An Observational Study to Characterize Patient Global Impression Questions for Activity-induced Symptoms in Patients With Pulmonary Arterial Hypertension (PAH)
Conditions: Pulmonary Arterial Hypertension
Sponsor: United Therapeutics

United Therapeutics Corp. 
RIN-PRN-201 Original Protocol 
Lung Biotechnology PBC 
Treprostinil for PRN Inhalation Spray 
CONFIDENTIAL AND PROPRIETARY, UNITED THERAPEUTICS CORPORATION 
All content contained herein is confidential and proprietary information of United Therapeutics 
Corporation and shall not be disclosed in whole or in part except as permitted by a signed contract with 
United Therapeutics Corporation. © 2019 United Therapeutics Corporation 
 
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An Observational Study to Characterize Patient Global 
Impression Questions for Activity-induced Symptoms in Patients 
with Pulmonary Arterial Hypertension 
IND Number 138,142 
Protocol RIN-PRN-201 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
31 January 2019 
 
 
 
 
 
 
 
 
 
 
 
 

United Therapeutics Corp. 
RIN-PRN-201 Original Protocol 
Lung Biotechnology PBC 
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LIST OF CONTACTS FOR STUDY 
Study Sponsor 
 
 
Study Medical Monitor 
 
 
United Therapeutics Corp. 
55 TW Alexander Drive  
Research Triangle Park, NC 27709 
 
 
 
 
 
Study Conducted by 
Lung Biotechnology PBC 
1040 Spring Street 
Silver Spring, MD 20910 
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
SAE Reporting 
UTC Global Drug Safety 
55 TW Alexander Drive  
Research Triangle Park, NC 27709 
Email: drugsafety@unither.com 
Fax: (919) 313-1297 
 
 

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RIN-PRN-201 Original Protocol 
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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “An Observational Study to Characterize Patient 
Global Impression Questions for Activity-induced Symptoms in Patients with Pulmonary 
Arterial Hypertension” dated 31 January 2019 and agree to abide by all provisions set forth 
therein. 
I agree to comply with the International Council for Harmonization (ICH) 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 evaluation or conduct of the clinical investigation without the 
prior written consent of United Therapeutics Corp. 
This protocol has been received for information only and must not be implemented before all 
necessary regulatory agency and Ethics Committee (EC)/Institutional Review Board (IRB) 
approval documents have been obtained. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 

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PROTOCOL SYNOPSIS 
Title  
An Observational Study to Characterize Patient Global 
Impression Questions for Activity-induced Symptoms in 
Patients with Pulmonary Arterial Hypertension 
Study Phase 
2 
Indication 
Pro Re Nata (PRN) “as needed” prevention and/or 
treatment of episodic/activity-induced symptoms in patients 
with pulmonary arterial hypertension (PAH)  
Primary Objective 
 To characterize the psychometric properties and 
performance of Patient Global Impression of Severity 
(PGI-S) questions, designed to measure severity, 
character, and duration of patients’ self-reported 
symptoms of PAH following effort.  
Secondary Objectives 
 To characterize the relationship of PGI-S questions 
with: 
o Borg dyspnea score 
o Oxygen saturation 
o Heart rate (HR) 
o HR recovery at 1 minute after the ISWT 
 To characterize the recovery profile for activity-induced 
symptoms 
Safety Objectives 
 To evaluate safety based on: 
o Adverse events (AEs) 
o Vital sign measurements 
Study Design 
This is an observational, multicenter, single-day, Phase 2 
study.  This study will include a 14-day Screening Period 
and Study Day 1 clinic visit.  Subjects will be required to 
perform an activity to induce symptoms of PAH, and 
subjects’ severity of self-reported symptoms of PAH will be 
measured from pre-activity, immediately after the activity, 
and through the 30-minute recovery.  Subjects will be asked 
about their PAH symptoms using 3 PGI-S questions that 
address their overall PAH symptoms, shortness of breath, 
and physical fatigue. 
 
PAH symptoms will be induced via the Incremental Shuttle 
Walk Test (ISWT). 
 
The total number of shuttles completed by a subject during 
the Screening ISWT will be the maximum targeted for that 
subject during the remaining ISWTs in the study.     
 

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After Screening, subjects will be assigned to 1 of 2 cohorts 
based on PAH medications as prescribed by their physician: 
Cohort A will include subjects who are currently prescribed 
and using inhaled treprostinil for the treatment of PAH and 
Cohort B will include subjects who are taking other PAH 
medications (instead of inhaled treprostinil).  
Subjects in Cohort A will be assigned to 1 of 2 sequences: 
Sequence 1: 
 Period 1: The ISWT will be initiated 3 to 4 hours after a 
subject’s previous dose of inhaled treprostinil (expected 
trough level).  Activity will be timed to allow all 
procedures, including recovery, to be completed prior to 
Period 2. 
 Period 2: The ISWT will be initiated within 
approximately 30 minutes of the previous inhaled 
treprostinil dose (expected peak level).  Following 
recovery and the Investigator’s confirmation of return to 
baseline status, the subjects will be discharged from the 
study.  
Sequence 2: 
 Period 1: The ISWT will be initiated within 
approximately 30 minutes of the previous inhaled 
treprostinil dose (expected peak level).  Activity will be 
timed to allow all procedures, including recovery, to be 
completed prior to Period 2.  
 Period 2: The ISWT will be initiated 3 to 4 hours after a 
subject’s previous dose of inhaled treprostinil (expected 
trough level). Following recovery and Investigator’s 
confirmation of return to baseline status, the subjects 
will be discharged from the study. 
 
Subjects in Cohort B will also undergo 2 activity periods: 
 Period 1: The ISWT will be initiated approximately 
4 hours after the morning dose of PAH medication.  
 Period 2: The ISWT will be initiated at least 1 hour 
following completion of the previous ISWT.  Following 
recovery and the Investigator’s confirmation of return to 

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baseline status, the subjects will be discharged from the 
study. 
 
The baseline PGI-S and Borg dyspnea score assessments 
will be conducted prior to (-15 and 0 minutes; pre-ISWT) 
activity that is typically expected to induce symptoms of 
PAH.  The subject will initiate activity (ISWT), and these 
same assessments will be performed immediately at the end 
of the ISWT (within 1 minute of completing the activity).  
The PGI-S assessments will also be performed throughout 
recovery following completion of the ISWT.  Continuous 
pulse oximetry will be performed at each clinic visit 
starting at each pre-ISWT and through recovery.  Vital sign 
assessments will be performed at the beginning and at the 
end of each clinic visit. 
 
On Day 1, subjects will be provided rest between the 
2 ISWTs (at least 1 hour).  
 
The total study duration for a subject, including the 
Screening Period, will be up to 15 days. 
Sample Size 
Approximately 40 subjects will be enrolled in this study to 
ensure at least 36 evaluable subjects complete the study.    
Summary of Subject 
Eligibility Criteria 
Inclusion criteria: 
Subjects who meet the following criteria may be included 
in the study: 
1. Subject voluntarily gives informed consent to 
participate in the study. 
2. Males and females aged 18 years and above at the time 
of informed consent. 
3. Established primary diagnosis of PAH that is either 
idiopathic or familial PAH (World Health Organization 
[WHO] Group 1), collagen vascular disease associated 
PAH, PAH associated with human immunodeficiency 
virus (HIV) infection, PAH induced by 
anorexigens/toxins, or PAH associated with repaired 
congenital systemic-to-pulmonary shunts (repaired 
≥1 year). 
4. Subject is deemed WHO Functional Class I, II, or III. 
5. Subject has shortness of breath upon exertion (exhibits a 
≥1-point change in Borg dyspnea score) as assessed by 
the ISWT and a minimum completion of 3 shuttles 
(30 meters) of the ISWT. Subject may have other 
symptoms as well. 

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6. Subject is on stable dose of all prescribed FDA-
approved PAH treatments (exceptions are 
anticoagulants and diuretics) for at least 60 days prior to 
Screening.  
7. In the opinion of the Investigator, the subject can 
communicate effectively with study personnel and is 
considered reliable, willing, and likely to be cooperative 
with protocol requirements. 
 
Exclusion Criteria: 
The following will exclude potential subjects from the 
study: 
1. The subject is known to be pregnant or nursing. 
2. The subject has 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, chronic thromboembolic pulmonary 
hypertension, or other conditions under WHO Group 2, 
3, 4, and 5 classifications. 
3. The subject has evidence of clinically significant left-
sided heart disease (including, but not limited to, left 
ventricular ejection fraction 40%, left ventricular 
hypertrophy) or clinically significant cardiologic 
conditions, such as congestive heart failure, coronary 
artery disease, or valvular heart disease.  
4. The subject has any form of congenital heart disease 
(repaired or unrepaired; other than a patent foramen 
ovale). 
5. 
The subject has any ambulatory or orthopedic 
limitations that would interfere with the ability to 
perform the activity. 
6. The subject has been hospitalized within 30 days of 
Screening. 
7. Current use of prostacyclin analogs/agonists, except 
inhaled treprostinil, for the treatment of PAH. 
8. Use of any other investigational drug/device, or 
participation in any investigational study with 
therapeutic intent within 30 days of Screening 
(concurrent participation in registry studies is allowed). 
9. Any other clinically significant illness 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.  

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Drug Dosage  
and Formulation 
Not applicable.  
 
Control Group 
None. 
Route of  
Administration 
Not applicable. 
Procedures 
The procedures are as follows: 
 PGI-S question assessments performed at each clinic 
visit at Pre-ISWT (-15 and at 0 minutes prior to 
inducement of symptoms), at the end of the ISWTs 
(within 1 minute of completing the activity), every 
minute for the first 5 minutes of recovery followed by 
every 5 minutes for the remainder of the 30-minute 
recovery. 
 Pulse oximetry to be performed continuously.  Pulse 
oximetry will include the collection of SpO2 and HR.  
Pulse oximetry will start at the beginning of pre ISWT 
(15 minutes prior to the ISWT) and will be continuous 
through the end of recovery of each individual period.  
The SpO2 and HR measures obtained at -15 and at 
0 minutes (prior to activity), every minute during the 
ISWT, every minute for the first 5 minutes of the 
recovery, followed by every 5 minutes for the 
remainder of the 30-minute recovery will be recorded in 
the subject’s source documents and eCRF.     
 Borg dyspnea score performed at each clinic visit at 
pre-ISWT (-15 and at 0 minutes prior to inducement of 
symptoms) and immediately at the end of the ISWTs 
(within 1 minute of completing the activity). 
 Vital signs (systolic blood pressure, diastolic blood 
pressure) will be assessed at Screening (prior to any 
activity and after recovery) and on Day 1 (prior to 
initiating Period 1 assessments and prior to discharge). 
 Following completion of all study procedures, and the 
Investigator deems that the subject has returned to 
baseline status, per pulse oximetry readings, the subject 
will be discontinued from the clinic. 
Statistical Considerations Sample size: Approximately 40 male and female subjects 
will be enrolled, with the plan to have at least 36 evaluable 
subjects complete the study.   
 

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Data for all measurements will be tabulated overall and by 
cohort using descriptive statistics appropriate to the data. 
No formal statistical analyses are planned. 
Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive 
Research Triangle Park, NC 27709 
United States of America 
 
Study Conducted by 
Lung Biotechnology PBC 
1040 Spring Street 
Silver Spring, MD 20910 
United States of America 

United Therapeutics Corp. 
RIN-PRN-201 Original Protocol 
Lung Biotechnology PBC 
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Version Date – 31 January 2019 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
DBP 
Diastolic blood pressure 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISWT 
Incremental Shuttle Walk Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
PAH 
Pulmonary arterial hypertension 
PGI-S 
Patient Global Impression of Severity 
PRN 
Pro Re Nata 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SpO2 
Saturation peripheral capillary oxygenation 
UTC 
United Therapeutics Corporation 
WHO 
World Health Organization 
WHODrug 
World Health Organization Drug Dictionary 
 

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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY .................................................................................... 2 
INVESTIGATOR’S AGREEMENT ..................................................................................... 3 
PROTOCOL SYNOPSIS ....................................................................................................... 4 
LIST OF ABBREVIATIONS .............................................................................................. 10 
TABLE OF CONTENTS ...................................................................................................... 11 
Table of In-Text Tables ........................................................................................................ 13 
1 BACKGROUND AND RATIONALE .......................................................................... 14 
1.1 
DEFINITION OF CLINICAL PROBLEM ............................................................. 14 
1.2 
CLINICAL HYPOTHESIS ....................................................................................... 15 
2 OBJECTIVES ................................................................................................................. 15 
2.1 
PRIMARY OBJECTIVES ........................................................................................ 15 
2.2 
SECONDARY OBJECTIVES .................................................................................. 15 
2.3 
SAFETY OBJECTIVES ............................................................................................ 16 
3 EXPERIMENTAL PLAN .............................................................................................. 16 
3.1 
STUDY DESIGN ........................................................................................................ 16 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ............................................ 20 
3.3 
CLINICAL ASSESSMENTS .................................................................................... 22 
3.3.1 
Efficacy ................................................................................................................... 22 
3.3.2 
Safety ...................................................................................................................... 22 
3.3.2.1 
Medical History and Demographics ................................................................. 22 
3.3.2.2 
Vital Signs ........................................................................................................... 22 
3.3.2.3 
Oxygenation (Pulse Oximetry).......................................................................... 22 
3.3.2.4 
Adverse Events ................................................................................................... 23 
3.3.3 
Concomitant Medications ..................................................................................... 23 
3.3.4 
Assessment of PGI-S Questions and Borg Dyspnea Scores ............................... 23 
3.3.4.1 
Incremental Shuttle Walk Test ......................................................................... 23 
3.3.4.2 
PGI-S Questions ................................................................................................. 24 
3.3.4.3 
Borg Dyspnea Score ........................................................................................... 24 
3.4 
NUMBER OF CENTERS .......................................................................................... 24 
3.5 
NUMBER OF SUBJECTS ........................................................................................ 25 
3.6 
ESTIMATED STUDY DURATION ......................................................................... 25 
4 SUBJECT ELIGIBILITY .............................................................................................. 25 
4.1 
INCLUSION CRITERIA .......................................................................................... 25 
4.2 
EXCLUSION CRITERIA ......................................................................................... 25 
4.3 
PRESCRIBED THERAPY ........................................................................................ 26 
5 SUBJECT ENROLLMENT ........................................................................................... 26 
5.1 
TREATMENT ASSIGNMENT ................................................................................ 26 
5.2 
ENROLLMENT ......................................................................................................... 26 

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5.3 
SEQUENCE ASSIGNMENT FOR COHORT A .................................................... 27 
5.4 
BLINDING .................................................................................................................. 27 
6 DRUGS AND DOSING (OR TREATMENT PROCEDURES) ................................. 27 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE ................................. 27 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT ..................................... 27 
6.3 
COMPLIANCE .......................................................................................................... 27 
7 EXPERIMENTAL PROCEDURES ............................................................................. 27 
7.1 
SCREENING PERIOD (STUDY DAYS -14 TO -1) ............................................... 27 
7.1.1 
Pre-ISWT ............................................................................................................... 28 
7.1.2 
ISWT ....................................................................................................................... 28 
7.1.3 
ISWT Recovery ...................................................................................................... 29 
7.2 
STUDY DAY 1 ............................................................................................................ 29 
7.2.1 
Cohort A ................................................................................................................. 30 
7.2.1.1 
Sequence 1/Period 1 ........................................................................................... 30 
7.2.1.2 
Sequence 1/Period 2 ........................................................................................... 31 
7.2.1.3 
Sequence 2/Period 1 ........................................................................................... 32 
7.2.1.4 
Sequence 2/Period 2 ........................................................................................... 34 
7.2.2 
Cohort B ................................................................................................................. 35 
7.2.2.1 
Period 1 ............................................................................................................... 35 
7.2.2.2 
Period 2 ............................................................................................................... 36 
7.2.3 
Discharge ................................................................................................................ 37 
8 STUDY TERMINATION ............................................................................................... 38 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ....................................................... 38 
8.2 
CRITERIA FOR TERMINATING THE STUDY .................................................. 38 
8.3 
CRITERIA FOR DISCONTINUING A SITE ........................................................ 38 
9 ADVERSE EVENT REPORTING ................................................................................ 38 
9.1 
DEFINITIONS ........................................................................................................... 39 
9.1.1 
Adverse Event ........................................................................................................ 39 
9.1.2 
Serious Adverse Event .......................................................................................... 39 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ..................................................... 39 
9.3 
FOLLOW UP OF ADVERSE EVENTS .................................................................. 40 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ....................... 40 
9.5 
SAFETY REPORTS .................................................................................................. 40 
10 STATISTICAL CONSIDERATIONS .......................................................................... 40 
10.1 DATA PROCESSING ................................................................................................ 41 
10.2 SAMPLE SIZE ........................................................................................................... 41 
10.3 ANALYSIS PLAN ...................................................................................................... 41 
10.3.1 
Efficacy Endpoint(s) .............................................................................................. 42 
10.3.2 
PGI-S Questions Assessment ................................................................................ 42 
10.3.3 
Safety Analyses ...................................................................................................... 43 

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10.4 INTERIM ANALYSIS ............................................................................................... 43 
10.5 OTHER ANALYSES ................................................................................................. 43 
10.6 DATA LISTINGS AND SUMMARIES ................................................................... 43 
11 PACKAGING AND FORMULATION ........................................................................ 43 
11.1 CONTENTS OF STUDY DRUG .............................................................................. 43 
11.2 LABELING ................................................................................................................. 43 
11.3 STORAGE AND HANDLING OF CLINICAL STUDY MATERIAL ................. 44 
11.4 SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL .......................... 44 
11.5 DRUG ACCOUNTABILITY .................................................................................... 44 
12 REGULATORY AND ETHICAL OBLIGATION ...................................................... 44 
12.1 US FDA OR APPLICABLE REGULATORY REQUIREMENTS ...................... 44 
12.2 INFORMED CONSENT REQUIREMENTS ......................................................... 44 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ....................................................................................................................... 44 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ......................................... 45 
12.5 SUBJECT CONFIDENTIALITY ............................................................................. 45 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 46 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .......................... 46 
13.2 STUDY DOCUMENTATION AND STORAGE .................................................... 46 
13.3 STUDY MONITORING AND DATA COLLECTION .......................................... 46 
13.4 QUALITY ASSURANCE .......................................................................................... 47 
14 REFERENCES ................................................................................................................ 48 
15 APPENDICES ................................................................................................................. 49 
15.1 PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) QUESTIONS ..... 49 
15.2 INCREMENTAL SHUTTLE WALK TEST ........................................................... 50 
15.3 MODIFIED BORG DYSPNEA SCALE .................................................................. 52 
15.4 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE 
EVENTS ...................................................................................................................... 53 
 
Table of In-Text Tables 
Table 3-1 
Schedule of Time and Events .......................................................................... 20 

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1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
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 (McLaughlin 2009, Rubin 1997).  PAH can present with 
shortness of breath, chest tightness, exercise intolerance, dizziness, syncope, elevated 
respiratory and/or heart rate, decreased appetite, fatigue, chest and abdominal pain, lower 
extremity edema, and cyanosis. 
In a Food and Drug Administration (FDA)-supported forum of PAH patients (summarized in 
The Voice of the Patient-PAH meeting summary report, December 2014) participants 
reported that despite the availability of current PAH medications, therapies specifically 
focused on treating debilitating and functionally limiting symptoms represent an area where 
patient needs are currently not met.  Patients reported shortness of breath and fatigue, 
followed by dizziness and swelling of the legs and ankles, as having the greatest adverse 
impact on their daily life.  Due to the episodic nature of the appearance of these symptoms, 
patients avoid physical activities that trigger these symptoms, such as household chores, 
playing with children, or simply walking around.  Therefore, a therapeutic option that 
provides patients with greater control over treatment of their disease symptoms on an “as 
needed” basis would be beneficial. 
Pro Re Nata (PRN) use of pharmacological agents has a long history in the treatment of 
various conditions.  Examples where PRN treatment options have empowered patients to 
proactively effect a positive change in their medical condition and daily activity include 
symptomatic treatment of several pulmonary diseases, eg, asthma (Ventolin® HFA [albuterol 
sulfate; GlaxoSmithKline], Proventil® HFA [albuterol sulfate; Merck & Co. Inc.]) and chronic 
obstructive pulmonary disease (Proair® HFA [albuterol sulfate; Teva Respiratory, LLC]), as 
well as nonpulmonary diseases, such as patient-controlled pain management (Actiq® [fentanyl 
citrate; Cephalon, Inc.). 

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Episodic symptoms can be evaluated through the use of Patient Global Impression (PGI) 
questions.  A published review of US package inserts for drug approvals occurring between 
2006 to 2010 identified 20 approvals based on symptom-related primary endpoints 
(Gnanasakthy 2012).  Specifically, the drugs Savella® (approved 2009 [milnacipran HCl; 
Allergan Pharmaceuticals International Limited) and Simponi® (approved 2009 [golimumab; 
Janssen Pharmaceutical Companies]) were approved based on PGI measures.  Measurement 
of symptoms associated with PAH (eg shortness of breath and fatigue) should be shown as 
feasible. 
1.2 
CLINICAL HYPOTHESIS 
PGI questions can be used as endpoints in clinical studies to evaluate episodic symptoms of 
PAH.  Subjects will be asked about their PAH symptoms using 3 Patient Global Impression of 
Severity (PGI-S) questions that address their overall PAH symptoms, shortness of breath, and 
physical fatigue (Appendix 15.1).  The hypothesis is that the PGI-S questions will be sensitive 
to detect changes in activity-induced symptoms of PAH.  The Incremental Shuttle Walk Test 
(ISWT; Singh 1992) will be the activity used to induce symptoms in patients.  This ISWT 
requires the subject to walk back and forth on a 10-meter course (Appendix 15.2).  The speed 
at which the subject walks is dictated by an audio signal. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective of this study is to characterize the psychometric properties and 
performance of PGI-S questions, designed to measure the severity, character, and duration of 
patients’ self-reported symptoms of PAH following effort. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are the following:  
 To characterize the relationship of PGI-S questions with: 
 Borg dyspnea score 
 Oxygen saturation  
 Heart rate (HR) 
 HR recovery at 1 minute after the ISWT 

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 To characterize the recovery profile for activity-induced symptoms. 
2.3 
SAFETY OBJECTIVES 
Safety will be evaluated based on: 
1. Adverse events (AEs) 
2. Vital sign measurements 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is an observational, multicenter, single-day, Phase 2 study.  This study will include a 
14-day Screening Period and a Study Day 1 clinic visit.  The ISWT (Appendix 15.2) will be 
conducted to induce PAH symptoms and to measure PGI-S (Appendix 15.1).  Subjects will be 
asked about their PAH symptoms using 3 PGI-S questions that address their overall PAH 
symptoms, shortness of breath, and physical fatigue. 
The total number of shuttles completed by a subject during the Screening ISWT will be the 
maximum targeted for that subject during the remaining ISWTs in the study. 
After Screening, subjects will be assigned to 1 of 2 cohorts based on PAH medications as 
prescribed by their physician; Cohort A will include subjects who are currently prescribed and 
using inhaled treprostinil for the treatment of PAH and Cohort B will include subjects who are 
taking other PAH medications (instead of inhaled treprostinil).  
Subjects in Cohort A will be assigned to 1 of 2 sequences: 
Sequence 1: 
 Period 1: The ISWT will be initiated 3 to 4 hours after a subject’s previous dose of 
inhaled treprostinil (expected trough level).  Activity will be timed to allow all 
procedures, including recovery, to be completed prior to Period 2. 
 Period 2: The ISWT will be initiated within approximately 30 minutes of the previous 
inhaled treprostinil dose (expected peak level).  Following recovery and the 
Investigator’s confirmation of return to baseline status, the subjects will be discharged 
from the study.  

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Sequence 2: 
 Period 1: The ISWT will be initiated within approximately 30 minutes of the previous 
inhaled treprostinil dose (expected peak level).  Activity will be timed to allow all 
procedures, including recovery, to be completed prior to Period 2.  
 Period 2: The ISWT will be initiated 3 to 4 hours after a subject’s previous dose of 
inhaled treprostinil (expected trough level).  Following recovery and the Investigator’s 
confirmation of return to baseline status, the subjects will be discharged from the 
study. 
Subjects in Cohort B will also undergo 2 activity periods: 
 Period 1: The ISWT will be initiated approximately 4 hours after the subject’s 
morning dose of PAH medication. 
 Period 2: The ISWT will be initiated at least 1 hour following the completion of the 
previous ISWT.  Following recovery and the Investigator’s confirmation of return to 
baseline status, the subjects will be discharged from the study. 
The baseline PGI-S and Borg dyspnea score assessments will be conducted prior to (-15 and 
0 minutes; pre-ISWT) an activity that is typically expected to induce symptoms of PAH.  The 
subject will initiate activity (ISWT; Appendix 15.2), and these same assessments will be 
performed immediately at the end of the ISWT (within 1 minute of completing the activity).  
The PGI-S assessments will also be performed throughout recovery following completion of 
the ISWT.  Continuous pulse oximetry will be performed at each clinic visit starting at each 
Baseline and through recovery.  
Vital sign assessments will be performed at the beginning and at the end of each clinic visit.  
On Day 1, subjects will be provided rest (at least 1 hour) between the 2 ISWTs.  Vital sign 
assessments will be performed at the beginning and at the end of each clinic visit. 
All AEs will be documented from the time of informed consent until the time screen failure is 
documented, the subject discontinues, or the subject completes the study.  
The study will consist of the following periods: 
Screening: During the Screening Period, subjects who sign the Informed Consent Form (ICF) 
will first undergo all Screening assessments to evaluate eligibility as listed in the 

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inclusion/exclusion criteria.  A window of up to 14 days is permitted to enroll a subject after 
Screening.  When feasible, Screening assessments should be completed on the same day.  
Rescreening will be allowed with the Sponsor’s Medical Monitor approval. 
During Screening, the ISWT will be performed to determine eligibility and the ability to 
induce symptoms.  Completion of a minimum of 3 shuttles (30 meters) of the test will be 
required for study eligibility.  Pre-ISWT, ISWT conduct, and ISWT recovery will be 
performed and specific assessments will be conducted as outlined below.  
Pre-ISWT: Baseline PGI-S (Appendix 15.1) and Borg dyspnea score (Appendix 15.3) 
assessments completed at -15 and 0 minutes prior to activity inducement of PAH symptoms 
will be performed.  Continuous pulse oximetry, for the assessment of oxygen saturation and 
HR, will be initiated at the beginning of pre-ISWT and performed until the end of recovery 
from the ISWT.  Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP]) 
will be assessed at the beginning of pre-ISWT.  
ISWT: PGI-S and Borg dyspnea scores will be assessed immediately upon completion of the 
ISWT.  Continuous pulse oximetry, for the assessment of oxygen saturation and HR, will be 
assessed continuously during the activity. 
ISWT Recovery: After completion of the ISWT, PGI-S assessments will be performed every 
minute during the first 5 minutes followed by every 5 minutes for the remainder of the 
30-minute recovery.  Continuous pulse oximetry, for the assessment of oxygen saturation and 
HR, will be assessed during recovery. 
Vital sign assessments will be performed at the end of this clinic visit. 
Day 1: The same assessments mentioned above will be performed during 2 ISWTs.  PGI-S 
assessments will be performed as outlined below.  At least a 1-hour rest period between the 
conduct of the 2 ISWTs will be required. 
During enrollment, subjects meeting eligibility criteria will be enrolled into the study and 
assigned to 1 of 2 cohorts.  

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For subjects who are currently taking inhaled treprostinil (Cohort A), the ISWT will be 
initiated either 3 to 4 hours (expected trough level) or within 30 minutes (expected peak level) 
of a subject’s previous dose in a cross-over manner.  Baseline PGI-S and Borg dyspnea score 
assessments, completed at -15 and 0 minutes prior to activity inducement of PAH symptoms, 
will be performed.  Continuous pulse oximetry will be performed from pre-ISWT until the 
end of recovery.  Vital signs (SBP and DBP) will be assessed at the beginning of the Day 1 
Visit.  
For subjects who are taking other PAH medications (instead of inhaled treprostinil) 
(Cohort B), the ISWT will be initiated approximately 4 hours after the subject’s morning dose 
of PAH medication. 
Discharge: Following completion of all study procedures, recovery from study 
symptom-induced activities, and when the Investigator is satisfied that the subject has 
returned to the baseline status, per pulse oximetry readings, the subject will be discharged 
from the clinic. 

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3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
Table 3-1 
Schedule of Time and Events 
Study Procedures 
Screening Periodm 
(Days -14 to -1) 
Day 1 
 
Period 1 
Resth 
Period 2 
Dischargej 
Pre-
ISWT 
ISWTa 
Recovery 
(30 minutes) 
Pre-
ISWT 
ISWTa 
Recovery  
(30 minutes) 
 
Pre-
ISWT 
ISWTa 
Recovery 
(30 minutes) 
 
Informed Consent 
Xl 
 
 
 
 
 
 
 
 
 
 
Demographics 
Xl 
 
 
 
 
 
 
 
 
 
 
Medical Historyi  
Xl 
 
 
X 
 
 
 
 
 
 
 
Vital Signsb 
Xl 
 
X 
X 
 
 
 
 
 
 
X 
Subject Eligibility 
Xl 
 
 
X 
 
 
 
 
 
 
 
Enrollmentc 
 
 
 
X 
 
 
 
 
 
 
 
Borg Dyspnea 
Scored 
X 
Xk 
 
X 
Xk 
 
 
X 
Xk 
 
 
PGI-S Questionse 
X 
Xk 
X 
X 
Xk 
X 
 
X 
Xk 
X 
 
Pulse Oximetryf  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse Eventsg 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse event; eCRF, electronic Case Report Form; HR, heart rate; ISWT, Incremental Shuttle Walk Test; PAH, pulmonary arterial hypertension; PGI-S, 
Patient Global Impression of Severity; SpO2, saturation of peripheral capillary oxygenation; WHO, World Health Organization 
a ISWTs will be performed during Screening and on Day 1 of the study.  Subjects receiving supplemental oxygen during the Screening assessment must continue to receive 
the same flow rate at all subsequent ISWTs.  The supplemental oxygen flow rate must be recorded for each activity, as applicable.  Supplemental oxygen therapy must 
not be introduced for subjects after the Screening assessment, unless there is an urgent medical need in the clinical judgement of the Investigator.  For Cohort A, the 
ISWT will be initiated either 3 to 4 hours after a subject’s previous dose of inhaled treprostinil (expected trough level) or within approximately 30 minutes of the last 
previous inhaled treprostinil dose (expected peak level).  For Cohort B, the ISWT will be initiated approximately 4 hours after the subject’s morning dose of PAH 
medication and then again at least 1 hour after the previous ISWT. 

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b Vital signs (systolic blood pressure, diastolic blood pressure) will be assessed at Screening (prior to any activity and after recovery) and on Day 1 (prior to initiating Period 
1 assessments and prior to discharge). 
c Subjects will be enrolled to 1 of 2 cohorts.  Cohort A: Subjects are currently prescribed and using inhaled treprostinil for the treatment of PAH; Cohort B: Subjects are 
taking other PAH medication (instead of inhaled treprostinil). 
d See Appendix 15.3.  The subject should be asked to rate his/her maximal breathlessness at pre-ISWT (-15 and 0 minutes prior to activity inducement of PAH symptoms) 
and immediately at the end of the ISWT (within 1 minute of completing the activity).  Assessments will be recorded in the subject’s source documents and eCRF. 
e Assessed at pre-ISWT (-15 and 0 minutes prior to activity inducement of PAH symptoms), at the end of the ISWT (within 1 minute of completing the activity), every 
minute for the first 5 minutes of the recovery, followed by every 5 minutes for the remainder of the 30-minute recovery.  Assessments will be recorded in the subject’s 
source documents and eCRF.  Assessments will be performed in the following order: 1) PGI-S global PAH question; 2) PGI-S shortness of breath question; 3) PGI-S 
physical fatigue question.  PGI-S assessments are to be conducted prior to the Borg dyspnea score assessments. 
f Pulse oximetry to be performed continuously.  Pulse oximetry will include the collection of SpO2 and HR.  Pulse oximetry will start at the beginning of pre-ISWT 
(15 minutes prior to the ISWT) and will be continuous through the end of recovery of each individual period.  The SpO2 and HR measures obtained at -15 and at 0 
minutes (prior to activity), every minute during the ISWT, every minute for the first 5 minutes of the recovery, followed by every 5 minutes for the remainder of the 
30-minute recovery will be recorded in the subject’s source documents and eCRF. 
g All AEs will be documented from time of informed consent until the subject discontinues or subject completes the study. 
h Subjects will be provided at least a 1-hour period for rest between ISWTs (until subject feels they are rested enough to perform again at their baseline level) prior to Period 
2 assessments.  The start and end times for this period should be documented in subject’s source documents and eCRF. 
i Includes PAH history and WHO Functional Class.  Any significant changes to the subject’s medical condition must be documented throughout the course of the study. 
j Following completion of all study procedures and once the Investigator deems that the subject has returned to their baseline status, per pulse oximetry readings, the subject 
will be discharged from the clinic.  If the subject permanently discontinues the study prior to completion of all study assessments, for any reason, the following 
assessments, which are also performed prior to discharge, should be conducted, if possible: vital signs, AEs, and concomitant medications. 
k Assessments will be performed immediately (within 1 minute) after the end of the ISWT. 
l Assessments to be performed prior to initiating other Screening pre-ISWT assessments. 
m A window of up to 14 days is permitted to enroll a subject after Screening.  When feasible, Screening assessments should be completed on the same day.  Rescreening will 
be allowed with the Sponsor’s Medical Monitor approval. 
 
 

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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
There are no efficacy measures since this is an observational study. 
3.3.2 
Safety 
Overall safety during the conduct of the study will be assessed on the following parameters: 
AEs, vital sign measurements, concomitant medications, and oxygenation. 
3.3.2.1 
Medical History and Demographics 
A complete medical history (inclusive of PAH and World Health Organization [WHO] 
Functional Class) and demographics will be collected during Screening.  Any known changes 
to the medical history prior to enrollment should be recorded.  Significant past or present 
illnesses, current prescription or nonprescription medications (including vitamins and herbal 
products), and history of allergies or idiosyncratic responses to drugs should be recorded.  
Any significant changes to the subject’s medical condition must be documented throughout 
the course of the study. 
3.3.2.2 
Vital Signs 
Vital signs will include SBP and DBP.  HR will be collected via continuous pulse oximetry 
(Section 3.3.2.3).  Vital signs will be collected at the beginning and at the end of each clinic 
visit. 
3.3.2.3 
Oxygenation (Pulse Oximetry) 
Pulse oximetry will be performed from the beginning of pre-ISWT (15 minutes prior to the 
ISWT) and will be continuous through the end of recovery.  Pulse oximetry will include the 
collection of saturation of peripheral capillary oxygenation (SpO2) and HR.  The SpO2 and 
HR measurements obtained at -15 and 0 minutes (prior to activity), every minute during the 
ISWT, every minute for the first 5 minutes of the recovery, followed by every 5 minutes for 
the remainder of the 30-minute recovery, will be recorded in the subject’s source documents 
and electronic Case Report Form (eCRF).  

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A specific pulse oximeter model will be recommended by the Sponsor and the site will 
purchase and provide the Sponsor an invoice for reimbursement.  In the event a pulse 
oximeter cannot be used (ie, subject has known issues with obtaining accurate readings from a 
finger probe, etc), an alternative device may be used with prior Sponsor approval, so long as 
the same device is used throughout the study. 
3.3.2.4 
Adverse Events 
Adverse events will be recorded throughout the course of the study from the time of informed 
consent until the time a subject discontinues or subject completes the study.  Each subject will 
be questioned for AEs at each study visit.  Subjects will also be instructed to voluntarily 
report all AEs throughout the study.   
All AEs should be followed until resolution (or return to normal or baseline values), until they 
are judged by the Investigator to no longer be clinically significant, or for at least 7 days if the 
AE extends beyond the end of study assessments.  All AEs meeting criteria for a serious 
adverse event (SAE) should be followed until resolution, death, or until the subject is lost to 
follow-up, even if they are ongoing more than 7 days after study completion.  All AEs/SAEs 
that occur while the subject is in the study will be recorded as instructed in this protocol. 
Section 9 and Appendix 15.4 provide definitions and guidelines for recording AEs, 
respectively. 
3.3.3 
Concomitant Medications 
All concomitant medications taken throughout the course of the study, including those taken 
for AEs, should be recorded in the subject’s source documents and captured in the eCRF as 
required. 
3.3.4 
Assessment of PGI-S Questions and Borg Dyspnea Scores 
3.3.4.1 
Incremental Shuttle Walk Test 
The ISWT is the activity that will be used to induce symptoms of PAH during Screening and 
on Day 1 of the study.  All activities will be conducted in a designated area which meets the 
requirements described in Appendix 15.2. 

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Subjects receiving supplemental oxygen during the Screening assessment must continue to 
receive the same flow rate at all subsequent ISWTs.  The supplemental oxygen flow rate must 
be recorded for each activity, as applicable.  Supplemental oxygen therapy must not be 
introduced for subjects after the Screening assessment, unless there is an urgent medical need 
in the clinical judgement of the Investigator. 
The total number of shuttles completed by a subject during the Screening ISWT will be the 
maximum targeted for that subject during the remaining ISWTs in the study. 
3.3.4.2 
PGI-S Questions 
Three PGI-S questions will be administered at pre-ISWT (-15 and 0 minutes prior to activity 
inducement of PAH symptoms), immediately at the end of the ISWTs (within 1 minute of 
completing the activity), every minute for the first 5 minutes of recovery followed by every 5 
minutes for the remainder of the 30-minute recovery.  Assessments will be recorded in the 
subject’s source documents and eCRF. 
PGI-S assessments will be performed in the following order prior to the Borg dyspnea score 
assessment: 
 
 
 
 
 
 
3.3.4.3 
Borg Dyspnea Score 
The Borg dyspnea score (Appendix 15.3) is a 10-point scale rating the level of dyspnea 
experienced during the study-defined activity and is administered at each clinic visit at 
pre-ISWT (-15 and 0 minutes prior to activity inducement of PAH symptoms) and 
immediately at the end of the ISWTs (within 1 minute of completing the activity).  Scores 
range from 0 (no shortness of breath) to 10 (maximal shortness of breath).  Assessments will 
be recorded in the subject’s source documents and eCRF.  
3.4 
NUMBER OF CENTERS 
Up to 20 US centers that treat PAH subjects will be identified and recruited for this study. 

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3.5 
NUMBER OF SUBJECTS 
The total sample size will be approximately 40 subjects to ensure at least 36 evaluable 
subjects complete the study. 
3.6 
ESTIMATED STUDY DURATION 
The total study duration for a subject, including the Screening Period, will be up to 15 days. 
4 
SUBJECT ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
Subjects who meet the following criteria may be included in the study: 
1. Subject voluntarily gives informed consent to participate in the study. 
2. Males and females aged 18 years and above at the time of informed consent. 
3. Established primary diagnosis of PAH that is either idiopathic or familial PAH (WHO 
Group 1), collagen vascular disease associated PAH, PAH associated with human 
immunodeficiency virus (HIV) infection, PAH induced by anorexigens/toxins, or PAH 
associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥1 years). 
4. Subject is deemed WHO Functional Class I, II, or III. 
5. Subject has shortness of breath upon exertion (exhibits a ≥1-point change in Borg 
dyspnea score) as assessed by the ISWT and a minimum completion of 3 shuttles 
(30 meters) of the ISWT.  Subject may have other symptoms as well. 
6. Subject is on stable dose of all FDA-approved PAH treatments (exceptions are 
anticoagulants and diuretics) for at least 60 days prior to Screening.  
7. In the opinion of the Investigator, the subject can communicate effectively with study 
personnel, and is considered reliable, willing, and likely to be cooperative with 
protocol requirements. 
4.2 
EXCLUSION CRITERIA 
The following will exclude subjects from the study: 
1. The subject is known to be pregnant or nursing. 
2. The subject has 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, chronic thromboembolic 
pulmonary hypertension, or other conditions under WHO Group 2, 3, 4, and 5 
classifications. 
3. The subject has evidence of clinically significant left-sided heart disease (including, 
but not limited to, left ventricular ejection fraction 40%, left ventricular hypertrophy) 

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or clinically significant cardiologic conditions, such as congestive heart failure, 
coronary artery disease, or valvular heart disease.  
4. The subject has any form of congenital heart disease (repaired or unrepaired; other 
than a patent foramen ovale). 
5. The subject has any ambulatory or orthopedic limitations that would interfere with the 
ability to perform the activity. 
6. The subject has been hospitalized within 30 days of Screening. 
7. Current use of prostacyclin analogs/agonists, except inhaled treprostinil, for the 
treatment of PAH. 
8. Use of any other investigational drug/device, or participation in any investigational 
study with therapeutic intent within 30 days of Screening (concurrent participation in 
registry studies is allowed). 
9. Any other clinically significant illness 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. 
4.3 
PRESCRIBED THERAPY 
Subjects must not be receiving any prostacyclin analogs/agonists other than inhaled 
treprostinil for the treatment of PAH.  All concomitant medications taken during the conduct 
of the study, including those taken for AEs, should be recorded in the subject’s source 
documents and transcribed into the eCRF. 
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
This is an observational study; therefore, no treatment will be provided in the study. 
5.2 
ENROLLMENT 
The same number of subjects will be enrolled into Cohort A (subjects taking inhaled 
treprostinil therapy) and Cohort B (subjects who are taking other PAH medications [instead of 
inhaled treprostinil]).  Subjects will be assigned to Cohort A or B based on the use of inhaled 
treprostinil as determined by the Investigator. 
Subjects meeting eligibility criteria will be enrolled into the study and assigned a sequential 
subject number within their cohort. 

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5.3 
SEQUENCE ASSIGNMENT FOR COHORT A 
Subjects in Cohort A will be assigned to either Sequence 1 or 2 by the Sponsor.  
5.4 
BLINDING 
Not applicable.  This is an observational study without an investigational medicinal product. 
6 
DRUGS AND DOSING (OR TREATMENT PROCEDURES) 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE 
Not applicable.  This is an observational study and no investigational drug will be 
administered. 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
This is an observational study of an assessment tool and involves no blinded treatments. 
6.3 
COMPLIANCE 
This is not applicable since this is an observational study. 
7 
EXPERIMENTAL PROCEDURES 
Procedures in this study will be performed at Screening and on Day 1.  Refer to Section 3.2 
for the Overall Schedule of Times and Events. 
7.1 
SCREENING PERIOD (STUDY DAYS -14 TO -1) 
A window of up to 14 days is permitted to enroll a subject after Screening.  When feasible, 
Screening assessments should be completed on the same day.  Rescreening will be allowed 
with the Sponsor’s Medical Monitor approval.  The following assessments for Screening are 
required prior to initiating the Screening pre-ISWT assessments: 
 Informed consent 
 Demographics 
 Medical history, including PAH history and WHO Functional Class 
 AEs (documented from time of informed consent) 
 Concomitant medications 
 Vital signs (SBP and DBP) 
 Assess subject eligibility per inclusion/exclusion criteria  

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If eligible after the above assessments, the pre-ISWT, ISWT, and ISWT recovery assessments 
will be conducted.  Any significant changes to the subject’s medical condition must be 
documented throughout the course of the study. 
7.1.1 
Pre-ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required at -15 and 0 minutes prior to activity inducement of 
PAH symptoms: 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will be started 15 minutes prior to initiating the ISWT and will be performed 
continuously through the end of recovery during Period 1.  The SpO2 and HR measurements 
obtained at -15 and 0 minutes (prior to activity) will be recorded in the subject’s source 
documents and eCRF.  Subjects receiving supplemental oxygen during the Screening 
assessment must continue to receive the same flow rate at all subsequent ISWTs.  The 
supplemental oxygen flow rate must be recorded for each activity, as applicable.  
Supplemental oxygen therapy must not be introduced for subjects after the Screening 
assessment, unless there is an urgent medical need in the clinical judgement of the 
Investigator. 
7.1.2 
ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The ISWT will be initiated and the following assessments will be performed immediately at 
the end of the test (within 1 minute of completing): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  

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Pulse oximetry will be performed continuously through the ISWT.  The SpO2 and HR 
measurements obtained every minute during the ISWT will be recorded in the subject’s 
source documents and eCRF. 
For subjects who meet the minimum level of activity (3 shuttles; ie 30 meters) per inclusion 
criterion #5, site personnel will schedule their appointment time for the Day 1 Visit based on 
their assigned cohort and sequence (for subjects on inhaled treprostinil). 
7.1.3 
ISWT Recovery 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required every minute for the first 5 minutes of recovery 
followed by every 5 minutes for the remainder of the 30-minute recovery: 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Pulse oximetry (SpO2 and HR measurements) 
Vital signs (SBP and DBP) will be measured prior to subject leaving the clinical site. 
7.2 
STUDY DAY 1 
AEs and concomitant medications will be assessed throughout the study. 
The following will be confirmed or updated prior to initiating the ISWT: 
 Eligibility per inclusion/exclusion criteria 
 Medical history, including PAH history and WHO Functional Class 
 Enrollment 
Subjects assigned to Cohort A and Sequence 1 will follow procedures presented in Sections 
7.2.1.1 and 7.2.1.2.  Subjects assigned to Cohort A and Sequence 2 will follow procedures 
presented in Sections 7.2.1.3 and 7.2.1.4. 
Subjects assigned to Cohort B will follow procedures presented in Sections 7.2.2.1 and 
7.2.2.2. 

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7.2.1 
Cohort A 
Cohort A will include subjects who are currently prescribed and using inhaled treprostinil for 
the treatment of PAH.  Subjects will be assigned to 1 of 2 sequences (Section 3.1). 
7.2.1.1 
Sequence 1/Period 1 
The ISWT will be initiated 3 to 4 hours after a subject’s previous dose of inhaled treprostinil 
(expected trough level). 
Pre-ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required (-15 and 0 minutes prior to activity inducement of 
PAH symptoms): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will start 15 minutes prior to initiating the ISWT and will be performed 
continuously through the end of recovery.  The SpO2 and HR measurements obtained at -15 
and 0 minutes (prior to activity) will be recorded in the subject’s source documents and eCRF. 
ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The ISWT will be initiated and the following assessments will be performed immediately at 
the end of the test (within 1 minute of completing): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will be performed continuously throughout.  The SpO2 and HR measurements 
obtained every minute during the ISWT will be recorded in the subject’s source documents 
and eCRF. 

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ISWT Recovery 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required every minute for the first 5 minutes of recovery 
followed by every 5 minutes for the remainder of the 30-minute recovery: 
 PGI-S questions measurements  
 Pulse oximetry (SpO2 and HR measurements) 
Rest Period 
Subjects will be provided at least a 1-hour period for rest between ISWTs (until subject feels 
they are rested enough to perform again at their baseline level) prior to Period 2 assessments. 
The start and end times for this period should be documented in the subject’s source 
documents and eCRF.  AEs and concomitant medications will be assessed throughout this 
period. 
7.2.1.2 
Sequence 1/Period 2 
The ISWT will be initiated within approximately 30 minutes of the previous inhaled 
treprostinil dose (expected peak level). 
Pre-ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required (-15 and 0 minutes prior to activity inducement of 
PAH symptoms): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will start 15 minutes prior to initiating the ISWT and will be performed 
continuously through the end of recovery.  The SpO2 and HR measurements obtained at -15 
and 0 minutes (prior to activity) will be recorded in the subject’s source documents and eCRF. 

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ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The ISWT will be initiated and the following assessments will be performed immediately at 
the end of the test (within 1 minute of completing): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will be performed continuously throughout.  The SpO2 and HR measurements 
obtained every minute during the ISWT will be recorded in the subject’s source documents 
and eCRF. 
ISWT Recovery 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required every minute for the first 5 minutes of recovery 
followed by every 5 minutes for the remainder of the 30-minute recovery: 
 PGI-S questions measurements  
 Pulse oximetry (SpO2 and HR measurements) 
7.2.1.3 
Sequence 2/Period 1 
The ISWT will be initiated within approximately 30 minutes of the previous inhaled 
treprostinil dose (expected peak level). 
Pre-ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required (-15 and 0 minutes prior to activity inducement of 
PAH symptoms): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  

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Pulse oximetry will start 15 minutes prior to initiating the ISWT and will be performed 
continuously through the end of recovery.  The SpO2 and HR measurements obtained at -15 
and 0 minutes (prior to activity) will be recorded in the subject’s source documents and eCRF. 
ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The ISWT will be initiated and the following assessments will be performed immediately at 
the end of the test (within 1 minute of completing): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will be performed continuously throughout.  The SpO2 and HR measurements 
obtained every minute during the ISWT will be recorded in the subject’s source documents 
and eCRF. 
ISWT Recovery 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required every minute for the first 5 minutes of recovery 
followed by every 5 minutes for the remainder of the 30-minute recovery: 
 PGI-S questions measurements  
 Pulse oximetry (SpO2 and HR measurements) 
Rest Period 
Subjects will be provided at least a 1-hour period for rest between ISWTs (until subject feels 
they are rested enough to perform again at their baseline level) prior to Period 2 assessments.  
The start and end times for this period should be documented in the subject’s source 
documents and eCRF.  AEs and concomitant medications will be assessed throughout this 
period. 

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7.2.1.4 
Sequence 2/Period 2 
The ISWT will be initiated 3 to 4 hours after a subject’s previous dose of inhaled treprostinil 
(expected trough level). 
Pre-ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required (-15 and 0 minutes prior to activity inducement of 
PAH symptoms): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will start 15 minutes prior to initiating the ISWT and will be performed 
continuously through the end of recovery.  The SpO2 and HR measurements obtained at -15 
and 0 minutes (prior to activity) will be recorded in the subject’s source documents and eCRF. 
ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The ISWT will be initiated and the following assessments will be performed immediately at 
the end of the test (within 1 minute of completing): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will be performed continuously throughout.  The SpO2 and HR measurements 
obtained every minute during the ISWT will be recorded in the subject’s source documents 
and eCRF. 

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ISWT Recovery 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required every minute for the first 5 minutes of recovery 
followed by every 5 minutes for the remainder of the 30-minute recovery: 
 PGI-S questions measurements  
 Pulse oximetry (SpO2 and HR measurements) 
7.2.2 
Cohort B 
7.2.2.1 
Period 1 
The ISWT will be initiated approximately 4 hours after the subject’s morning dose of PAH 
medication. 
Pre-ISWT 
AEs and concomitant medications will continue to be assessed throughout the study. 
The following assessments are required (-15 and 0 minutes prior to activity inducement of 
PAH symptoms): 
 PGI-S question measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will start 15 minutes prior to initiating the ISWT and will be performed 
continuously through the end of recovery.  The SpO2 and HR measurements obtained at -15 
and 0 minutes (prior to activity) will be recorded in the subject’s source documents and eCRF. 
ISWT 
AEs and concomitant medications will be assessed throughout the study. 
The ISWT will be initiated and the following assessments will be performed immediately at 
the end of the test (within 1 minute of completing): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 

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 Borg dyspnea score measurement  
Pulse oximetry will be performed continuously throughout.  The SpO2 and HR measurements 
obtained every minute during the ISWT will be recorded in the subject’s source documents 
and eCRF. 
ISWT Recovery 
AEs and concomitant medications will be assessed throughout the study. 
The following assessments are required every minute for the first 5 minutes of recovery 
followed by every 5 minutes for the remainder of the 30-minute recovery: 
 PGI-S questions measurements  
 Pulse oximetry (SpO2 and HR measurements) 
Rest Period 
Subjects will be provided at least a 1-hour period for rest between ISWTs (until subject feels 
they are rested enough to perform again at their baseline level) prior to Period 2 assessments.  
The start and end times for this period should be documented in the subject’s source 
documents and eCRF.  AEs and concomitant medications will be assessed throughout this 
period. 
7.2.2.2 
Period 2 
The ISWT will be initiated at least 1 hour after completion of the previous ISWT. 
Pre-ISWT 
AEs and concomitant medications will continue to be assessed throughout the study. 
The following assessments are required (-15 and 0 minutes prior to activity inducement of 
PAH symptoms): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  

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Pulse oximetry will start 15 minutes prior to initiating the ISWT and will be performed 
continuously through the end of recovery.  The SpO2 and HR measurements obtained at -15 
and 0 minutes (prior to activity) will be recorded in the subject’s source documents and eCRF. 
ISWT 
AEs and concomitant medications will continue to be assessed throughout the study. 
The ISWT will be initiated and the following assessments will be performed immediately at 
the end of the test (within 1 minute of completing): 
 PGI-S questions measurements (to be conducted prior to Borg dyspnea score 
assessment) 
 Borg dyspnea score measurement  
Pulse oximetry will be performed continuously throughout.  The SpO2 and HR measurements 
obtained every minute during the ISWT will be recorded in the subject’s source documents 
and eCRF. 
ISWT Recovery 
AEs and concomitant medications will continue to be assessed throughout the study. 
The following assessments are required every minute for the first 5 minutes of recovery 
followed by every 5 minutes for the remainder of the 30-minute recovery: 
 PGI-S questions measurements  
 Pulse oximetry (SpO2 and HR measurements)  
7.2.3 
Discharge 
If the subject permanently discontinues the study prior to completion of all study assessments, 
for any reason, the following assessments, which are also performed prior to discharge, 
should be conducted, if possible: 
 Vital signs (SBP and DBP)  
 AEs 
 Concomitant medications 

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Following completion of all study procedures and once the Investigator deems that the subject 
has returned to their baseline status, per pulse oximetry readings, the subject will be 
discharged from the clinic. 
8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A subject may voluntarily withdraw from the study at any time for any reason.  A withdrawal 
of consent would preclude data collection regarding that subject after the date of withdrawal.   
In the event a subject discontinues prematurely due to an AE, the subject will be followed 
until either the Investigator determines that the AE has resolved, it is no longer considered 
clinically significant, the subject is lost to further follow-up, or for 7 days if the AE extends 
beyond the final visit.  A Subject Discontinuation Form must be completed for all subjects 
discontinued from the study. 
8.2 
CRITERIA FOR TERMINATING THE STUDY 
The study may be stopped at any time if, in the opinion of the Sponsor, continuation of the 
study represents a serious medical risk to the subjects.  This 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. 
8.3 
CRITERIA FOR DISCONTINUING A SITE 
The study may also be terminated at a given site if any of the following occur: 
 The Principal Investigator elects to discontinue the study 
 The Sponsor elects to discontinue the study at the site 
 US FDA regulations are not observed 
 Concerns with protocol violations 
 Changes in personnel or facilities adversely affect performance of the study 
9 
ADVERSE EVENT REPORTING  
All AEs/SAEs that occur while the subject is participating in the study will be recorded as 
instructed in Section 9.2. 

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9.1 
DEFINITIONS 
9.1.1 
Adverse Event  
An AE is any untoward or unfavorable medical event experienced by a subject during a 
clinical study.  An AE may include an intercurrent illness, injury, or any other concomitant 
impairment of the subject’s health if deemed to have clinical significance.  Adverse events 
may also include worsening of pre-existing symptoms or conditions that occur as a result of 
protocol-mandated procedures. 
9.1.2 
Serious Adverse Event  
An SAE is an AE that results in any of the following outcomes: 
 Death 
 A life-threatening AE 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
In addition, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they jeopardize the subject and require medical/surgical intervention to prevent any 
of the outcomes listed above.   
Life-threatening means that the subject was at immediate risk of death from the event as it 
occurred.  It does not mean that the event, had it occurred in a more severe form, might have 
caused death. 
9.2 
DOCUMENTATION OF ADVERSE EVENTS 
All AEs will be documented from time of informed consent until the subject discontinues or 
subject completes the study.  An AE or SAE occurring during the study must be documented 
in the subject’s source documents and on the appropriate eCRF page(s).  Information relating 
to the AE, such as onset and cessation date and times, intensity, seriousness, and outcome, is 
also to be documented in the eCRF (see Appendix 15.4 for definitions).  Where possible, AEs 
should be recorded using standard medical terminology.  If several signs or symptoms are 

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clearly related to a medically defined diagnosis or syndrome, the diagnosis or syndrome 
should be recorded on the eCRF page, not the individual signs and symptoms. 
9.3 
FOLLOW UP OF ADVERSE EVENTS 
In the event a subject discontinues prematurely due to an AE, the subject will be followed 
until either the Investigator determines that the AE has resolved, it is no longer considered 
clinically significant, the subject is lost to further follow-up, or for 7 days if the AE extends 
beyond the final visit.   
Follow-up of AEs and SAEs considered related (either possible or probable) to inhaled 
treprostinil will be processed as a post-marketing case.  
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
All SAEs, as defined in Appendix 15.4, must be reported using the SAE report form via 
e-mail or fax within 24 hours of the investigator’s knowledge of the SAE occurrence:  
 Email to drugsafety@unither.com (primary method)  
 Fax to (919) 313-1297 (back-up method)  
The Investigator or Sponsor (if appropriate) must also notify their Institutional Review Board 
(IRB), Independent Ethics Committee (IEC), and/or other local equivalent agency of the 
reported 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 
Investigator’s study file.   
9.5 
SAFETY REPORTS 
Any SAE that is possibly or reasonably attributable to concomitant PAH treatment (inhaled 
treprostinil) will be processed as a post-marketing case and requires immediate notification 
via email to drugsafety@unither.com (primary) or via fax at (919) 313-1297 (back-up) using 
the SAE report form.   
10 
STATISTICAL CONSIDERATIONS 
This section briefly describes the planned statistical analyses.  A complete description of the 
methodology will be specified in the Statistical Analysis Plan (SAP), which will be finalized 

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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 SAP and will not require a protocol 
amendment. 
10.1 
DATA PROCESSING 
The results of assessments will be transcribed into an eCRF for each subject who signs an ICF 
until study completion, or study discontinuation for any reason.  A representative from the 
Sponsor will verify eCRF data fields against source documentation.  Data clarifications will 
be generated, and the database will be edited as appropriate.  The eCRFs will be reviewed by 
the Investigator for completeness and accuracy.  The Investigator must electronically sign 
each subject’s eCRF to signify his/her approval of the data.  The Investigator will be required 
to re-sign an eCRF if changes are made to a subject’s eCRF by the site after the Investigator 
initially signs the eCRF.  The database will be final when all data management and quality 
assurance procedures are complete. 
10.2 
SAMPLE SIZE 
Approximately 40 subjects will be enrolled to ensure at least 36 evaluable subjects complete 
the study.  A sample size of 36 is expected to provide sufficient power in the context of this 
study to evaluate change in the PGI-S items.  Assuming a change from baseline endpoint with 
values that may range between -4 and 4, a common standard deviation as the 50th percentile of 
the range (~2 units) for each PGI-S item, a correlation between post-activity and baseline 
measurements of 0.75, and a standard deviation of the difference scores as ~1.3, a 2-sided 
95% confidence interval for a paired mean difference, based on the large sample z statistic, 
will extend approximately 0.52 units.  With a confidence interval length at the mid-point of 
PGI-S response ratings, reasonable confidence in the point estimates observed for the PGI-S 
items should be achieved. 
10.3 
ANALYSIS PLAN 
The data collected in this study will be presented in listings and tables.  No inferential 
statistical analyses are planned.  Presentations will be appropriate to the data analyzed.  
Summary statistics may include the mean, N, standard deviation, median, minimum, 
maximum, the 25th and 75th percentile values for continuous variables, and frequencies and 

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percentages for categorical variables.  Confidence intervals may be included for informal 
purposes.  
Medical history and prior/concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHODrug), and AEs will be coded using the Medical 
Dictionary for Regulatory Affairs (MedDRA).  Coding dictionary versions will be specified in 
the SAP. 
All statistical analyses will be performed by the Sponsor’s biostatistics department personnel 
(or appropriate designees) using SAS®, Version 9.3 or higher, or other validated software. 
10.3.1 
Efficacy Endpoint(s) 
There are no efficacy measures since this is an observational study. 
10.3.2 
PGI-S Questions Assessment  
The primary objective is to characterize the psychometric properties and performance of 
3 PGI-S questions (Appendix 15.1) in PAH subjects during pre-ISWT, at the end of activity, 
and through recovery.  
The focus of the analyses will be to describe PGI-S measurement sensitivity of the subjects’ 
self-reported symptoms of PAH at the end of the activity and during recovery from activity.  
The Sponsor will tabulate symptom scores and compute changes from baseline (pre-activity) 
scores for each question.  Data may be displayed graphically and will be summarized overall 
and by cohort and sequence/period (as appropriate). 
Additionally, for Cohort A, the sensitivity to a known inhaled treprostinil drug effect will be 
assessed tabulating, across time, the PGI-S measurements with inhaled treprostinil to PGI-S 
measurements without inhaled treprostinil.  Test-retest assessments for PGI-S measurements 
will be conducted for Cohort B.  
Correlations between the 3 PGI-S questions and with Borg dyspnea scores, oxygen saturation, 
and HR will be assessed.  Data for HR recovery at 1 minute after the ISWT will be examined 
in an exploratory fashion overall and as related to PGI-S measurements.  

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The onset and recovery profile for activity-induced symptoms will also be characterized. 
10.3.3 
Safety Analyses 
Safety will be evaluated on AEs, vital signs, and oxygenation.  All AEs as recorded by the 
Investigators will be assigned a MedDRA Preferred Term and System Organ Class by the 
Sponsor for reporting purposes.  The summary of AEs will include the number and percentage 
of subjects, as well as the number of events reported for each Preferred Term.  No inferential 
analyses are planned for the AEs. 
Data collected at pre-ISWT will serve as baseline values for the evaluation of data collected 
during ISWT and recovery.  Summary statistics will be calculated for measured values and 
changes from baseline values.  No inferential analyses are planned on these safety endpoints. 
10.4 
INTERIM ANALYSIS 
There is no planned interim analysis for the study.  However, given the open-label nature of 
the study, results may be tabulated by the Sponsor during the course of the study.  
10.5 
OTHER ANALYSES 
Other analyses may be conducted based on available study data.  Details for any other 
planned statistical analyses will be specified in the SAP. 
10.6 
DATA LISTINGS AND SUMMARIES 
All scientifically relevant data gathered in this study will be presented in summary tables and 
listings in the clinical study report. 
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG  
Not applicable.  This is an observational study and no investigational drug will be 
administered. 
11.2 
LABELING  
Not applicable.  This is an observational study and no investigational drug will be 
administered. 

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11.3 
STORAGE AND HANDLING OF CLINICAL STUDY MATERIAL 
Not applicable.  This is an observational study and no investigational drug will be 
administered. 
11.4 
SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL 
Not applicable.  This is an observational study and no investigational drug will be 
administered. 
11.5 
DRUG ACCOUNTABILITY 
Not applicable.  This is an observational study and no investigational drug will be 
administered. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
US FDA OR APPLICABLE REGULATORY REQUIREMENTS 
The study will be conducted in accordance with International Council for Harmonisation 
(ICH), Good Clinical Practices (GCP) guidelines, and all applicable national regulations.  The 
Sponsor will obtain the required approval from the regulatory authority to conduct the study.  
During the conduct of the study, an annual safety report will be compiled by the Sponsor for 
submission to those regulatory authorities and IRBs/IECs that require it.  Any additional 
national reporting requirements specified by the applicable regulations, regulatory authorities, 
or IRB/IEC will also be fulfilled during the conduct of the study. 
12.2 
INFORMED CONSENT REQUIREMENTS 
Before a subject is enrolled in the study, the Investigator or his/her designees must explain the 
purpose and nature of the study, including potential benefits and risks and all study 
procedures to the subject.  The subject must sign and date an IRB/IEC-approved ICF prior to 
the conduct of any study-related activities.  A copy of the signed consent form will be given 
to the subject, and the original will be retained in the study site’s records.  
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
Prior to study initiation at each site, the Investigator will obtain approval for the study from an 
appropriate IRB/IEC and provide the Sponsor or designee with a copy of the approval letter.  
The IRB/IEC must also review and approve the study site’s ICF and any other written 

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information provided to the subject prior to enrollment, as well as any advertising materials 
used for subject recruitment.  Copies of the site-specific ICF and advertising materials must 
be forwarded to the Sponsor or designee for review before submission to the IRB/IEC and 
prior to the site starting the study. 
If, during the study, it is necessary to amend either the protocol or the ICF, the Investigator is 
responsible for obtaining IRB/IEC approval of these amended documents prior to 
implementation.  Copies of the IRB/IEC correspondence and approval letters must be sent to 
the Sponsor or designee. 
During the conduct of the study, an annual progress report will be compiled by the Sponsor 
for submission to those IRBs/IECs that require it. 
A written summary of the study will be provided by the Investigator to the IRB/EC following 
study completion or termination according to the IRB/IEC standard procedures.  Additional 
updates will also be provided in accordance with the IRB/IEC’s standard procedures. 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical study, the following documents will be provided to 
the site: protocol, ICF, budget agreement, and eCRF. 
The site will be required to provide the following documents to United Therapeutics 
Corporation’s (UTC’s) designee (Lung Biotechnology PBC) prior to study start: signature 
page of the protocol, Form FDA 1572, Financial Disclosure Form, IRB/IEC Composition and 
Roster, IRB/IEC protocol and informed consent approval letters, and Curriculum Vitae of 
study staff listed on the 1572. 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  UTC, Lung 
Biotechnology PBC, the FDA or other regulatory bodies, and the IRB/IEC governing this 
study may inspect the medical records of any subject involved in this study.  The Investigator 
may release the subject’s medical records to employees or agents of the Sponsor, the 
IRB/IEC, or the FDA or appropriate local regulatory agencies for purposes of checking the 

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accuracy of the data.  A number will be assigned to all subjects, and any report published will 
not identify the subject’s name. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially affect the safety of participating subjects or that 
alter the scope of the investigation, the scientific quality of the study, the experimental design, 
duration of therapy, assessment variables, the number of subjects treated, or subject selection 
criteria may be made only after consultation between UTC, its designee (Lung Biotechnology 
PBC), and the Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory 
authorities and IRB/IEC prior to implementation. 
A report documenting study termination must also be submitted to and acknowledged by the 
appropriate IRB/IEC for each study site. 
At the end of the study, where applicable, a final report will be provided to the local 
regulatory agencies. 
13.2 
STUDY DOCUMENTATION AND STORAGE 
In accordance with federal/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 UTC or its 
designee, Lung Biotechnology PBC, before any disposal or change in location of study 
records. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
In accordance with federal/national regulations, ICH, and GCP guidelines, monitors for UTC 
or its designee, Lung Biotechnology PBC, will periodically contact the site and conduct 
on-site visits.  During these visits, the monitor will, at a minimum, confirm ethical treatment 

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of subjects, assess study progress, review data collected, conduct source document 
verification, verify drug accountability periodically, and identify any issues requiring 
resolution. 
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and his/her staff to the monitor to discuss any findings or any relevant 
issues. 
13.4 
QUALITY ASSURANCE 
The Sponsor is responsible for ensuring that the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, GCP guidelines, and applicable 
regulatory requirements.   
The Sponsor or a contracted representative of 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 source data and to allocate time to discuss findings 
and any relevant issues.  In addition, this study is subject to an 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 and source data. 

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14 
REFERENCES 
Center for Drug Evaluation and Research.  The voice of the patient.  A series of reports from 
the U.S. Food and Drug Administration's (FDA's) patient-focused drug development 
initiative.  Pulmonary arterial hypertension.  Silver Spring, MD: Center for Drug Evaluation 
and Research, U.S. Food and Drug Administration; December 2014. 
Gnanasakthy A, Mordin M, Clark M, et al.  A review of patient-reported outcome labels in 
the United States: 2006 to 2010.  Value Health.  2012;15(3):437-442. 
McLaughlin VV, Archer SL, Badesch DB, et al.  ACCF/AHA 2009 expert consensus 
document on pulmonary hypertension: a report of the American College of Cardiology 
Foundation Task Force on Expert Consensus Documents and the American Heart 
Association: developed in collaboration with the American College of Chest Physicians, 
American Thoracic Society, Inc., and the Pulmonary Hypertension Association.  Circulation.  
2009;119(16):2250-2294. 
Rubin LJ.  Primary pulmonary hypertension.  N Engl J Med.  1997;336(2):111-117. 
Singh SJ, Morgan MD, Scott S, et al.  Development of a shuttle walking test of disability in 
patients with chronic airways obstruction.  Thorax.  1992;47(12):1019-1024. 

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15 
APPENDICES 
15.1 
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) QUESTIONS 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 

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15.2 
INCREMENTAL SHUTTLE WALK TEST 
Standardization 
Standardization of the ISWT is very important for obtaining meaningful outcomes.  It is 
advisable to time the performance as an additional measure, to confirm manual recording of 
the number of shuttles completed. 
Please note that: 
 If a repeat test is performed on the same day, at least a 1-hour rest should be allowed 
between tests. 
 Only standardized instructions from the provided media should be used. 
 No encouragement should be given throughout the ISWT.   
 A comfortable ambient temperature and humidity should be maintained for all tests. 
 The walking track must be the same for all tests for a patient: 
 Cones are placed 9 meters apart. 
 The distance walked around the cones is 10 meters. 
The total number of shuttles completed by a subject during the Screening ISWT will be the 
maximum targeted for that subject during the remaining ISWTs in the study. 
Before the ISWT 
 Instruct the patient to dress comfortably and to wear appropriate footwear. 
During the ISWT 
Follow the instructions: 
The objective of the ISWT is to walk as long as possible, there and back, along the 10-meter 
course (identified for the patient by 2 cones with an insert of 0.5 meters from either end), 
keeping to the speed indicated by the beeps on the audio recording.  
Instructions for the subject: You will hear these beeps at regular intervals.  You should walk 
at a steady pace, aiming to turn around the cone at 1 end of the course when you hear the first 
beep, and at the other end when you hear the next.  At first, your walking speed will be very 
slow, but you will need to speed up at the end of each minute.  Your aim should be to follow 

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the set rhythm for as long as you can.  Each single beep signals the end of a shuttle and each 
triple beep signals an increase in walking speed.  You should stop walking only when you 
become too breathless to maintain the required speed or can no longer keep up with the set 
pace. 
The test is maximal and progressive.  In other words, it is easier at the start and harder at the 
end.  The walking speed for the first minute is very slow.  You have 20 seconds to complete 
each 10-meter shuttle, so don’t go too fast.  The test will start in 15 seconds, so get ready at 
the start now.  Level 1 starts with a triple beep after the 4-second countdown. 
Ending the ISWT 
The ISWT ends if any 1 of the following occur: 
 The patient is more than 0.5 meters away from the cone when the beep sounds (allow 
1 lap to catch up to the pace of the audio recording). 
 The patient reports that they are too breathless to continue. 
At the End of the ISWT 
 Seat the patient or, if the patient prefers, allow the patient to stand. 
 Record 1 of the following reasons for terminating the test (the patient can be asked, 
“What do you think stopped you from keeping up with the beeps?”): 
 Shortness of breath 
 Physical fatigue 
 Chest pain 
 Other 
The patient should remain in a clinic area for at least 15 minutes following an uncomplicated 
test. 
Modified from https://pulmonaryrehab.com.au/patient-assessment/assessing-exercise-
capacity/incremental-shuttle-walking-test/ 
 
 

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15.3 
MODIFIED BORG DYSPNEA SCALE 
The person administering the test will obtain a rating of dyspnea using the Borg dyspnea 
scale.  The person will use the following dialogue:  
“I would like to use the following scale to indicate your shortness of breath at this moment 
(indicate the Borg dyspnea scale).  If there is no shortness of breath at all you will point to 0; 
if the shortness of breath is not very great you will choose from 0.5 to 2; if you are somewhat 
more short of breath you will select 3; and if the breathing is getting very difficult, you will 
choose 4 to 9, depending on just how hard it is; 10 represents 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 at this moment, then you can choose a fraction in between.  For 
example, if you have shortness of breath somewhere between 4 and 5, you can choose 4.5.”  
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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15.4 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Investigator or a designated member of his/her staff will probe each subject for any AEs 
that may have occurred.  The Investigator should always ask the same question when 
conducting the verbal probe in order to ensure uniformity between subjects.  The Investigator 
should ask: 
 
“How are you doing (feeling)?” 
Based on the subject’s response to this question, the Investigator should ask additional 
questions relevant to the specific complaint such as: 
 
“How severe is/was the symptom?” 
 
“How often did the symptom occur?” 
 
“How long did the symptom last?” 
It is the Investigator’s responsibility to review the results of all diagnostic and laboratory tests 
as they become available and ascertain if there is a clinically significant change from baseline.  
If the results are determined to be a clinically significant change from baseline, this should be 
reported as an AE.  The Investigator may repeat the diagnostic procedure or laboratory test or 
request additional tests to verify the results of the original tests.  When possible, a diagnosis 
associated with the abnormality should be used as the reported AE. 
Using provided definitions, the Investigator will then: 
(1) rate the intensity and seriousness of the AE and (2) note actions taken to counteract the 
AE. 
Definitions of Intensity, Seriousness, and Outcome 
INTENSITY 
An assessment of the relative intensity (severity) of an AE is based on the Investigator’s 
clinical judgment.  The maximum intensity encountered during the evaluation period should 
be checked.  The assessment of intensity should be independent of the assessment of the 
seriousness of the AE.   

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SERIOUSNESS 
An SAE is one that represents an actual or potential significant hazard.  This includes, but is 
not limited to, an event that is fatal, life-threatening, permanently or severely disabling, 
requires or prolongs inpatient hospitalizationa, is a congenital abnormality (offspring of 
subject) or is medically significant (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 1 of the outcomes listed in this definition). 
a Hospitalizations that would not be considered SAEs include those for: 
 Routine treatment or monitoring of the study indication not associated with any 
deterioration in condition (eg, hospitalization for a routine right heart catheterization). 
 Treatment which was elective or pre-planned, for a pre-existing condition not 
associated with any deterioration in condition (eg, pre-planned operation which does 
not lead to further complications etc). 
 Treatment of an emergency, in an outpatient setting for an event not fulfilling any of 
the definitions of serious as given above and not resulting in hospital admission. 
OUTCOME 
 Fatal – The study subject died. 
 Not Recovered/Not Resolved – The AE was ongoing at the time of death or at the time 
the subject was lost to follow up. 
 Recovered/Resolved – The AE resolved. 
 Recovered/Resolved with Sequelae – The AE is considered resolved; however, there 
is residual sequelae.  Some events do not return to baseline, such as metastasis or 
progression of disease; however, once these events are determined by the Investigator 
to be stable or chronic, the Investigator may consider the event to be resolved or 
resolved with sequelae. 
 Recovering/Resolving – The AE is improving but is not yet completely 
recovered/resolved. 
 Unknown – The outcome of the AE cannot be determined.