATISTICAL POWER 
4.1 
Design  
The primary efficacy endpoint is clinical worsening confirmed by an independent EAC.  The 
primary efficacy endpoint analysis will evaluate clinical worsening as the time to first clinical 
worsening event (TtCW; Sections 2.1, and 5.1.1).  
Only a few published articles discuss the observed rates of clinical worsening in patients treated 
with inhaled treprostinil.  Benza et al (2011) reported that, in an open-label extension study of 
206 PAH patients involved in an inhaled treprostinil registration trial, 12-, 18- and 24-month 
clinical worsening rates were 18%, 26%, and 31%, respectively.  Voswinckel et al (2009) 
investigated the long-term safety and efficacy of inhaled treprostinil in 24 PAH patients over 
approximately 3 years of follow-up in a small, open-label study.  They reported 12-, 24- and 
36-month clinical worsening rates of 15%, 30%, and 50%, respectively. 
Using the aforementioned published literature, the sponsor anticipates the one-year rate of 
clinical worsening will be approximately 15% for the population treated with inhaled treprostinil.  
As such, the sponsor considers the sample size necessary to show a clinically meaningful 
difference between the esuberaprost and the placebo groups treated with inhaled treprostinil to be 
prohibitively large.  The sponsor intends to restrict recruitment to inhaled treprostinil subjects 
where an esuberaprost treatment effect will be more readily discerned.  Following guidance from the 
Food and Drug Administration in 2012 (UCM332181) on clinical study enrichment strategies, the 
inclusion criteria of the current study (protocol, Section 5.2) specified that patients will be 
randomized into this study only if they are showing signs of deterioration after initial improvement 
on inhaled treprostinil treatment or have had a clinically suboptimal response to inhaled 
treprostinil treatment.  The specific exclusion of subjects who are likely to be at a lower risk of 
clinical worsening will reduce the proportion of subjects available for recruitment; however, the 
targeted study population of those who have shown suboptimal response will be expected to have 
a higher event rate than would a broader population.  Therefore, fewer subjects will be needed to 
test the hypothesized absolute effect size.  Moreover, the target study population is one most 
likely to benefit from an additional therapy; without additional treatment, approximately 45% of 
these patients are expected to experience clinical worsening in a year. 
Initial start-up activities and recruitment are restricted to ensure the safety of subjects.  
Therefore, the sample size calculations do not include the initial 6 months of the study to make 
certain the study has adequate power.  The sample size calculations were based on the following 
assumptions:   
• a one-year clinical worsening rate of: 
- 
45% in the placebo group (inhaled treprostinil alone)  
- 
25% in the esuberaprost group  
• proportional hazards over time  
• an accrual period of 1.5 years  
• total follow-up time of 2.5 years (follow-up time for last subject randomized 1 year; total 
study duration 2.5 years) 
• 0.01 two-sided significance level   


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This study will randomize approximately 240 subjects (120 subjects per treatment group). 
Calculation of the sample size was based on the assumptions listed above. Under those 
assumptions, an exponential maximum likelihood test of equality of survival curves would 
require 113 events overall to detect a treatment difference at a power of 90% at a 0.01 two-sided 
significance level. Given the expected accrual period and follow-up time, an appropriate sample 
size is 240 subjects. There was no restriction or quota with respect to number of subjects by 
country.  
Study sample size is based on a 0.01 two-sided significance level to provide sufficient power to 
observe ‘substantial evidence’ of effectiveness within a single clinical study. However, at the 
time of the analysis, the effect will be tests at a significance level of 0.05 (see Section 6.10). The 
power at a 0.05 two-sided significance level is 97%.   
Sample size calculations were performed with nQuery Advisor 7.0 (2014) and PASS (Hintze, 
2013) using sample size methods for the log-rank statistic based on Lakatos & Lan (1992).  
4.2 
Study Design Review  
The sponsor has continuously monitored the overall (pooled) event and drop-out rates during the 
course of the study.  Sample size may be increased during the study to maintain the planned 
target of 113 events. Only pooled blinded data will be used to increase sample size. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5 
EFFICACY AND SAFETY ENDPOINTS 
This section lists the study’s efficacy and safety variables.  Section 7 of the study protocol 
provides details regarding the description, timing, and collection of the variables.  See the 
schedule of events in Appendix 1 of the study protocol.  
5.1 
Efficacy Endpoints  
The efficacy analyses are defined in three stages for statistical inference. Stage 1 refers to the 
primary efficacy endpoint; Stage 2 to the key secondary endpoints; and Stage 3 to the other 
secondary endpoints. Section 6.10 addresses the planned formal testing to ensure control of type 
1 error rate.   
5.1.1 
Primary Efficacy Endpoint (Stage 1) 
The primary efficacy endpoint is the time to first occurrence of clinical worsening (see 
Section 2.1).  The time is defined as follows:   
Time-to-clinical-worsening (TtCW, in days) = Date of first EAC-confirmed clinical 
worsening  Date of randomization + 1. 
In addition to the primary composite endpoint, individual components of TtCW (Section 2.1) 
will be presented and examined in an exploratory manner (see Section 6.12.7).  
5.1.2 
Key Secondary Endpoints (Stage 2) 
The study has the following three key secondary efficacy endpoints: 
1. TtCF as defined in Section 2.2.  
Time-to-clinical-failure (TtCF, in days) = Date of first clinical failure composite 
endpoint  Date of randomization + 1 
2. Exercise capacity at Week 24 as measured by the change from baseline in distance walked on 
a 6MWT 
3. PAH status at Week 24, as defined as the change from baseline in WHO Functional Class 
 
5.1.3 
Other Secondary Endpoints (Stage 3) 
The study has the following other secondary outcomes: 
• Outcomes at 24 weeks  change from baseline in the following: 
- 
Borg Dyspnea Score 
- 
NT-pro-BNP levels 
• Total mortality (censored at last contact if lost to follow-up or if vital status is missing at 
study termination) 


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5.1.4 
Exploratory Endpoints 
• 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
5.2 
Safety Variables  
The following safety variables will be assessed: 
• AEs 
• Clinical laboratory parameters 
• ECG findings  
• Vital signs 
5.3 
Exploratory Endpoints  
 
 
  
 


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6 
STATISTICAL METHODS  
6.1 
Datasets for Analyses 
This study has the following three analysis populations: 
• Randomized Population:  All subjects randomized to the study.  Tabulations for disposition 
of subjects will be generated from this population. 
• Full Analysis Set (FAS) Population:  All randomized subjects who received at least one dose 
of IMP (esuberaprost or placebo) in the study.  Efficacy analyses will be conducted on this 
population.  Subjects whose randomized treatment differs from the actual treatment received 
will be classified in their randomized treatment group. 
• Safety Analysis Population:  All randomized subjects who received at least one dose of IMP.  
Safety analyses will be conducted on this population.  Subjects whose randomized treatment 
differs from the actual treatment received will be classified in the treatment group for actual 
treatment received. A subject who received some esuberaprost and some placebo will be 
assigned to the esuberaprost group. 
 
A summary table presenting the number and percentages of subjects for each analysis 
populations will be presented by treatment group.  
After the study database is locked and before treatment codes are unblinded, the sponsor will 
generate the list of subjects to be excluded from the FAS and Safety Analysis Populations.   
The sponsor must approve this list before treatment is unblinded and thus before performing any 
analyses. 
6.2 
General Methodology 
Treatment groups will be described as “Esuberaprost” and “Placebo” to correspond with 
esuberaprost with inhaled treprostinil and placebo with inhaled treprostinil, respectively. 
Subjects who are not retained will not be replaced during the study; the data analysis will include 
the subjects who were not assessed in a manner described in the various sections that follow.  
Subjects completing the study will be defined as those on study, whether or not they have 
remained on IMP at time of the close of study or those subjects who have experienced a clinical 
worsening event during the study.  Early terminations from the study or IMP for any other reason 
will be identified.  
If an evaluation is repeated, such as to confirm an observed aberrant laboratory value, the 
analyses will use the later value.  Evaluations from Unscheduled Visits are to be included with 
Scheduled Visits following these rules to the extent possible.  
Continuous variables will be summarized with standard descriptive statistics such as mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum.  For categorical 
data, descriptive analyses will be based on the number of subjects and related percentages.  


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Tabular presentations will display two columns of results, one for each treatment group, with the 
labels “Esuberaprost” and “Placebo”.  Throughout this analysis plan, the phrase “by treatment 
group” will refer to these two groups.  If useful, some tables will include a third column 
representing the total population. 
All tables will be presented in landscape format.  For practical reasons, the point size may be 
reduced to (but not less than) 7 point for tables that contain too much information to fit into a 
single page.  SAS version 9.3 or higher (2011) will be used.  The sponsor’s Biostatistics 
Department will analyze the efficacy and safety data.   
Prior to unblinding, an addendum will be written that will describe the data conventions to be 
used to implement this SAP. 
6.3 
Definition of Analysis Time Points 
6.3.1 
Baseline  
The protocol designates two days as ‘baseline’ for the protocol Baseline Visit:  Day 1 (the day on 
which the subject is randomized) and Day 2 (the day the subject is first administered IMP).  
Analyses designated as a change from baseline will use the results of evaluations collected on the 
Day 1 Visit as the baseline, except for analyses of the 6MWT and Borg Dyspnea Score data, 
which will use the average of the Day 1 and Day 2 values.  In the case of a single, missing 
Baseline Visit Day 1 or Day 2 value for 6MWT or Borg Dyspnea Score, the single value will be 
used as baseline.  
For other variables, the baseline value will be defined as the value immediately prior to 
randomization.  For some measures, the baseline will be as defined as the last evaluation closest 
to, but prior to, the first dose of IMP.  If helpful for clarity, analyses will specify the time of 
baseline.    
6.3.2 
Change from Baseline  
For parameters measured at baseline, the variables of interest are the change from baseline of the 
original measurements.  Unless otherwise specified, all changes from baseline (for all variables 
where this is applicable) will be calculated as follows: 
 
Change from baseline = Post baseline  baseline 
6.3.3 
Study Day 
Study day will be calculated relative to randomization (Baseline, Day 1). Specifically: 
Study day pre-randomization = (Date of occurrence  Date of randomization). 
Study day on or post-randomization = (Date of occurrence  Date of randomization) + 1. 
6.3.4 
Visit Windows 
Evaluations will be counted as occurring at the Scheduled Visit designated by the protocol and as 
recorded on the eCRF irrespective of deviations from protocol-specified visit windows.  


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Unscheduled Visits will be mapped to Scheduled Visits for the purposes of analyses or 
summaries according to the following rules: 
• Evaluations observed at Unscheduled Visits will be mapped to the Scheduled Visits if, and 
only if, the evaluations for that Scheduled Visit are missing and within a logical visit 
window.  If more than one Unscheduled Visit is present, then the evaluation closest to the 
projected Scheduled Visit will be used.  
The following rule will apply for mapping Unscheduled Visits to missing data for End of Study 
Visits: 
• Evaluations observed at an Unscheduled Visit will be allotted to an End of Study Visit if, and 
only if, the End of Study Visit evaluations are missing and the Unscheduled Visit occurred 
on the same day as the End of Study Visit.  
The following rule will apply for mapping End of Study Visits to Scheduled Visits: 
• The End of Study Visit will be mapped to the next Scheduled Visit if the subject has 
completed the study, the End of Study Visit occurs within the window of the next planned 
Scheduled Visit, and the subject has not changed the dose of IMP.  For example, this rule 
applies to the last site visit before a subject is transferred to an open label extension study 
while the subject is on IMP but not to subject who has weaned from study drug during early 
termination.  
6.4 
Data Handling 
6.4.1 
Stratification Variable 
Subjects are randomized using a centrally administered randomization scheme stratified by use 
of inhaled treprostinil (current user at the time of the Screening Visit:  yes or no) (Section 3.2.4).  
The clinical site enters the subject’s inhaled treprostinil experience into the IRT system.  If data 
entry errors occur and subjects are incorrectly stratified, no changes will be made to the assigned 
randomization, but subjects will be reclassified into the correct stratum for statistical analyses 
based on data from the concomitant medications CRF (100% source verified).  


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6.4.2 
Handling of Missing Data 
The sponsor acknowledges the implications of missing data on the integrity of study outcomes 
and, consistent with Fleming’s recommendations (2011), implemented the following strategies to 
minimize the extent of missing data:  
1. All subjects were allowed to continue in the study until the close of study, whether on 
IMP or not. Subjects were not to be summarily discontinued from the study, unless 1) the 
subject withdrew informed consent; 2) the subject met a primary endpoint and declined 
continuation in the study; or 3) ) the subject continued to be non-adherent to study 
protocol after repeated attempts to correct (at least 6 months). However, the subject has 
the right to discontinue from the study at any time. All subjects who discontinue the 
study, unless they withdraw informed consent, will continue to be followed, to the extent 
possible, for vital status until the sponsor concludes the study.  
2. Recent publications (Sitbon et al., 2015; Galiè et al., 2015) have shown that roughly 20% 
of subjects prematurely terminate from mortality and morbidity studies in PAH. The 
sponsor has throughout the study engaged with study investigators to encourage subjects’ 
retention in the study, adherence with the protocol, and compliance with IMP.  
3. While the study protocol is necessarily complex in order to obtain the scientific data to 
evaluate the safety and efficacy of the IMP, the sponsor designed the protocol in the 
manner that was not burdensome  the subjects: 1) Much of the data collected for 
secondary endpoints is derived from assessments performed for ‘standard of care’ visits; 
2) Study visits are minimal (quarterly) with permissive visit windows (± 10 days); 3) Use 
of optional substudies for exploratory endpoints; and 4) Sponsor-provided Tyvaso to all 
subjects in the study. 
Methods for handling missing data will be described in the sections discussing each outcome. 
No imputation is planned for missing safety or exploratory data.  


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6.5 
Disposition of Subjects 
The Randomized and FAS analysis populations will be used to describe subject disposition.  The 
number and percentage of randomized subjects who completed and who discontinued (with 
reason for discontinuation) will be summarized by treatment group.  In addition, a summary table 
will show subject status by clinical site.  
A CONSORT diagram (Schulz et al 2010) will display the disposition by treatment group. 
6.6 
Protocol Deviations 
Significant protocol deviations occurring during the study, major or minor, that could impact the 
completeness, accuracy, and/or reliability of the study data or that may affect a subject's rights, 
safety, or well-being will be determined by the sponsor (which will be completed prior to 
database lock) and will be presented for all subjects randomized.   
6.7 
Demographic and Other Baseline Characteristics 
The following summaries will be based on the FAS population. 
6.7.1 
Demographic and Baseline Characteristics   
Descriptive statistics will be presented overall and by treatment group for the following 
demographic data at randomization:   
• age (in years);  
• age (<65, ≥65 years);  
• sex (males, females);  
• race (white, black or African-American, Asian, other);  
• ethnicity (Hispanic or Latino, non-Hispanic or Latino);  
• weight (in kg);  
• height (in m);  
• BMI (in kg/m2);  
• smoking status (never, former, current smoked cigarettes/cigars); and  
• country of clinical site (US, Israel).   
 
6.7.2 
PAH Disease Characteristics  
Descriptive statistics presented overall and by treatment group for subjects’ PAH history at 
randomization will include the following:   
• PAH etiology [idiopathic or familial, associated with collagen vascular disease, associated 
with HIV infection, induced by anorexigens/toxins, associated with repaired congenital 
systemic-to-pulmonary shunts (repaired ≥1 years)];  


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• background PAH therapy (Endothelin receptor antagonist [ERA], Phosphodiesterase Type 5 
Inhibitor [PDE-5 inhibitor], inhaled treprostinil [experienced or naïve], and riociguat); 
• background inhaled treprostinil (experienced or naïve) 
• age of PAH diagnosis (date of diagnosis minus date of birth, in years);  
• years of PAH (date of Screening Visit minus date of diagnosis);  
• 6MWT and Borg Dyspnea Score at Screening;  
• baseline average 6MWT;  
• baseline average Borg Dyspnea Score; and  
• baseline WHO Functional Class.   
    
6.7.3 
Medical History  
Medical conditions and surgical history identified prior to randomization will be summarized 
overall and by treatment group.  The number and percentage of subjects with any occurrence will 
be summarized by System Organ Class (SOC; alphabetically) and by preferred term in 
decreasing order of incidence.   
For subjects experiencing the same medical condition multiple times, the summaries will count 
the condition only once for the corresponding preferred term.  Similarly, the summaries will 
count a subject with multiple medical conditions within the same SOC only once for that SOC.  
SOCs will be tabulated alphabetically; within each SOC, preferred terms will be presented in 
decreasing order of incidence. 
Medical conditions are coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary (the database will document the version current at time of data 
lock). 
6.7.4 
Medications 
All medications will be coded using the WHO-Drug Global Dictionary (the database will 
document the version current at time of data lock). 
Medications will be summarized overall and by treatment in two separate analyses, one for prior 
and one for concomitant medications.  The number and percentage of subjects with any 
medication will be summarized by decreasing order of incidence.  The number and percentage of 
subjects who have taken a medication within a primary drug category will be summarized by 
treatment group under that drug category by the most specific level available.   
For these summaries, a subject taking the same medication multiple times will only be counted 
once for the corresponding most specific level available.  Similarly, a subject who took multiple 
medications within the same drug category will be counted only once for that drug category.  
Prior medications will be presented in alphabetical order of drug category; within each drug 
category, drug most specific level available will be presented in decreasing order of incidence. 


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6.7.4.1 
Prior Medications 
Any medication or therapy reported before the first dose of IMP will be considered a prior 
medication.  
6.7.4.2 
Concomitant Medications 
Any medication or therapy initiated after the first dose of IMP during the study will be 
considered a concomitant medication.  
In addition, summary tabulations may be prepared to illustrate the extent and use of: 1) P-
glycoprotein and BCRP inhibitors taken with IMP; 2) Concomitant meds that may be of interest 
from potential drug-drug interactions with IMP; and 3) Concomitant medications that are 
commonly co-administered for the treatment of PAH. 
6.8 
Treatment Compliance 
Study drug accountability was to be performed on an ongoing basis by the study staff and 
checked by the monitor during site visits and at the completion of the study. Subjects were asked 
to return all unused study drug as well as the empty packages at each visit. The study coordinator 
or designee will document the unused study drug and verify that the quantity is consistent with 
the intended dosing schedule. 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 
non-compliance may lead to termination of the subject from the study after consultation between 
the Investigator and the Sponsor. Treatment compliance will be presented by two analyses: by 
analysis of IMP pill count data and IMP dosing as reported during the study. 
6.8.1 
Analysis of Pill Count Data 
Coupled with the typical issues of lost and irretrievable IMP tablets, the protocol allowed that a 
subject could dose adjust during the study, a dose interruption could occur if medically 
warranted, and subjects were asked to remain on study (on or off IMP) pending adjudication of 
the primary clinical worsening event, pill count data will not provide an absolutely accurate 
compliance measurement. The following will be calculated:   
• the number of tablets dispensed during the study (Baseline Visit through End of Study Visit) 
• the number of tablets returned during the study 
• the number of used tablets (calculated as tablets dispensed minus tablets returned) 
• the duration of exposure (see Section 7.1)  
• the number of expected pills taken at 15 µg and 30 µg QID 
• percent of used tablets for number of expected pills for 15 µg and 30 µg QID overall and by 
20% increments 
 
Descriptive statistics will be presented by treatment group and subgroups, including, but not 
limited to, age, sex, racial, country, PAH etiology, background PAH therapy, background 
inhaled treprostinil, baseline WHO (see Sections 6.7.1 and 6.7.2).   


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6.8.2 
IMP Dosing  
Sites were not required to record each dose of IMP taken during the study but IMP dosing was to 
be reported on the eCRF for first and last IMP dose as well as any doses taken while on site, any 
missed doses and any dose modification. The subjects are to receive QID dosing of IMP with 
some titration (see protocol). Three different summaries of compliance to IMP will be reported:  
Summary of Daily Dosing  
The first summary will measure if any of the 4 doses to be taken on a given day is taken than the 
subject is compliant for that day. The following will be calculated:   
• the number of minimally compliant days [≥1 of QID doses taken during the study (Baseline 
Visit through End of Study Visit)] 
• the duration of exposure (see Section 7.1)  
• percent of minimally compliant days (as divided by duration of exposure) overall and by 
20% increments 
  
Summary of QID Dosing  
The second summary will measure if all of the 4 doses to be taken on a given day are taken than 
the subject is compliant for that day. The following will be calculated:   
• the number of maximally compliant days [all of QID doses taken during the study (Baseline 
Visit through End of Study Visit)] 
• the duration of exposure (see Section 7.1)  
• percent of maximally compliant days (as divided by duration of exposure) overall and by 
20% increments 
 
Summaries of IMP and Inhaled Treprostinil Dosing 
The plan for administration of drug in this study was predicated on the hypothesis that dual 
dosing, hitting the receptors in two different ways at the same time, is beneficial.  To measure the 
extent to which the dosing of IMP and inhaled treprostinil was performed nearly simultaneously, 
the two treatment groups will be compared with respect to the frequency of times dosing with 
IMP and inhaled treprostinil not separated by more than (a) 5 minutes and (b) 10 minutes. 
Descriptive statistics will be presented by treatment group and subgroups, including, but not 
limited to, age, sex, racial, country, PAH etiology, background PAH therapy, background 
inhaled treprostinil, baseline WHO (see Sections 6.7.1 and 6.7.2).  Other analyses may be 
performed as suggested by the data. Analogous summaries will be presented for use of inhaled 
treprostinil. 


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6.9 
Analysis of Efficacy  
All statistical analyses of efficacy will include the stratification variable, baseline inhaled 
treprostinil use, as a covariate.  The sections that describe the analysis of the other secondary 
outcomes list other planned covariates. 
Because the number of subjects in each investigational site is expected to be small, site will not 
be used as a covariate in the analyses.  Moreover, no pooling algorithm will be used.  
6.10 Hypothesis Testing  
A three-stage process of hypothesis testing will be employed to control for the multiplicity of 
secondary endpoints. 
6.10.1 
Stage 1: Testing for Primary Endpoint 
If, at a two-sided alpha level of 0.05, the comparison of esuberaprost to placebo on the primary 
endpoint, TtCW,  
• is significant, then hypothesis testing will continue to Stage 2. 
• is not significant, then formal hypothesis testing will stop.  
 
6.10.2 
Stage 2: Testing the Key Secondary Endpoints 
Stage 2 hypothesis testing will employ the Simes’ procedure for control of multiplicity (Simes, 
1986).  Testing in this stage will be at a two-sided Type I error rate of 0.05 for the three 
secondary endpoints:  
• The comparison of esuberaprost to placebo on baseline-adjusted change from baseline 
6MWT at Week 24  
• The comparison of esuberaprost to placebo on TtCF 
• The comparison of esuberaprost to placebo on worsening from baseline in WHO Functional 
Class at Week 24  
 
Hypothesis testing will continue to Stage 3 only if at least one of the comparisons of 
esuberaprost to placebo on these endpoints is significant by the Simes’ procedure.  The Simes’ 
procedure’s critical value from the final significant test in Stage 2 will be carried forward and 
used for the critical value in Stage 3.  
6.10.3 
Stage 3: Testing for Other Secondary Endpoints 
Stage 3 hypothesis testing will employ simple hierarchical testing on the pre-specified endpoints 
listed in Section 5.1.3.  Testing in this stage will be performed at the final Simes’ procedure’s 
critical value carried forward from Stage 2.  


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If any comparison of esuberaprost to placebo is not significant at the critical value carried 
forward from Stage 2, then formal testing will stop. 
As described in Section 5.1.3, endpoints in Stage 3 will be reviewed at the time of the Blinded 
Data Review (see Section 6.11) and the order of testing will be determined on the basis of 
clinical importance and likely statistical power.  The order will be designed to protect Type I 
error rate. 
Statistical analyses for exploratory endpoints not otherwise predefined for hypothesis testing will 
be presented as point estimates with associated 95% CIs. 
6.12 Primary Efficacy Analysis 
As described in Section 2.1, the primary efficacy outcome is the TtCW, measured in days, where 
clinical worsening is defined as the first occurrence of any of the following: 
• Death (all causes) 
• Hospitalization due to worsening PAH 
• Initiation of a parenteral (infusion or sub-cutaneous) prostacyclin directly related to 
worsening PAH   
• Disease progression  


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• Unsatisfactory long-term clinical response  
 
As described above, a blinded Event Adjudication Committee (EAC) will review all suspected 
clinical worsening events and make a final determination for each (see Appendix 1). The EAC 
Charter, Version 
, specifies evidence to be provided to the EAC along 
with the general rules and criteria for EAC confirmation of a primary endpoint of clinical 
worsening. Because the EAC Charter cannot address every possible scenario, the EAC Charter 
shall be viewed as a framework under which the EAC will operate. Each case will be determined 
on the basis of a consensus of the EAC, the members of whom are independent experts in PAH. 
Please see Appendix 2 for general rules and criteria excerpted from the EAC Charter.  
Subjects were not required to discontinue from the study after meeting a primary endpoint; thus, 
more than one clinical worsening event may be reported for the same subject. This section 
defines the calculation of time to each component of the primary outcome.  The protocol 
specifies that investigators follow each subject for 30 days after the subject discontinues from the 
study to assess the occurrence of SAEs and for 90 days after the subject stops study medication 
for vital status.  Further, the investigators are instructed to provide all clinical worsening events 
that occur after the primary clinical worsening event, as well as the vital status of all subjects at 
the time the sponsor terminates the study.  
6.12.1 
Death (All Cause) 
Deaths that occur at any time from randomization to 90 days after the subject’s last study visit is 
counted as a death for the primary efficacy analysis.  All those still alive 90 days after their last 
visit are censored for death at the 90 day time even if it is known that they died after the 90 day 
window. 
6.12.2 
Hospitalization due to worsening PAH 
Any hospitalization due to worsening PAH that occurs from randomization to the 30 days 
following subject’s last study visit is counted as an event for the primary outcome.  The date of 
the event is the actual date of hospitalization.  All those without a reported hospitalization during 
the 30 days following their last visit are censored for hospitalization at the 30 day time even if it 
is known that they were hospitalized after the 30 day window. 
6.12.3 
Initiation of a Parenteral (infusion or sub-cutaneous) Prostacyclin  
Any initiation of a parenteral prostacyclin, directly related to worsening PAH (transient use [≤ 7 
days] for non-PAH related illness allowable, that occurs from randomization to the 30 days 
following subject’s last study visit is counted as an event for the primary outcome.  The date of 
the event is the actual date of transition to parenteral prostacyclin.  All those without a reported 
parenteral prostacyclin during the 30 days following their last visit are censored for parenteral 
prostacyclin at the 30 day time even if it is known that they received parenteral prostacyclin after 
the 30 day window. 
 


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6.12.4 
Disease Progression  
Disease progression is assessed at each study visit.  In order to declare disease progression, a 
subject must meet the 6MWT decrement criterion and worsening of PAH symptoms. To satisfy 
the 6MWT criterion, subject must attend two study visits for 6MWT measurements: initial test 
and confirmatory test. Any disease progression that occurs from randomization to the subject’s 
last study visit is counted as an event for the primary outcome.  The date of the event is the 
actual date of disease progression as defined by the initial 6MWT test.  All those without a 
reported disease progression up to their last visit are censored for disease progression at the last 
study visit even if it is known that disease progression occurred after the last study visit. 
6.12.5 
Unsatisfactory long-term clinical response 
Only subjects who have been on treatment for at least 24 weeks are eligible for meeting this 
definition. In order to declare unsatisfactory long-term clinical response, a subject must meet the 
6MWT decrement criterion and show lack of sustained improvement in WHO functional class. 
Similar to disease progression, a subject must attend two study visits for 6MWT measurements: 
initial test and confirmatory test. Any unsatisfactory long-term clinical response that occurs from 
randomization to the subject’s last study visit is counted as an event for the primary outcome.  
The date of the event is the actual date of unsatisfactory long-term clinical response (initial 
6MWT test).  All those without a reported unsatisfactory long-term clinical response up to their 
last visit are censored for unsatisfactory long-term clinical response at the last study visit. 
6.12.6 
First Occurrence Derivation and Analysis 
Each subject will be assigned responses for each component of the primary efficacy endpoint.  
The response will be either the date the event occurred or the date of censoring.  Then, the 
subject will receive one date as the outcome.  For subjects who experience at least one of the 
component outcomes, the event date will be the earliest of the dates of the component outcomes.  
For those who do not experience any of the outcomes, the date of censoring will be the date of 
the last study visit. 
Prior to unblinding, an addendum will describe in detail the methods to be used to account for 
missing data in the analysis of the primary outcome.  
The TtCW (in days) will be analyzed using the SAS procedure LIFETEST to calculate the 
log-rank statistic and the associated p-value for testing whether the treatment groups differ.  The 
program will be of the form:   
proc lifetest data= set plots=survival; 
  
time TtCW * status(0); 
  
strata treprostinil_use /  group=treatment test=logrank; 
  
run; 
The results of the statistical test for the primary study endpoint will be evaluated using a 
two-sided Type I error rate of 5%.  A Cox Proportional Hazards Model (SAS PHREG) will be 
used to estimate the hazard ratio and its associated 95% confidence interval (CI).  This model 


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will stratify by baseline treprostinil.  Graphical displays and tabulations of TtCW will be 
presented by treatment group.   
6.12.7 
Supportive Analyses for Primary Analyses 
Two distinct analyses will be performed for the components of the primary outcome. 
1. “Contribution” outcome.  A table will show the contribution of each component of the 
primary outcome. 
2. “Incidence” outcome.  Each component will be analyzed as a time-to-event variable.  
 
These two analyses differ in that the analysis of the contribution shows only the first event in the 
primary outcome while the second considers the time to each component even if it is not the first 
event in the primary.  For example, a subject who dies after experiencing disease progression 
would not show as a death in the analysis of the contribution of the component; however, the 
death of such a subject would be included in the second analysis.  
Analysis of the “contribution” outcome will be descriptive.  It will consist of a simple table 
showing the number of events of each type by treatment group contained in the primary 
outcome.   
For the “incidence” outcomes, LIFETEST and PHREG will be used for each of the five 
individual components of the composite outcome.  These analyses will use the 
component-specific dates of event or censoring. They will produce Kaplan-Meier curves, hazard 
ratios, 95% CIs, and other statistics as appropriate. 
6.12.8 
Sensitivity Analyses for the Primary Outcome 
In addition to the primary and supportive analysis, two planned sensitivity analyses will be 
performed. 
The first sensitivity analysis will mimic the methods Sitbon et al (2015) used in their primary 
analysis of selexipag in the GRIPHON study.  As those authors say, “The primary analysis was 
an on-treatment analysis with follow-up data censored at the time selexipag or placebo was 
discontinued.”  The first sensitivity analysis will follow this method and censor subjects at the 
time they stopped study medication. 
The second sensitivity analysis, which is really a set of analyses, will explore the impact of 
censoring and missing data. These analyses will use a tipping point approach, in which subjects 
will be censored at Day 1, Day 2, …, Day 90 after stopping study medication in order to explore 
the effect of various censoring rules on the inference from the study. 
Because of the complexity of the primary and secondary outcomes, and the many possible ways 
that data might be censored or missing, the statistical team will examine the pattern of missing 
data and censoring for the pooled efficacy variables at the time of the Blind Data Review (see 
Section 6.11).  At that point, armed with the knowledge of the patterns of divergence from full 
follow-up that actually occur in the trial, the sponsor may add additional sensitivity analyses, 
which will be described in an addendum to this SAP (completed prior to database lock).  


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6.13 Key Secondary Analyses 
As described in Section, 5.1.2, the study has three key secondary outcomes. The following 
sections describe the plan for analyzing them. 
6.13.1 
 Change from Baseline Six Minute Walk Test at Week 24 
Descriptive statistics showing the raw values and changes from baseline for the 6MWT will be 
presented for each scheduled visit by treatment group.  
A longitudinal model with change from baseline as the outcome variable, implemented through 
SAS PROC MIXED, will be used to analyze the data.  The model will include all measurements 
of 6MWT.  Baseline treprostinil use at time of randomization and baseline average 6MWT will 
be covariates. The model will include terms for the interaction between visit number and 
treatment.  The contrast between treatment groups as Week 24 will be calculated from the model.  
proc mixed data=(INPUT DATA SET) alpha=0.05; 
 
class subjid treatment treprostinil_use visitnum; 
 
model change_in_6MWT = baseline_6MWT treprositinal_use treatment visitnum 
visitnum*treatment /ddfm=kr; 
 
repeated visitnum / subject=subject type=UN r; 
 
lsmeans treatment*visitnum/diff om cl; 
 
run; 
Note that visit numbers are used as categorical variables, not as continuous measures of time. 
Note also the use of om as an option in the lsmeans statement.  This option allows the 
distribution of the categories, as observed in the data, to be used for the computation of the 
estimates.  
Least square (LS) means for baseline-adjusted 6MWT for each treatment group, LS means of 
treatment group differences with their associated p-values and 95% CIs for both will be 
summarized and presented.   
Multiple imputation, assuming that patients who stop study medication will adopt the experience 
in the placebo group, will be used to account for missing data. An addendum to this protocol, to 
be written before the data are unblinded, will present the SAS program to be used for the 
multiple imputation. 
Sensitivity analyses will explore the extent to which multiple imputation of Week 24 data 
influences the interpretation of the outcome.  One sensitivity analysis will assume that all 
subjects without Week 24 data would have continued on their assigned treatment through the end 
of the study; another sensitivity analysis will use the longitudinal model described above without 
any imputation for missing data.  Other planned sensitivity analyses will be described in an 
addendum to this SAP, which will be completed after the Blind Data Review. 


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6.13.2 
Time to Clinical Failure  
As with TtCW, subjects who did not experience a clinical worsening and who did not receive at 
least 24 weeks of treatment will be censored at their last study visit. 
The TtCF (in days) will be analyzed using the SAS procedure LIFETEST to calculate the log-
rank statistic and p-value to compare treatment groups.  The analysis statement will be of the 
form:   
proc lifetest data= set plots=survival; 
      time TtCF * status(0); 
      strata treprostinil_use /  group=treatment test=logrank; 
      run; 
A Cox model, with baseline treprostinil use as a covariate, will be used to estimate the hazard 
ratio and its 95% CI. 
Graphical displays, including Kaplan-Meier curves, and tabulations of TtCF and the individual 
components and the composite endpoint will be presented by treatment group.  
Supportive and sensitivity analyses similar to those planned for TtCW will be conducted. 
6.13.3 
Worsening from Baseline of WHO Functional Class at Week 24 
The WHO defines four functional classes for patients with PAH.  In order to enter this trial, 
subjects had to be in Class III or IV.  For the purpose of analysis of worsening WHO functional 
class, the WHO categorization will be augmented with a fifth class, death.  At Week 24, each 
subject will be classified as improved, unchanged, or worsened from baseline.  Those who die 
will be classified as worsened.  
Multiple imputation will be used to impute those who are still alive but do not have a 
measurement of WHO Functional Class at Week 24.  Predictor variables will be baseline and 
Week 12 WHO class, 6MWT, and Borg score.  Imputation of missing data for subjects in either 
treatment group will be based on subjects in the placebo arm to minimize assumptions of missing 
at random for the treated group. One hundred datasets will be imputed and SAS PROC 
MIANALYZE will be used to compare the treatment groups will respect to the proportion of 
worsening from baseline in WHO Functional Class at Week 24 using Cochran-Mantel-Haenszel 
statistics stratified by baseline inhaled treprostinil use.   
Summaries will include the rates by treatment, test statistic, p-value, and the odds ratio.  
6.14 Other Secondary Analyses 
The study has the following other secondary outcomes: 
• Outcomes at 12 weeks  change from baseline in the following: 
- 
6MWT  
- 
WHO Functional Class 


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- 
Borg Dyspnea Score 
- 
NT-pro-BNP levels 
• Outcomes at 24 weeks  change from baseline in the following: 
- 
Borg Dyspnea Score 
- 
NT-pro-BNP levels 
• Total mortality (censored if lost to follow up) 
 
6.14.1 
Change from Baseline in 6MWT at Week 12 
The model used to test the 6MWT at Week 24 (see Section 6.13.1) will be applied to Week 12; 
however, the contrast at Week 12 will be used instead of the contrast at Week 24. 
6.14.2 
Worsening from Baseline in WHO Functional Class at Week 12 
The method described in Section 6.13.3 will be used to analyze the data at Week 12 substituting 
the phrase “Week 12” for “Week 24”.  For the multiple imputation, only baseline variables will 
be used. 
6.14.3 
Change in Borg Dyspnea Score at Weeks 12 and 24 
The Borg Dyspnea Score is an 11 point scale measuring the degree of dyspnea from 0, or 
“nothing at all”, to 10, or “panic level”.  Descriptive statistics of the raw and change from 
baseline values for Borg Dyspnea Score will be presented for each scheduled visit by treatment 
group.  A score of 11 will be assigned to subjects who died.  The Borg score will be treated as a 
continuous variable. 
A longitudinal model will be used to describe the change from baseline in Borg score over time.  
Contrasts will be calculated at Weeks 12 and 24 to compare the treatment groups with respect to 
change.  The outcome variable will be change from baseline.  Independent variables will be 
treatment, inhaled treprostinil use baseline Borg, visit number, and the interaction of visit and 
treatment. 
Multiple imputation, assuming that patients who stop study medication will adopt the experience 
in the placebo group, will be used to account for missing data. An addendum to this protocol, to 
be written before the data are unblinded, will present the SAS program to be used for the 
multiple imputation. 
Sensitivity analyses will explore the extent to which multiple imputation of Week 24 data 
influences the interpretation of the outcome.  One sensitivity analysis will assume that all 
subjects without Week 24 data would have continued on their assigned treatment through the end 
of the study; another sensitivity analysis use the longitudinal model described above without any 
imputation for missing data.  Other planned sensitivity analyses will be described in an 
addendum to this SAP, which will be completed after the Blind Data Review. 


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6.14.4 
NT-pro-BNP at Weeks 12 and 24 
Descriptive statistics of the raw values and changes from baseline NT-pro-BNP will be presented 
for each scheduled visit by treatment group.  Because the parameter is highly skew, the data will 
be log-transformed before analysis.  A longitudinal model will be used to describe log NT-pro-
BNP over time.  The outcome variable will be the value at each time of measurement, not the 
change from baseline.  Independent variables will be treatment, inhaled treprostinil use, baseline 
log NT-pro-BNP, visit number, and the interaction of visit and treatment.  Contrasts will be 
calculated at Weeks 12 and 24 to compare the treatment groups with respect to level of the 
parameter.  
These contrasts will be on the log scale.  In order to provide summary statistics that are easily 
clinically interpretable, the estimates may be back transformed to the natural scale and the 
change from baseline may be calculated as the difference between the mean of the back-
transformed estimates and the mean of the baseline value.  
Multiple imputation, assuming that patients who stop study medication will adopt the experience 
in the placebo group, will be used to account for missing data. An addendum to this protocol, to 
be written before the data are unblinded, will present the SAS program to be used for the 
multiple imputation. 
Sensitivity analyses will explore the extent to which multiple imputation of Week 24 data 
influences the interpretation of the outcome.  One sensitivity analysis will assume that all 
subjects without Week 24 data would have continued on their assigned treatment through the end 
of the study; another sensitivity analysis use the longitudinal model described above without any 
imputation for missing data.  Other planned sensitivity analyses will be described in an 
addendum to this SAP, which will be completed after the Blind Data Review. 
6.14.5 
Total Mortality 
Vital status will be assessed for each randomized subject through the end of the study. All 
subjects who discontinue the study, either for premature termination or for meeting a primary 
endpoint of clinical worsening, will continue to be followed, to the extent possible, for vital 
status until the sponsor concludes the study. Subjects who are lost to follow-up will be censored 
at the date known alive.  The total mortality (all cause death) in the two treatment groups will be 
evaluated with a Cox regression analysis to provide an estimated hazard ratio and corresponding 
95% CI.   
Time-to-death analyses will use the following SAS code with different rules for the variable 
status(0). 
proc lifetest data= set plots=survival; 
  
time TtCW * status(0); 
  
strata treprostinil_use /  group=treatment test=logrank; 
  
run; 


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Deaths are categorized as Cardiovascular related, PAH related, and other.  A table will show the 
proportion of deaths, by treatment arm, in each category.  Sensitivity analyses for this table will 
be described in an addendum to this SAP, which will be completed after the Blind Data Review. 
6.15 Subgroup Analysis 
Primary and secondary efficacy analyses will be conducted on the overall subject population.  
Subgroup analyses will be performed to explore the efficacy of esuberaprost in different subject 
populations.  The subgroups will include, but not be limited to: 
• age (<65, ≥65 years);  
• sex (males, females);  
• race (white, non-white);  
• ethnicity (Hispanic or Latino, non-Hispanic or Latino);  
• PAH etiology [idiopathic or familial, associated with collagen vascular disease, associated 
with HIV infection, induced by anorexigens/toxins, associated with repaired congenital 
systemic-to-pulmonary shunts (repaired ≥1 years)];  
• background PAH therapy (ERA, PDE-5 inhibitor, and riociguat); 
• background inhaled treprostinil (experienced or naïve); 
• baseline WHO Functional Class;   
• years of PAH;  
• baseline average 6MWT;  
• baseline average Borg Dyspnea Score; and  
• country of clinical site (US, Israel).   
 
Continuous covariates will be presented by quartiles. Results will be presented using point 
estimates and associated 95% CIs both in tables and forest plots.  Because the study was not 
designed to have high power for small or even moderate sized subgroups, these analyses will be 
considered exploratory. 
 
7 
ANALYSIS OF SAFETY 
The safety assessments will consist of extent of exposure, AEs including SAEs, laboratory 
evaluations, vital signs, and ECG findings.   
All safety analyses will be based on the Safety Population.  No formal inferential testing will be 
reported for routine safety analyses.  
7.1 
Extent of Exposure  
Exposure to study drug will be calculated as the date of last dose of IMP minus the date of the 
first dose of IMP plus 1. If the date of last dose of study drug was missing or unknown and the 


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last drug record had no return date, no assumption will be made for exact exposure. These 
analyses will include: 
• Duration of exposure (in months) 
• Number exposed by time (weekly to 3 months, 3-6 months, 6-12 months, 12-24 months, 
24-36 months, ≥36 months) 
• Number exposed by dose (15 µg, 30 µg) by time (weekly to 3 months, 3-6 months, 6-12 
months, 12-24 months, 24-36 months, ≥36 months) 
• Maintenance dose during the study (dose subject maintained on IMP after titration period) 
 
Exploratory analyses may be conducted to assess IMP exposure within subgroups (see Sections 
6.7.1 and 6.7.2).  If appropriate, graphs will display the use of IMP over time.  
Similar presentations will be made for inhaled treprostinil use during the study.  
7.2 
Adverse Events 
AEs are recorded throughout the study and at early termination.  They are coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary (the database will 
document the version current at time of data lock).  
7.2.1 
Treatment-Emergent Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the IMP or any event already present that worsens in either intensity or frequency 
following exposure to the IMP.  
Only TEAEs occurring after IMP exposure will be summarized.  Any AE starting prior to the 
first dose of IMP (i.e., during the screening period) will be excluded from the summary analyses.    
The following notes the planned presentations of TEAEs. Other presentations for TEAEs may be 
produced to support the sponsor’s review and analyses of events of special interest.  
7.2.2 
Date of Onset of Adverse Event 
The onset date of each AE will be assigned the date recorded on the eCRF.  
If the day part of the onset date is missing, then the onset date will be imputed as having 
occurred on the first day of the given month and year; however, when the first dose of IMP was 
taken in the same given month and year, then the onset date will be imputed as the day of the 
first dose of IMP. 
If the month and day of the onset date are missing, then the onset date will be imputed as having 
occurred on the first month and first day of the given year; however, when the first dose of IMP 
was taken in the same given year, then the onset month and day parts will be imputed as the 
month and day of the first dose of IMP. 


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In the unlikely event that the onset date is fully missing, then the onset date will be set to the date 
of first dose of IMP. 
If the imputed date is later than the reported stop date, the imputed date will be set equal to the 
stop date.  This conservative scheme ensures that an AE with partial or complete onset date will 
be treated as a TEAE. 
7.2.3 
Intensity Rating 
The Investigator classifies AEs into one of the following intensity categories:  ‘Mild’, 
‘Moderate’, and ‘Severe’ (see study protocol). 
7.2.4 
Relationship to Study Drug 
The Investigator classifies AEs into one of the following categories with respect to IMP 
causality: ‘Certain’, ‘Probably related’, ‘Possibly related’, ‘Unlikely to be related’, ‘Unrelated 
‘or ‘Unassessable/Unclassifiable’ (see study protocol). 
For analytic purposes, ‘Certain’, ‘Probably related’, and ‘Possibly related’ will be classified as 
“Related” AEs and ‘Unlikely to be related’, ‘Unrelated’ and ‘Unassessable/Unclassifiable’ as 
“Unrelated” AEs. 
7.2.5 
Relationship to Background Therapy 
The Investigator classifies AEs into one of the following categories with respect to background 
PAH drug causality, including treprostinil inhaled: ‘Certain’, ‘Probably related’, ‘Possibly 
related’, ‘Unlikely to be related’, ‘Unrelated ‘or ‘Unassessable/Unclassifiable’ (see study 
protocol). 
For analytic purposes, ‘Certain’, ‘Probably related’, and ‘Possibly related’ will be classified as 
“Related” AEs and ‘Unlikely to be related’, ‘Unrelated’ and ‘Unassessable/Unclassifiable’ as 
“Unrelated” AEs. 
7.2.6 
Action Taken with Study Drug 
For each AE, the investigator classifies the action taken with the IMP under one of the following: 
‘IMP Dose Increased’, ‘IMP Dose Not Changed’, ‘IMP Dose Reduced’, ‘IMP Drug Temporarily 
Discontinued’, ‘IMP Withdrawn’, ‘Unknown’, or ‘Not applicable’ (see study protocol). 
7.2.7 
Summary of Treatment-Emergent Adverse Events 
A summary of all TEAEs will present numbers and percentages of the following by treatment 
group: 
• Subjects with at least one TEAE 
• Subjects with at least one IMP-related TEAE 
• Subjects with at least one TEAE related to PAH background medication 
• Subjects with at least one serious TEAE 


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• Subjects with a TEAE leading to permanent discontinuation of IMP 
 
7.2.8 
Subjects with a TEAE leading to dose modifications of IMP Summaries of 
Adverse Events 
TEAEs will be separately summarized by treatment group for the following: 
• Total number of TEAEs, total number subjects with at least one TEAE 
• TEAEs by severity  
• TEAEs by relationship to IMP  
• TEAEs by relationship to PAH background medication  
• TEAEs by action taken with IMP  
• TEAEs leading to study withdrawal 
 
TEAEs will be presented in alphabetical order of SOC and by decreasing order of incidence of 
the preferred terms. 
For these summaries, a subject having the same TEAE multiple times will only be counted once 
for the corresponding preferred term.  Similarly, a subject who experienced multiple TEAEs 
within the same SOC will be counted only once for that SOC.  
A subject experiencing the same TEAE multiple times or at multiple severities will only be 
counted once under that preferred term at the worst severity rating.  Similarly, a subject who 
experiences the same TEAE multiple times or at multiple severities across multiple preferred 
terms within the same SOC will only be counted once for the worst severity rating within the 
SOC. 
A subject experiencing the same TEAE multiple times or at multiple relationships to IMP will 
only be counted once for the worst relationship to IMP within a preferred term.  Similarly, a 
subject who experiences the same TEAE multiple times or at multiple relationships to IMP 
across multiple preferred terms within the same SOC will only be counted once for the worst 
relationship to IMP within the SOC.  The same procedure will be used for relationship to PAH 
background medication. 
A subject experiencing the same TEAE multiple times or at multiple actions taken to IMP will 
only be counted once for the worst action taken with IMP within a preferred term.  Similarly, a 
subject who experiences the same TEAE multiple times or at multiple actions taken to IMP 
across multiple preferred terms within the same SOC will only be counted once for the worst 
action taken to IMP within the SOC. 
 


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7.2.9 
Subgroup Analysis 
TEAEs will be summarized similarly within subgroups: male, female, <65 years old, ≥ 65 years 
old, Caucasian, Non-Caucasian, and each PAH etiology. Other subgroups may be examined if 
suggested by the data. 
7.2.10 
Clinical Laboratory Evaluations 
Laboratory tests for serum chemistry, hematology, coagulation, urinalysis, and pro-NT-BNP 
were performed by a certified central laboratory 
 
, and laboratory results were forwarded to the 
site.  Electronic data were automatically uploaded weekly into the subject’s eCRF as specified 
with the eCRF vendor and 
.   
If a clinical site used a local laboratory instead of the central laboratory, the local laboratory will 
provide the values to the investigator and the sponsor.  These data will be included into the 
database.  Results will be transformed for consistency into the same units and normal ranges 
used by the study’s central laboratory (
), applying the formula: 
 
where x = original value, Li and Ui = lower and upper limits of normal for individual laboratory, 
Lc and Uc = lower and upper limit for central laboratory 
If the lower limit of the central laboratory is 0, values below the lower limit of normal for a 
laboratory value prior to transformation will be assigned the value 0.  If there is no upper limit 
for a test, the following formula will be used: 
 
In cases of missing units for a test, missing limits of central laboratory or an alternative test is 
performed than specified in the study protocol (e.g., absolute value instead of percent for 
hematology), transformed values will be set to missing; however, the non-missing flags for 
clinically significant values, as defined by the investigator, will be retained with transformed 
values for summaries.  Transformed results for clinical laboratory tests will be used for all 
summaries and presentations. Summaries and presentations will be made using standard units. 
Descriptive statistics for each clinical laboratory parameters (hematology, serum chemistry and 
coagulation) will be presented by treatment group at baseline, each post-baseline assessment, and 
End of Study visits for raw data and change from baseline (see Section 6.3.2).  
Post-baseline clinically significant values, as defined by the investigator, for hematology, serum 
chemistry, coagulation, and urinalysis parameters will be summarized as transition tables from 
baseline to each post-baseline assessment and End of Study visits.  


Lc
Li
Lc
Li
x
y





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Tables will contain the number and percentage of subjects by treatment group with post-baseline 
clinically significant categories (low, high, and normal for hematology, chemistry, and 
coagulation; abnormal and normal for urinalysis) compared to baseline category for each 
parameter. 
7.2.11 
Vital Signs 
Descriptive statistics for vital signs (temperature, heart rate/pulse, systolic blood pressure, 
diastolic blood pressure, respiration rate, weight, height, BMI) will be presented by treatment 
group at baseline, at each post-baseline assessment, and End of Study visits for the raw data and 
change from baseline.    
7.2.12 
ECG Evaluations 
Descriptive statistics for ECG findings (heart rate, PR interval, QRS interval, QT interval, QTc 
interval (original and standardized across reports), sinus rhythm (normal, abnormal), ECG results 
(normal, abnormal), abnormality reported) will be presented by treatment group, at baseline, at 
each post-baseline assessment, and End of Study visits for raw data and change from baseline 
(see Section 6.3.2).  Whenever more than one ECG are read occurs on the same day, the data 
summaries will use the average of these readings. 
In addition, a summary of subjects with treatment-emergent clinically significant values will be 
presented by treatment group.  Presentation will be made in order of decreasing incidence by 
type of abnormality with the number and percentage of subjects who experienced the type of 
abnormality. 
7.3 
Physical Examinations 
Any value the Investigator judges to be a clinically significant abnormal change after the 
subject’s consent to the study was to be recorded as an AE.   
7.4 
Interim Analyses and Data Monitoring 
No formal interim efficacy analyses were planned or conducted.  
An independent external statistical group (
 performed interim safety 
analyses.  Only the Data Safety Monitoring Board reviewed these data in order to monitor the 
safety of the subjects in the study.  Lung Biotechnology and all other employees of 
 
remained blinded throughout the conduct of this 
study. 


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8 
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2. Benza, R. L., W. Seeger, V.V. McLaughlin, R. N. Channick, R. Voswinckel, V. F. Tapson, I. 
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8. Lakatos, E., and K. K. G. Lan. 1992. "A comparison of sample size methods for the logrank 
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11. Royston, P., and F.M.-S. Barthel. 2010. "Projection of power and events in clinical trials with 
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12. Schulz, K.F., D.G. Altman, and D. Moher. 2010. "CONSORT 2010 Statement: updated 
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13. Simes, R. J. (1986). An improved Bonferroni procedure for multiple tests of significance. 
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14. Sitbon, O., R. Channick, K. M. Chin, A. Frey, S. Gaine, N. Galie, H.-A. Ghofrani, et al. 
2015. "Selexipag for the treatment of pulmonary arterial hypertension." New England 
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15. 2011. "The SAS System,Version 9.3." SAS Institute, Inc. Cary, NC. 
16. Voswinckel, R., F. Reichenberger, H. Gall, T. Schmehl, T. Gessler, R. T. Schermuly, F. 
Grimminger, et al. 2009. "Metered dose inhaler delivery of treprostinil for the treatment of 
pulmonary hypertension." Pulmonary Pharmacology & Therapeutics 22 (1): 50-56. 


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Appendix 1 Adjudication Committee Case Report Form 




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