Clinical trial NCT01560624
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary arterial hypertension (PAH) Pulmonary hypertension (PH) Clinical Worsening Freedom Freedom-EV Treprostinil UT-15C 6 Minute walk test
Sponsor: United Therapeutics
Start date: 2012-06-26; Completion date: 2018-06-24
Enrollment: 690 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an international, multicenter, randomized, double-blind, placebo-controlled, event driven study in subjects with pulmonary arterial hypertension.

Detailed description:
Study TDE-PH-310 is an international, multicenter, randomized (1:1 oral treprostinil (UT-15C): placebo), double-blind, placebo-controlled study in subjects with pulmonary arterial hypertension (PAH) who are receiving background oral monotherapy for PAH for at least 30 days at randomization. Subjects are randomly allocated to receive oral treprostinil extended-release tablets or placebo by a stratified randomization by type of background therapy (Strata 1: phosphodiesterase type 5 inhibitor \[PDE5-I\] or soluble guanylate cyclase \[sGC\] stimulator; Strata 2: endothelin receptor antagonist \[ERA\]. Subjects are also stratified by baseline 6-minute walk distance (6MWD) less than or equal to 350 m or greater than 350 m. Subjects receive their first dose of study drug (0.125 mg) or matching placebo on the day of randomization. Oral dosing of study drug is continued at 0.125 mg 3 times daily (TID; every 6 to 8 hours) with food. The dose (or matching placebo) is titrated throughout the study up to a maximum dose of 12 mg TID to reach and maintain a tolerated dosing regimen that provided optimal clinical benefit. Once randomized, subjects return for study visits every 4 weeks for the first 12 weeks, then every 12 weeks for the duration of the study. Subjects continue in the study until experiencing clinical worsening, the number of adjudicated events necessary for study closure occurr, or prematurely discontinue participation in the study for any reason other than protocol-specified clinical worsening. At each scheduled visit, subjects undergo efficacy assessments for clinical worsening, exercise capacity (6MWD and Borg dyspnea score), WHO functional class (FC), and plasma N-Terminal pro-brain natriuretic peptide (NT-proBNP). Subjects could participate in an optional hemodynamic sub-study (assessed by RHC). Safety assessments consist of adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiograms (ECGs), and clinical laboratory parameters. Patients who complete all required assessments are eligible to enter a long-term, open-label, extension study (TDE-PH-311).

Arms: arm 1: Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID arm 2: Matching placebo tablets (oral)
Interventions: intervention 1: Treprostinil Diolamine intervention 2: Placebo
Intervention descriptions: intervention 1: Active intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
United Therapeutics Corporation 
TDE-PH-310 Amendment 8 
 
Oral Treprostinil 
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. © 2017 United 
Therapeutics Corporation 
 
Page 1 
A Phase III, International, Multi-Center, Randomized, 
Double-Blind, Placebo-Controlled, Clinical Worsening Study of 
UT-15C in Subjects with Pulmonary Arterial Hypertension 
Receiving Background Oral Monotherapy 
Protocol TDE-PH-310 
IND# 71,537 
EudraCT Number 2012-000097-26 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
26 January 2012 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Amendment 5: 
Amendment 6: 
Amendment 7: 
Amendment 8: 
01 March 2012 
04 June 2012 
05 December 2012 
10 March 2014 
06 January 2015 
07 October 2015 
29 September 2016 
09 August 2017 
 


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LIST OF CONTACTS FOR STUDY 
Contract Research 
Organization: 
 
 
 
 
 
 
 
  
  
 
 
 
Study Sponsor: 
United Therapeutics Corp. 
55 T.W. Alexander Drive 
Research Triangle Park, NC  
27709  
USA 
 
 
 
 
 
 
 
 
United Therapeutics Europe 
Limited 
Unither House, Curfew Bell 
Road 
Chertsey, Surrey, KT16 9FG 
United Kingdom  
 
 
 
 
 
 
 
 
 
 
 
 
Medical Monitor 
 
  
 
 
 
SAE Reporting 
UT Global Drug Safety 
  
 
 
 
 
 
 
   
 
   
 
 
 
Clinical Laboratory 
 
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “A Phase III, International, Multi-Center, 
Randomized, Double-Blind, Placebo-Controlled, Clinical Worsening Study of UT-15C in 
Subjects with Pulmonary Arterial Hypertension Receiving Background Oral Monotherapy” 
Amendment 8 dated 09 August 2017, and agree to abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Guideline for Good 
Clinical Practice (GCP) and applicable Food and Drug Administration regulations/guidelines 
set forth in 21 Code of Federal Regulations Parts 50, 54, 56, and 312 and 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 Corporation. 
I also have read the current Clinical Investigator’s Brochure for UT-15C (treprostinil 
diethanolamine) and acknowledge that review of the information contained in the Clinical 
Investigator’s Brochure is a requirement for Investigators before using UT-15C (treprostinil 
diethanolamine) in a clinical trial. 
This protocol has been received for information only and must not be implemented before all 
necessary regulatory agency and ethics approval documents have been obtained. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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LIST OF ABBREVIATIONS 
6MWD 
Six Minute Walk Distance 
6MWT 
Six Minute Walk Test 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CI 
Cardiac Index 
Cmax 
Maximum Concentration 
CO 
Cardiac Output 
CO2 
Carbon Dioxide 
CTD 
Connective Tissue Disease 
CTM 
Clinical Trial Material 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
dL 
Deciliters 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
ERA 
Endothelin Receptor Antagonist 
FEV1 
Forced Expiratory Volume at One Second 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GLP 
Good Laboratory Practice 
Hg 
Mercury 
HIV 
Human Immunodeficiency Virus 
H-L 
Hodges-Lehmann 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional/Independent Review Board 
ITT 
Intent-to-Treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 


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LFTs 
Liver Function Tests 
mol 
Micromols 
NTP 
National Toxicology Program 
NT-proBNP N-Terminal Pro-Brain Natriuretic Peptide 
PAH 
Pulmonary Arterial Hypertension 
PAPd 
Diastolic Pulmonary Artery Pressure 
PAPm 
Mean Pulmonary Artery Pressure 
PAPs 
Systolic Pulmonary Artery Pressure 
PCWPm 
Mean Pulmonary Capillary Wedge Pressure 
PDE5-I 
Phosphodiesterase-5 Inhibitor 
PGI2 
Prostacyclin 
PFO 
Patent Foramen Ovale 
PhRMA 
Pharmaceutical Manufacturers Association 
PT 
Prothrombin Time 
PVR 
Pulmonary Vascular Resistance 
RAPm 
Mean Right Atrial Pressure 
RHC 
Right Heart Catheterization 
SAE 
Serious Adverse Event 
SaO2 
Arterial Oxygen Saturation 
SAPd 
Diastolic Systemic Arterial Pressure 
SAPm 
Mean Systemic Arterial Pressure 
SAPs 
Systolic Systemic Arterial Pressure 
SAS 
Statistical Analysis System 
sGC 
Soluble Guanylate Cyclase 
SvO2 
Mixed Venous Oxygen Saturation 
T4 
Thyroxine 
TID 
Three Times Daily 
TLC 
Total Lung Capacity 
TSH 
Thyroid Stimulating Hormone 
UT-15C 
Treprostinil Diethanolamine (also known as treprostinil diolamine) 
WHO 
World Health Organization 
WOCBP 
Woman of Childbearing Potential 


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PROTOCOL SYNOPSIS 
Title  
A Phase III, International, Multi-Center, Randomized, 
Double-Blind, Placebo-Controlled, Clinical Worsening Study 
of UT-15C in Subjects with Pulmonary Arterial Hypertension 
Receiving Background Oral Monotherapy 
Study Phase 
III 
Indication 
Pulmonary Arterial Hypertension (PAH) 
Primary Objective 
To assess the effect of oral UT-15C with PAH-approved oral 
monotherapy compared to placebo with PAH-approved oral 
monotherapy on time to first adjudicated clinical worsening 
(morbidity or mortality) event, as defined by at least one of 
the events listed below: 
 Death (all causes) 
 Hospitalization due to worsening PAH defined as: 
o Non-elective hospitalization lasting at least 
24 hours in duration caused by clinical conditions 
directly related to PAH and/or right heart failure; 
or 
o Lung or heart/lung transplantation; or 
o Atrial septostomy 
 Initiation of an inhaled or infused prostacyclin (PGI2) 
for the treatment of worsening PAH 
 Disease progression (all criteria required): 
o A decrease in six minute walk distance (6MWD) 
of at least 15% from Baseline (or too ill to walk) 
directly related to PAH progression with other 
co-morbidities ruled out, confirmed by 
2 six-minute walk tests (6MWT) performed on 
different days  
o Worsening of PAH symptoms, which must 
include either: 
 An increase in functional class from Baseline 
or 
 Appearance or worsening of symptoms of 
right heart failure since Baseline 
 Unsatisfactory long-term clinical response (all criteria 
required) 
o Randomized to receive study drug for at least 
24 weeks 


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o A decrease from Baseline in 6MWD at Week 24 
and beyond at two consecutive visits on different 
days  
o Sustained WHO Functional Class III or IV 
symptoms for at least 24 weeks consecutively 
Secondary Objectives 
To assess the effect of oral UT-15C with PAH-approved oral 
monotherapy compared to placebo with PAH-approved oral 
monotherapy on the following: 
 Exercise capacity as assessed by 6MWD measured at 
Week 24 
 Plasma N-terminal pro-brain natriuretic peptide 
(NT-proBNP) at Week 24 
 Combined 6MWD/Borg dyspnea score at Week 24 
 Exercise capacity as assessed by 6MWD measured at 
each visit up to Week 48 other than Week 24 
 Borg dyspnea score 
 World Health Organization (WHO) Functional Class 
 Right heart catheterization (RHC) hemodynamics at 
Week 24 (optional) 
 Safety (vital signs, adverse events [AEs], clinical 
laboratory parameters, electrocardiograms) 
Exploratory Objectives 
 Optional evaluation of biomarkers 
 Optional evaluation of pharmacogenomics 
Study Design 
International, multi-center, randomized, double-blind, 
placebo-controlled, clinical worsening study in subjects with 
PAH receiving background oral monotherapy. 
Sample Size 
At least 610 subjects with a maximum of 850 subjects will be 
enrolled and randomly allocated (1:1) to receive either 
UT-15C or placebo. 
Summary of Subject 
Eligibility Criteria 
Eligible subjects must be 18 to 75 years of age (inclusive) at 
the time of signing informed consent, have a diagnosis of 
idiopathic or heritable PAH, PAH associated with connective 
tissue disease (CTD), PAH associated with repaired 
congenital systemic-to-pulmonary shunt (at least one year 
since repair), PAH associated with human immunodeficiency 
virus (HIV) infection, PAH associated with appetite 
suppressant or toxin use.  Eligible subjects may not have 
received a PGI2 (except if used during acute vasoreactivity 
testing) within 30 days before randomization.  Subjects must 
be receiving only one PAH-approved oral therapy for at least 
30 days prior to randomization and at a stable dose for a 
minimum of 10 days prior to randomization.  The Baseline 
6MWD must be at least 150 meters. 


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Drug Dosage  
and Formulation 
Background Regimen:  Every subject must have been 
receiving background monotherapy with one PAH-approved 
oral therapy for at least 30 days at randomization, and must 
have been receiving a stable dose for a minimum of 10 days at 
randomization.  Once randomized, subjects must remain on 
the same dose of background oral PAH monotherapy for the 
duration of the study.  In the event a subject must discontinue 
their background PAH oral therapy for any reason (e.g. AE), 
they must be switched to another agent within the same class 
of medication, if available and clinically appropriate per the 
Investigator’s discretion.  If no alternative therapy in the same 
class of medication is available and appropriate, the subject 
should be switched to a different class of approved oral PAH 
therapy. 
The minimum dose of oral PAH therapy used during the study 
must comply with the approved prescribing information for 
the product. 
Experimental Regimen:  All subjects will receive oral 
treprostinil (UT-15C) sustained release tablets or matching 
placebo.  Study drug may be provided in 0.125, 0.25, 0.5, 1, 
and 2.5 mg sustained-release tablets to be administered three 
times (TID) daily.  The first dose of study drug (0.125 mg) 
should be taken by the subject at the study site within 
10 minutes of consuming food.  Oral dosing of study drug 
will then continue at 0.125 mg TID (every 6 to 8 hours) with 
food.  Dose escalations can occur no more than every 
24 hours (three consecutive doses) in 0.125 mg increments 
TID during the first four weeks of the study.  Following 
4 weeks of treatment, dose escalation may occur no more than 
every 24 hours in either 0.125 mg or 0.25 mg increments TID.  
The maximum dose allowed will be 12 mg TID.  Note that 
sudden dose escalations or reductions may lead to intolerable 
adverse effects or worsening of PAH, respectively, and 
gradual dose titrations are recommended to reduce the risk to 
subjects.  Placebo will be identical in size, shape, and color to 
the respective active tablets. 
Control Group 
Placebo with PAH-approved oral monotherapy 
Route of  
Administration 
Oral 


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Procedures 
Study Visit Schedule: Subjects will be assessed during 
Screening and Baseline visits to determine eligibility for the 
study.  Once randomized, subjects will return for visits every 
4 weeks for the first 12 weeks, then every 12 weeks for the 
duration of the study.  Subjects will continue in the study until 
they meet the definition of clinical worsening or 
approximately 205 adjudicated clinical worsening events have 
occurred.  If a subject clinically worsens during the study and 
receives short-term (28 days or less) treatment with parenteral 
or inhaled PGI2 therapy for treatment of PAH, they will be 
permitted to enter the open-label extension study 
(TDE-PH-311).  If a subject discontinues the study for any 
reason other than clinical worsening, they will not be 
permitted to enter the open-label extension study.  Otherwise, 
all subjects participating in the study will have the 
opportunity to transition to the open-label study once 
approximately 205 adjudicated clinical worsening events have 
occurred. 
The following efficacy and safety assessments will occur 
during the course of the study: 
Efficacy Assessments:  Clinical worsening, exercise capacity 
(6MWD and Borg dyspnea score) measured within 3 to 
6 hours following the last dose of study drug, WHO 
Functional Class, and NT-proBNP.  Optional assessments 
include hemodynamics, biomarkers, and pharmacogenomics. 
Safety Assessments:  AE reports, vital signs, clinical 
laboratory parameters, electrocardiograms (ECG). 


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Statistical Considerations 
Approximately 205 adjudicated clinical worsening events will 
provide at least 90% power with a Type I error rate of 
0.05 (two-sided hypothesis) to detect a difference in the time 
to clinical worsening between treatment groups, assuming 
exponential distributions and an underlying hazard ratio of 
0.62.  Assuming a placebo median event time of 32 months 
(which corresponds to an event rate of 23% at Month 12), this 
hazard ratio corresponds to a median time to event of 
51 months for the UT-15C group, or an event rate of 15% at 
Month 12.  If accrual of subjects is completed during the first 
three years and 10% of the subjects drop out by the end of the 
study, a total sample size of at least 610 subjects with a 
maximum of 850 subjects is expected to generate 
approximately 205 adjudicated events over the course of the 
study.  
The primary efficacy endpoint will be tested at an interim 
analysis when 75% of total adjudicated events have occurred 
with an alpha spending of 0.020 and at the final analysis at an 
alpha of 0.044 with the overall Type I error rate at 0.05.  
Efficacy boundaries for early stopping of the trial for efficacy 
is calculated based on O’Brien-Fleming alpha-spending 
function. 
Sponsor 
United Therapeutics Corporation 
55 TW Alexander Dr. 
Research Triangle Park, NC  27709 
USA 


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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY .................................................................................... 2 
INVESTIGATOR’S AGREEMENT ..................................................................................... 3 
LIST OF ABBREVIATIONS ................................................................................................ 4 
PROTOCOL SYNOPSIS ....................................................................................................... 6 
TABLE OF CONTENTS ...................................................................................................... 11 
Table of In-Text Tables ........................................................................................................ 14 
Table of In-Text Figures ....................................................................................................... 14 
1 BACKGROUND AND RATIONALE .......................................................................... 15 
1.1 
DEFINITION OF CLINICAL PROBLEM ............................................................. 15 
1.2 
TREPROSTINIL DIETHANOLAMINE BACKGROUND .................................. 16 
1.2.1 
General Pharmacology .......................................................................................... 16 
1.2.2 
General Toxicology ................................................................................................ 17 
1.2.3 
Clinical Pharmacology .......................................................................................... 20 
1.2.4 
Efficacy and Safety Data ....................................................................................... 23 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN PAH ................... 28 
1.4 
CLINICAL HYPOTHESIS ....................................................................................... 29 
2 OBJECTIVES ................................................................................................................. 29 
2.1 
PRIMARY OBJECTIVE .......................................................................................... 29 
2.2 
SECONDARY OBJECTIVES .................................................................................. 30 
2.3 
EXPLORATORY OBJECTIVES ............................................................................ 31 
3 EXPERIMENTAL PLAN .............................................................................................. 31 
3.1 
STUDY DESIGN ........................................................................................................ 31 
3.2 
CLINICAL ASSESSMENTS .................................................................................... 35 
3.2.1 
Efficacy ................................................................................................................... 35 
3.2.2 
Safety ...................................................................................................................... 40 
3.3 
NUMBER OF CENTERS .......................................................................................... 41 
3.4 
NUMBER OF SUBJECTS ........................................................................................ 42 
3.5 
ESTIMATED STUDY DURATION ......................................................................... 42 
4 SUBJECT ELIGIBILITY .............................................................................................. 42 
4.1 
INCLUSION CRITERIA .......................................................................................... 42 
4.2 
EXCLUSION CRITERIA ......................................................................................... 44 
4.3 
PRESCRIBED THERAPY ........................................................................................ 46 
4.3.1 
PAH-Approved Therapies .................................................................................... 46 
4.3.2 
Concomitant Medications ..................................................................................... 47 
5 SUBJECT ENROLLMENT ........................................................................................... 48 
5.1 
TREATMENT ASSIGNMENT ................................................................................ 48 
5.2 
RANDOMIZATION .................................................................................................. 48 
5.3 
BLINDING .................................................................................................................. 48 


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6 DRUGS AND DOSING .................................................................................................. 48 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE ................................. 48 
6.1.1 
Dosing of Study Drug in Relation to Meals ......................................................... 51 
6.1.2 
Dosing and Administration of Adjunctive Medications ..................................... 51 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT ..................................... 52 
6.3 
COMPLIANCE .......................................................................................................... 53 
7 EXPERIMENTAL PROCEDURES ............................................................................. 54 
7.1 
SCREENING PHASE ................................................................................................ 54 
7.2 
BASELINE VISIT ...................................................................................................... 56 
7.3 
TREATMENT PHASE .............................................................................................. 56 
7.4 
STUDY DRUG TERMINATION VISIT ................................................................. 58 
7.5 
ACCESS TO THE OPEN-LABEL STUDY ............................................................ 59 
8 STUDY TERMINATION ............................................................................................... 60 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ....................................................... 60 
8.2 
CRITERIA FOR TERMINATING THE STUDY .................................................. 60 
8.3 
CRITERIA FOR DISCONTINUING THE SITE ................................................... 61 
9 ADVERSE EVENT REPORTING ................................................................................ 61 
9.1 
DEFINITIONS ........................................................................................................... 61 
9.1.1 
Adverse Event ........................................................................................................ 61 
9.1.2 
Serious Adverse Event .......................................................................................... 61 
9.1.3 
Adverse Events Associated with Progression of PAH ........................................ 62 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ..................................................... 62 
9.2.1 
Clinical Worsening Events .................................................................................... 63 
9.3 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ....................... 63 
9.4 
PREGNANCY ............................................................................................................ 64 
9.5 
SAFETY REPORTS .................................................................................................. 64 
10 STATISTICAL CONSIDERATIONS .......................................................................... 64 
10.1 DATA PROCESSING ................................................................................................ 64 
10.2 SAMPLE SIZE ........................................................................................................... 65 
10.3 ANALYSIS PLAN ...................................................................................................... 66 
10.3.1 
Primary Efficacy Endpoint ................................................................................... 66 
10.3.2 
Secondary Efficacy Endpoint(s) ........................................................................... 66 
10.3.3 
Exploratory Endpoints .......................................................................................... 68 
10.3.4 
Safety Analyses ...................................................................................................... 68 
10.4 INTERIM ANALYSIS ............................................................................................... 68 
10.5 OTHER ANALYSES ................................................................................................. 69 
10.6 DATA LISTINGS AND SUMMARIES ................................................................... 69 
10.7 DATA MONITORING COMMITTEE ................................................................... 69 
10.8 CLINICAL WORSENING ADJUDICATION COMMITTEE ............................. 69 
11 PACKAGING AND FORMULATION ........................................................................ 70 


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11.1 CONTENTS OF STUDY DRUG .............................................................................. 70 
11.2 LABELING ................................................................................................................. 70 
11.3 STORAGE AND HANDLING OF CTM ................................................................. 70 
11.4 SUPPLY AND RETURN OF CTM .......................................................................... 71 
11.5 DRUG ACCOUNTABILITY .................................................................................... 71 
12 REGULATORY AND ETHICAL OBLIGATION ...................................................... 71 
12.1 ICH GCP AND APPLICABLE NATIONAL REGULATORY 
REQUIREMENTS ..................................................................................................... 71 
12.2 INFORMED CONSENT REQUIREMENTS ......................................................... 72 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ....................................................................................................................... 72 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ......................................... 73 
12.5 SUBJECT CONFIDENTIALITY ............................................................................. 73 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 73 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .......................... 73 
13.2 STUDY DOCUMENTATION AND STORAGE .................................................... 74 
13.3 STUDY MONITORING AND DATA COLLECTION .......................................... 74 
14 REFERENCES ................................................................................................................ 75 
15 APPENDICES ................................................................................................................. 77 
15.1 PROCEDURE FOR 6-MINUTE WALK EXERCISE TEST AND BORG 
DYSPNEA SCALE ..................................................................................................... 77 
15.2 WHO FUNCTIONAL CLASSIFICATION FOR PULMONARY 
HYPERTENSION ...................................................................................................... 79 
15.3 CLINICAL LABORATORY PARAMETERS ....................................................... 80 
15.4 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE 
EVENTS ...................................................................................................................... 81 
15.5 CHILD-PUGH SCORE ............................................................................................. 83 
15.6 EXPECTED EVENTS ATTRIBUTABLE TO THE PROGRESSION OF 
PULMONARY ARTERIAL HYPERTENSION (SYSTEM ORGAN CLASS 
AND PREFERRED TERM, VER. 16.0) .................................................................. 84 
15.7 A SUB-STUDY TO COLLECT THE VITAL STATUS OF SUBJECTS WHO 
DISCONTINUE FROM THE STUDY OR OPEN-LABEL EXTENSION 
STUDY (TDE-PH-311) .............................................................................................. 85 


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Table of In-Text Tables 
Table 3-1 
Overall Schedule of Times and Events ........................................................... 33 
Table 4-1 
Minimum Allowable Doses of Background PAH Oral Therapy .................... 46 
Table 6-1 
Study Drug Goal Dose Titration Ranges ........................................................ 49 
Table 7-1 
Continued Visits by Week Beyond Week 24 .................................................. 57 
 
Table of In-Text Figures 
Figure 1-1 
Mean Plasma Treprostinil Concentration vs Time Curve Following the 
First Single 0.5 mg Dose of UT-15C on Day 1 and Following the Last 
Dose of 0.5 mg on Day 8 at Steady State ........................................................ 22 
Figure 1-2 
Mean Steady-State Plasma Treprostinil Concentration vs Time Curve 
Following Administration of 0.5 mg TID of UT-15C .................................... 23 
 


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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. 
The typical etiologies of PAH include idiopathic, heritable or associated with collagen 
vascular/connective tissue disease, portal hypertension, infection with the human 
immunodeficiency virus (HIV), history of cocaine inhalation and exposure to appetite 
suppressant drugs.  An estimated annual incidence of approximately 2 cases per million has 
been reported for idiopathic PAH [Rich, 1987; Rubin 1997]. 
There are three major factors thought to contribute to the increased pulmonary vascular 
resistance seen in this disease: vasoconstriction, remodeling of the vessel wall, and 
thrombosis.  There are a number of metabolic pathways which contribute to these changes 
that involve vasoactive mediators such as the vasodilators nitric oxide and prostacyclin 
(PGI2), and the vasoconstrictor endothelin-1.  These substances affect both vascular tone and 
remodeling leading to their use as pharmacologic targets [Farber, 2004]. 
Approved pharmacotherapies for PAH include: (1) intravenous PGI2 (epoprostenol sodium or 
Flolan®, Veletri®); (2) the PGI2 analogues subcutaneous (SC), intravenous (IV), and inhaled 
treprostinil (Remodulin®, Tyvaso®), oral treprostinil diethanolamine (also referred to as 
treprostinil diolamine; Orenitram®), oral selexipag (Uptravi®), and inhaled iloprost 
(Ventavis®); (3) the phosphodiesterase-5 inhibitors (PDE5-I), tadalafil (Adcirca®) and 
sildenafil (Revatio®); (4) the oral endothelin receptor antagonists (ERA), bosentan 
(Tracleer®), ambrisentan (Letairis®, Volibris®), and macitentan (Opsumit®), and (5) a soluble 
guanylate cyclase (sGC) stimulator, riociguat (Adempas®). 
Approval of current PAH-specific pharmacotherapies has traditionally been based upon the 
6MWT.  The 6MWT is an assessment of exercise capacity and remains a standard measure of 


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efficacy for trials of investigational medicines in subjects with PAH.  However, recent 
literature has questioned the clinical relevance, variability, and sensitivity of the 6MWT as a 
primary endpoint to assess the efficacy of treatments for PAH.  Although the 6MWT is still 
viewed as a valuable tool for measuring clinical efficacy of PAH therapies, a composite 
endpoint of ‘time to clinical worsening’ is emerging as an alternative endpoint that allows for 
assessment of long-term efficacy of investigational drugs for PAH [McLaughlin, 2009]. 
1.2 
TREPROSTINIL DIETHANOLAMINE BACKGROUND 
1.2.1 
General Pharmacology 
Treprostinil, [[(1R,2R,3aS,9aS) 2,3,3a,4,9,9a hexahydro 2 hydroxy 1 [(3S) 3 hydroxyoctyl] 
1H benz [f]inden 5 yl]oxy]acetic acid, is a chemically stable tricyclic analogue of PGI2. 
The pharmacology of treprostinil has been extensively characterized in well-established 
models, all confirming the suitability of the drug for the treatment of PAH following either 
the SC, IV, inhaled (as treprostinil sodium) or oral (as treprostinil diethanolamine) routes of 
administration. 
The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and 
systemic arterial vascular beds and inhibition of platelet aggregation.  In vitro, treprostinil 
induced concentration dependent relaxation of rabbit isolated precontracted mesenteric 
arteries, and inhibition of adenosine diphosphate (ADP) induced platelet aggregation in 
human and rat platelet rich plasma.  In animals, the vasodilatory effects of treprostinil reduce 
right and left ventricular afterload, thereby increasing cardiac output and stroke volume.  
Prostacyclins lower pulmonary artery pressure, increase cardiac output without affecting the 
heart rate, improve systemic oxygen transport as well as possibly reversing pulmonary artery 
remodeling.  There is also increasing evidence that the ability to block the proliferation of 
pulmonary artery smooth muscle cells may contribute, along with vasodilation, to the 
therapeutic effects of PGI2 in the treatment of PAH.  The mechanism of action is therefore 
likely to be multifactorial. 
Treprostinil diethanolamine (UT-15C) was selected from a series of treprostinil salts based on 
critical physicochemical characteristics (e.g., solubility, hygroscopicity, melting point) with a 


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goal of delivering treprostinil by the oral route as a sustained release (SR) dosage form. 
In solution, both treprostinil sodium and treprostinil diethanolamine are disassociated from 
their respective salt counter-ions and exist as the freely ionized form of treprostinil. As a 
result, the bioactive form present in the bloodstream is identical irrespective of the selection 
of the counter-ion. 
A rat blood pressure model study confirmed that the diethanolamine salt of treprostinil 
exhibits dose dependent pharmacological activity with a cardiovascular profile comparable to 
that of treprostinil.  Overall, no highly active metabolite has been identified, as all the 
metabolites evaluated had greatly reduced activity compared to UT-15C.  Thus, it would 
appear that the observed pharmacological profile of UT-15C reflects the activity of the parent 
molecule, treprostinil, and that the contribution to that profile of any known metabolite that 
would be formed in vivo would be minimal. 
1.2.2 
General Toxicology 
UT-15C is a novel salt form of Remodulin® (treprostinil) Injection and Tyvaso® (treprostinil) 
Inhalation Solution, which are approved in the United States and other countries for the 
treatment of patients with PAH. The active pharmaceutical ingredient, treprostinil, exists as 
the sodium salt in the drug product of Remodulin and Tyvaso. Given that the only change to 
the drug substance synthesis route for UT-15C is the diethanolamine addition step, and 
treprostinil is not altered, the bioactive form of treprostinil diethanolamine and treprostinil 
sodium is predicted to be identical.  Therefore, in addition to the nonclinical studies 
conducted with UT-15C, an extensive amount of pharmacology, pharmacokinetic, and 
toxicology information on treprostinil sodium is available from Remodulin and Tyvaso 
development. 
During the development of Remodulin, treprostinil sodium was administered SC and/or IV in 
acute toxicity studies, repeat-dose toxicity studies, reproductive toxicity studies, and 
genotoxicity studies, and has a well-defined clinical safety profile.  Treprostinil sodium was 
administered via continuous infusion to both rats and dogs in toxicity studies for up to 
6 months, which supported the chronic administration of Remodulin to patients. 


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In addition to the extensive toxicology data with treprostinil sodium, the toxicity and 
toxicokinetic profiles of UT-15C have been evaluated in acute and repeat dose oral toxicity 
studies of up to 13 weeks in duration in rodents and up to 9 months duration in dogs.  UT-15C 
has also been evaluated in reproductive-developmental toxicity studies in pregnant rats and 
rabbits and in an in vivo rat micronucleus assay. 
Nonclinical findings from 13 week toxicology studies with UT-15C have included dose 
dependent, yet transient decreases in mean body weight gain and food consumption in both 
rats and dogs and soft/mucoid stools, diarrhea, and vomitus in dogs.  Many of these findings 
have been seen previously during development of Remodulin and are consistent with PGI2-
induced effects.  In addition, post-mortem findings in rats administered UT-15C included 
changes in organ weight data and histological findings related to the adrenal gland, heart, 
spleen, thymus and bone marrow; some of which were not seen with Remodulin.  The 
majority of these findings were reversible following a 4-week recovery period.  Data from a 
9-month dog study provides additional toxicology information following chronic dosing.  
UT-15C was reasonably well-tolerated following daily oral administration at dose levels up to 
35 mg/dog/day for 9 months.  The primary adverse effect was judged to be gastrointestinal 
disturbance, evidenced by increased incidence of soft stools, mucoid stools and diarrhea.  By 
the end of the study, all dogs were in good condition.  No systemic adverse effects were 
detected as judged by ophthalmology, ECG, clinical pathology and histopathological 
examination. 
In vitro genotoxicity studies with UT-15C have not been conducted; however, data are 
available for such studies using high doses of Remodulin (treprostinil sodium).  Remodulin 
(treprostinil sodium) was non-mutagenic in bacterial reverse mutation assays (Ames assay) at 
concentrations up to 5000 mcg/plate with and without S9 metabolic activation, and in the 
mouse lymphoma assay at concentrations up to 400 mcg/mL without S9 metabolic activation 
and up to 300 mcg/mL in the presence of S9. 
UT-15C was tested in vivo in the rat micronucleus assay, which aimed to evaluate the 
potential of UT-15C to increase the incidence of micronucleated polychromatic erythrocytes 
in bone marrow of rats.  The results of the assay indicated that oral administration of UT-15C 


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at total doses up to and including a dose of 50 mg treprostinil (equivalent to 63.4 mg 
UT-15C/kg) did not induce a significant increase in the incidence of micronucleated 
polychromatic erythrocytes in either male or female SD rats.  Mortality observed at the high 
dose indicates systemic exposure of animals to the test article.  Based upon these findings, 
treprostinil diethanolamine (UT-15C) was concluded to be negative in the rat micronucleus 
assay. 
Segment I (rat) and Segment II (rat and rabbit) reproductive and developmental toxicology 
studies have also been conducted. No adverse effects for fetal viability/growth and fetal 
development (teratogenicity) were seen in rats at or below 20 mg/kg/day or rabbits at or 
below 0.5 mg/kg/day.  At high doses, there were teratogenic effects of UT-15C observed 
when administered to rabbits.  Findings included increased fetal incidence of external, soft 
tissue, and skeletal malformations.  Additionally, a Segment III reproductive and 
developmental toxicology study has been conducted in female rats.  F0 female rats receiving 
10 mg/kg/day had decreased food consumption and body weights during gestation, increased 
duration of gestation, had slight decreases in the viability and number of pups per litter, and 
pups with decreased mean neonatal body weights.  F1 pups of females that received 
20 mg/kg/day had abnormalities in physical development (developmental landmarks), reflex 
development, exploratory behavior, learning and memory, and sexual maturation. 
A six month carcinogenicity study in hemizygous Tg.rasH2 mice administered UT-15C at 
daily oral doses of 3, 7.5, 15 mg/kg and 5, 10, 20 mg/kg in females and males, respectively, 
for 26 weeks did not increase the incidence of neoplastic lesions. A two year rat 
carcinogenicity study is ongoing. 
Studies have been conducted by the United States National Toxicology Program (NTP) to 
determine whether diethanolamine by itself (without treprostinil or any other drug) causes 
cancer.  Two years of topical administration of diethanolamine to mice produced an increased 
incidence (compared to a control group) of malignant liver tumors in males and females, as 
well as an increased incidence of malignant kidney tumors in males.  Doses used in this study 
were approximately 720 to 2900 times higher (based on mg/m2 dosing) than the proposed 
starting doses for the UT-15C clinical studies.  However, in transgenic mice and rats, topical 


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administration of diethanolamine for twenty weeks and two years, respectively, was not 
associated with the development of any cancers.  The relevance of the mouse tumor findings 
to humans is currently unknown.  Diethanolamine is listed on the FDA database of inactive 
ingredients for a number of approved drug products with no apparent safety concerns. 
A Good Laboratory Practices (GLP) cardiovascular safety pharmacology study 
(Study 1259DU16.003) to evaluate diethanolamine effects, independent of treprostinil, on 
cardiovascular function in telemetered dogs was conducted.  Since there are 0.269 grams of 
diethanolamine per each gram of treprostinil in UT-15C, for this study, doses of 
diethanolamine were selected that were similar or higher than the amount of diethanolamine 
contained in the doses of UT-15C assessed in the UT-15C cardiovascular safety 
pharmacology study (Study 1259DU16.002).  Doses of 0, 2, 3, and 4 mg/kg/day of 
diethanolamine (equivalent to the amount of diethanolamine administered with 7, 11, and 
15 mg/kg/day of treprostinil, the free acid of UT-15C), were selected to be administered to 
each of one group of four telemetered male dogs.  Data support that oral administration of 
diethanolamine at doses up to 2 mg/kg/dose twice daily (BID; 4 mg/kg/day) to male beagle 
dogs was not associated with any definitive changes in arterial pressure, heart rate or 
electrocardiogram parameters.  In addition, no abnormal clinical signs were noted in the 
animals dosed with the vehicle or with any of the doses of diethanolamine. 
1.2.3 
Clinical Pharmacology 
In solution, both treprostinil sodium and treprostinil diethanolamine are disassociated from 
their respective salt counter-ions and exist as the freely ionized form of treprostinil.  As a 
result, the bioactive form present in the bloodstream is identical irrespective of the selection 
of the counter-ion. Given this premise, the development of this new diethanolamine salt of 
treprostinil is expected to retain the bioactivity and safety profile of treprostinil sodium. 
The most frequent adverse events (AE) associated with Remodulin in clinical trials of patients 
with PAH were related to the pharmacological properties of Remodulin and were generally 
not serious.  These PGI2-related AEs included diarrhea, headache, and nausea.  Remodulin 
has not been associated with any significant changes in laboratory parameters or end-organ 
toxicity.  The safety profile noted in the open label extension study, with much longer 


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durations of exposure and a larger, more diverse patient population, was consistent with the 
profile noted in the controlled trials.  To date, well over 7000 subjects and patients have been 
exposed to Remodulin.  This number includes patients who have received single 
administration, to patients receiving continuous infusion for greater than 10 years. 
UT-15C has been administered to approximately 1800 subjects in Phase 1 to 3 clinical trials.  
UT-15C doses of up to 3 mg BID have been administered to healthy volunteers and patients 
with PAH have received up to 27.5 mg three times daily (TID) in the ongoing Phase 2 to 
3 development program. The average exposure is approximately two years; the longest 
exposure is approximately seven years.  
The absolute bioavailability of the UT-15C 1 mg tablet is 17% compared with IV Remodulin.  
Following administration, treprostinil diethanolamine is widely distributed.  Treprostinil is 
approximately 96% protein bound with no effect on warfarin or digoxin displacement.  
Pharmacokinetic data (area under the curve; AUC) indicate that Day 1 pharmacokinetic data 
are predictive of Day 13 and linearity was observed in plasma exposure comparing 1 mg and 
2 mg doses in healthy volunteers.  Food, particularly a high calorie meal, has been observed to 
increase absorption and prolong the systemic exposure to treprostinil, contributing to the 
desired pharmacokinetic profile.  Consistent with in vitro studies, clinical studies assessing 
the impact of induction and inhibition of the cytochrome P450 (CYP) 2C8 and CYP 2C9 
metabolic pathways on treprostinil diethanolamine indicate that CYP 2C8 appears to be of 
major importance and CYP 2C9 of minor importance to in vivo metabolism of UT-15C in 
humans. 
To date, the majority of UT-15C studies have been conducted with BID dosing.  In an attempt 
to understand the pharmacokinetics of TID dosing a study was conducted in healthy 
volunteers.  In this open-label, single-center study 19 healthy subjects received 0.5 mg TID 
for 7 days.  On the morning of Day 1 subjects received a single 0.5 mg dose, on Days 2 to 7 
the subjects received TID dosing of 0.5 mg (approximately 8AM, 2PM, and 8PM) with a 
meal.  On the morning of Day 8, the subjects received a final dose of 0.5 mg. 


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Intensive 24 hour PK sampling occurred following the 8AM doses on Days 1, 7, and 8. 
Trough samples were collected prior to the morning (8 AM) and evening (8PM) doses on 
Days 4, 5, and 6.   
Nineteen subjects (9F: 10M) with a mean age of 35.2 years (range: 20 to 54) were enrolled.  
On Day 1 the mean (±SD) maximum plasma concentration (Cmax) of treprostinil was 
0.574±0.22 ng/mL, occurring at a median time of 4 hours (range: 2 to 6 hrs).  In comparison, 
the Day 8 mean (±SD) Cmax was 0.615±0.32 ng/mL, occurring at a median time of 4 hours 
(range: 1 to 6 hrs) (Figure 1-1). 
Figure 1-1 
Mean Plasma Treprostinil Concentration vs Time Curve Following the 
First Single 0.5 mg Dose of UT-15C on Day 1 and Following the Last Dose 
of 0.5 mg on Day 8 at Steady State  
 
 
On Day 7, the mean Cmax (±SD) was 0.810±0.491 ng/mL, occurring at a median time of 
14 hours (range: 6 to 20) following the morning dose (Figure 1-2).  This indicates that 
maximum concentration during a daily interval at steady state occurs after the evening (or 
third) dose of the day.  


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Figure 1-2 
Mean Steady-State Plasma Treprostinil Concentration vs Time Curve 
Following Administration of 0.5 mg TID of UT-15C 
 
Mean trough plasma concentrations prior to the morning dose on Days 5, 6, 7, and 8 were 
0.049, 0.049, 0.050, and 0.053 ng/mL, respectively.  Mean trough concentrations prior to the 
evening dose on Days 4, 5, 6, and 7 were 0.487, 0.396, 0.437, and 0.353 ng/mL, respectively. 
Fifteen AEs occurred in seven subjects and primarily included known PGI2 class-effect 
related AEs (e.g., headache, diarrhea, and jaw pain). 
A comprehensive description of UT-15C (treprostinil diethanolamine), including the 
pharmacology, toxicology, and clinical studies completed to date may be found in the most 
recent Investigator’s Brochure. 
1.2.4 
Efficacy and Safety Data 
UT-15C has previously been evaluated in three randomized, placebo-controlled Phase 3 
studies (TDE-PH-301, TDE-PH-302, and TDE-PH-308).  Additionally, subjects completing 
these studies have been provided long-term access to UT-15C in an open-label extension 
study (TDE-PH-304).  To date, over 1000 PAH patients have been exposed to study drug 
(UT-15C or placebo) in the TDE-PH-301, TDE-PH-302, and TDE-PH-308 studies and over 
890 patients have received UT-15C in the open-label extension study. 
Dosing 
Dosing
Dosing


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TDE-PH-301 was a 16-week, randomized, double-blind, placebo-controlled, international 
Phase 3 efficacy and safety study of treprostinil diethanolamine (UT-15C), in patients with 
PAH.  Patients received UT-15C or placebo BID in combination with an ERA, a PDE5-I, or 
both.  The primary endpoint was placebo-corrected change in 6MWD from Baseline to 
Week 16.  Secondary endpoints included Borg dyspnea score, dyspnea-fatigue index, WHO 
Functional Class, and time to clinical worsening.  Study drug dose was titrated up to a 
maximum of 16 mg BID based on clinical response and study drug tolerability. 
Three-hundred fifty-four subjects were enrolled with 30% receiving an ERA alone, 25% a 
PDE5-I alone, and 45% both agents.  The population was 81% female, predominantly WHO 
Functional Class III (76%), and had a mean baseline 6MWD of 346 m.  PAH etiology 
included idiopathic or heritable PAH (66%), or PAH associated with CTD (26%), repaired 
congenital systemic-to-pulmonary shunt (7%), or HIV infection (1%).  There were no 
remarkable demographic differences between treatment groups. 
Twenty-two percent of subjects discontinued UT-15C therapy compared to 14% in the 
placebo group.  The primary reason for discontinuation was AEs: 14% in the UT-15C group 
compared to 5% in placebo.  There were three deaths in each of the treatment groups. 
The Hodges-Lehmann (H-L) estimate of 6MWD placebo corrected median change from 
baseline at Week 16 was +11 m (p=0.072). The change in 6MWD was significant at Week 12 
(+13 m, p=0.015).  The lack of significance at Week 16 may be attributable to the number of 
subjects who did not provide an efficacy measure at Week 16 due to discontinuing from the 
study prematurely. 
Secondary endpoints of the combined 6MWD and Borg dyspnea score and the dyspnea-
fatigue index demonstrated statistically significant changes at Week 16 for UT-15C compared 
to Baseline (p=0.013 and 0.01, respectively). 
TDE-PH-301 was initiated with subjects administered a 1 mg starting dose with dose 
increases in 1 mg increments.  Additional tablet strengths of 0.5 and 0.25 mg were made 
available to subjects at sequentially later times in the study.  A post-hoc analysis demonstrated 


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that during the course of the study those subjects with access to 0.25 mg tablets at 
randomization had a lower discontinuation rate due to AEs (0%, n=23) as well as a higher 
H-L estimate of 6MWD treatment effect (+28.5 m) at Week 16.  Presumably titrating up the 
dose of study drug slowly with smaller increments may allow subjects to tolerate and thereby 
maintain therapy on UT-15C and achieve optimal dosing.  In addition, those subjects that 
were able to titrate to doses between 1.25 and 3.25 mg BID and doses greater than or equal to 
3.5 mg BID also demonstrated a more robust treatment effect of +18 and +34 m, respectively.  
Thus, premature discontinuations and inability to achieve doses greater than 1 mg BID during 
TDE-PH-301 appear to have muted the overall treatment effect detected by the study. 
TDE-PH-302 was a 12-week, randomized (2:1 UT-15C to placebo), double-blind, placebo-
controlled, international Phase 3 efficacy and safety study of UT-15C in patients with PAH 
not currently receiving approved background therapy.  The primary endpoint was placebo 
corrected median change in 6MWD from Baseline to Week 12. Secondary endpoints included 
Borg dyspnea score, dyspnea-fatigue index, WHO Functional Class and time to clinical 
worsening.  Study drug dose was titrated up to a maximum of 12 mg BID based on clinical 
response and study drug tolerability. 
The study enrolled 349 subjects who were not receiving any approved PAH medication, with 
the population for primary analysis consisting of 228 subjects who had access to the 0.25 mg 
tablet strength at randomization.  These subjects were administered UT-15C or placebo BID, 
with the doses titrated to effect over the course of the 12-week study.  The majority of 
subjects were in WHO Functional Class II (33%) and class III (66%) of varied etiologies, 
including idiopathic or heritable PAH (75%), CVD associated PAH (19%), and PAH 
associated with HIV or other associated conditions (6%).  The subjects’ mean Baseline 
6MWD was approximately 330 m. 
The primary efficacy analysis comparing change in 6MWD from Baseline to Week 12 
between treatment groups in the primary analysis population (n=228) was +23 m (p=0.0125, 
H-L estimate).  The UT-15C group improved by a median of +25 m compared to -5 m change 
in the placebo group. 


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The combined 6MWD and Borg dyspnea score was also significantly improved (p=0.0497) at 
Week 12.  Preliminary analysis of other secondary efficacy measures, including change in 
trough 6MWD at Week 11, change in dyspnea fatigue index, change in Borg dyspnea score, 
change in WHO Functional Class, time to clinical worsening (as defined by death, 
transplantation, atrial septostomy, hospitalization due to PAH or at least a 20% decrease in 
6MWD and initiation of another approved PAH therapy), and PAH signs and symptoms at 
Week 12 did not differ significantly between the UT-15C and placebo groups (p>0.05). 
An analysis of all 349 subjects enrolled in the study demonstrated that those subjects 
receiving UT-15C improved their median 6MWD by approximately +25.5 m (H-L estimate, 
p=0.0001) as compared to subjects receiving placebo. 
AEs during the study included headache, nausea, diarrhea, and flushing, which were expected 
in subjects receiving prostanoid therapy.  A low discontinuation rate due to AEs in the 
primary analysis population and the type of AEs resulting in discontinuation (mostly PGI2 
related, which are not life threatening) indicate that use of UT-15C may provide a significant 
improvement in the safety profile of treprostinil and result in a reduction in the occurrence of 
life-threatening AEs compared with parenteral treprostinil therapy (e.g., central venous 
catheter-related blood stream infection). 
TDE-PH-308 was a 16-week, randomized, double-blind, placebo-controlled, international 
Phase 3 efficacy and safety study of UT-15C in patients with PAH.  Patients received UT-15C 
or placebo BID in combination with either an ERA, a PDE5-I, or both.  The primary endpoint 
was placebo-corrected change in 6MWD from Baseline to Week 16.  Secondary endpoints 
included Borg dyspnea score, dyspnea-fatigue index, WHO Functional Class and time to 
clinical worsening.  Study drug dose was titrated up to a maximum of 16 mg BID based on 
clinical response and study drug tolerability. 
Three-hundred-ten subjects (157 UT-15C and 153 placebo) were randomized, received a dose 
of study drug, and contributed to the analysis population for the study.  The study population 
had a mean age of 51 years (range 18 to 76 years), was 78% female and had a diagnosis of 
idiopathic or heritable PAH (65%), PAH related to CVD (31%), PAH related to HIV infection 


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(2%), or PAH related to repaired systemic-to-pulmonary shunts (1%).  The population was 
predominantly WHO Functional Class III (73%) with a mean Baseline 6MWD of 333 m.  As 
for PAH-approved background therapy, 53 (17%) subjects were receiving ERA therapy alone, 
132 (43%) subjects were receiving a PDE5-I alone, and 125 (40%) subjects were receiving 
the combination of an ERA and a PDE5-I at Baseline.  The UT-15C and placebo groups were 
well balanced across all Baseline indices. 
The primary efficacy analysis comparing change in 6MWD from Baseline to Week 16 
between treatment groups was +10 m (H-L estimate; p=0.089).  The UT-15C group improved 
by a median of +15 m compared to a +11 m median change in the placebo group.  Placebo-
corrected changes from Baseline in 6MWD at Week 16 by PAH-approved background 
therapy were as follows: ERA only (H-L estimate of treatment effect = +7.7 m; p=0.739), 
PDE5-I only (H-L estimate = +15.0 m; p=0.054), and combination ERA and PDE5-I (H-L 
estimate = +4.0 m; p=0.674).  The mean ± SD maximum dose of UT-15C was 3.1±1.9 mg 
BID in the UT-15C group as compared to 6.1±3.6 mg BID in the placebo group.  Secondary 
endpoints including change in 6MWD at Weeks 4, 8, and 12, combined 6MWD and Borg 
dyspnea score, dyspnea-fatigue index, clinical worsening, serum NT-proBNP, WHO 
Functional Class, quality of life, and symptoms of PAH at Week 16 were not found to be 
statistically significant. 
TDE-PH-304 is a long-term, open-label, international, Phase 3 study designed to provide 
access to UT-15C for subjects previously enrolled in studies TDE-PH-301, TDE-PH-302, 
TDE-PH-308, or other specified studies conducted during the UT-15C development program.  
Secondary objectives of the study are to assess the long-term safety of UT-15C in PAH 
patients and to assess the effect of continued therapy on exercise capacity via 6MWD 
following one year of treatment with UT-15C.  As of 01 September 2015, over 896 subjects 
were enrolled, representing 2377.7 patient-years of exposure.  The mean and maximum 
duration of exposure was 138.8 and 444.9 weeks (2.66 and 8.53 years), respectively.  The 
mean dose of oral treprostinil achieved was 3.9, 4.5, 4.8, 5.0, 5.5, 5.9, and 5.9 mg BID at 
1 year (N=605), 2 years (N=472), 3 years (N=337), 4 years (N=230), 5 years (N=119), 6 years 
(N=77), and 7 years (N=37), respectively.  AEs were typical of PGI2 therapy; laboratory 


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findings were unremarkable and did not suggest any specific safety concerns related to long-
term treatment with UT-15C.  Following 12 months of oral treprostinil treatment, the mean 
6MWD increased by +25 meters as compared with Baseline.  Kaplan-Meier analysis of 
subject survival demonstrated 1-, 2-, and 3-year survival estimates of approximately 93.6%, 
87.9%, and 82.2%, respectively. 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN PAH 
Prostacyclin is a potent endogenous vasodilator and inhibitor of platelet aggregation.  A 
synthetic salt of PGI2 (i.e., Flolan) has been previously shown to prolong survival in patients 
with PAH [Barst 1996].  However, due to its very short half-life and chemical instability, 
Flolan has to be continuously infused by intravenous delivery.  Treprostinil sodium is a 
chemically stable, longer acting analogue that has shown clinical effectiveness when 
administered by subcutaneous, intravenous (Remodulin) [Remodulin package insert, 2013], or 
inhaled routes (Tyvaso) [Tyvaso package insert, 2013]. 
Parenteral PGI2 are considered by many providers as the “gold standard” for treatment of 
PAH; however, they are typically used later in the course of the disease due to the risks and 
difficulties associated with administration.  Consequently, physicians managing patients with 
PAH commonly initiate oral monotherapy, to allow patients to benefit from the simplicity of 
an oral dosage form. 
Effective treatment of PAH often requires combination therapy with several drugs.  Current 
guidelines suggest that if patients in WHO Functional Classes II, III, or IV do not demonstrate 
improvement, sequential combination therapy with several PAH-specific drugs is appropriate 
[Barst 2009].  Several studies have previously demonstrated a benefit of sequential 
combination therapy, particularly when combining PGI2 treatment with other PAH-specific 
treatments.  The STEP-1 study evaluated the efficacy of iloprost and bosentan combination 
therapy over 12 weeks, resulting in a near significant increase in 6MWD (p=0.051) after 
iloprost inhalation (McLaughlin et al., 2006).  The PACES study demonstrated improvements 
in exercise capacity and hemodynamic parameters when sildenafil and intravenous 
epoprostenol were used in combination (Simonneau et al., 2008).  The TRIUMPH-I study 
evaluated the efficacy of inhaled treprostinil (Tyvaso®) compared with placebo in patients 


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already receiving treatment with either bosentan or sildenafil and found a statistically 
significant increase in 6MWD at peak and trough treprostinil exposure (p<0.0006 and p<0.01, 
respectively) (McLaughlin et al., 2010).  An innovative salt form, treprostinil diethanolamine, 
has been developed to deliver PGI2 therapy via the oral route in a solid dosage form.  Because 
the bioactive species is the same, treprostinil diethanolamine is expected to retain a similar 
safety and efficacy profile as parenteral treprostinil sodium in the convenience of an oral 
dosage form.  It has been suggested combination therapy, particularly with a PGI2, may 
prevent or delay the progression of the disease and thereby prolong the time to clinical 
worsening. 
1.4 
CLINICAL HYPOTHESIS 
The hypothesis of this study is that treatment with oral UT-15C combined with 
PAH-approved oral monotherapy as compared with placebo with PAH-approved oral 
monotherapy will: 
 Delay time to first clinical worsening (morbidity or mortality) event  
The hypothesis for the change of dosing frequency from BID to TID is that delivering more 
sustained concentrations of treprostinil may allow for systemic exposure to drug that more 
closely resembles the approved parenteral product, Remodulin, and reduce the occurrence of 
PGI2 AEs previously seen with the BID regimen.  Both of these improvements may allow 
study subjects to titrate to a more effective UT-15C dose and thus study drug may show a 
clinically and statistically significant difference compared to placebo in delaying time to first 
clinical worsening. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is: 
To assess the effect of oral UT-15C with PAH-approved oral monotherapy compared to 
placebo with PAH-approved oral monotherapy on time to first adjudicated clinical 
worsening (morbidity or mortality) event, as defined by at least one of the events listed 
below: 
 Death (all causes) 


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 Hospitalization due to worsening PAH defined as: 
 Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure; or 
 Lung or heart/lung transplantation; or 
 Atrial septostomy 
 Initiation of an inhaled or infused PGI2 for the treatment of worsening PAH 
 Disease progression (all criteria required): 
 A decrease in 6MWD of at least 15% from Baseline (or too ill to walk) directly 
related to PAH progression with other co-morbidities ruled out, confirmed by two 
6MWTs performed on different days* 
 Worsening of PAH symptoms, which must include either 
An increase in functional class from Baseline or  
Appearance or worsening of symptoms of right heart failure since Baseline 
 Unsatisfactory long-term clinical response (all criteria required) 
 Randomized to receive study drug for at least 24 weeks 
 A decrease from Baseline in 6MWD at Week 24 and beyond at two consecutive 
visits on different days*  
 Sustained WHO Functional Class III or IV symptoms for at least 24 weeks 
consecutively  
*Confirmatory 6MWTs should be conducted within 30 days of the qualifying decrease in 
6MWD; however, confirmatory 6MWTs occurring outside of this window will still be 
considered to have met the definition of clinical worsening and sent to the adjudication 
committee for review. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are to assess the effect of oral UT-15C combined with 
PAH-approved oral monotherapy compared to placebo combined with PAH-approved oral 
monotherapy on the following:  
 Exercise capacity as assessed by 6MWD measured at Week 24 
 NT-proBNP at Week 24 
 Combined 6MWD/Borg dyspnea score at Week 24 
 Exercise capacity as assessed by 6MWD measured at each visit up to Week 48 other 
than Week 24 
 Borg dyspnea score 
 WHO Functional Class 
 Right heart catheterization (RHC) hemodynamics at Week 24 (optional) 


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 Safety 
 Clinical laboratory parameters 
 Vital signs 
 AEs 
 ECG 
2.3 
EXPLORATORY OBJECTIVES 
 Optional evaluation of biomarkers 
 Optional evaluation of pharmacogenomics 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is an international, multi-center, randomized, double-blind, placebo-controlled, event 
driven study in subjects with PAH.  Subjects will be assessed during the Screening period to 
determine eligibility for the study, which will be confirmed during the Baseline visit prior to 
randomization.  Once randomized, subjects will return for study visits every 4 weeks for the 
first 12 weeks, then every 12 weeks for the duration of the study.  Subjects will continue in 
the study until either they experience clinical worsening as defined in the protocol, 
approximately 205 adjudicated events have occurred, or they prematurely discontinue 
participation in the study for any reason other than protocol-specific clinical worsening.  If a 
subject meets the definition of clinical worsening during the study and receives only short 
term (28 days or less) treatment with an infused or inhaled PGI2 therapy for worsening PAH, 
they will be permitted to enter the open-label extension study (TDE-PH-311).  If a subject 
prematurely discontinues the study for any reason other than clinical worsening, or receives 
long-term (29 days or more) treatment with an infused or inhaled PGI2 therapy for worsening 
PAH, they will not be permitted to enter the open-label extension study.  Otherwise, all 
subjects actively participating in the study will be allowed to transition to the open-label 
extension study after approximately 205 adjudicated clinical worsening events have occurred. 
At each scheduled visit, subjects will undergo the following efficacy assessments: clinical 
worsening, exercise capacity (6MWD and Borg dyspnea score), and WHO Functional Class.  
Plasma samples will also be collected for measurement of NT-proBNP at Baseline, Week 12 


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Week 24, Continued Visit 1 and at every other Continued Visit thereafter.  See Table 3-1 for 
the overall schedule of times and events. 
Additionally, subjects may participate in an optional hemodynamic sub-study in which 
hemodynamic parameters will be assessed by RHC before randomization and following 
24 weeks of treatment with study drug. 
Safety will be assessed via vital signs, AEs, and clinical laboratory parameters.  Subjects will 
also undergo a 12-lead ECG at Screening and Week 24.  At every protocol-required visit, 
measures of exercise capacity will occur within 3 to 6 hours following administration of the 
last dose of study drug. 
Subjects must receive only one PAH-approved oral therapy at a dose that complies with the 
approved prescribing information for the product for at least 30 days before the day of 
randomization to participate in the study.  The dose of background oral monotherapy may be 
titrated as clinically indicated during the Screening period.  Subjects must be on a stable dose 
of their background oral monotherapy for a minimum of 10 days prior to being randomly 
allocated to receive either oral UT-15C or placebo at randomization.  Subjects will receive 
their first dose of study drug (0.125 mg) in the clinic on the day of randomization.  Oral 
dosing of study drug will be continued at 0.125 mg TID (every 6 to 8 hours) with food.  The 
dose will be slowly titrated throughout the study up to a maximum dose of 12 mg TID in an 
effort to reach a well-tolerated dose that provides optimal clinical benefit. 


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Table 3-1 
Overall Schedule of Times and Events 
STUDY PROCEDURES 
Screen/Baselinea 
Treatmentk,m 
End of Studym 
Study Timeline 
Day 
-30 to -1 
Day 1 
(Baseline) Week 4j Week 8j 
Week 12j 
Week 24j 
Continued 
Visits every 12 
weeksj 
Study Drug 
Termination Visitl 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
PAH & Medical History 
X 
 
 
 
 
 
 
 
Vital Signsb 
X 
X 
X 
X 
X 
X   
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
X 
Clinical Worsening 
Assessment 
 
 
X-------
- 
--------- 
--------- 
-------- 
----X 
X 
6MWT/Borg Dyspnea Score 
Xc,d 
X 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
WHO Functional Class for 
PAH 
 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests 
Xa 
Xa 
 
 
X 
X 
Xe 
X 
Plasma N-terminal proBNP 
 
X 
 
 
X 
X 
Xe 
X 
Urine Pregnancy Test for 
WOCBP 
X 
X 
X 
X 
X 
X 
X 
X  
12-lead ECGf 
X 
 
 
 
 
X 
 
X 
Right Heart Catheterization 
(optional) 
 
Xg 
 
 
 
Xh 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Administration of Study 
Drug 
 
Xi--------- 
---------
-- 
-------- 
-------- 
------- 
-----X 
 
Weekly Telephone Contactn 
 
X--------- 
---------
-- 
-------- 
------- 
------X 
 
 


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a  The Screening and Baseline assessments may be combined if all entry criteria are satisfied within 48 hours prior to randomization.  Sites should provide a completed Pre-
Baseline review form to the Medical Monitor which will be reviewed, signed and returned to the site prior to randomization. Sites may conduct pre-Screening activities 
prior to a specific subject signing an informed consent.  Pre-Screening activities may include review of the site’s database to identify potential patients that may be 
eligible for the study.  
b  Vital signs should be conducted prior to, or at least 30 minutes following, the corresponding 6MWT.  Subjects should rest for 5 minutes prior to collection of vital signs 
c  If the subject has not previously undergone a 6MWT at the study site, a practice 6MWT must be conducted during the Screening period 
d Subject should rest for 5 minutes prior to each 6MWT.  All 6MWTs following randomization must be conducted 3 to 6 hours after the last dose of study drug 
e  During the Continued Visits, laboratory samples and NT-proBNP will only be collected at the first Continued Visit and at every other Continued Visit thereafter 
f  To be conducted following a minimum of 5 minutes rest in the semi-recumbent position 
g  To be conducted within 5 days prior to Randomization (inclusive) and following a minimum of 10 days on stable background PAH oral monotherapy  
h  To be conducted within 72 hours after all other Week 24 assessments; as best as possible to be performed 3 to 6 hours after previous dose of study drug  
i  First dose of study drug will be administered in the clinic following randomization; study drug dosing will continue at 0.125 mg TID (every 6 to 8 hours) 
j  The window for Week 4, 8, 12 and 24 visit assessments is ± 7 days; the window for visits following Week 24 is ±14 days.  
k  At any time during the Treatment Period, subjects may return to the study site for additional assessments as required 
l  The Study Termination Visit includes the study drug termination which should be pconducted at the time the decision is made to discontinue the study drug (prior to down 
titration), either because the subject has met clinical worsening criteria or is being permanently discontinued from the 310 study. The 6MWD should be conducted within 
3 to 6 hours after the most recent dose of study medication and preferably before the drug is down titrated (if the subject is being permanently discontinued rather than 
transitioning to the TDE-PH-311 study) 
m If subject permanently discontinues study drug before Week 24 and is ineligible for the TDE-PH-311 study, subject should be encouraged to remain in study and attend 
visits up to and including Week 24. The end of study assessments (survival status, AE assessment, drug accountability, concomitant medications, etc.) should be 
conducted after the subject has stopped taking the study medication (before or at Week 24)   
n Weekly telephone contact should be completed and subject study drug dose must also be recorded at Week 16 and Week 20 in the eCRF.  More frequent telephone calls 
may be necessary depending on the frequency of dose titration and to manage AEs or signs and symptoms of disease 
o For subjects consenting to the optional biomarker samples. 
p For subjects consenting to the optional pharmacogenomic sample. 
Monthly Telephone Contact 
 
 
 
 
 
X------ 
------ 
------X 
Drug Accountability 
 
X 
X 
X 
X 
X 
X 
X 
Compliance 
 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
X----- 
---------- 
--------- 
-------- 
-------- 
------- 
------- 
X 
Concomitant Medications  
X----- 
---------- 
--------- 
-------- 
-------- 
------- 
------- 
X 
Serum Biomarker Sample 
(Optional)o 
 
 
 
 
 
 
 
Xo 
Urine Biomarker Sample 
(Optional)o 
 
 
 
 
 
 
 
Xo 
Pharmacogenomic Sample 
(Optional)p 
 
 
 
 
 
 
 
Xp 


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3.2 
CLINICAL ASSESSMENTS 
3.2.1 
Efficacy 
3.2.1.1 
Clinical Worsening 
Clinical worsening will be assessed continuously from randomization until the subject’s last 
study visit.  All clinical worsening events will be reviewed by the sponsor Medical Monitors.  To 
ensure subject eligibility for the open-label extension study (TDE-PH-311), subjects should 
remain on study drug until the clinical worsening event has been reviewed and confirmed by the 
Medical Monitor unless the Investigator feels it is medically necessary to discontinue study drug 
for the welfare of the subject.  Clinical worsening (adjudicated) is defined as the occurrence of 
any one of the following clinical worsening (morbidity or mortality) events: 
 Death (all causes) 
 Hospitalization due to worsening PAH defined as: 
 Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure; or 
 Lung or heart/lung transplantation; or 
 Atrial septostomy 
 Initiation of an inhaled or infused PGI2 for the treatment of worsening PAH 
 Disease progression (all criteria required): 
 A decrease in 6MWD of at least 15% from Baseline (or too ill to walk) directly 
related to PAH progression with other co-morbidities ruled out, confirmed by two 
6MWTs performed on different days* 
 Worsening of PAH symptoms, which must include either 
 An increase in functional class from Baseline or 
 Appearance or worsening of symptoms of right heart failure since Baseline 
 Unsatisfactory long-term clinical response (all criteria required) 
 Randomized to receive study drug for at least 24 weeks 
 A decrease from Baseline in 6MWD at Week 24 and beyond at two consecutive visits 
on different days* 
 Sustained WHO Functional Class III or IV symptoms for at least 24 weeks 
consecutively 
*Confirmatory 6MWTs should be conducted within 30 days of the qualifying decrease in 
6MWD; however, confirmatory 6MWTs occurring outside of this window will still be 
considered to have met the definition of clinical worsening and sent to the adjudication 
committee for review. 


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Once a clinical worsening event occurs, it must be entered on the specified form in the electronic 
case report form (eCRF) and should be submitted within 48 hours after the event becomes 
known to the Investigator or designee.  When the form is submitted, the sponsor Medical 
Monitor will review the event and correspond with the Investigator and site, as appropriate.  
Although subjects may be discontinued from the study for medical necessity at any time, 
subjects should not be discontinued for a clinical worsening event until the event has been 
reviewed by the Medical Monitor.  Once the clinical worsening event has occurred, the subject 
will then complete the Study Drug Termination visit assessments. 
Clinical worsening events that meet the definition of a serious adverse event (SAE) will follow 
the same reporting requirements as all SAEs (Section 9.3).  These events must also be entered on 
the specified form in the eCRF. 
In addition to the Medical Monitor reviewing all clinical worsening events as and when they 
occur, an independent adjudication committee will review all clinical worsening events 
periodically throughout the study (Section 10.8). 
3.2.1.2 
Six-Minute Walk Test 
The intent of the 6MWT is to evaluate exercise capacity associated with carrying out activities of 
daily living.  All 6MWTs will be conducted by qualified, trained personnel in a designated 
6MWT area which meets the requirements as described in Section 15.1.  Prior to the start of each 
6MWT the subject should rest (seated) for at least 5 minutes. 
3.2.1.2.1 
Practice Six Minute Walk Test 
All subjects must have a documented 6MWT conducted at the study site on the course intended 
for use during the study.  If no previous 6MWT has been performed at the study site, a practice 
6MWT must be conducted at least 1 day prior to the Randomization 6MWT for applicable 
subjects. 
3.2.1.2.2 
Baseline Six Minute Walk Test 
A Baseline 6MWT must be performed prior to initiation of study drug and should be conducted 
on the day of randomization.  The Baseline 6MWT must be conducted no earlier than 1 day 
following the practice 6MWT, for applicable subjects.  Once the Baseline 6MWT has been 


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conducted, the site will enter the subject’s six-minute walk distance into an interactive voice or 
web response system (IVRS/IWRS).  IVRS/IWRS will confirm to site personnel the subject’s 
eligibility to participate in the study based on 6MWD, and if eligible, randomize the subject into 
a treatment group and allocate appropriate study drug. 
3.2.1.2.3 
Treatment Six-Minute Walk Tests 
6MWTs will be conducted at Weeks 4, 8, 12, 24, and every 12 weeks thereafter.  The 6MWT 
should be conducted 3 to 6 hours following the last dose of study medication.  Subjects receiving 
supplemental oxygen during the Baseline 6MWT must continue to receive the same flow rate 
and mode of oxygen therapy at all subsequent 6MWT assessments; any changes in oxygen 
therapy administration should be noted in the eCRF.  In addition, subjects receiving pulmonary 
rehabilitation prior to study entry should continue on the same schedule up to and including 
Week 24.  Following Week 24, pulmonary rehabilitation may be adjusted per standard of care.  
Pulmonary rehabilitation may not be added to a subject’s regimen between randomization and 
Week 24.  Documentation of pulmonary rehabilitation should occur in the special circumstances 
section of the eCRF.  Additional 6MWTs may be conducted as appropriate throughout the course 
of the study for the purposes of evaluating clinical worsening status. 
Each 6MWT conducted after Randomization should be documented and compared to the 
subject’s Baseline 6MWD.  If a subject has a decrease of 15% or more in walk distance 
compared to Baseline, a second confirmatory 6MWT should be performed on a different day to 
assess for clinical worsening (confirmatory 6MWTs should be conducted within 30 days of the 
qualifying decrease in 6MWD; however, confirmatory 6MWTs occurring outside of this window 
will still be considered to have met the definition of clinical worsening and sent to the 
adjudication committee for review).  If the second 6MWT also shows at least 15% decrease in 
6MWD as compared to Baseline and the subject has either worsened in WHO Functional Class 
compared to Baseline or has the appearance or worsening of symptoms of right heart failure 
since Baseline, the subject will meet the ‘disease progression’ definition of clinical worsening 
and should follow steps as outlined in Section 3.2.1.1.  Prior to exiting the study, the Study Drug 
Termination visit assessments should be conducted at the time the decision is made to 
discontinue study drug (prior to down titration).  For subjects who meet the definition of clinical 


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worsening for disease progression due to at least a 15% decrease in 6MWD from Baseline, the 
date of the clinical worsening event will be the date of the second confirmatory 6MWT. 
After the first 24 weeks of study participation, if a subject has any two consecutive 6MWTs on 
different days that demonstrate any decrease in 6MWD from Baseline accompanied with 
sustained WHO Functional Class III or IV symptoms for at least 24 weeks, consecutively, the 
subject will meet the clinical worsening definition of unsatisfactory long-term clinical response 
and should follow steps outlined in Section 3.2.1.1. 
Details regarding the conduct of the 6MWT are described in Section 15.1. 
3.2.1.3 
Borg Dyspnea Score 
The Borg dyspnea score will be assessed following each 6MWT.  The Borg dyspnea score is a 
10-point scale rating the maximum level of dyspnea experienced during the 6MWT 
(Section 15.1).  Scores range from 0 (for the best condition) to 10 (for the worst condition). 
3.2.1.4 
WHO Functional Classification 
The WHO functional classification for PAH (Section 15.2) will be assessed at Baseline prior to 
starting study drug and at all subsequent scheduled study visits, and every time the 6MWT is 
performed for purposes of assessing clinical worsening status.  
3.2.1.5 
N-terminal pro-BNP 
Plasma NT-proBNP concentration is a useful biomarker for PAH as it is associated with changes 
in right heart morphology and function [Fijalkowska 2006].  NT-proBNP sample collection will 
occur at Baseline (prior to starting study drug), Week 12, Week 24, the first Continued Visit, and 
every other Continued Visit thereafter (i.e., Continued Visits #3, #5, #7, etc.).  NT-proBNP will 
also be assessed at the Study Drug Termination visit. 
3.2.1.6 
Right Heart Catheterization (Optional Assessment) 
This section describes the optional RHC assessments that may be conducted at Baseline and 
Week 24. 
If a subject agrees to participate in the optional hemodynamic assessments, a RHC must be 
performed within 5 days before randomization (inclusive).  The subject must be on stable 


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background therapy for a minimum of 10 days prior to this RHC.  If a RHC is performed on the 
day of randomization, all other study-related assessments, other than initiation of study drug, 
should be performed prior to conduct of the RHC.  A follow-up RHC must be performed within 
72 hours following completion of Week 24 assessments.  As best as possible, follow-up RHC 
should be performed within 3 to 6 hours of previous dose.  Hemodynamic parameters to be 
assessed and recorded include heart rate (HR), systolic systemic arterial pressure (SAPs), 
diastolic systemic arterial pressure (SAPd), mean systemic arterial pressure (SAPm), systolic 
pulmonary artery pressure (PAPs), diastolic pulmonary artery pressure (PAPd), mean pulmonary 
artery pressure (PAPm), mean right atrial pressure (RAPm), mean pulmonary capillary wedge 
pressure (PCWPm), cardiac output (CO), arterial oxygen saturation (SaO2), and mixed venous 
oxygen saturation (SvO2).  Additional hemodynamic parameters may also be calculated based on 
these measurements (e.g., pulmonary vascular resistance [PVR] and cardiac index [CI]).  Weight 
and height will be collected to calculate body surface area (BSA) and index the cardiac output. 
While this section describes the optional RHC assessments at Baseline and Week 24, all subjects 
eligible to participate in this study must either have data available from a historical RHC 
conducted within three years prior to the start of screening (i.e., date of signing the Informed 
Consent Form [ICF]), or undergo a RHC during the screening period prior to randomization with 
results consistent with the diagnosis of PAH as described in Section 4.1. 
3.2.1.7 
Optional Biomarker 
For subjects consenting to the optional biomarker samples, blood and urine will be collected at 
the End of Study Visit for the evaluation of biomarkers.  These samples will be shipped to the 
central laboratory for processing and storage prior to analysis.  Subjects who do not wish to 
participate in the optional biomarker research may still participate in the clinical study. 
3.2.1.8 
Optional Pharmacogenomic 
For subjects consenting to pharmacogenomic analysis, blood samples will be collected at the 
End of Study Visit for pharmacogenomics analyses.  These samples will be shipped to the central 
laboratory for processing and storage prior to analysis.  Genetic variants and/or gene expression 
patterns will be analyzed to evaluate their association with observed clinical response and 


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tolerability to prostacyclin therapy.  Subjects who do not wish to participate in the optional 
pharmacogenomic research may still participate in the clinical study. 
3.2.2 
Safety  
3.2.2.1 
Medical History and Physical Examinations 
A complete medical history, demographics, PAH history, and physical examination will be 
conducted during the Screening period.  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 noted in the eCRF.  Any significant changes to the 
subject’s medical condition, physical examination, and concomitant medications must be 
documented throughout the course of the study.  A complete physical examination will be 
conducted at the Study Drug Termination Visit. 
3.2.2.2 
Clinical Laboratory Tests 
Clinical laboratory tests will be assessed at the Screening and Baseline visits prior to starting 
study drug.  Screening and Baseline clinical laboratory assessments can be combined into a 
single blood draw if all eligibility criteria are met within 48 hours prior to randomization.  
Central laboratory data are ultimately used to qualify patients for the study.  However, for 
patients who are well known to the Investigator and who are clinically stable, the Investigator 
may choose not to delay randomization while waiting for central laboratory confirmation of local 
laboratory values.  Clinical laboratory assessments will also be assessed at Weeks 12 and 24, at 
the first Continued Visit, and every other Continued Visit thereafter (i.e., Continued Visits #3, 
#5, #7, etc.) as displayed in Appendix 15.3.  Clinical laboratory tests will also be assessed at the 
Study Drug Termination visit. 
A urine pregnancy test will be collected at Screening, Baseline, Weeks 4, 8, 12, 24, every 
12 weeks thereafter, and at the Study Drug Termination Visit for women of child bearing 
potential (WOCBP).  Screening and Baseline urine pregnancy tests can be combined into a 
single test if all eligibility criteria are met within 48 hours prior to randomization. 


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3.2.2.3 
Vital Signs  
Vital signs will be assessed at Screening and Baseline prior to starting study medication and at 
Weeks 4, 8, 12, and 24.  After Week 24, vital signs will be assessed every 12 weeks and at the 
Study Drug Termination Visit.  All vital signs will be collected prior to or at least 30 minutes 
following the corresponding 6MWT.  Vital signs include blood pressure, peripheral 
(radial/brachial artery) heart rate, respiration rate, and weight.  Height will be collected at the 
Baseline visit.  Vital signs must be collected following at least 5 minutes of rest (or at least 
30 minutes after a 6MWT) to ensure accurate measurement. 
3.2.2.4 
Adverse Events 
AEs will be captured from the time the ICF is signed.  All AEs should be followed until either 
resolution (or return to normal or Baseline values), until they are judged by the Investigator to no 
longer be clinically significant, or for up to 30 days if the AE extends beyond the final visit.  All 
SAEs should be followed until resolution, death, or the subject is lost to follow-up even if they 
are ongoing more than 30 days after completion of the final visit.  Sections 9 and 15.4 provide 
the guidelines and definitions for recording AEs. 
Symptoms of PAH (disease related events) should only be recorded as an AE if the event is 
either serious, new, or unusual with respect to intensity, frequency, duration as compared to 
symptoms in the subject’s medical history; or there is a reasonable possibility that the event was 
caused by the study drug. 
3.2.2.5 
12-Lead ECG 
Twelve-lead ECGs will be recorded after at least 5 minutes rest in the semi-recumbent position 
at Screening, Week 24, and at the Study Drug Termination Visit.  Recordings should include 
lead II as a rhythm strip and contain at least five QRS complexes.  ECG parameters collected 
include heart rate, PR interval, QT interval, QRS duration, and any clinically significant 
abnormalities. 
3.3 
NUMBER OF CENTERS 
The study is an international multi-center study with approximately 150 centers participating. 


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3.4 
NUMBER OF SUBJECTS 
At least 610 subjects with a maximum of 850 subjects will be randomized (1:1 UT-15C: 
placebo) across all sites participating in the study in order to obtain the required number of 
adjudicated clinical worsening (morbidity and mortality) events. 
3.5 
ESTIMATED STUDY DURATION 
Subjects will remain in the study until they either experience a clinical worsening event, 
discontinue the study for any other reason, or approximately 205 adjudicated clinical worsening 
events have occurred.  It is estimated that the overall study duration will last for 4 years; 
however, this is dependent on the rate of clinical worsening events. 
Subjects that discontinue and do not roll into the open-label extension study (TDE-PH-311) will 
be contacted approximately 30 days (±5 days) after study drug discontinuation to confirm their 
survival status.  Subjects that complete TDE-PH-310 and roll in to the open-label extension 
study will also be contacted approximately 30 days (±5 days) after study drug discontinuation in 
study TDE-PH-310 to confirm their survival status. 
Subjects may also continue to be contacted after the final study visit to assess ongoing 
AEs/SAEs (see Section 9.2 for additional details). 
4 
SUBJECT ELIGIBILITY 
Inclusion and exclusion criteria are to be assessed during the Screening period and reconfirmed 
at the Baseline visit prior to randomization.  If necessary, certain procedures may be conducted 
during the Screening period after obtaining informed consent to determine subject eligibility for 
the study.   
4.1 
INCLUSION CRITERIA 
A subject is eligible for inclusion in this study if all of the following criteria apply: 
1. The subject voluntarily gives informed consent to participate in the study. 
2. The subject is 18 to 75 years of age (inclusive) at Screening (i.e., date of providing 
written informed consent). 
3. Women of child bearing potential (WOCBP) includes any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as 


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amenorrhea for at least 12 consecutive months).  Women of childbearing potential must 
practice true abstinence from intercourse when it is in line with their preferred and usual 
lifestyle, or use two different forms of highly effective contraception for the duration of 
the study, and for at least 30 days after discontinuing study medication.  Medically 
acceptable forms of effective contraception include:  (1) approved hormonal 
contraceptives (such as birth control pills), (2) barrier methods (such as a condom or 
diaphragm) used with a spermicide, (3) an intrauterine device (IUD), or (4) partner 
vasectomy.  For women of childbearing potential, a negative urine pregnancy test is 
required at Screening and Baseline prior to initiating study medication. 
4. The subject, if male, must use a condom during the length of the study, and for at least 
48 hours after discontinuing study medication. 
5. The subject has a diagnosis of symptomatic idiopathic or heritable PAH, PAH associated 
with CTD, PAH associated with HIV infection, PAH associated with repaired congenital 
systemic-to-pulmonary shunt (at least 1 year since repair with respect to the date of 
providing informed consent) or PAH associated with appetite suppressant or toxin use. 
6. The subject, if known positive for HIV infection, has a CD4 lymphocyte count of at least 
200 cells/mm3 assessed at Screening and is receiving current standard of care 
anti-retroviral or other effective medication for treatment of HIV infection. 
7. The subject must have a Baseline 6MWD greater than or equal to 150 meters, in the 
absence of a concurrent injury, illness (other than PAH or a PAH related condition), or 
other confounding factor including, but not limited to, use of an aid for ambulation (e.g., 
use of a cane or walker) or connection to a non-portable machine, that would prevent the 
accurate assessment of the subject’s exercise capacity. 
8. The subject must be optimally treated with conventional pulmonary hypertension therapy 
(e.g., oral vasodilators, oxygen, digoxin, diuretics, anticoagulants as deemed appropriate 
by the Investigator) with no additions, discontinuations, or dose changes for a minimum 
of 10 days prior to randomization.  The exceptions are the discontinuation or dose 
changes of anticoagulants and/or dose change of diuretics. 
9. The subject must have been receiving a PAH-approved oral monotherapy at a minimum 
dose that complies with the approved prescribing information for the product for at least 
30 days prior to randomization and must have been receiving a stable dose for at least 
10 days prior to randomization.  The subject who previously received two PAH-approved 
oral therapies at the same time (specifically, a PDE5-I, an ERA, or an sGC stimulator) 
will be eligible provided they received these medications concomitantly for less than or 
equal to 90 days cumulatively.  The subject must have taken only one PAH-approved 
therapy for at least 30 days prior to randomization and must have been receiving a stable 
dose for at least 10 days prior to randomization. 
10. The subject has previously undergone a cardiac catheterization either within three years 
prior to the start of screening, or during the screening period, and the most recent 
assessment has documented a mean pulmonary artery pressure (PAPm) of at least 
25 mmHg, a pulmonary capillary wedge pressure (PCWP) (or in the event a PCWP 
cannot be reliably obtained, a left ventricular end diastolic pressure [LVEDP]) less than 
or equal to 15 mmHg, and absence of unrepaired congenital heart disease (other than 
patent foramen ovale [PFO]).  In the event that a reliable PCWP or LVEDP are unable to 


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be obtained during cardiac catheterization, subjects with clinically normal left heart 
function and absence of clinically relevant mitral valve disease on echocardiography are 
eligible for enrollment. 
11. The subject has undergone echocardiography with evidence of clinically normal left 
systolic and diastolic ventricular function and absence of any clinically significant left 
sided heart disease (e.g. mitral valve disease).  Subjects with clinically insignificant left 
ventricular diastolic dysfunction due to the effects of right ventricular overload (i.e., right 
ventricular hypertrophy and/or dilatation) are eligible. 
12. The subject has a previous ventilation perfusion lung scan, and/or high resolution 
computerized tomography scan of the chest, and/or pulmonary angiography that are 
consistent with the diagnosis of PAH (e.g., low probability of pulmonary embolism; 
absence of major perfusion defects).  
13. The subject has pulmonary function tests conducted within 6 months before screening or 
during the Screening period to confirm the following: 
a. Total lung capacity (TLC) is at least 60% (predicted value) assessed by either whole 
body plethysmography or helium dilution or nitrogen washout technique  
b. Forced expiratory volume at one second (FEV1) of at least 50% (predicted value) 
14. In the opinion of the Principal Investigator, the subject is able to communicate effectively 
with study personnel, and is considered reliable, willing and likely to be cooperative with 
protocol requirements, including attending all study visits.  
4.2 
EXCLUSION CRITERIA 
A subject is not eligible for inclusion in this study if any of the following criteria apply: 
1. The subject is pregnant or lactating. 
2. The subject has previously received UT-15C. 
3. The subject has received a PGI2, (except if used during acute vasoreactivity testing) 
within 30 days prior to randomization or had previous intolerance or significant lack of 
efficacy to any PGI2, or PGI2 analogue, that resulted in discontinuation or inability to 
titrate that therapy effectively. 
4. The subject has had any background conventional therapies for PAH added, removed or 
dose adjusted (including but not limited to oxygen, vasodilators, diuretics, digoxin, 
anticoagulants) within 10 days prior to randomization.  The exceptions are removal or 
dose adjustments of anticoagulants and/or dose adjustments of diuretics. 
5. The subject has received their first dose of a PAH-approved therapy less than 30 days 
prior to randomization, or has had their PAH-approved oral monotherapy dose changed 
within 10 days prior to Randomization, or the subject discontinued any PAH-approved 
therapy within 30 days prior to Screening, or the subject previously received two 
PAH-approved oral therapies at the same time (specifically, a PDE5-I, an ERA, or an 
sGC stimulator) concomitantly for more than 90 days cumulatively. 
6. The subject has any disease associated with PAH other than CTD, HIV infection, 
repaired (for at least one year) congenital systemic-to-pulmonary shunt, PAH associated 


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with appetite suppressant/toxin use (e.g., portal hypertension, chronic thromboembolic 
disease, pulmonary veno-occlusive disease, etc.) or has had an atrial septostomy. 
7. The subject has a current diagnosis of uncontrolled sleep apnea as defined by their 
physician. 
8. The subject has a history of ischemic heart disease, including a previous myocardial 
infarction or symptomatic coronary artery disease within 6 months prior to Screening or a 
history of left sided myocardial disease as evidenced by a mean PCWP (or a left 
ventricular end diastolic pressure [LVEDP]) greater than 15 mmHg or left ventricular 
ejection fraction less than 40% as assessed by either multigated angiogram (MUGA), 
angiography, or echocardiography. 
9. The subject has uncontrolled systemic hypertension as evidenced by systolic blood 
pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg. 
10. The subject has ALT or AST levels at least greater than 3 times the upper limit of normal, 
clinically significant liver disease/dysfunction, or known Child-Pugh Class C hepatic 
disease (Appendix 15.5) at Screening. 
11. The subject has any other disease or condition that would interfere with the interpretation 
of study assessments. 
12. The subject has a musculoskeletal disorder (e.g., arthritis affecting the lower limbs, recent 
hip or knee joint replacement, artificial leg), is using a device to assist walking (e.g. cane 
or walker), or any disease that is likely to limit ambulation, or is connected to a machine 
that is not portable. 
13. The subject has an unstable psychiatric condition or is mentally incapable of 
understanding the objectives, nature, or consequences of the trial, or has any condition 
which in the Investigator’s opinion would constitute an unacceptable risk to the subject’s 
safety. 
14. The subject is receiving an investigational drug, has an investigational device in place, or 
has participated in an investigational drug or device study within 30 days prior to 
Screening. 
15. The subject has chronic renal insufficiency as defined by either a Screening creatinine 
value greater than 2.5 mg/dL (221 μmol/L) or the requirement for dialysis. 
16. Subjects must not have 3 or more of the following left ventricular disease/dysfunction 
risk factors:  
i. 
Body Mass Index (BMI) ≥30 kg/m2 
ii. 
History of essential hypertension  
iii. 
Diabetes mellitus – any type  
iv. 
Historical evidence of significant coronary disease established by any one of: 
history of myocardial infarction or percutaneous coronary intervention or 
angiographic evidence of coronary artery disease (>50% stenosis in at least one 
coronary artery), positive stress test with imaging, previous coronary artery bypass 
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4.3 
PRESCRIBED THERAPY 
4.3.1 
PAH-Approved Therapies 
All subjects must be receiving a dose of one PAH-approved oral therapy that complies with the 
approved prescribing information (as described in Table 4-1) for the product for a minimum of 
30 days and at the current dose for at least 10 days prior to randomization.  All subjects must be 
willing to remain on the same background approved PAH oral therapy at the same dose for the 
duration of the study.  In the event a subject must undergo a change in background therapy, they 
should be switched to another approved agent in the same medication class if possible.  If 
another agent in the same class is not available, the subject should be switched to an agent from 
another class of approved PAH oral medications.  If no alternative therapy is available, the 
subject will continue in the study until either a clinical worsening event has occurred, the subject 
withdraws from the study, or the study is completed/discontinued. 
Table 4-1 
Minimum Allowable Doses of Background PAH Oral Therapy 
PAH-Approved Background Therapy 
Dosing Schedule 
ambrisentan 
5 mg once daily 
bosentan* 
125 mg twice daily 
macitentan 
10 mg once daily 
sildenafil 
20 mg three times daily 
tadalafil** 
40 mg once daily 
riociguat*** 
1 mg three times daily 
* 62.5 mg twice daily is permitted if used per prescribing guidelines (e.g., subject weighs less than 40 kg or has elevated 
liver function tests) 
** 20 mg once daily is permitted if used per prescribing guidelines (e.g., subject has mild or moderate renal insufficiency) 
*** 0.5 mg three times daily permitted if used per prescribing guidelines (e.g. subject cannot tolerate hypotensive effects) 
Prior to Week 24, if the Investigator, for any reason, initiates a second PAH-approved oral 
therapy in addition to the PAH-approved oral therapy initiated prior to Screening (e.g., due to 
disease progression without meeting the definition of clinical worsening as defined in 
Section 2.1), the subject must be discontinued from the study drug.  The subject should be 
encouraged to remain in the study and attend all visits up to and including Week 24; however, 
the subject will not be eligible for enrollment in the open-label study (TDE-PH-311).  After 
Week 24, if the Investigator initiates a second PAH-approved oral therapy due to any reason in 
addition to the PAH-approved oral therapy initiated prior to Screening, the subject must be 
discontinued from the study and will not be eligible for enrollment in the open-label study. 


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All changes in drug or dosage regimens during the study will be recorded in the subject’s source 
documents and transcribed as required to the eCRF. 
Product labeling for the background PAH-approved oral therapy should be consulted in order to 
guide the monitoring of AEs.  The dose of study drug should be adjusted first in response to any 
new AEs that occur during the study, rather than adjusting the dose of PAH-approved oral 
therapy; unless the event is considered causally related to the PAH-approved oral therapy.  If a 
subject meets the definition of clinical worsening during the study and receives only short term 
(28 days or less) treatment with an infused or inhaled PGI2 therapy for worsening PAH, they will 
be permitted to enter the open-label extension study (TDE-PH-311).  If a subject prematurely 
discontinues the study for any reason other than clinical worsening, or receives long-term 
(29 days or more) treatment with an infused or inhaled PGI2 therapy for worsening PAH, they 
will not be permitted to enter the open-label extension study.  During the course of the study, if 
the Investigator initiates a second PAH-approved oral therapy due to any reason (e.g. disease 
progression without meeting the definition of clinical worsening as defined in Section 2.1) in 
addition to the PAH-approved oral therapy initiated prior to Screening, the subject must be 
discontinued from the study and will not be eligible for enrollment in the open-label study 
(TDE-PH-311). 
4.3.2 
Concomitant Medications 
All subjects must have been stabilized on optimal doses of conventional PAH therapies (e.g., 
oral vasodilators, digoxin, diuretics, oxygen, anticoagulants) for at least 10 days prior to Baseline 
assessments.  The exceptions are the discontinuation or dose changes of anticoagulants and/or 
dose change of diuretics.  After randomization, additions, deletions, and dose changes may occur 
if the Investigator determines it is medically necessary.  For the purposes of the 6MWT, if the 
subject was assessed at Baseline using oxygen therapy then all future 6MWTs during the study 
must be conducted with the same oxygen flow rate and mode of administration; any changes in 
oxygen therapy administration should be noted in the eCRF. 
All concomitant medications taken during conduct of the study, including those taken for AEs or 
other medical events, should be recorded in the subject’s source documents and transcribed as 
required to the eCRF. 


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5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
Eligible subjects will be randomly allocated to receive either UT-15C or placebo at 
randomization.  During the Screening period a screening number will be assigned using an 
electronic data capture (EDC) system to identify individual subject data until the subject is 
randomized.  Upon randomization, each subject will be assigned a new unique study subject 
number via the IVRS/IWRS.  The IVRS/IWRS will also be responsible for allocation of all study 
drug. 
5.2 
RANDOMIZATION 
The study will be randomized 1:1 UT-15C to placebo.  All subjects will be randomly allocated to 
receive UT-15C or placebo through the IVRS/IWRS using a centrally administered stratified 
permuted block randomization by type of background therapy (Strata 1: PDE5-I and sGC 
stimulator; Strata 2: ERA) which will be balanced across the two treatment groups.  Subjects will 
also be stratified by Baseline 6MWD (less than or equal to 350 meters and greater than 
350 meters).  Block sizes will be variable and not disclosed to Investigators so that no inferences 
can be made about possible treatment assignments of current or future subjects. 
Prior to randomization, site personnel should complete a Pre-Baseline Review Form for review 
and approval by the Medical Monitor. 
5.3 
BLINDING 
The Investigator, study site, subject, and sponsor will not be aware of the treatment allocation.  
All clinical trial material (CTM) will be provided as blinded study drug.  See Section 6.2 for the 
procedure for unblinding subjects at the end of study to determine appropriate starting dose for 
the open-label study (TDE-PH-311). 
6 
DRUGS AND DOSING 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE 
The UT-15C tablets are sustained release osmotic tablets.  Active treatment is UT-15C tablets 
provided as 0.125, 0.25, 0.5, 1, and 2.5 mg strengths. The 0.125, 0.25, 0.5, 1, and 2.5 mg tablets 
are colored blue, green, white, yellow, and pink, respectively.  The formulation contains 


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pharmaceutically acceptable excipients used in other approved drug products.  Placebo tablets 
are identical in size, shape, and color to the respective UT-15C tablets. 
Once all entry criteria have been met and random treatment assignment confirmed, the first dose 
of study drug (0.125 mg) should be taken at the site by the subject immediately after 
(~10 minutes) consuming food. Oral dosing of study drug will be continued at 0.125 mg TID 
(every 6 to 8 hours) immediately after (~10 minutes) consuming food.  Subjects must be 
instructed to take the appropriate amount of UT-15C tablets based upon their prescribed dose.  
Prior to the Week 4 visit, each dose of study drug should be adjusted in 0.125 mg increments 
every 24 hours as clinically indicated.  Following the Week 4 visit throughout the remainder of 
the study, each dose of study drug may be adjusted in 0.125 or 0.25 mg increments every 
24 hours as clinically indicated.  The maximum allowable dose of study drug will be 12 mg TID.   
Doses of study drug should continue to be increased in the absence of dose-limiting drug-related 
adverse effects, to ensure that each subject receives the optimal clinical dose throughout the 
study.  Table 6-1 provides a range of doses that may be reasonable targets for a subject to 
achieve by visit notwithstanding any AEs that limit dose escalation.  
Table 6-1 
Study Drug Goal Dose Titration Ranges 
Study Week 
Dose (mg) Three Times Daily 
4 
0.5 – 1.5 
8 
1.5 – 2.5 
12 
2.5 – 3.5 
24 
5.5 – 6.5 
 
Dose changes should be conducted under appropriate medical supervision in consultation with 
the study site.  Each dose of study drug is not required to be the same during titration. For 
example, doses of 1.125 mg morning, 1.125 mg afternoon, and 1.25 mg evening, are acceptable 
during titration.  It is recommended that the difference between any of the three doses not exceed 
0.125 mg prior to Week 4 or 0.25 mg after Week 4. 
At least weekly telephone calls between site personnel and the subject should be made during the 
first 24 weeks of the study to monitor AEs and make decisions about dose titration.  More 


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frequent telephone calls may be necessary depending on the frequency of dose titration and to 
manage AEs or signs and symptoms of disease.  If dose titration is considered appropriate, site 
personnel will instruct the subject to modify their dose.  Study drug dosing should be recorded at 
each study visit between Baseline and Week 24. Dose changes between Baseline and Week 24 
will be recorded in source documentation and the subject’s eCRF by site personnel.  Beyond 
Week 24, study drug dose will be recorded on the day of Continued Visits (e.g. Weeks 36, 48, 
etc.) and every 30 days between Continued Visits in source documentation and the eCRF by site 
personnel.  If it becomes necessary for a subject to modify their dose (e.g., due to an AE) without 
prior instructions from site personnel, the subject should be instructed to contact the site as soon 
as possible and report any dose changes to site personnel for updating in source documentation 
and the eCRF as appropriate. 
After Week 24, at least monthly telephone calls should be made to continue to monitor AEs and 
make decisions regarding appropriate dose titrations.  More frequent telephone calls may be 
necessary depending on the frequency of dose titration and to manage AEs or signs and 
symptoms of disease.  Site personnel should record all dose changes in source documentation 
from Week 24 until Study Termination. 
In the event a subject requires to be permanently discontinued from study drug (e.g. as a result of 
clinical worsening or the subject wishes to withdraw from further participation in the study), the 
Investigator should conduct the study drug termination assessments and then gradually down 
titrate the study drug, taking into consideration the subject’s clinical condition, current study 
drug dosing regimen, and previous clinical response to study drug. 
Throughout the course of the study, the dose of study drug should continue to be increased at the 
discretion of the Investigator up to a maximum allowable dose of 12 mg TID.  Dose escalation 
may be made less frequently or temporarily suspended if a subject experiences an intolerable AE 
that may worsen as a result of an increase in study drug dose.  If an AE remains intolerable, the 
Investigator may decrease the dose of study drug.  In the event of continued intolerable AEs, 
dose reductions may occur. The exact dose reduction and frequency of dose reduction should be 
based on the clinical condition of the subject and the severity/seriousness of the event.  In 
general, dose reductions may occur in 0.125 mg or 0.25 mg increments every 12 to 24 hours. 


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Larger dose reductions may be necessary in the event of an emergency situation. If the subject is 
still experiencing an intolerable AE then the Investigator may temporarily or permanently 
withdraw the subject from study drug.  Following temporary discontinuation of study drug, all 
attempts should be made to re-initiate study drug in affected subjects.  Subjects should be 
re-started on study drug at a reduced dose or at 0.125 mg TID depending on the clinical 
condition of the subject, the subject’s previous response to study drug, the dose at the time of 
discontinuation, and the duration of temporary discontinuation from study drug.  Following 
restart of study drug, all efforts should be made to increase the dose until the desired clinical 
improvement in the subject’s symptoms of PAH occurs. 
Notwithstanding these study drug dosing guidelines, the well-being of each subject is paramount 
and all Investigators must act in accordance with the best medical interests of the subjects at all 
times during their participation in the study. 
6.1.1 
Dosing of Study Drug in Relation to Meals 
Subjects should take study drug approximately every 6 to 8 hours with approximately 240 mL 
(8 ounces) of water or other beverage (e.g. juice, milk, soda, etc.) immediately after 
(~ 10 minutes) consuming food. 
Subjects should be instructed to be careful not to break, chew, or disrupt the integrity of the 
tablet as this will result in inappropriate delivery of the active ingredient.  If the tablet is 
inadvertently damaged during administration, the subject should contact site personnel in order 
to be monitored for the onset of symptoms due to possible overdose.  Any tablet damaged during 
handling by the subject should not be consumed by the subject.  The subject should be instructed 
to notify the study personnel and return the damaged study drug at the next scheduled visit. 
6.1.2 
Dosing and Administration of Adjunctive Medications 
Every subject must be receiving one PAH-approved oral monotherapy (e.g., sildenafil, tadalafil, 
bosentan, ambrisentan, macitentan, or riociguat) for at least 30 days prior to randomization and 
on the same dose for at least 10 days prior to randomization.  Dosing of background 
PAH-approved oral monotherapy must comply with the prescribing information for the product. 


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All attempts should be made to adjust the dose of study drug rather than the dose of 
PAH-approved oral therapy to obtain the desired clinical response.  Throughout the course of the 
study, dose and frequency of the PAH-approved oral therapy may not be increased to 
compensate for lack of efficacy.  Similarly, the dose and frequency of PAH-approved oral 
therapy should not be reduced during the study unless it is considered medically necessary to 
protect the safety of the subject.  If the dose of PAH-approved oral therapy is inadvertently 
titrated during the course of the study, the dose should be titrated back to the dose used at the 
time of randomization, if medically appropriate.  If the dose of PAH-approved oral therapy is 
increased during the Treatment Phase and is not subsequently titrated back to the dose used at the 
time of randomization, the subject will need to be removed from the study. 
In the event a subject must undergo a change in background therapy, they should be switched to 
another agent in the same PAH-approved medication class if possible.  If another agent in the 
same class is not available, the subject should be switched to an agent from another class of 
PAH-approved medication.  If no alternative therapy is available, the subject will continue in the 
study until either a clinical worsening event has occurred, the subject withdraws from the study, 
or the study is completed/discontinued.  
All subjects must have been stabilized on optimal doses of conventional PAH therapies (e.g., 
oral vasodilators, digoxin, diuretics, oxygen, anticoagulants) for at least 10 days prior to 
randomization.  The exceptions are the discontinuation or dose changes of anticoagulants and/or 
dose change of diuretics.  After randomization, additions, deletions, and dose changes may occur 
if the Investigator determines it is medically necessary. 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
During the study, neither the site personnel, subject, nor sponsor should be unblinded to the 
treatment assignment of any subject for any reason except in the event of a medical emergency 
(e.g., a life threatening event), if and when knowledge of the treatment assignment is considered 
necessary to determine the optimal medical management.  Appropriate communications should 
take place between the site and the sponsor before accessing the IVRS/IWRS to allow unblinding 
of a subject’s treatment assignment. In the event of a medical emergency that requires immediate 


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unblinding, the IVRS/IWRS may be accessed by the Investigator to determine treatment 
assignment. 
Subjects who remain on study drug, complete required study assessments, and meet the 
definition of clinical worsening will be eligible for an open-label study (TDE-PH-311).  Subjects 
requiring long term treatment (29 days or more) with infused or inhaled PGI2 for treatment of 
worsening PAH are not eligible for the open-label study. Following completion of the Study 
Drug Termination assessments for a subject (see Table 3-1) and entry of required data into the 
IVRS/IWRS, the site personnel will be unblinded to that subject’s treatment assignment.  If the 
subject received UT-15C during the study then the subject may remain on the same dose of study 
drug upon entry into the open-label study.  If the subject received placebo during the study then 
the subject should start treatment with UT-15C in the open-label study in accordance with that 
protocol. 
Subjects who permanently discontinue study drug for any reason other than meeting the 
definition of clinical worsening are not eligible for entry into the open-label study.  The site 
personnel will not be unblinded to the treatment assignment of these subjects unless required for 
safety reasons. 
Following completion of all Study Drug Termination assessments (see Table 3-1) and entry of 
required data into the IVRS/IWRS, the site personnel will be unblinded to that subject’s 
treatment assignment at the time of enrollment into the open-label study.  After approximately 
205 adjudicated clinical worsening (morbidity or mortality) events have occurred, all ongoing 
subjects will be eligible for enrollment in the open-label study or gain access to drug 
commercially if approved. 
6.3 
COMPLIANCE  
The Principal Investigator or other site personnel under the direction of the Principal Investigator 
will be responsible for dose titration of study drug and recording all dosing information in source 
documents.  During telephone calls, site personnel will record the current dose of study drug and 
determine if the subject is taking study drug as prescribed. 


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Each subject will be provided with a dosing diary in order to record dosing information from 
Randomization until Week 24; the use of the dosing diary is optional after Week 24.  At 
scheduled study visits, subjects should be instructed to bring all study drug (including empty and 
unused bottles) and their dosing diary to the investigational site.  Upon return of study drug and 
dosing diary at the Week 4, 8, 12, and 24 visits, the study coordinator or pharmacist must 
document the number of returned tablets of each strength and determine if the appropriate 
amount of study drug remains based upon the dose of study drug prescribed. Each subject will 
also be asked at each visit whether he or she has been compliant with dosing instructions.  
Subject compliance with the prescribed dosage regimen will be monitored throughout the study.  
If it is determined that a subject is not compliant with study drug then site personnel must re-
educate the subject on proper dosing compliance and its importance.  Continued non-compliance 
may lead to withdrawal of the subject from the study, after consultation between the Investigator 
and the Sponsor.   
Upon return of study drug at all protocol-required on-site study visits (e.g. Weeks 4, 8, 12, 24, 
etc.), all bottles of study drug will be collected.  Study drug returned will not be re-dispensed to 
the subject.  Site personnel will dispense a new supply of study drug at each protocol-required 
visit for the subsequent interval.  If necessary, additional study drug may be dispensed in 
between protocol-required visits.   
7 
EXPERIMENTAL PROCEDURES 
7.1 
SCREENING PHASE 
Sites may conduct pre-Screening activities prior to a specific subject signing an informed 
consent.  Pre-Screening activities may include review of the site’s database to identify potential 
patients that may be eligible for the study.  The Screening Phase will be conducted within 
30 days prior to randomization and after informed consent has been obtained.  The Screening and 
Baseline assessments may be conducted in one visit if all assessments are performed and all 
entry criteria are satisfied within the 48 hours prior to randomization and dosing with study drug.  


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The recommended sequence of events for Screening assessments are displayed below: 
 Informed consent 
 Inclusion/exclusion criteria 
 If necessary, the following procedures may be performed during the 30 day Screening 
window if required to satisfy inclusion/exclusion criteria.  
 RHC 
 Echocardiography 
 Ventilation Perfusion Scan  
 High Resolution Computerized Tomography (CT) Scan 
 Multigated angiogram (MUGA) 
 Pulmonary Angiography 
 Pulmonary Function Tests 
 Previous medical records documenting eligibility criteria may also be used provided 
the previous records document subject eligibility within the protocol mandated 
timelines, as applicable.    
 Demographics 
 PAH history 
 Medical history 
 Vital signs (following at least 5 minutes of rest) 
 Physical examination 
 12- lead ECG (following at least 5 minutes rest in the semi-recumbent position) 
 Practice 6MWT/Borg dyspnea score (optional; serves as a practice test if the subject has 
not previously performed this test at the study site; 6MWT to be conducted following at 
least 5 minutes of rest and Borg dyspnea score to be conducted immediately following 
6MWT) 
 Clinical laboratory tests 
 Urine pregnancy test (for WOCBP) 
 Concomitant medications 
 AE assessment 
 Complete and submit Pre-Baseline Review Form  


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7.2 
BASELINE VISIT 
The recommended sequence of events for the Baseline Visit is displayed below: 
 RHC (optional; must be performed within 5 days before randomization (inclusive) and on 
one stable PAH-approved oral monotherapy for a minimum of 10 days prior to RHC) 
 Confirmation of inclusion/exclusion criteria 
 Vital signs (following at least 5 minutes of rest); including height 
 WHO Functional Class for PAH 
 AE assessment 
 6MWT/Borg dyspnea score (6MWT to be conducted following at least 5 minutes of rest; 
Borg dyspnea score to be conducted immediately following 6MWT) 
 Clinical laboratory tests/NT-proBNP 
 Urine pregnancy test (for WOCBP) 
 Randomization (to be performed after all other Baseline assessments are completed) 
 First administration of study drug immediately (~10 minutes) after consuming food 
 Drug accountability 
 Concomitant medications 
 At least weekly telephone calls begin following initiation of study drug up to Week 24 of 
treatment, to monitor compliance, AEs, use of concomitant medications, occurrence of 
clinical worsening and to make decisions regarding dose titration 
7.3 
TREATMENT PHASE 
Weeks 4, 8, 12, and 24 assessments are listed below (in the recommended order): 
 Vital signs (following at least 5 minutes of rest) 
 WHO Functional Class for PAH 
 AE assessment 
 Drug accountability/compliance 
 12-lead ECG (Week 24 only; following at least 5 minutes rest in the semi-recumbent 
position) 
 Concomitant medications 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after last dose of study 
drug and following at least 5 minutes of rest; Borg dyspnea score to be conducted 
immediately following 6MWT) 
 Clinical worsening assessment 
 Urine pregnancy test (for WOCBP) 
 Clinical laboratory tests/NT-proBNP (Weeks 12 and 24 only) 
 Continue administration of study drug and dose titration 


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 Continue at least weekly telephone contact (study drug dose at Weeks 16 and 20 must be 
recorded in the eCRF; at least monthly telephone contact initiated at Week 24)  
 RHC (optional - Week 24 only; to be conducted within 72 hours following all other 
Week 24 assessments; as best as possible to be performed 3 to 6 hours after previous dose 
of study drug) 
Continued Visits beyond Week 24 assessments include (in the recommended order):  
 Vital signs (following at least 5 minutes of rest) 
 WHO Functional Class for PAH 
 AE assessment 
 Drug accountability/compliance 
 Concomitant medications 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after last dose of study 
drug and following at least 5 minutes of rest; Borg dyspnea score to be conducted 
immediately following 6MWT) 
 Clinical worsening assessment 
 Clinical laboratory tests/NT-proBNP (at the first Continued Visit and every other 
Continued Visit thereafter, e.g., Continued Visits #3, #5, #7, etc.) 
 Urine pregnancy test (for WOCBP) 
 Continue administration of study drug and dose titration 
 Continue at least monthly telephone contact (study drug dose should be recorded in the 
eCRF on the day of Continued Visits (e.g. Weeks 36, 48, etc.) and every 30 days between 
Continued Visits) 
Table 7-1 
Continued Visits by Week Beyond Week 24 
Continued Visit 
Corresponding Study Week* 
#1 
36 
#2 
48 
#3 
60 
#4 
72 
#5 
84 
#6 
96 
#7 
108 
#8 
120 
#9 
132 
#10 
144 
#11 
156 
#12 
168 
#13 
180 


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Continued Visit 
Corresponding Study Week* 
#14 
192 
#15 
204 
#16 
216 
#17 
228 
#18 
240 
* Visit window is ±14 days 
Unscheduled Visits 
Subjects may return to the study site at any time for additional assessments, including but not 
limited to clinical worsening, 6MWTs/Borg dyspnea score, AEs, or dispensing of additional 
study drug. 
7.4 
STUDY DRUG TERMINATION VISIT 
Subjects will continue in the study until they experience clinical worsening, prematurely 
discontinue the study for any reason, or approximately 205 adjudicated clinical worsening events 
have occurred.  If a subject remains ongoing with study treatment at the time when 
approximately 205 adjudicated clinical worsening events have occurred, the Study Drug 
Termination Visit should be scheduled as soon as possible.  The following assessments will be 
conducted immediately after the decision is made to discontinue study drug (prior to down 
titration). 
 Vital signs (following at least 5 minutes of rest) 
 Physical examination 
 Clinical worsening assessment 
 WHO Functional Class for PAH 
 AE assessment 
 Drug accountability/compliance 
 12-lead ECG (following at least 5 minutes rest in the semi-recumbent position) 
 Concomitant medications 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after last dose of study 
drug and following at least 5 minutes of rest; Borg dyspnea score to be conducted 
immediately following 6MWT) 
 Urine pregnancy test (for WOCBP) 
 Clinical laboratory tests/NT-proBNP 


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 Collection of blood sample for evaluation of blood biomarkers (optional) 
 Collection of urine sample for evaluation of urine biomarkers (optional) 
 Collection of blood sample for evaluation of pharmacogenomics (optional) 
If the subject permanently discontinues study drug prior to Week 24 for any reason other than 
clinical worsening (e.g., AEs, addition of second PAH-approved oral therapy), the subject should 
immediately complete the study drug termination visit assessments and be encouraged to remain 
in the study and complete all visits up to and including Week 24. The Study Drug Termination 
Visit assessments should be conducted immediately after the decision is made to discontinue 
study drug (prior to down titration). 
7.5 
ACCESS TO THE OPEN-LABEL STUDY 
Subjects who discontinue the study due to clinical worsening as reviewed by the Medical 
Monitor and undergo Study Drug Termination assessments will be eligible for the open-label 
extension study (TDE-PH-311) unless long-term (29 days or more) treatment with an infused or 
inhaled PGI2 was initiated.  Subjects who prematurely discontinue the study for any reason other 
than clinical worsening (e.g., AEs, withdrew consent, etc.) will not be eligible for entry into the 
open-label study. 
Subjects who remain on study drug at the time that approximately 205 adjudicated clinical 
worsening events have occurred and complete Study Drug Termination assessments will be 
eligible for entry into the open-label extension study (TDE-PH-311) or may gain access to 
commercial drug if approved. 
If a subject is eligible for the open-label extension study and received UT-15C during the blinded 
study then the subject may remain on the same dose of study drug upon entry into the open-label 
study.  If the subject received placebo during the blinded study then the subject should start 
treatment with UT-15C in the open-label study in accordance with that protocol. 
An IVRS/IWRS will be utilized to record appropriate efficacy data prior to providing each 
individual subject’s treatment assignment to appropriate site personnel in order to start each 
subject on the appropriate dose of UT-15C in the open-label study. 


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See protocol TDE-PH-311 for more details regarding the open-label extension trial. 
8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A subject may voluntarily withdraw or will be withdrawn from the study and/or study drug by 
the Investigator at any time for reasons including, but not limited to, the following: 
 The subject wishes to withdraw from further participation 
 A serious or life-threatening AE occurs or the Investigator considers that it is necessary to 
discontinue study drug to protect the safety of the subject 
 The subject violated the protocol 
 The subject’s behavior is likely to undermine the validity of his/her results 
 The subject experiences clinical worsening 
 The subject becomes pregnant 
If a subject is discontinued from the study prematurely, the Investigator will complete the End of 
Study Record for that subject and provide an explanation, if needed.  For subjects who meet the 
definition of clinical worsening, the site must complete the specified eCRF page (see 
Section 3.2.1.1).  If study drug has been administered, the Investigator should make every effort 
to perform all Study Drug Termination Visit assessments prior to study drug dose down-titration 
and study discontinuation. 
8.2 
CRITERIA FOR TERMINATING THE STUDY 
The study may be stopped at any time if, in the opinion of the Investigator and/or 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. 
The end of the study (study completion) will be declared and subjects will be transitioned out of 
the study based on the Data Monitoring Committee (DMC) and Sponsor’s decision following the 
interim analysis, or approximately 205 adjudicated clinical worsening events have occurred, or 
the sponsor stops the study for any other reason. 


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8.3 
CRITERIA FOR DISCONTINUING THE SITE 
The study may also be terminated at a given center if: 
 The Principal Investigator elects to discontinue the study 
 The sponsor elects to discontinue the study at the site 
 Applicable regulations are not observed 
 The protocol is repeatedly violated or critical violations are documented 
 Changes in personnel or facilities adversely affect performance of the study 
9 
ADVERSE EVENT REPORTING  
9.1 
DEFINITIONS 
9.1.1 
Adverse Event  
An AE is any untoward medical experience occurring to a subject during a clinical trial whether 
or not it is related to the study drug.  An AE may include an intercurrent illness, injury, or any 
other concomitant impairment of the subject’s health, as well as abnormal laboratory findings if 
deemed to have clinical significance.  AEs may also include worsening of an existing symptom 
or condition or pre/post-treatment events that occur as a result of protocol-mandated procedures. 
9.1.2 
Serious Adverse Event  
An SAE is an AE occurring at any dose 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 
may jeopardize the subject and require medical/surgical intervention to prevent one of the 
outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug abuse. 


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Life-threatening means that the subject was, in the view of the Investigator, 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. 
Planned hospitalization for elective treatment or procedure for a pre-existing condition that did 
not worsen from the time of randomization (e.g. routine RHC) is not considered an SAE and 
does not meet the definition for clinical worsening. 
9.1.3 
Adverse Events Associated with Progression of PAH 
Expected events that are related to the progression of a subject’s PAH are defined in 
Appendix 15.6. All events that occur during the course of the study that are included on this list 
and felt to be related to the progression of the disease by the Investigator should not be recorded 
as AEs in the eCRF as these PAH symptoms will be evaluated and recorded as an efficacy 
endpoint and/or will be captured as disease related events. 
However, an event must be recorded as an AE/SAE in the eCRF, if it meets one or more of the 
following criteria: 
 There is a reasonable possibility that it may have been caused by study drug. 
 It is serious. 
 It has occurred at greater than expected severity (intensity, frequency, or duration). 
9.2 
DOCUMENTATION OF ADVERSE EVENTS 
AEs will be captured from the time the ICF is signed. An AE or SAE occurring during the study, 
following completion of the ICF, must be documented in the subject’s source documents and on 
the appropriate eCRF page.  Information relating to the AE such as onset and cessation date and 
times, intensity, seriousness, relationship to study drug, and outcome is also to be documented in 
the eCRF (see Section 15.4 for definitions).  Where possible, AEs should be recorded using 
standard medical terminology.  If several signs or symptoms are clearly related to a medically 
defined diagnosis or syndrome, the diagnosis or syndrome should be recorded on the eCRF page, 
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All AEs should be followed until either resolution (or return to normal or pre-randomization 
values), until they are judged by the Investigator to no longer be clinically significant, or for up 
to 30 days if the AE extends beyond the final visit.  All SAEs that occur during the study will be 
followed until resolution, death, or the subject is lost to follow-up even if they are ongoing more 
than 30 days after completion of the final visit.  Supplemental measurements and/or evaluations 
may be necessary to investigate fully the nature and/or causality of an AE or SAE.  This may 
include additional laboratory tests, diagnostic procedures, or consultation with other healthcare 
professionals.  The eCRF pages should be updated with any new or additional information as 
appropriate. 
9.2.1 
Clinical Worsening Events 
Clinical worsening events for this study include all clinical worsening (morbidity or mortality) 
events that meet the definition for clinical worsening (Section 3.2.1.1).  When these events 
occur, they must be documented in the subject’s source documents and on the specified page of 
the eCRF and should be electronically submitted using the electronic eCRF platform within 
48 hours after the event becomes known to the Investigator or designee.  The Medical Monitor 
will review the event and correspond with the Investigator and site, as appropriate.  Although 
subjects may be discontinued from the study for medical necessity at any time, subjects should 
not be discontinued for a clinical worsening event until the event has been reviewed by the 
Medical Monitor.  Any clinical worsening event that is also an SAE(s) will be reported per the 
guidelines as specified in Sections 9.2 and 9.3. 
9.3 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
All SAEs, regardless of expectedness or causality, must be reported to the sponsor within 
24 hours of awareness by fax 
 
 or e-mail 
.  A completed SAE report form along with 
any relevant hospital records and autopsy reports should be provided to Global Drug Safety at 
United Therapeutics Corporation.  A follow-up SAE report form must be forwarded to Global 
Drug Safety at United Therapeutics Corporation within 48 hours of the receipt of any 
new/updated information.  The Investigator must also promptly notify their Investigational 
Review Board (IRB) or Ethics Committee (EC) of the SAE, including any follow-up 


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information, in accordance with applicable national regulations and guidelines set forth by the 
IRB or EC. 
9.4 
PREGNANCY 
If a study subject becomes pregnant during participation in this clinical study, site staff must 
notify the sponsor within 24 hours of learning of the pregnancy by completing the Pregnancy 
Notification Form and either faxing or e-mailing this form to Global Drug Safety at United 
Therapeutics Corporation 
 
.  Subjects who become pregnant during the trial will be withdrawn 
from active participation in the trial and will discontinue study drug after an appropriate period 
of down-titration.   
United Therapeutics Global Drug Safety will follow up with the Investigator to ensure 
appropriate data are provided regarding the outcome of the pregnancy, and to request the 
Investigator to complete a Pregnancy Outcome Report Form.  Pregnancy only becomes an 
AE/SAE if there is an abnormal outcome, a spontaneous abortion, a termination for medical 
reasons other than PAH, or a congenital anomaly in the offspring. 
9.5 
SAFETY REPORTS 
In accordance with national regulations, the sponsor or designee, will notify the regulatory 
agencies, Investigators, and/or IRBs and ECs of all relevant AEs (usually those that are 
considered to be possibly attributable to study drug and are both serious and unexpected) in 
accordance with the applicable national regulations.  The Investigator must report these SAEs to 
their IRB or EC in accordance with applicable national regulations and guidelines set forth by 
the IRB or EC. 
10 
STATISTICAL CONSIDERATIONS 
10.1 
DATA PROCESSING 
Subject data will first be documented in the subject’s source documents, and then transferred into 
the eCRF.  Site personnel will be responsible for recording all subject data into the eCRF.  Data 
for any subject who signs an ICF will be captured in the eCRF.  The eCRF screens are to be 
reviewed by the Principal Investigator for completeness and accuracy.  The Principal 


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Investigator must sign each subject’s eCRF to signify their approval of the data.  The database 
will be final when final query resolution has been completed and all data management quality 
control procedures are complete. 
10.2 
SAMPLE SIZE 
Approximately 205 adjudicated events will provide at least 90% power with a Type I error rate 
of 0.05 (two-sided hypothesis) to detect a difference in the time to clinical worsening between 
treatment groups, assuming exponential distributions and an underlying hazard ratio of 0.62.  
Assuming a placebo median event time of 32 months (which corresponds to an event rate of 23% 
at Month 12), this hazard ratio corresponds to a median time to event of 51 months for the 
UT-15C group, or an event rate of 15% at Month 12.  If accrual of subjects is completed during 
the first three years and 10% of the subjects drop out by the end of the study, a total sample size 
of at least 610 subjects with a maximum of 850 subjects is expected to generate approximately 
205 adjudicated events over the course of the study. 
Based on the results of other PAH studies, (e.g., AMBITION [ambrisentan and tadalafil] and 
GRIPHON [selexipag]; Galiè, 2015; Sitbon, 2015) an interim analysis for efficacy is planned 
when 75% of the total adjudicated worsening events have occurred.  In order to control the total 
alpha at a two-sided 0.05 level, the method of Lan and DeMets with O’Brien-Fleming-type alpha 
spending function will be used to calculate the boundaries for stopping the study for efficacy at 
the interim analysis [Lan and DeMets, 1983].  If the interim analysis is performed with 
154 events, the boundary on the p-value scale will be 0.020 and 0.044 for the final analysis.  
Calculations will be performed in EAST version 6.4, Cytel Inc, using simulated power. 
If enrollment continues beyond the interim efficacy analysis, final enrollment will be stopped 
when approximately 190 clinical worsening (morbidity or mortality) events have been reported 
by Investigators and reviewed by the Medical Monitor.  Subjects will be followed until the 
occurrence of approximately 205 adjudicated clinical worsening events, at which time all 
remaining subjects will be transitioned to the open-label extension study.  No more than 
850 subjects will be enrolled. 


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10.3 
ANALYSIS PLAN 
Details of various efficacy and safety analyses are provided below.  Further details will be 
documented in a statistical analysis plan prior to any unblinding of study data by the sponsor.  
All statistical calculations will be done using the latest version of SAS (currently version 9.2). 
The Intent-to-Treat (ITT) population will be defined as all subjects randomized into the study 
that receive at least one dose of study drug; all subjects will be counted as being in the group to 
which they were randomized, regardless of the treatment they were actually given.  All efficacy 
analyses will be performed on this ITT population.  Additional efficacy analyses may be 
performed on further populations to be defined in a detailed statistical analysis plan. 
10.3.1 
Primary Efficacy Endpoint 
The primary hypothesis is that PAH-approved oral monotherapy in combination with UT-15C 
will prolong the time to clinical worsening when compared with PAH-approved oral 
monotherapy in combination with placebo in subjects with PAH.  The primary efficacy endpoint 
will be tested at an interim analysis when 75% of total adjudicated events have occurred with an 
alpha spending of 0.020 and at the final analysis at an alpha of 0.044 with the overall Type I 
error rate at 0.05.  Efficacy boundaries for early stopping of the trial for efficacy is calculated 
based on O’Brien-Fleming alpha-spending function. 
10.3.2 
Secondary Efficacy Endpoint(s) 
The effect of treatment will be formally tested on the following secondary endpoints: 
1. Exercise capacity as assessed by 6MWD measured at Week 24 
2. NT-proBNP at Week 24 
3. Combined 6MWD/Borg dyspnea score at Week 24 
In order to control the Type 1 error rate, the secondary efficacy endpoints will be tested using a 
hierarchical (fixed-sequence) testing procedure.  The 6MWD at Week 24 will be tested at a 
two-sided Type I error rate of 0.05.  The subsequent tests for NT-proBNP at Week 24 and then 
the combined 6MWD/Borg dyspnea score at Week 24 will be tested only if the preceding test is 
statistically significant.  All other secondary endpoints will be summarized using descriptive 
statistics or analyzed using an exploratory approach. 


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10.3.2.1 
Borg Dyspnea Score 
The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced 
during the 6MWT.  Scores range from 0 (for the best condition) to 10 (for the worst condition). 
The difference between treatment groups for the change from Baseline to each follow-up 
assessment will be tested using the Wilcoxon rank-sum test. 
10.3.2.2 
Combined 6MWD and Borg Dyspnea Score 
The intent of the 6MWT is to evaluate exercise capacity associated with carrying out activities of 
daily living.  However, the capacity of subjects to function is determined not only by what they 
can do when they exert themselves to the fullest, but also by how they feel when they are 
carrying out their usual activities of daily living.  It is therefore important not only to look at the 
distance traversed during the unencouraged 6MWT but also the symptoms experienced at the 
end of the effort.  To do so, walk distances and Borg dyspnea scores from each follow-up 6MWT 
will be simultaneously compared between treatment groups using non-parametric analysis of 
covariance within the framework of the extended Cochran-Mantel-Haenszel test (analogous to 
the analysis methodology for 6MWD). This methodology will be carried out as follows: 
1. Standardized mid-ranks of walk distance will be calculated as described for the analysis 
of 6MWD; 
2. Standardized mid-ranks of Borg dyspnea score will be calculated in an analogous 
manner; 
3. The standardized mid-ranks for walk distance and for Borg dyspnea score will be 
combined by calculating their arithmetic average; 
4. A Cochran-Mantel-Haenszel mean score test will be used on the standardized mid-ranks 
of these combined ranks. 
10.3.2.3 
WHO Functional Class for Pulmonary Hypertension 
Changes from Baseline to each follow up assessment in WHO Functional Class will be 
summarized and compared between treatment groups using the Wilcoxon rank-sum test. 
10.3.2.4 
N-terminal pro-BNP 
Changes from Baseline to each follow up assessment in plasma NT-proBNP will be summarized 
and compared between treatment groups. 


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10.3.2.5 
Hemodynamics (optional) 
Changes from Baseline to Week 24 in hemodynamic parameters as assessed by RHC will be 
summarized and compared between treatment groups. 
10.3.3 
Exploratory Endpoints 
The following parameters will be evaluated: 
 Optional evaluation of biomarkers 
 Optional evaluation of pharmacogenomics 
10.3.4 
Safety Analyses 
The safety population will be defined as all subjects in the study that receive study drug, and all 
subjects will be counted as being in the group corresponding to the treatment that they actually 
received.  If a subject received UT-15C at any point during the study, they will be counted in the 
UT-15C treatment group within the safety population.  All safety analyses will be performed on 
the safety population. 
The safety of UT-15C will be evaluated by comparisons of AEs, clinical laboratory parameters, 
and vital signs in the two treatment groups.  All AEs as recorded by the Investigators will be 
assigned MedDRA preferred terms by the sponsor for reporting purposes.  For all safety 
endpoints, tabular summaries will be provided. 
10.4 
INTERIM ANALYSIS 
Interim safety analyses are intended to be performed after approximately 200, 400, and 
600 subjects are enrolled in the study, or ad hoc per request of the independent DMC, as 
necessary (see Section 10.7). 
In addition, the independent DMC will review the results of a single efficacy interim analysis 
after 75% of total adjudicated clinical worsening events have occurred (which corresponds to 
154 events).  
All interim analyses for safety and efficacy will be performed by a statistical group independent 
of the study conduct.  All unblinded results will only be reviewed by the independent DMC 
members. 


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10.5 
OTHER ANALYSES 
Exploratory analyses may be conducted based on available study data. 
10.6 
DATA LISTINGS AND SUMMARIES 
All data gathered in this study will be presented in summary tables and listings in the clinical 
study report. 
10.7 
DATA MONITORING COMMITTEE 
A DMC will be established for the study, composed of up to five independent members 
including physicians knowledgeable in the treatment of PAH and a statistician.  Throughout the 
course of the study, the DMC will meet on a regular basis to monitor the safety of the study.  
Meetings will occur after approximately 200, 400, and 600 subjects are enrolled in the study or 
ad hoc per request of the DMC, as necessary.  In addition, the DMC will review the interim 
analysis results for efficacy data when 75% (corresponding to 154 events) of the total 
approximately 205 adjudicated clinical worsening (morbidity and mortality) events have 
accrued.  The DMC will be blinded to individual subject treatment allocation during the review 
process.  All analyses will be prepared by an independent external consultant and reviewed only 
by the DMC as defined in the DMC charter.  The DMC will also review the formal interim 
analysis results and recommend continuation or early termination of the study based on stopping 
criteria defined in the DMC charter.  The sponsor will only have access to blinded study data 
until the database lock for the primary analysis.  
10.8 
CLINICAL WORSENING ADJUDICATION COMMITTEE 
An adjudication committee, comprised of at least three members, including physicians 
knowledgeable in the treatment of PAH, has been established for the study.  Members of the 
adjudication committee are independent of the DMC and cannot participate as Investigators in 
this study.  The adjudication committee will be blinded to individual subject treatment allocation 
during the review process.  If the adjudication committee does not agree with an Investigator’s 
assessment of clinical worsening for a given subject, this subject will not be included in the 
analysis and their worsening event will not count towards the total number of adjudicated events 
needed to complete the study. 


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11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG 
United Therapeutics Corporation will supply study drug (UT-15C and placebo) for 
administration during the study.  The UT-15C tablets are sustained release osmotic tablets.  
Active treatment will be UT-15C tablets provided as 0.125, 0.25, 0.5, 1, and 2.5 mg strengths for 
the study.  Each tablet contains either 0.125 mg treprostinil (equivalent to 0.15875 mg 
treprostinil diethanolamine), 0.25 mg treprostinil (equivalent to 0.3175 mg treprostinil 
diethanolamine), 0.5 mg treprostinil (equivalent to 0.635 mg treprostinil diethanolamine), 1 mg 
of treprostinil (equivalent to 1.27 mg treprostinil diethanolamine), 2.5 mg of treprostinil 
(equivalent to 3.17 mg treprostinil diethanolamine), or no treprostinil (placebo).  The 0.125, 0.25, 
0.5, 1, and 2.5 mg tablets are colored blue, green, white, yellow, and pink, respectively.  UT-15C 
tablets and matching placebo tablets will be provided in child resistant bottles each containing 
100 tablets. 
11.2 
LABELING  
Each bottle and/or kit will be labeled in accordance with applicable national regulations, to 
include at least the following information:  study drug, trial reference code, strength, quantity, 
route of administration, manufacture or expiry date, lot number, sponsor name, address and 
telephone number, and storage conditions.  The labels on the bottles may include blank fields for 
sites to document the following information specific to each bottle, including but not limited to, 
Investigator name, subject number/initials, and date dispensed. 
11.3 
STORAGE AND HANDLING OF CTM 
All study drug will be stored at room temperature (do not store above 25°C with excursions 
permitted up to 30°C).  Study drug should not be frozen, refrigerated, or exposed to heat.  Site 
personnel should refer to investigational medicinal product labeling or regulatory submissions 
for specific requirements by country or region in accordance with local regulations or guidance. 
Study drug at the investigational site will be stored in a securely locked cabinet or enclosure with 
appropriate temperature monitoring.  Access should be strictly limited to the Investigators and 
their designees.  Neither the Investigators nor any designees may provide study drug to any 
person not participating in this study. 


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The pharmacist or appropriate personnel at the investigational site will deliver and retrieve each 
assigned bottle to the subject at each study visit as needed for use during the course of the study.  
Subjects should be instructed to return all study drug, including empty bottles, to the appropriate 
study personnel at every protocol-required visit. 
11.4 
SUPPLY AND RETURN OF CTM 
Study sites will be supplied with a sufficient quantity of study drug to begin enrollment in the 
study.  At Randomization, an IVRS/IWRS will be utilized by site personnel to randomize each 
subject and assign the appropriate study drug bottles for the first 4-week treatment interval.  At 
subsequent visits to the clinic the IVRS/IWRS will be utilized by site personnel to assign new 
study drug bottles to each subject based upon their current dose of study drug and the length of 
time until the next protocol-required visit.  Additional study drug supply may occur between 
protocol-required visits as required.  At each protocol-required study visit all unused study drug 
dispensed to the subject should be returned to the study site (including empty and unopened 
bottles). 
11.5 
DRUG ACCOUNTABILITY 
The Investigator is responsible for study drug accountability and reconciliation overall and on a 
per subject basis.  Drug accountability records will be maintained during the study and these 
records will include:  the amount of study drug received from the sponsor, the amount dispensed 
to each subject, and the amount of unused drug.  At each visit, site personnel should assess drug 
dispensed, drug returned, and dosing information to confirm drug accountability and compliance. 
Once a representative from the sponsor is able to confirm drug accountability for that subject, 
study drug will be returned to a sponsor designated location for destruction. Study drug will not 
be destroyed on-site by the study staff or in the pharmacy. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
ICH GCP AND APPLICABLE NATIONAL REGULATORY REQUIREMENTS 
The study will be conducted in accordance with ICH GCP guidelines and all applicable national 
regulations.  The sponsor will obtain the required approval from each national regulatory 
authority to conduct the study.  During the conduct of the study, an annual development safety 
update report will be compiled by the sponsor for submission to those regulatory authorities and 


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IRBs/ECs that require it.  Any additional national reporting requirements as specified by the 
applicable regulations, regulatory authorities, or IRB/EC 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 authorized 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/EC-approved ICF prior to the 
conduct of any study-related activities.  A copy of the signed ICF 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/EC and provide the sponsor with a copy of the approval letter.  The IRB/EC 
must also review and approve the study site’s ICF and any other written information provided to 
the subject’s prior to enrollment, as well as any advertising materials used for subject 
recruitment.  Copies of the ICF and advertising materials must be forwarded to the sponsor for 
review before submission to the IRB/EC prior to the start of the study. 
If, during the study, it is necessary to amend either the protocol or the ICF, the Investigator is 
responsible for obtaining IRB/EC approval of these amended documents prior to 
implementation.  Copies of the IRB/EC correspondence and approval letters must be sent to the 
sponsor. 
During the conduct of the study, an annual progress report will be compiled by the sponsor for 
submission to those IRBs/ECs 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 or EC standard procedures.  Additional 
updates will also be provided in accordance with the IRB/EC’s standard procedures. 


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12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical trial, the following documents (at minimum) will be 
provided to the site:  Investigators’ Brochure, Protocol, ICF, Budget Agreement, and access to 
the eCRF. 
The site will be required to provide the following documents (at minimum) to United 
Therapeutics Corporation or designee prior to study start:  Signature page of the protocol, Form 
FDA 1572, Financial Disclosure Form, IRB/EC Composition and Roster, IRB/EC protocol and 
ICF approval letters, Curriculum Vitae of study staff listed on the Form FDA 1572, and 
authorized clinical trial agreement (as required). 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  United Therapeutics 
Corporation, regulatory bodies, and the IRB/EC 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/EC or appropriate local regulatory 
agencies for purposes of checking the accuracy of the data.  A unique number will be assigned to 
all subjects and any report published will not identify the subjects by name. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially adversely affect the safety of participating subjects 
or that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, duration of therapy, assessment variables, the number of subjects treated, or 
subject selection criteria may be made only after consultation between United Therapeutics 
Corporation or its designee and the Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory 
authorities and IRB/EC prior to implementation. 
A report documenting study termination must also be submitted to and acknowledged by the 
appropriate IRB/EC for each study site. 


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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 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.  For Investigators in the European Economic Area (EEA), the 
study records should be maintained for at least 15 years after study discontinuation.  The 
Investigator must notify United Therapeutics Corporation before any disposal or change in 
location of study records. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
In accordance with federal/national regulations, ICH GCP guidelines, monitors for United 
Therapeutics Corporation or its designee will periodically contact the site and conduct on-site 
visits.  During these visits, the monitor will at a minimum:  confirm ethical treatment of subjects, 
assess study progress, review data collected, conduct source document verification, verify drug 
accountability periodically, and identify any issues requiring resolution.   
The Investigator must agree 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.  In addition, auditors for United Therapeutics Corporation or its designee may 
periodically contact the site and conduct on-site visits. 


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14 
REFERENCES 
ATS Statement:  Guidelines for the six-minute walk test.  Am J Respir Crit Care Med.  2002; 
166:111-117. 
Barst RJ, Rubin LJ, Long WA, et al.  A comparison of continuous intravenous epoprostenol with 
conventional therapy for primary pulmonary hypertension.  The Primary Pulmonary 
Hypertension Study Group.  N Engl J Med.  1996; 334:296-302. 
Barst RJ, et al.  Updated evidence-based treatment algorithm in pulmonary arterial hypertension.  
J of Amer College of Cardiology 2009; 54 (1) S78-S84. 
Farber, H., & Loscalzo, J.  Mechanisms of disease:  Pulmonary arterial hypertension.  N Engl J 
Med.  2004; 3511(16):1655-1665. 
Fijalkowska A, Kurzyna M, Torbicki A, et al.  Serum N-Terminal Brain Natriuretic Peptide as a 
Prognostic Parameter in Patients With Pulmonary Hypertension.  Chest.  2006; 129: 1313-1321. 
Galiè N, JA Barberà, AE Frost, et al.  Initial use of ambrisentan plust tadalafil in pulmonary 
arterial hypertension.  N Engl J Med.  2015; 373:834-844. 
George SL and Desu MM.  Planning the size and duration of a clinical trial studying the time to 
some critical event.  Journal of Chronic Diseases.  1973; 27, 15-24. 
Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials.  Biometrika 1983; 
70(3):659-663. 
McLaughlin VV, et al. Randomized study of adding inhaled iloprost to existing bosentan in 
pulmonary arterial hypertension. Am J Resp Crit Care Med.  2006; 174(11):1257-1263. 
McLaughlin VV, et al.  Addition of inhaled treprostinil to oral therapy for pulmonary arterial 
hypertension:  a randomized controlled clinical trial.  J Am Coll Cardiol.  2010; 
55(18):1915-1922. 
McLaughlin VV, et al.  End points and clinical design in pulmonary arterial hypertension.  
Journal of American College of Cardiology.  2009; 54 (1):S97-S107. 
Remodulin U.S. Package Insert. United Therapeutics Corporation, 2013; Research Triangle Park, 
NC. 
Rich S, et al.  Primary pulmonary hypertension. A national prospective study.  Ann Intern Med; 
1987:107:216-223. 
Rubin LJ. Primary Pulmonary Hypertension. N Engl J Med.  1997; 336:111-117. 
Simmoneau G, et al.  Addition of sildenafil to long-term intravenous epoprostenol therapy in 
patients with pulmonary arterial hypertension:  a randomized trial.  Ann Intern Med.  2008; 
149(8):521-530. 


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Sitbon O, R Channick, KM Chin, et al.  Selexipag for the treatment of pulmonary arterial 
hypertension.  N Engl J Med.  2015; 373:2522-2533. 
Tyvaso U.S.  Package Insert. United Therapeutics Corporation, 2013; Research Triangle Park, 
NC. 


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15 
APPENDICES 
15.1 
PROCEDURE FOR 6-MINUTE WALK EXERCISE TEST AND BORG 
DYSPNEA SCALE 
General Procedures 
The 6 minute walk exercise test should be administered by the same tester and on the same 
course at each study site throughout the study for a given subject.  The administration of the test 
and specifications of the testing area should be generally consistent with the American Thoracic 
Society guidelines and the usual practice of the investigative site [ATS guidelines; 2002]. 
The area used for the 6 minute walk test should be pre-measured at approximately 30 m in length 
(but no shorter than 15 m [16 yards or 50 feet] in length at minimum) and at least 2 to 3 m in 
width.  There should be no turns or curves to the 6 minute walk area.  The length should be 
marked with gradations at least every 3 meters to ensure the accurate measurement of the 
distance walked.  The area should be well ventilated.  The tester may be at the starting end of the 
corridor or at the midpoint of the corridor with a stop-watch.  Intermittent rest periods are 
allowed if the subject can no longer continue.  If the subject needs to rest briefly, he/she may 
stand or sit and then begin again when he/she is sufficiently rested but the clock will continue to 
run.  At the end of 6 minutes, the tester will call “stop” while simultaneously stopping the watch 
and then measure the distance walked.  The Borg dyspnea rating will be administered 
immediately following completion of the 6MWT. 
Instructions to the Subject  
Subjects will be instructed that the preceding meal should be light.  Subjects should be told to 
wear comfortable clothing and sneakers or comfortable walking shoes.  The person 
administering the test will use the following exact dialogue with the subject: 
“The purpose of this test is to find out how far you can walk in six minutes.  You will start from 
this point and follow the hallway to the marker (e.g. chair) at the end, turn around and walk back.  
When you arrive back at the starting point you will go back and forth again.  You will go back 
and forth as many times as you can in the 6-minute period.  You may stop and rest if you need 
to.  Just remain where you are until you can go on again.  However, the most important thing 
about the test is that you cover as much ground as you possibly can during the 6 minutes.  I will 


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tell you the time, and I will let you know when the 6 minutes are up.  When I say STOP, please 
stand right where you are.” 
After these instructions are given to the subject, the person administering the test will then ask: 
“Do you have any questions about the test?” 
“Please explain to me what you are going to do.” 
The person administering the test will then start the test by saying the following to the subject: 
“Are you ready?” 
“Start when I say “GO.” 
The person administering the test will tell the subject the time at 2 and 4 minutes by saying: 
“You have completed 2 minutes.” 
And then by saying: 
“You have completed 4 minutes.” 
No other instruction or encouragement will be given during the test.  Eye contact with the subject 
should be avoided during the test. 
Following the walk, the person administering the test will obtain a rating of dyspnea using the 
Borg Scale.  The person will use the following dialogue: 
“I would like to use the following scale to indicate the maximal shortness of breath you had 
during the walk test (indicate the Borg Scale).  If there was no shortness of breath at all you 
would point to 0; if the shortness of breath was not very great you would choose from 0.5 to 
2; if you were somewhat more short of breath you would select 3; and if the breathing was 
getting very difficult, you would choose 4 to 9, depending on just how hard it was; 10 
represents the greatest shortness of breath you have ever experienced in your life, and if you 
feel more short of breath than you have ever been in your life before, choose a number 
greater than 10 that represents how short of breath you feel.  If one of the numbers does not 
exactly represent how short of breath you are, then you can choose a fraction between.  For 
example, if you had shortness of breath somewhere between 4 and 5, you could choose 4 ½. 


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15.2 
WHO FUNCTIONAL CLASSIFICATION FOR PULMONARY HYPERTENSION 
Class I:  Patients with pulmonary hypertension but without resulting limitation of physical 
activity.  Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near 
syncope. 
Class II:  Patients with pulmonary hypertension resulting in slight limitation of physical activity. 
These subjects are comfortable at rest, but ordinary physical activity causes undue dyspnea or 
fatigue, chest pain or near syncope. 
Class III:  Patients with pulmonary hypertension resulting in marked limitation of physical 
activity. They are comfortable at rest.   Ordinary activity causes undue dyspnea or fatigue, chest 
pain, or near syncope. 
Class IV:  Patients with pulmonary hypertension with inability to carry out any physical activity 
without symptoms. These subjects manifest signs of right heart failure. Dyspnea and/or fatigue 
may be present even at rest. Discomfort is increased by any physical activity. 


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15.3 
CLINICAL LABORATORY PARAMETERS 
Blood Chemistries 
Hematology 
Other 
Sodium 
Red Blood Cell Count 
NT-proBNP (plasma) 
Potassium 
Hemoglobin 
Urine dipstick analysis* 
Chloride 
Hematocrit 
Urine pregnancy test** 
Bicarbonate/CO2 
Platelet Count 
CD4 lymphocyte count**** 
Albumin 
White Blood Cell Count 
 
Blood Urea Nitrogen/Urea 
 
 
Total Bilirubin 
 
 
Indirect Bilirubin 
 
 
Direct Bilirubin 
 
 
Alkaline Phosphatase 
 
 
Alanine Aminotransferase (ALT) 
 
 
Aspartate Aminotransferase (AST) 
 
 
Gamma-glutamyl transferase (GGT) 
 
 
Creatinine 
Thyroid Stimulating Hormone (TSH)*****  
 
Thyroxine (T4; free) if TSH  
is abnormal ***** 
 
 
 
Visit Test Schedule 
Visit 
Labs Collected 
Screen*** 
Chemistries, Hematology, TSH*****, CD4****, Urine dipstick, 
urine pregnancy** 
Baseline*** 
Chemistries, Hematology, NT-proBNP, urine pregnancy** 
Weeks 4 and 8 
Urine pregnancy** 
Week 12 
Chemistries, Hematology, NT-proBNP, urine pregnancy** 
Week 24 
Chemistries, Hematology, NT-proBNP, urine pregnancy** 
Continued Visits 1, 3 etc. 
Chemistries, Hematology, NT-proBNP, urine pregnancy** 
Continued Visits 2, 4, etc 
Urine pregnancy** 
Study Drug Termination Visit 
Chemistries, Hematology, NT-proBNP, Urine dipstick, Urine 
pregnancy** 
       *  pH, specific gravity, presence of protein or blood 
     **  Urine pregnancy tests for WOCBP 
   ***  If combining Screening and Baseline visit, utilize Baseline laboratory kit 
****  At screen only; only for subjects with known HIV infection 
***** If abnormal, free T4 will be automatically assessed at the central laboratory 


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15.4 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Principal 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?” 
Using provided definitions, the Investigator will then: 
(1) rate the intensity and seriousness of the AE, (2) estimate the causality of the AE to study 
drug, and (3) note actions taken to counteract the AE. 
Definitions of Intensity, Seriousness, Causality, Action Taken, 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.  
SERIOUSNESS 
A serious AE 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 hospitalization, 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 a serious AE when, based upon appropriate medical 


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judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition). 
CAUSALITY 
An estimate of causality between a specified AE and the study drug is made by the Investigator.  
Definitions of the categories follow: 
 NOT RELATED - there is not a temporal relationship to study drug administration (too 
early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, or concurrent disease and the SAE 
 POSSIBLE - there is a reasonable causal relationship between the study drug and the 
SAE.  Dechallenge information is lacking or unclear 
 PROBABLE - there is a reasonable causal relationship between the study drug and the 
SAE.  The event responds to dechallenge.  Rechallenge is not required 
ACTION TAKEN 
TEST AGENT DOSE MODIFICATION* 
 Dose Increased - the dose or regimen of the test agent was increased 
 Dose Not Changed - the dose or regimen of the test agent was not changed 
 Dose Reduced - the dose or regimen of the test agent was decreased 
 Drug Interrupted - administration of the test agent was stopped temporarily 
 Drug Withdrawn - administration of the test agent was stopped permanently and not 
restarted 
 Unknown - changes to the administration of the test agent cannot be determined 
*NOTE:  Only the last test agent action should be recorded in the eCRF. 
OUTCOME 
 Fatal - The study subject died 
 Not Recovered/Not Resolved - The AE was ongoing 
 Recovered/Resolved - The AE resolved 
 Recovered/Resolved with Sequelae - The AE is considered resolved however there is a 
residual sequelae 
 Recovering/Resolving - The AE is improving but is not yet completely 
recovered/resolved 
 Unknown - The outcome of the AE cannot be determined 


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15.5 
CHILD-PUGH SCORE 
Parameter 
Points 
1 
2 
3 
Hepatic encephalopathy 
None 
(absent) 
Stage I-II (mild or 
suppressed with medication) 
Stage III-IV (severe 
or refractory) 
Ascites 
None 
(absent) 
Mild-moderate (suppressed 
with medication) 
Moderate-severe 
(refractory) 
Bilirubin (total) µmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time (s)/INR 
<4/(<1.7) 
4-6/(1.71-2.20) 
>6/(>2.20) 
Class A (mild) = 5-6 points 
Class B (moderate) = 7-9 points 
Class C (severe) = 10-15 points (subjects in this class are excluded from participation) 


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15.6 
EXPECTED EVENTS ATTRIBUTABLE TO THE PROGRESSION OF 
PULMONARY ARTERIAL HYPERTENSION (SYSTEM ORGAN CLASS AND 
PREFERRED TERM, VER. 16.0) 
Abdominal pain (Gastrointestinal disorders; 
ABDOMINAL PAIN) 
Hemoptysis (Respiratory, thoracic & mediastinal 
disorders; HAEMOPTYSIS) 
Anorexia (Metabolism and nutrition disorders; 
ANOREXIA) 
Hypoxia (Respiratory, thoracic & mediastinal 
disorders; HYPOXIA) 
Ascites (Gastrointestinal disorders; ASCITES) 
Loss of consciousness  
(Nervous system disorders; LOSS OF 
CONSCIOUSNESS) 
Cardiac arrhythmia (Cardiac disorders; 
ARRHYTHMIA) 
Nausea (Gastrointestinal disorders; NAUSEA) 
Cardiac arrest (Cardiac disorders; CARDIAC 
ARREST) 
Edema (General disorders and administration site 
conditions; OEDEMA) 
Heart failure (including exacerbation of) 
(Cardiac disorders; CARDIAC FAILURE) 
Orthopnea (Cardiac disorders; ORTHOPNOEA) 
Chest pain (General disorders and 
administration site conditions; CHEST PAIN) 
Pallor (Vascular disorders; PALLOR) 
Cardiovascular collapse (Vascular disorders; 
CIRCULATORY COLLAPSE) 
Palpitations (Cardiac disorders; PALPITATIONS) 
Cor pulmonale (Cardiac disorders;  
COR PULMONALE) 
Cool extremities  
(General disorders and administration site 
conditions; PERIPHERAL COLDNESS) 
Cough (Respiratory, thoracic & mediastinal 
disorders; COUGH) 
Pulmonary arterial hypertension, exacerbation of 
(Vascular disorders; PULMONARY ARTERIAL 
HYPERTENSION) 
Cyanosis (Cardiac disorders; CYANOSIS) 
Sudden death (Cardiac disorders; SUDDEN 
DEATH) 
Dizziness (Cardiac disorders; DIZZINESS) 
Syncope (Cardiac disorders; SYNCOPE) 
Dyspnea at rest (Respiratory, thoracic & 
mediastinal disorders; DYSPNOEA) 
Vasovagal reaction (Nervous system disorders; 
SYNCOPE VASOVAGAL) 
Dyspnea on exertion  
(Respiratory, thoracic & mediastinal disorders; 
DYSPNOEA EXERTIONAL) 
Tachycardia (Cardiac disorders; TACHYCARDIA) 
Paroxysmal nocturnal dyspnea  
(Cardiac disorders; DYSPNOEA 
PAROXYSMAL NOCTURNAL) 
Vomiting (Gastrointestinal disorders; VOMITING) 
Exercise intolerance (General disorders and 
administration site conditions; EXERCISE 
TOLERANCE DECREASED) 
Weight loss  (Investigations; WEIGHT 
DECREASED) 
Fatigue (General disorders and administration 
site conditions; FATIGUE) 
Weight gain (Investigations; WEIGHT 
INCREASED) 
 


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15.7 
A SUB-STUDY TO COLLECT THE VITAL STATUS OF SUBJECTS WHO 
DISCONTINUE FROM THE STUDY OR OPEN-LABEL EXTENSION STUDY 
(TDE-PH-311) 


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A Sub-study to Collect the Vital Status of Subjects Who Discontinue 
from the Study or Open-Label Extension Study (TDE-PH-311)  
1 
BACKGROUND AND RATIONALE 
Even though subjects may discontinue from the study or open-label extension study 
(TDE-PH-311) for a variety of reasons, it is important to continue collecting vital status data on 
such subjects until the study is completed.  Collection of the vital status data will allow an 
intention-to-treat overall survival analysis to be conducted using actual rather than imputed vital 
status data. This will be a separate analysis from the primary and secondary efficacy analysis and 
will provide supportive data for regulatory filings of oral treprostinil. 
If and when a subject discontinues from the study or open-label extension study (TDE-PH-311), 
attempts should be made to obtain their consent to record their vital status up to the date of final 
completion of the study (i.e., when all patient have exited the study).  Attempts should be made 
to collect survival data on all subjects, even those who are apparently lost to follow-up.  
2 
OBJECTIVE 
To collect vital status data for subjects who discontinue from the study or open-label extension 
study (TDE-PH-311) to support an overall survival analysis of study participants 
3 
EXPERIMENTAL PLAN 
Vital status for subjects who discontinue from the study or open-label extension study 
(TDE-PH-311) will be assessed every 6-months from their date of discontinuation via telephone 
calls and/or other methods as described below for the duration of the study. The data will 
continue to be collected in this study until the last subject has exited from the study.  
Subjects are considered to have discontinued from the study if and when they discontinue and do 
not enroll into the open-label extension study (TDE-PH-311). Subjects are considered to have 
prematurely discontinued from the open-label extension study (TDE-PH-311) if they discontinue 
before the completion of the study (i.e., before the last subject has exited the study).  


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4 
ESTIMATED STUDY DURATION 
Vital status data will be collected every 6 months beginning from the date that each subject 
discontinues either the study or open-label extension study (TDE-PH-311) until the last subject 
exits the study. 
5 
DATA COLLECTION AND FOLLOW-UP OF SUBJECTS 
Survival status for discontinued subjects will be collected every 6 months from the date of 
discontinuation via telephone calls or other methods as described below. The collection of vital 
status should include whether or not the subject is alive.  
 If dead, the date of death must be obtained.  
 If alive, the last known date the subject was confirmed to be alive must be provided.  
 For those subjects who are lost to follow-up, the last known date that the subject was 
confirmed to be alive will be their date of the last contact with the site.  
Methods to confirm subjects’ survival status other than the recommended telephone calls every 
6 months, may include and are not limited to, in-person study visits, searching of hospital 
records, and searching local and/or national public registries following applicable laws and 
regulations.  
Any AEs that are spontaneously reported by the subject that occur on the commercially-available 
United Therapeutics drug should not be submitted as part of the study, rather, they will be 
subject to AE/SAE reporting under local government post-marketing AE/SAE reporting 
requirements.  
6 
STATISTICAL CONSIDERATIONS 
Vital status data collected from subjects who discontinue from the study or open-label extension 
study (TDE-PH-311) will be combined with the data collected during the study and the 
open-label extension study (TDE-PH-311) for sensitivity analysis of overall survival.  Vital 
status data collection from subjects who have discontinued the study minimizes the missing data 
for these analysis. 

SAP_001.pdf: 
United Therapeutics Corp. 
TDE-PH-310 Statistical Analysis Plan 
 
Oral Treprostinil 
 
Page 1 
Document Type: 
Statistical Analysis Plan 
Protocol / Study No.: 
TDE-PH-310 
Finalization Date: 
 
08 MAY 2018 
 
Total Number of Pages 
including Appendices: 
52 
Classification: 
Confidential 
Version:  
Final 2.0 
Title: 
A Phase III, International, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 
Clinical Worsening Study of UT-15C in Subjects with Pulmonary Arterial Hypertension 
Receiving Background Oral Monotherapy 
 
 
Author: 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. © 2018 
United Therapeutics Corporation 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................ 2 
Table of In-Text Tables .......................................................................................................... 4 
ABBREVIATIONS AND DEFINITIONS ............................................................................ 5 
1 PREFACE .......................................................................................................................... 7 
2 OBJECTIVES ................................................................................................................... 7 
2.1 
PRIMARY OBJECTIVES .......................................................................................... 7 
2.2 
SECONDARY OBJECTIVES .................................................................................... 8 
2.3 
SAFETY ........................................................................................................................ 8 
3 STUDY DESIGN ............................................................................................................... 9 
4 SEQUENCE OF PLANNED ANALYSES ................................................................... 10 
4.1 
INTERIM SAFETY ANALYSES ............................................................................. 10 
4.2 
INTERIM EFFICACY ANALYSIS ......................................................................... 11 
4.3 
FINAL ANALYSIS AFTER DATABASE LOCK AND STUDY 
UNBLINDING ............................................................................................................ 11 
5 SAMPLE SIZE CONSIDERATIONS .......................................................................... 11 
6 ANALYSIS POPULATIONS ......................................................................................... 12 
7 INTERIM ANALYSES .................................................................................................. 13 
8 GENERAL CONSIDERATIONS FOR DATA ANALYSES ..................................... 13 
8.1 
COVARIATES ........................................................................................................... 14 
8.2 
EXAMINATION OF SUBGROUPS ........................................................................ 14 
8.3 
PREMATURE DISCONTINUATION AND MISSING DATA ............................ 15 
8.3.1 
Missing Data Handling for Time to Clinical Worsening ................................... 15 
8.3.2 
Missing Data Handling for 6MWD ...................................................................... 16 
8.3.3 
Missing Data Handling for Other Efficacy Assessments ................................... 17 
8.4 
MULTIPLE COMPARISONS AND MULTIPLICITY ......................................... 18 
8.5 
DERIVED AND TRANSFORMED DATA ............................................................. 19 
8.6 
ASSESSMENT WINDOWS ...................................................................................... 20 
8.6.1 
Assessment Windows for Scheduled Visits ......................................................... 20 
8.6.2 
Multiple Evaluations within the Same Analysis Window .................................. 21 
9 STUDY POPULATION.................................................................................................. 22 
9.1 
SUBJECT ACCOUNTABILITY .............................................................................. 22 
9.2 
PROTOCOL DEVIATIONS ..................................................................................... 23 
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATIONS ..................................... 23 
9.3.1 
Demographics ........................................................................................................ 23 
9.3.2 
Medical History and PAH History ....................................................................... 24 
9.3.3 
Concomitant Medications ..................................................................................... 24 
10 EFFICACY ANALYSES ................................................................................................ 25 
10.1 PRIMARY EFFICACY MEASURES ...................................................................... 25 


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10.1.1 
Time to Clinical Worsening .................................................................................. 25 
10.1.1.1 
Hypothesis ........................................................................................................... 25 
10.1.1.2 
Primary Efficacy Analyses ................................................................................ 26 
10.1.1.3 
Sensitivity and Subgroup Analyses .................................................................. 27 
10.2 KEY SECONDARY EFFICACY MEASURES ...................................................... 29 
10.2.1 
Analysis of 6MWD Including Change from Baseline to Week 24 .................... 29 
10.2.1.1 
Sensitivity and Sub-group Analyses ................................................................. 32 
10.2.2 
NT-proBNP ............................................................................................................ 33 
10.2.3 
Combined 6MWD and Borg Dyspnea Score ....................................................... 34 
10.3 OTHER SECONDARY EFFICACY MEASURES ................................................ 35 
10.3.1 
6MWD at Other Visits Except Week 24 .............................................................. 35 
10.3.2 
Borg Dyspnea Score .............................................................................................. 35 
10.3.3 
WHO FC ................................................................................................................. 36 
10.3.4 
NT-proBNP ............................................................................................................ 36 
10.3.5 
Hemodynamic Parameters ................................................................................... 36 
10.4 EXPLORATORY ANALYSIS .................................................................................. 37 
10.4.1 
The low risk-profile analysis ................................................................................. 37 
10.4.2 
Optional Evaluation of Biomarkers ..................................................................... 37 
10.4.3 
Optional Evaluation of Pharmacogenomics ........................................................ 37 
11 HEALTH OUTCOMES ................................................................................................. 37 
11.1 QUALITY OF LIFE MEASURES ........................................................................... 37 
11.2 RESOURCE UTILIZATION MEASURES ............................................................ 37 
12 SAFETY ANALYSES ..................................................................................................... 38 
12.1 EXTENT OF EXPOSURE ........................................................................................ 38 
12.2 ADVERSE EVENTS .................................................................................................. 38 
12.3 DEATHS ..................................................................................................................... 39 
12.4 PREGNANCIES ......................................................................................................... 39 
12.5 CLINICAL LABORATORY EVALUATIONS ...................................................... 39 
12.5.1 
Clinical Chemistry ................................................................................................. 39 
12.5.2 
Hematology ............................................................................................................ 40 
12.5.3 
Urinalysis ................................................................................................................ 41 
12.6 ELECTROCARDIOGRAMS ................................................................................... 41 
12.7 VITAL SIGNS ............................................................................................................ 41 
12.8 DISEASE-RELATED EVENTS ............................................................................... 42 
13 PHARMACOKINETICS ............................................................................................... 42 
14 REFERENCES ................................................................................................................ 43 
15 APPENDICES ................................................................................................................. 44 
15.1 INCLUSION AND EXCLUSION CRITERIA ........................................................ 44 
16 LIST OF TABLES, LISTINGS, AND FIGURES ........................................................ 48 
16.1 LIST OF TABLES ..................................................................................................... 48 


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SUMMARY AND ANALYSIS OF 6MWD (METER) AT WEEK 24 BY UT-15C 
DOSE QUARTILE AT WEEK 24 ................................................................................ 49 
16.2 LIST OF LISTINGS .................................................................................................. 51 
16.3 LIST OF FIGURES ................................................................................................... 52 
 
Table of In-Text Tables 
Table 8-1 
Assessment Windows for Scheduled Visits .................................................... 21 
 


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ABBREVIATIONS AND DEFINITIONS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Classification 
BMI 
Body Mass Index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CO 
Cardiac output 
CTD 
Connective tissue disease 
eCRF 
electronic Case Report Form 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ERA 
Endothelin receptor antagonist 
FC 
Functional Class 
FEV1 
Forced expiratory volume at 1 second 
HIV 
Human immunodeficiency virus 
ITT 
Intent-To-Treat 
IUD 
Intrauterine device 
LOCF 
Last observation carried forward 
LVEDP 
Left ventricular end-diastolic pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
Multigated angiogram 
MMRM 
Mixed model repeated measurement 
NYHA 
New York Heart Association 
NT-proBNP 
N-Terminal pro-brain natriuretic peptide 
PAH 
Pulmonary arterial hypertension 
PAPd 
Pulmonary artery pressure diastolic 
PAPm 
Pulmonary artery pressure mean 
PAPs 
Pulmonary artery pressure systolic 
PCWPm 
Pulmonary capillary wedge pressure mean 
PDE5-I 
Phosphodiesterase type 5 inhibitor 
PFO 
Patent foramen ovale 
PT 
Preferred term 


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PVR 
Pulmonary vascular resistance 
PVRI 
Pulmonary Vascular Resistance Index 
RBC 
Red blood cell 
RAPm 
Right atrial pressure mean 
RHC 
Right heart catheterization 
SAE 
Serious adverse event 
SaO2 
Systemic arterial oxygen saturation 
SAP 
Statistical Analysis Plan 
SAPd 
Systemic arterial pressure diastolic 
SAPm 
Systemic arterial pressure mean 
SAPs 
Systemic arterial pressure systolic 
SDF 
Survival distribution function 
sGC 
Soluble guanylate cyclase 
SOC 
System organ class 
SvO2 
Mixed venous oxygen saturation 
SVR 
Systemic vascular resistance 
SVRI 
Systemic vascular resistance index 
TID 
3 times daily 
TLC 
Total lung capacity 
WBC 
White blood cell 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of childbearing potential 
 


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1 
PREFACE 
This document describes the planned analyses for the TDE-PH-310 clinical study.  This plan 
is based on the original TDE-PH-310 protocol dated 26 Jan 2012 and subsequent protocol 
amendments (latest version protocol amendment 8 dated 9 Aug 2017), and provides further 
details of the analyses presented in the protocol as well as additional planned analyses.  
Additional post-hoc or unplanned analyses that are not defined in this statistical analysis plan 
(SAP) may be performed.  Such analyses will be documented in the Clinical Study Report 
(CSR). 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective of this study is: 
To assess the effect of oral UT-15C with pulmonary arterial hypertension (PAH)-
approved oral monotherapy compared with placebo with PAH-approved oral monotherapy 
on time to first clinical worsening event (adjudicated), as defined by at least 1 of the 
events listed below: 
 Death (all causes) 
 Hospitalization due to worsening PAH, defined as: 
 Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure; or 
 Lung or heart/lung transplantation; or 
 Atrial septostomy 
 Initiation of an inhaled or infused prostacyclin for the treatment of worsening PAH 
 Disease progression (all criteria required): 
 A decrease in 6-Minute Walk Distance (6MWD) of at least 15% from Baseline (or 
too ill to walk) directly related to PAH progression with other co-morbidities ruled 
out, confirmed by two 6-Minute Walk Tests (6MWTs) performed on different 
days.  
 Worsening of PAH symptoms, which must include either: 
 An increase in Functional Class (FC) from Baseline or 
 Appearance or worsening of symptoms of right heart failure since Baseline 
 Unsatisfactory long-term clinical response (all criteria required): 
 Randomized to receive study drug for at least 24 weeks 


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 A decrease from Baseline in 6MWD at Week 24 and beyond at 2 consecutive 
visits on different days 
 Sustained World Health Organization (WHO) FC III or IV symptoms for at least 
24 weeks, consecutively 
Please note that all time to worsening events reported by the investigators are adjudicated by 
an independent adjudication committee.  The independent adjudication committee is blinded 
to the treatment assignment.  
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are to assess the effect of oral UT-15C combined with 
PAH-approved oral monotherapy compared to placebo combined with PAH-approved oral 
monotherapy on the following:  
Key Secondary Endpoints: 
 Exercise capacity as assessed by 6MWD measured at Week 24 
 Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) at Week 24 
 Combined 6MWD/Borg dyspnea score at Week 24 
Other Secondary Endpoints: 
 Exercise capacity as assessed by 6MWD measured at visits other than Week 24 
 Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) at visits other than 
Week 24 
 Borg dyspnea score  
 WHO FC 
 Right heart catheterization (RHC) hemodynamics at Week 24 (optional) 
Exploratory Endpoints: 
 Optional evaluation of biomarkers 
 Optional evaluation of pharmacogenomics 
2.3 
SAFETY  
The safety objective of this study is to assess the safety of oral UT-15C combined with 
PAH-approved oral monotherapy compared to placebo combined with PAH-approved oral 
monotherapy on the following: 


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 Clinical laboratory parameters 
 Vital signs 
 Adverse events (AEs) 
 Electrocardiogram (ECG) 
3 
STUDY DESIGN 
This is an international, multicenter, randomized, double-blind, placebo-controlled, event-
driven study in subjects with PAH receiving background oral monotherapy.  Subjects will be 
assessed during the Screening Period to determine eligibility for the study, which will be 
confirmed during the Baseline Visit prior to randomization.  Once randomized, subjects will 
return for study visits every 4 weeks for the first 12 weeks, then every 12 weeks for the 
duration of the study.  Subjects will continue in the study until they experience clinical 
worsening, as defined in the protocol, or they prematurely discontinue participation in the 
study for any reason other than protocol-specific clinical worsening. 
If a subject meets the definition of clinical worsening during the study and receives only 
short-term (28 days or less) treatment with an infused or inhaled prostacyclin therapy for 
worsening PAH, they will be permitted to enter the open-label extension study 
(TDE-PH-311).  If a subject prematurely discontinues the study for any reason other than 
clinical worsening, or receives long-term (29 days or more) treatment with an infused or 
inhaled prostacyclin therapy for worsening PAH, they will not be permitted to enter the open-
label extension study. 
An interim analysis for efficacy is planned when 75% (154) of the total (205) adjudicated 
clinical worsening events have occurred.  All subjects actively participating in the study will 
be allowed to transition to the open-label extension study if the interim efficacy analysis is 
positive.  If enrollment continues beyond the interim efficacy analysis, final enrollment will 
be stopped when approximately 190 clinical worsening (morbidity or mortality) events have 
been reported by Investigators and reviewed by the Medical Monitor.  Subjects will be 
followed until the occurrence of approximately 205 adjudicated clinical worsening events, at 
which time all remaining subjects will be transitioned to the open-label extension study.  No 
more than 850 subjects will be enrolled. 


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At each scheduled visit, subjects will undergo the following efficacy assessments:  clinical 
worsening, exercise capacity (6MWD and Borg dyspnea score), and WHO FC. 
Plasma samples will also be collected for measurement of NT-proBNP at Baseline, Week 12, 
Week 24, Continued Visit 1, and at every other continued visit thereafter. 
Additionally, subjects may participate in an optional hemodynamic sub-study in which 
hemodynamic parameters will be assessed by RHC before randomization at Baseline and 
following 24 weeks of treatment with study drug. 
Safety will be assessed via vital signs, AEs, and clinical laboratory parameters.  Subjects will 
also undergo a 12-lead ECG at Screening and Week 24. 
Subjects must receive only 1 PAH-approved oral therapy at a dose that complies with the 
approved prescribing information for the product for at least 30 days before the day of 
randomization to participate in the study.  The dose of background oral monotherapy may be 
titrated as clinically indicated during the Screening Period.  Subjects must be on a stable dose 
of their background oral monotherapy for a minimum of 10 days prior to being randomly 
allocated to receive either oral UT-15C or placebo at randomization.  Subjects will receive 
their first dose of study drug (0.125 mg) in the clinic on the day of randomization.  Oral 
dosing of study drug will be continued at 0.125 mg 3 times daily (TID) every 6 to 8 hours 
with food.  The dose will be slowly titrated up throughout the study to a maximum dose of 
12 mg TID in an effort to reach a well-tolerated dose that provides optimal clinical benefit. 
4 
SEQUENCE OF PLANNED ANALYSES 
4.1 
INTERIM SAFETY ANALYSES 
Interim safety analyses are intended to be performed after approximately 200, 400, and 
600 subjects are enrolled in the study, or on an ad hoc basis per request of the independent 
Data Monitoring Committee (DMC) as necessary.  All analyses will be prepared by an 
independent external consultant and reviewed only by the DMC as defined in the DMC 
charter.  The sponsor will only have access to blinded study data during this process.   


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4.2 
INTERIM EFFICACY ANALYSIS 
One interim analysis for efficacy is planned when 75% (154 events) of the total (205) 
adjudicated clinical worsening events have occurred.  All analyses will be prepared by an 
independent external consultant and reviewed only by the independent DMC as defined in the 
DMC charter.  The sponsor will only have access to blinded study data during this process.  
The details of the interim efficacy analysis will be included in a separate SAP for interim 
analyses. 
4.3 
FINAL ANALYSIS AFTER DATABASE LOCK AND STUDY UNBLINDING 
After the database has been quality assured and locked, the treatment assignments will be 
provided to the sponsor’s project statistician by the central randomization service, and all 
planned analyses described in this document will be performed.  By intent, no changes will be 
made to these data after unblinding.  However, any changes that are deemed absolutely 
necessary subsequent to unblinding will be clearly documented in the CSR.  
5 
SAMPLE SIZE CONSIDERATIONS 
Approximately 205 adjudicated clinical worsening events will provide at least 90% power 
with a type I error rate of 0.05 (2-sided hypothesis) to detect a difference in the time to 
clinical worsening between treatment groups, assuming exponential distributions and an 
underlying hazard ratio of 0.62.  Assuming a placebo median event time of 32 months (which 
corresponds to an event rate of 23% at Month 12), this hazard ratio corresponds to a median 
time to event of 51 months for the UT-15C group (which corresponds to an event rate of 15% 
at Month 12).  Further assuming subject accrual is completed during the first 3 years with a 
10% dropout rate at the end of the study, a total sample size of at least 610 subjects with a 
maximum of 850 subjects is expected to generate approximately 205 adjudicated clinical 
worsening events over the course of the study.   
The primary efficacy endpoint of time to adjudicated clinical worsening events will be tested 
at an interim analysis when 75% of total adjudicated clinical worsening events have occurred 
with an alpha level of 0.020, and at the final analysis at an alpha of 0.044 with the overall 
Type I error rate at 0.05.  Efficacy boundaries for early stopping of the study for efficacy are 
calculated based on O’Brien-Fleming alpha-spending function. 


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6 
ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) Population is defined as all subjects randomized into the study who 
received at least 1 dose of study drug.  All subjects will be counted as being in the group to 
which they were randomized, regardless of the treatment they actually received.  All original 
stratification information used in the randomization procedure will be used for analyses, 
regardless of whether it was later found to be incorrect.  All efficacy analyses will be 
performed primarily on the ITT Population. 
The Safety Population is defined as all subjects in the study actually receiving study drug 
(regardless of randomization), and all subjects will be counted as being in the group 
corresponding to the treatment that they actually received.  If a subject incorrectly received 
active drug during the study, they will be counted in the active treatment group.  All safety 
analyses will be performed on the Safety Population. 
The Per-protocol Population will include all subjects in the ITT Population, excluding 
subjects with major protocol deviations that may have an impact on the primary efficacy 
analyses.  The major protocol deviations and the subject’s exclusion from the Per-protocol 
Population will be reviewed at a blinded data review meeting and documented prior to the 
database lock and the study unblinding.  The major protocol deviations that exclude the 
subjects from the Per-protocol Population include, but are not limited to the following:  
 Subject had violation of inclusion criterion #5 or exclusion criteria #6 
 Subject had violation of exclusion criterion #3 
 Subject interrupted intake of study drug for a total of at least 50% of the time between 
first and last study drug dosing  
 Subject had been off-treatment for at least 4 weeks at any point between first and last 
dosing of study drug in study 
 Subject started and continued treatment with any prohibited medications for extensive 
duration during the study 
 Individual unblinding of study drug to the investigator prior to the subject completing 
the study 


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7 
INTERIM ANALYSES 
An independent DMC will be established for the study, composed of 3 members, including 
2 physicians knowledgeable in the treatment of PAH and a statistician.  Throughout the 
course of the study, the DMC will meet on a regular basis to monitor the safety of the study.  
Meetings will occur after approximately 200, 400, and 600 subjects are enrolled in the study, 
or on an ad hoc basis per request of the independent DMC, as necessary.  The DMC will be 
semi-blinded (ie, labelled as Group X and Group Y) to individual subject treatment allocation 
during the review process, and can be unblinded to individual subject treatment allocation if 
requested. 
In addition, the independent DMC will review the results of a single efficacy interim analysis 
after 75% of total adjudicated clinical worsening events have occurred (which corresponds to 
154 events).  For interim efficacy analysis, treatment groups will be unblinded to DMC 
members. 
All analyses will be prepared by an independent external consultant and reviewed only by the 
DMC as defined in the DMC charter.  The sponsor will only have access to blinded study data 
during this process. 
8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All the data collected in the electronic Case Report Form (eCRF) will be listed.  In general, 
listings will be sorted by treatment group, subject number, and scheduled assessment (if 
applicable).  Listings will include assessment date, assessment time (if available), study day, 
and all relevant data collected in the eCRFs.  For data collected on a fixed schedule, the 
assessment identifier will also be included on the listing.  Repeat or redundant observations 
within an assessment window and observations that do not fall within any predefined 
assessment window (and will, therefore, be excluded from summaries) will be flagged in 
these listings.  Subjects who will not be included in the analysis population (eg, Safety 
Population, Per-protocol Population) will be flagged. 
In general, the data will be summarized by scheduled assessment (if applicable) within each 
treatment group.  For continuous variables, summary statistics will include the mean, standard 


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deviation, median, minimum, and maximum.  For summaries of non-normal data, such as 
6MWD, interquartile range (lower quartile, upper quartile) may also be included.  Minimums 
and maximums will be expressed using the level of precision in which the variable was 
collected.  All other statistics will be rounded, using an additional decimal place than was 
collected.  For discrete variables, summaries will include the frequency and percentage in 
each category.  Percentages will be rounded to 1 decimal place.  For all inferential analyses 
and descriptive comparisons, p-values will be rounded to 4 decimal places.  Values less than 
0.0001 will be denoted as <0.0001, and values greater than 0.9999 will be denoted as 
> 0.9999.  Wherever practical, categories of discrete variables will be ordered and labelled as 
they appear in the eCRF. 
All analyses are performed using the statistical software SAS® (SAS Institute 2015). 
8.1 
COVARIATES 
Primary efficacy analyses of time to clinical worsening will be adjusted for Baseline 6MWD 
category (≤350 meters versus >350 meters) and background PAH therapy (as a categorical 
variable: phosphodiesterase type 5 inhibitor [PDE5-I] or soluble guanylate cyclase [sGC] 
stimulator only versus endothelin receptor antagonist [ERA] only). 
The efficacy analyses of change from Baseline in 6MWD at Week 24 and other time points 
will be adjusted for Baseline 6MWD (as a continuous variable) and background PAH therapy 
(as a categorical variable: PDE5-I or sGC stimulator only versus ERA only). 
The efficacy analyses of change from Baseline in NT-proBNP at Week 24 and other time 
points will be adjusted for Baseline NT-proBNP. 
8.2 
EXAMINATION OF SUBGROUPS 
For the primary efficacy endpoint (time to adjudicated clinical worsening event), subgroup 
analyses will be performed.  These subgroups will include: 
 Background PAH therapy (PDE5-I or sGC stimulator only versus ERA only) 
 Etiology of PAH (idiopathic/heritable, associated with collagen vascular disease, and 
other etiologies) 


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 Baseline walk categories (≤350 m versus >350 m) 
 Baseline WHO FC (class 1-2 versus class 3-4)  
 Age group (<65 years versus ≥65 years)  
 Sex (male versus female) 
 Maximum dose achieved (<9 mg versus ≥9 mg total daily dose) 
 Geographic region, categorized as North America (United States and Canada), Asia-
Pacific (China, Taiwan, India, Australia, Singapore, South Korea), Europe (Germany, 
United Kingdom, Israel, Italy, Netherlands, Poland, France, Denmark, Greece, 
Austria, and Sweden), and South and Latin America (Mexico, Brazil, Chile, and 
Argentina) 
Similarly, the subgroup analyses for subgroups listed above will also be performed for the key 
secondary endpoint of change from Baseline in 6MWD at Week 24. 
No adjustment for multiplicity will be performed for these subgroup analyses. 
8.3 
PREMATURE DISCONTINUATION AND MISSING DATA 
Clinical worsening events are evaluated up to the end of the study.  In this event-driven study, 
at the end of the study, some subjects will not have clinical worsening events; some will 
discontinue the study early or be lost-to-follow-up before experiencing a clinical worsening 
event.  For the time to clinical worsening event data, a censoring algorithm will be employed. 
The 6MWD and other secondary efficacy endpoints are evaluated up to the end of the study; 
however, the analyses are mainly focused on the data up to Week 48.  For 6MWD and other 
key secondary efficacy endpoints, missing data will be imputed as described in the sections 
below. 
8.3.1 
Missing Data Handling for Time to Clinical Worsening 
For the analysis of time to clinical worsening, subjects who do not have an adjudicated 
clinical worsening event will be censored at the time of their last known study drug dose.  For 
subjects who are reported as having a clinical worsening event by the Investigator and 
subsequently are classified as not having a clinical worsening event by the adjudication 
committee, the time to clinical worsening is also censored at the time of their last assessment 
date.  For subjects who dropped out of the study early without experiencing a clinical 


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worsening event, the subjects will be censored at the time of their last assessment prior to 
down-titration or discontinuation of study drug. 
In addition, the following 2 additional analyses will be performed on the primary efficacy 
endpoint (adjudicated time to clinical worsening) to assess the impact of missing data: 
1. Early termination treated as clinical worsening event 
2. Early termination due to AEs treated as clinical worsening events 
For the mortality analysis, the vital status (live/dead status) for all subjects will be collected 
throughout the study to the study closure (the last patient last visit).  Vital status for subjects 
who discontinued the study early is included in this mortality analysis.  If the vital status is 
unknown at study closure, the time to death will be censored at the last known date the subject 
is alive. 
8.3.2 
Missing Data Handling for 6MWD 
For the analysis of 6MWD, subjects may not have completed the treatment with study drug 
prior to the Week 48 visit for the following reasons: death, clinical worsening (per protocol 
definition), progressive disease (not meeting protocol definition of clinical worsening), AE 
unrelated to disease, withdrawal of consent by the subject, protocol deviation, loss to 
follow-up, termination of study by the sponsor, or withdrawal for other reasons.  Every 
attempt must be made to perform all efficacy assessments immediately prior to premature 
termination of study drug or within 6 hours of the final study drug dose.  In addition, subjects 
still receiving study drug may be too clinically ill to perform the 6MWT, resulting in missing 
data for that assessment. 
In the analyses of 6MWD using nonparametric and parametric analysis of covariance 
methods, for subjects whose 6MWD measures at visits up to Week 48 are missing, the 
missing value will be imputed. 
 For those subjects who have no 6MWD measurement due to death, too ill to perform 
6MWT, or clinical worsening event, the 6MWD is set to the worst score of 0 meter. 
 For missing data at visits prior to death or clinical worsening event, missing data will 
be imputed by the last observation carried forward (LOCF) approach. 


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 For all other reasons without 6MWD measurement, the LOCF approach will be used 
for imputation. 
For missing 6MWD measures beyond Week 48, the missing data will not be imputed, and all 
analyses will be based on the observed cases. 
8.3.3 
Missing Data Handling for Other Efficacy Assessments 
Similar to 6MWD, analogous rules will be used for the main analyses of Borg dyspnea score 
and WHO FC.  For subjects whose Borg dyspnea score or WHO FC at visits up to Week 48 
or NT-proBNP values up to Week 36 are missing, the value will be imputed as follows: 
Borg dyspnea score: 
 For those subjects who withdrew early due to death, are too ill to perform 6MWT, or 
have no Borg dyspnea score due to clinical worsening event, the Borg dyspnea score is 
set to the worst score of 10. 
 For missing data occurred at visits prior to death or clinical worsening event, missing 
data will be imputed by the LOCF approach. 
 For all other withdrawals, the LOCF approach will be used for imputation. 
For missing Borg dyspnea score at visits beyond Week 48, the missing data will not be 
imputed, and all analyses will be based on the observed case. 
WHO FC:  
 For those subjects who withdrew early due to death or have no WHO FC due to a 
clinical worsening event, the WHO FC is set to the worst value of class IV. 
 For missing data occurred at visits prior to death or clinical worsening event, missing 
data will be imputed by the LOCF approach. 
 For all other withdrawals, the LOCF approach will be used for imputation.  
For missing WHO FC at visits beyond Week 48, the missing data will not be imputed, and all 
analyses will be based on the observed case. 
NT-proBNP: 
 For NT-proBNP, the missing value at visits up to Week 36 will be imputed using the 
LOCF approach. 
 Subjects with missing Baseline NT-proBNP values, the Baseline measure will not be 
imputed, and these subjects will be excluded from the analyses of the NT-proBNP. 


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 Subjects with NT-proBNP values reported below the lower limit of quantification, half 
of the lower limit of quantification will be used for summary and analysis.  For 
example, if the result is reported as ‘<2.4 pmol/L’, a numeric value of 
2.4/2=1.2 pmol/L will be used. 
The missing values at visits beyond Week 36 will not be imputed and all analyses will be 
based on the observed cases. 
Hemodynamics: 
Missing values for hemodynamic parameters will not be imputed.  The summary and analyses 
will be based on the observed cases.  
8.4 
MULTIPLE COMPARISONS AND MULTIPLICITY 
Experimental wise Type I error rate will be controlled at no greater than 0.05 (for 2-sided 
hypotheses).  The study will include an interim analysis for efficacy when 75% of the 
pre-specified total adjudicated events have occurred.  The primary efficacy endpoint will be 
tested at an interim analysis with an alpha level of 0.020 (2-sided) and at the final analysis at 
an alpha of 0.044 (2-sided) with the overall Type I error rate controlled at 0.05.  Efficacy 
boundaries for early stopping of the study are calculated based on the O’Brien-Fleming alpha-
spending function.  
The effect of treatment will be formally tested on the following 3 key secondary efficacy 
endpoints: 
 Change from Baseline in 6MWD at Week 24  
 Change from Baseline in NT-proBNP at Week 24 
 Change from Baseline in combined 6MWD/Borg dyspnea score at Week 24 
In order to control the Type I error rate, the hierarchical (fixed-sequence) test procedure will 
be used.  The p-value for the change from Baseline in 6MWD at Week 24 will be tested at a 
2-sided Type I error rate of 0.05.  The subsequent tests for change from Baseline in 
NT-proBNP at Week 24 and then the change from Baseline in combined 6MWD/Borg 
dyspnea score at Week 24 will be tested only if the preceding test is statistically significant. 


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The statistical tests for other secondary endpoints below are considered exploratory and no 
multiplicity adjustment will be applied.  For data collected beyond the specified week (eg, 
Week 48 for 6MWD, Borg score, WHO FC; Week 24 for RHC hemodynamics; and Week 36 
for NT-proBNP), descriptive summaries will be provided with no statistical testing.  
 6MWD at all time points prior to Week 48 (other than Week 24) 
 Borg dyspnea score at visits prior to Week 48  
 WHO FC at visits prior to Week 48  
 RHC hemodynamics at Week 24 
 NT-proBNP at all time points prior to Week 36 (other than Week 24) 
8.5 
DERIVED AND TRANSFORMED DATA 
Time to Clinical Worsening will be derived as follows: 
Parameter 
Scenario 
Formula 
Status 
Time to 
Clinical 
Worsening 
(weeks) 
Subjects with clinical worsening 
event reported during the study 
that is adjudicated/confirmed 
= (Worsening date – Randomization 
date)/7 Note: for subjects with clinical 
worsening due to worsening 6MWD, the 
clinical worsening date is date of the 
second/confirmatory 6MWT 
0 (event) 
Subjects who died during the 
study 
= (Death date – Randomization date)/7 
0 (event) 
Subjects with clinical worsening 
event reported during the study 
that is adjudicated as not meeting 
the clinical worsening event 
criteria by the adjudication 
committee 
For analysis of investigator reported 
clinical worsening event: 
= (Worsening date – 
Randomization date)/7  
 
For analysis of adjudicated clinical 
worsening event: 
= (Last assessment date – 
Randomization date)/7 
0 (event) 
 
 
 
1 (censored) 
Subjects without clinical 
worsening event during the study 
= (Last assessment date – 
Randomization date)/7 
1 (censored) 
Subjects discontinued from the 
study prematurely that did not 
have a clinical worsening event 
= (Last assessment date – 
Randomization date)/7 
1 (censored) 
 
For subjects with clinical worsening due to the decrease from Baseline in 6MWD, 
confirmatory 6MWT should be conducted.  The event time is based on the date of the 


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confirmatory 6MWT.  As a sensitivity analysis, the event time based on the date of the first 
reported 6MWT will also be performed.  
Hemodynamic parameters will be derived as follows: 
Parameter 
Formula 
Cardiac index in L/min/m2 
= cardiac output (CO) Fick / body surface area (BSA) 
Systemic vascular resistance (SVR) in 
dynes*sec/cm5 
=80 * (systemic arterial pressure mean [SAPm] – right 
atrial pressure mean [RAPm]) / CO Fick 
SVR index (SVRI) in dynes*sec/cm5/m2 
=80 * (SAPm – RAPm) / cardiac index 
Pulmonary vascular resistance (PVR) in 
dynes*sec/cm5 
=80 * (Pulmonary artery pressure mean [PAPm] – 
Pulmonary capillary wedge pressure mean [PCWPm]) / 
CO Fick 
PVR Index (PVRI) in dynes*sec/cm5/m2 
=80 * (PAPm – PCWPm) / cardiac index 
Electrocardiogram parameters will be derived as follows: 
Parameter 
Formula 
QTc (Bazett) 
60
QT
HR

 
QTc (Fridericia) 
3 60
QT
HR

 
 
8.6 
ASSESSMENT WINDOWS 
8.6.1 
Assessment Windows for Scheduled Visits 
The study protocol included visit windows of +/− 7 or 14 days. However, for any data 
summarized by scheduled visit, an analysis visit window (proposed in the table below) will be 
used.  The scheduled visits, as recorded on the eCRFs, and the corresponding target days and 
study day intervals are specified in Table 8-1.  The analysis visit window will be derived 
based on the information specified in Table 8-1. 


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Table 8-1 
Assessment Windows for Scheduled Visits 
Visit 
Target  
Study Day 
Study Day Interval 
ECGs and hemodynamics: 
Baseline 
1 
Study Day 1 (prior to the first dose) 
Week 24 
169 
148  Study Day 190 
Clinical laboratory assessments and NT-proBNP: 
Baseline 
1 
Study Day 1 (prior to the fist dose) 
Week 12 
85 
2< Study Day 127 
Week 24 
169 
127< Study Day 211 
Week 36 
253 
211< Study Day 337 
Week 60 
421 
337< Study Day 505  
Weeks 84, 108, etc 
589, 757, etc 
(Target Study Day ±84 days) 
6MWT, WHO FC, and vital signs: 
Baseline 
1 
Study Day 1 (prior to the first dose) 
Week 4 
29 
15 Study Day 43 
Week 8 
57 
43< Study Day 71 
Week 12 
85 
71< Study Day 127 
Week 24 
169 
127< Study Day 211 
Week 36 
253 
211< Study Day  295 
Weeks 48, 60, etc 
337, 421, etc 
(Target Study Day ±42 days) 
Note: Study Day = (Assessment Date) - (First Dosing Date) + 1 
8.6.2 
Multiple Evaluations within the Same Analysis Window 
After all the observations have been slotted based on the table above, if there are multiple 
valid observations for an assessment within an assigned analysis visit window, only 1 of these 
observations will be used for summary statistics and analyses.  The observation to be used is 
determined using the following hierarchy (in decreasing order): 
 The observation closest to the target study day 
 The later observation, if 2 observations are equally close to the target study day  
For missing values prior to Week 48 where the LOCF algorithm is applied, it is always the 
last valid observation on treatment carried forward, even though this might not be the 
observation obtained by the above hierarchy and used in the summaries by visit window. 


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9 
STUDY POPULATION 
Detailed definitions for analysis populations (ITT, Per-Protocol, and Safety Populations) are 
provided in Section 6.  Unless otherwise specified, all efficacy analyses will be performed on 
the ITT Population and all safety analyses will be based on the Safety Population.  In the ITT 
Population, the treatment assignment is based on the assignment upon randomization.  In the 
Safety Population, the treatment assignment is based on the actual treatment the subject 
received.  Study population will be summarized by the treatment group in the ITT population 
and overall. 
The comparability between the 2 treatment groups will be checked for demographic and 
Baseline characteristics.  The p-values from Fisher’s exact test (for discrete variables), group 
t-test, or Wilcoxon rank sum test (for continuous variables) will be included in summaries but 
are not intended to be used to test formal hypotheses.  For these comparisons, missing or 
unknown values will be excluded from the calculations. 
9.1 
SUBJECT ACCOUNTABILITY 
All subjects’ disposition information will be listed, including the study population the subjects 
belong to, whether or not subjects completed the study drug treatment, reason study drug was 
stopped, whether or not subjects completed at least 24 weeks of study assessments, primary 
reason for not completing 24 weeks of assessments, whether or not subjects completed the 
study, reason for not completing the study, and whether or not subjects rolled over to the 
open-label extension study (TDE-PH-311). 
The listing of subject accountability will include dates of informed consent, randomization, 
first study drug dose, last study drug dose, last dose week, and last assessment week.  
Whether subjects received study drug; whether subjects completed the Weeks 4, 8, 12, and 24 
assessments, and every 12-week follow-up assessment thereafter; study drug termination 
status; and study discontinuation status will be summarized by treatment group and overall. 
Information regarding whether each subject is included in each analysis population (see 
Section 6) will be listed.  If a subject is not included in a particular analysis population, the 
reason for exclusion will be noted on the listing.  Also noted on the listing will be the 


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randomized treatment assignment and the actual treatment subjects have received.  The 
summary will include the frequency and percentage of all subjects in each analysis population 
by treatment group and overall. 
All stratification information used in the random assignment of subjects to treatment group 
(from the central randomization database) will be listed, including date and time of 
randomization, background PAH therapy, Baseline walk distance category, whether or not the 
treatment is unblinded, and if so, date/time of blind break.  For observations where any 
stratification information has been corrected, both the original and corrected information will 
be listed.  Background PAH therapy and Baseline walk distance used for randomization 
stratification will be summarized by treatment group and compared using Fisher’s exact test 
or Wilcoxon rank sum test, as appropriate. 
9.2 
PROTOCOL DEVIATIONS 
The status of the entry criteria will be listed for all subjects.  The listing will include the date 
of the initial screening assessment and a list of any specific entry criteria not met.  Entry 
criteria violations will be summarized by treatment group and overall. 
Additional protocol deviations will be documented throughout the study, and protocol 
deviations and their severity categories will be summarized by treatment group and included 
in the data listing.  
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATIONS 
9.3.1 
Demographics 
All demographic data will be listed for all subjects, including country, age at randomization, 
sex, ethnicity, race, weight, height, and Body Mass Index (BMI).  Age, age category 
(<65 years versus ≥65 years), sex, ethnicity, race, weight, height, and BMI will be 
summarized by treatment group.  The summary will include p-values (2-sided) from Fisher’s 
exact test (for age category, sex, ethnicity, and each race), group t-test, or Wilcoxon rank sum 
test (for age, weight, height, and BMI) comparing treatment groups. 


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9.3.2 
Medical History and PAH History 
All significant past or ongoing medical conditions will be listed for all subjects.  The listing 
will include the Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
(SOC) and preferred term (PT) for each condition listed.  These medical conditions will be 
summarized by PT within each SOC by treatment group. 
Information related to subjects’ PAH history will be listed.  The listing will include the date of 
initial PAH diagnosis, time since diagnosis at randomization, and etiology of PAH.  A 
separate listing will include details of the subjects’ background PAH therapy (eg, 
PDE5-I/sGC stimulator or ERA use). 
Time since diagnosis and etiology of PAH will be summarized by treatment group.  The 
summary will include p-values (2-sided) from Fisher’s exact test (for etiology of PAH) or 
Wilcoxon rank sum test (for time since diagnosis) comparing treatment groups. 
Background PAH therapy at Baseline will be summarized by treatment group.  The summary 
will include the number and percentage of each PAH therapy use, time on background PAH 
therapy, and the total daily dose of the background PAH therapy. 
9.3.3 
Concomitant Medications 
All concomitant medications specified on the eCRF will be mapped to a standard term using 
the WHO Drug Dictionary (WHO-DD). 
The standard name and verbatim term of all concomitant medications will be listed for all 
subjects.  This listing will include the date started (or indication that drug was ongoing at 
randomization), date discontinued (or indication that drug was ongoing at end of study), and 
the condition treated/indications.  If a subject received no medications, this will be indicated 
in the listing.  The summary of concomitant medications will include the frequency and 
percentage of subjects in each treatment group receiving each drug (by coded standard name).  
Concomitant medications ongoing at Baseline and those added during the study will be 
summarized separately. 


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Changes to ERA, PDE5-I, and sGC stimulator dosing that are collected separately from the 
concomitant medication page will be listed. 
10 
EFFICACY ANALYSES 
Except where otherwise noted, all efficacy analyses will only be performed on the ITT 
Population (see Section 6). 
10.1 
PRIMARY EFFICACY MEASURES 
10.1.1 
Time to Clinical Worsening 
Clinical worsening is defined as the occurrence of any of the following: 
 Death (all causes) 
 Hospitalization due to worsening PAH defined as: 
 Non-elective hospitalization lasting at least 24 hours in duration caused by clinical 
conditions directly related to PAH and/or right heart failure; or 
 Lung or hearg transplantation; or 
 Atrial septostomy 
 Initiation of an inhaled or infused prostacyclin for the treatment of worsening PAH 
 Disease progression (all criteria required): 
 A decrease in 6MWD of at least 15% from Baseline (or too ill to walk) directly 
related to PAH progression with other co-morbidities ruled out, confirmed by 
2 6MWTs performed on different days.  
 Worsening of PAH symptoms, which must include either: 
 An increase in FC since Baseline or 
 Appearance or worsening of symptoms of right heart failure since Baseline 
 Unsatisfactory long-term clinical response (all criteria required) 
 Randomized to receive study drug for at least 24 weeks 
 A decrease from Baseline in 6MWD at Week 24 and beyond at 2 consecutive 
visits on different days 
 Sustained WHO FC III or IV symptoms for at least 24 weeks, consecutively 
10.1.1.1 
Hypothesis 
The study is designed to determine the efficacy of UT-15C compared with placebo in subjects 
with PAH.  The null hypothesis tested for the primary endpoint of time to adjudicated clinical 
worsening is that there is no difference in hazard ratio in the time to clinical worsening of 
PAH when treated with UT-15C compared with placebo: 
𝐻0: ℎ𝑎𝑧𝑎𝑟𝑑 𝑟𝑎𝑡𝑖𝑜= 1 


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The 2-sided alternative hypothesis is that there is a difference: 
𝐻𝑎: ℎ𝑎𝑧𝑎𝑟𝑑 𝑟𝑎𝑡𝑖𝑜≠1 
Due to the alpha spending on interim analysis, for the final analysis, the significance level for 
the primary efficacy analysis of time to adjudicated clinical worsening is 0.044. 
10.1.1.2 
Primary Efficacy Analyses 
Data on the Clinical Worsening Assessment page of the eCRF will be used in determining 
clinical worsening status.  Investigator-reported clinical worsening events will be reported 
directly from the eCRF data, regardless of the outcome of the adjudication committee review.  
An independent adjudication committee will be utilized to adjudicate all investigator-reported 
clinical worsening events.  Adjudicated clinical worsening events will be reported using data 
received from the adjudication committee. 
Subjects who discontinue study drug for reasons other than clinical worsening will be 
censored at the time of discontinuation of the study drug.  Non-fatal clinical worsening events 
that occur more than 7 days after permanent study drug discontinuation will not be included in 
the summary and analysis of clinical worsening events.  However, all deaths within the study 
follow-up period (30 days after the last study drug dose) will be included as clinical 
worsening events.  Time to clinical worsening will be summarized by treatment group using 
product-limit estimates calculated by the Kaplan-Meier method, and displayed graphically as 
Kaplan-Meier curves.  A tabular summary of this analysis will include the number of subjects 
at risk (sample size), estimated median duration, and a 95% confidence interval for the 
median duration for each treatment group. 
For the primary efficacy analysis of time to adjudicated clinical worsening, the log-rank test 
adjusted for the type of background therapy (PDE5-I or sGC stimulator versus ERA) and the 
Baseline 6MWD (≤350 meters versus >350 meters) will be used to calculate the p-value for 
treatment differences in the ITT Population. 


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The SAS Procedure LIFETEST will be used. The pseudo SAS statements are listed below: 
proc lifetest; 
     time TimeToWorsening*Censor_Status(1); 
     strata BGTX B_6MWD / group=Treatment test=all; 
run; 
where BGTX variable denotes the background therapy and B_6MWD denotes the Baseline 
6MWD category (≤350 meters versus >350 meters).  
10.1.1.3 
Sensitivity and Subgroup Analyses 
The primary efficacy analysis of time to adjudicated clinical worsening events will also be 
provided for the Per-protocol Population. 
The following sensitivity analyses will be performed: 
 For all subjects who drop out from the study early, they are considered as having a 
clinical worsening event.  Time to event will be calculated from randomization to 
subject’s discontinuation date. 
 For all subjects who drop out from the study early due to AEs, they are considered as 
having a clinical worsening event.  Time to event is calculated from randomization to 
subject’s study discontinuation date. 
The time from randomization to clinical worsening will also be compared between treatment 
groups using a Cox proportional-hazards regression model, adjusting for Baseline 6MWD 
category ((≤350 meters versus >350 meters) and background PAH therapy (as a categorical 
variable: PDE5-I/sGC stimulator or ERA).  Hazard ratio and its 95% confidence interval will 
be calculated.  SAS Procedure PHREG will be used and the pseudo SAS statements are listed 
below:  
proc phreg; 
  Model TimeToWorsening*Censor_Status(1) = treatment; 
  Strata BGTX B_6MWD / risklimits ties=efron; 
run; 
where BGTX variable denotes the background therapy and B_6MWD denotes the Baseline 
6MWD category≤350 meters versus >350. 


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Subgroup analyses will be performed on the following factors: background PAH therapy, 
PAH etiology, Baseline WHO FC, age group (<65 years versus ≥65 years), Baseline 6MWD 
category, sex (male versus female), maximum dose achieved (<9 mg versus ≥9mg total daily 
dose) , and geographic region as specified in Section 8.2.  The estimated hazard ratio between 
the active and placebo groups from this model will be calculated and displayed along with its 
95% confidence interval on the summary and analysis table and plot. 
Since clinical worsening is a composite endpoint, the following components of this composite 
endpoint will also be summarized and analyzed with the same approach as the composite 
endpoint:  
 Time to death (all causes) during the study 
 Time to hospitalization due to worsening PAH 
In addition, time to death (all causes) by the end of the study will also be summarized and 
analyzed.  For time to death by the end of the study analysis, the vital status for all subjects 
will also be collected throughout the study to the completion of the last subject in the study 
including subjects who discontinued the study early and subjects who rolled over to the 
extension study (TDE-PH-311). 
For each of the above time-to-event variables, the assumption of proportional hazards will be 
assessed using a log-log survival plot, with log of time as the x-axis and log negative log 
survival distribution function (SDF) as the y-axis.  This plot will be reviewed to assess if the 
curves were parallel and thus the proportional hazards assumption for treatment is met.  In 
additional, the proportional hazards assumptions will also be checked by using the time * 
treatment or time*covariate interactions in the model. The PROC LIFETEST procedure in 
SAS will be used to calculate the survival function estimates for the plots.  If the 
non-proportional hazard model is suggested, the alternative approaches, such as an extension 
of the Cox regression model, may be explored. 


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10.2 
KEY SECONDARY EFFICACY MEASURES 
The effect of treatment will be formally tested on the following 3 secondary endpoints: 
 Change from Baseline in 6MWD at Week 24 
 Change from Baseline in NT-proBNP at Week 24 
 Change from Baseline in combined 6MWD/Borg dyspnea score at Week 24 
The tests for these 3 key secondary efficacy endpoints will be hierarchal with a fixed 
sequence approach as described in Section 8.4. 
10.2.1 
Analysis of 6MWD Including Change from Baseline to Week 24 
The efficacy endpoint of 6MWD assesses if UT-15C increases the distance traversed in the 
6MWT at Week 24 over placebo in subjects with PAH.  The null and alternative hypotheses 
are: 
𝐻0: 𝜇1 = 𝜇2 
𝐻𝑎: 𝜇1 ≠𝜇2 
where µ1 and µ2 are the mean change from Baseline in 6MWD of the UT-15C and placebo 
treatment groups, respectively. 
A longitudinal data analysis using mixed model repeated measurement (MMRM) will be 
performed to estimate the treatment difference in change in 6MWD at Week 24.  The MMRM 
model will be based on the observed measures up to Week 24 and will include the changes 
from Baseline in 6MWD as the dependent variable; treatment, week, treatment by week 
interaction, and background PAH therapy as fixed effects; and Baseline 6MWD as a 
covariate.  An unstructured variance/covariance structure shared across treatment groups will 
be used to model the within-subject errors and Kenward-Roger method will be used for 
calculating the denominator degree of freedom.  The appropriate contrasts will be constructed 
in order to estimate treatment effect at Week 24 and other visits.  The pseudo SAS codes are 
as following: 
proc mixed; 
  class trt01p(ref='PLACEBO') BGTX avisitn usubjid; 
  model DistC = trt01p BGTX avisitn trt01p*avisitn      


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        Dist0/ddfm = kr; 
  repeated avisitn /type= un subject = usubjid; 
  lsmeans trt01p*avisitn/diff; 
  estimate "at Week 24" trt01p 1 -1  
                        trt01p*avisitn  0 0 0 1               
                                        0 0 0 -1/cl; 
run; 
where BGTX is background PAH therapy, DistC is the change from Baseline in 6MWD, and 
Dist0 is the Baseline measure of the 6MWD. 
From the same model, the contrasts will also be constructed to estimate the treatment effects 
at Weeks 4, 8, 12 assessments. 
All 6MWT data will be listed for all subjects.  For each scheduled assessment, this listing will 
include the date test was performed (or date test was intended to be performed if subject is 
unable to attempt the test), start time of the test, nominal time point, total distance walked (in 
meters), Borg dyspnea score, whether subject received oxygen during the test, and any 
circumstances that adversely affected the walk (if any), including reason for not attempting 
test (if any). 
For each visit (Week 24 for key secondary efficacy endpoint, and other visits for exploratory 
efficacy endpoints), the effect of UT-15C versus placebo on 6MWD will also be evaluated 
using non-parametric analysis of covariance within the framework of the extended Cochran-
Mantel-Haenszel test (Koch 1990, Koch 1998, Stokes 2000).  Specifically, a Cochran-Mantel-
Haenszel mean score test will be used on the standardized mid-ranks (ie, overall rank divided 
by the number of ranks +1, or “modified ridit” scores) of the residuals from an ordinary least 
squares regression with change from Baseline in 6MWD at Week 24 as a linear function of 
background therapy (as a categorical variable: PDE5-I/sGC stimulator or ERA) and distance 
walked at Baseline (as a continuous variable).  This methodology will be carried out as 
follows: 
1. Walk distances obtained subsequent to study drug termination or unblinding will be 
excluded (as described in Section 8). 
2. Calculating ranks by background PAH therapy subgroup.  The pseudo SAS codes are 
as following: 


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proc rank nplus1 ties=mean out=ranks; 
   by BGTX;  
   var DistC Dist0; 
run; 
where BGTX is background PAH therapy, DistC is the change from Baseline in 
6MWD, and Dist0 is the Baseline measure of the 6MWD. 
3. Separate linear regression models for each background PAH therapy group will be fit 
using the rank values generated above.  The pseudo SAS codes are as following: 
proc reg data=ranks noprint;  
   by BGTX; 
   model DistC=Dist0; 
   output out=residual r=resid; 
run; 
where BGTX is background PAH therapy, DistC is the rank value of the change from 
Baseline in 6MWD, and Dist0 is the rank value of the Baseline measure of the 
6MWD. 
4. A stratified mean score test, using the values of the residuals as scores, compares the 
treatment groups.  Cochran-Mantel-Haenszel mean score statistic and p-value will be 
calculated using the NOPRINT and CMH2 options in the TABLES statement of the 
FREQ procedure of SAS.  The actual stratification used to randomize each subject will 
be used.  The pseudo SAS codes are as following: 
proc freq; 
   tables BGTX*treatment*resid / noprint cmh2; 
run; 
where BGTX is background PAH therapy, Treatment indicates the randomized 
treatment group, and Resid is the residuals obtained from the above linear regression 
models.  
In addition to the p-value from the non-parametric analyses of covariance described above, 
the Wilcoxon rank sum test and the Hodges-Lehmann estimate of median difference (as an 
estimate of location shift between 2 treatment groups for the placebo-controlled treatment 
effect) will be provided.  The Wilcoxon rank sum test and the Hodges-Lehmann estimate can 
be obtained through the following pseudo SAS codes: 
proc npar1way hl Wilcoxon; 
     class treatment; 
     var DistC; 
      run; 
where DistC is the change from Baseline in 6MWD at a specific visit.  


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The least square mean, least square mean difference, and p-value for treatment group 
comparison will also be provided using the parametric method — analysis of covariance 
model where the change from Baseline in 6MWD is the dependent variable, treatment and 
background PAH therapy are fixed effects, and Baseline 6MWD is a covariate.  
10.2.1.1 
Sensitivity and Sub-group Analyses 
This methodology for key secondary efficacy analysis of change in 6MWD at Week 24 using 
MMRM will also be carried out with data up to Week 48 included in the model.  The 
treatment effects at weeks 36 and 48 will be estimated.  
With non-parametric analysis of covariance method, in order to analyze walk distances at 
each scheduled assessment, values for missing or excluded assessments up to Week 48 will be 
imputed according to rules described under “Missing data handling for 6MWD” in 
Section 8.3.  Missing values beyond Week 48 will not be imputed.  The visits beyond 
Week 48 will only be summarized using the observed values.  
To further support the robustness and assess the sensitivity of efficacy analysis of change in 
6MWD at Week 24, the above MMRM method will be repeated using each of the following 
modifications: 
 MMRM model with the Per-Protocol Population 
 MMRM model with only subjects achieve total daily dose ≥ 9 mg. 
Analyses using non-parametric analysis of covariance will be repeated using each of the 
following modifications (as data permit): 
 Wth the Per-Protocol Population 
 Using only the observed values without imputation 
 Including data collected after termination of the study drug 
 Analyses will be carried out within PAH etiology categories 
 Analyses will be carried out within Baseline WHO FC categories 
 Analyses will be carried out within PAH background therapy categories 
 Analyses will be carried out within Baseline 6MWD categories (≤350 meters versus 
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 Analyses will be carried out within geographic regions 
 Analyses will be carried out within sex 
 Analyses will be carried out within age group (<65 years versus ≥65 years) 
 Analyses will be carried out by study drug dose at Week 24 (total daily dose <9 mg 
and ≥9 mg) 
 Analyses will be carried out within UT-15C dose quartile at Week 24 
 Plot of 6MWD at Week 24 by UT-15C dose 
10.2.2 
NT-proBNP 
The efficacy endpoint of NT-proBNP assesses if UT-15C decreases the level of NT-proBNP 
at Week 24 over placebo in subjects with PAH.  The null and alternative hypotheses are: 
𝐻0: 𝜇1 = 𝜇2 
𝐻𝑎: 𝜇1 ≠𝜇2 
Where µ1 and µ2 are the mean change from Baseline for log-transformed data in NT-proBNP 
of the UT-15C and placebo treatment groups, respectively, and the change from Baseline is 
calculated as log (value at week 24) – log (value at Baseline). 
The NT-proBNP values will be listed for all subjects.  The values and their respective changes 
from Baseline will be summarized for each assessment.  The summary will also include the 
geometric mean and geometric standard deviation. The difference between treatment groups 
for the change from Baseline for log-transformed data at each assessment at Week 24 will be 
tested using an analysis of covariance model with change from Baseline for log-transformed 
data in NT-proBNP as the dependent variable, treatment as a fixed effect, and Baseline 
NT-proBNP as a covariate.  The pseudo SAS codes are as following:  
proc mixed;  
   class treatment; 
   model BNP_C=Treatment BNP_B; 
run; 
where BNP_C is the change from Baseline for log-transformed data in NT-proBNP at a 
specific visit and BNP_B is the NT-proBNP for log-transformed data at Baseline. 


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Subjects who do not have a valid NT-proBNP measurement at Baseline or Week 24 will be 
excluded from the analysis. Additional analyses will also be performed for the data with 
imputation where for subjects who do not have NT-proBNP measurements at Week 24, the 
LOCF imputation will be used.    
A longitudinal data analysis using MMRM will also be performed to estimate the treatment 
difference in changes from Baseline for log-transformed data in NT-proBNP at Week 24.  The 
MMRM will include the change from Baseline for log-transformed data in NT-proBNP as the 
dependent variable; treatment, week, and treatment by week interaction as fixed effects; and 
Baseline NT-proBNP for log-transformed data as a covariate.  An unstructured 
variance/covariance structure shared across treatment groups will be used to model the 
within-subject errors and Kenward-Roger method will be used for calculating the 
denominator degree of freedom.  The appropriate contrasts will be constructed in order to 
estimate treatment effect at Week 24 and other visits. 
NT-proBNP data in observed cases will be descriptively summarized for other visits with 
measurements.  
10.2.3 
Combined 6MWD and Borg Dyspnea Score 
The intent of the 6MWT is to determine how much exercise subjects can do during the course 
of carrying out activities of daily living.  However, the capacity of subjects to function is 
determined not only by what they can do when they exert themselves to the fullest, but also 
by how they feel when they are carrying out their usual activities of daily living.  It is 
therefore important not only to look at the distance traversed during the unencouraged 
6MWT, but also the symptoms experienced at the end of the effort.  To do so, walk distances 
and Borg dyspnea scores from the Week 24 6MWT will be simultaneously compared between 
treatment groups using a nonparametric analysis of covariance within the framework of the 
extended Cochran-Mantel-Haenszel test (analogous to the key secondary analysis 
methodology for 6MWD at week 24).  This methodology will be carried out as follows:  
 Standardized mid-ranks of change in walk distance will be calculated as described in 
Section 10.2.1 


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 Standardized mid-ranks of change in Borg dyspnea score will be calculated in an 
analogous manner, but in reverse (descending) order 
 The standardized mid-ranks for change in walk distance and for change in Borg 
dyspnea score will be combined by calculating their arithmetic average 
 A Cochran-Mantel-Haenszel mean score test will be carried out on the standardized 
mid-ranks of these combined ranks in an analogous manner to that described in 
Section 10.2.1 
The treatment distributions of these combined ranks at Week 24 will be displayed graphically 
using Kaplan-Meier plots.  These plots will include the information from the treatment 
comparison analysis described above. 
10.3 
OTHER SECONDARY EFFICACY MEASURES 
10.3.1 
6MWD at Other Visits Except Week 24 
The method for analysis of change in 6MWD at other visits up to Week 48 (except Week 24) 
is the same as for the analysis of 6MWD at Week 24, and it has been described in 
Section 10.2.1. 
The observed values for 6MWD at all visits, including visits beyond Week 48, will be listed 
and descriptively summarized according to the requirements described in Section 8. 
10.3.2 
Borg Dyspnea Score 
The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced 
during the 6MWT.  Scores range from 0 (for the best condition) to 10 or more (for the worst 
condition).  Scores will be listed with the corresponding 6MWT data for each subject.  
Change from Baseline for visits up to Week 48 will be compared between the 2 treatment 
groups using non-parametric Hodges-Lehmann estimator and Wilcoxon rank-sum test as well 
as parametric 2-sample t-test.  Values for missing or excluded assessments up to Week 48 will 
be imputed.  For those patients who withdrew early due to death, or a clinical worsening event 
without Borg dyspnea score measurement at visits up to Week 48, the Borg dyspnea score is 
set to worst score of 10; for all other withdrawals without Borg measurement, the LOCF 
method is used for imputation. 


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The observed values for Borg dyspnea score at all visits, including visits beyond Week 48, 
will be descriptively summarized according to the requirements described in Section 8. 
10.3.3 
WHO FC 
WHO FC values (ie, class I, II, III, or IV) will be listed for all subjects at each assessment 
time point. Class I, II, III, or IV will be assigned values 1, 2, 3, 4 for the calculations. The 
shift from Baseline in WHO FC (categorized as Improved, No Change, and Deteriorated) for 
visits up to Week 48 will be compared between the 2 treatment groups using Fisher’s exact 
test.  The change from Baseline in WHO FC for visits up to Week 48 will be compared 
between the 2 treatment groups using the non-parametric Hodges-Lehmann estimator and 
Wilcoxon rank-sum test.  Values for missing or excluded assessments up to Week 48 will be 
imputed.  For those patients who withdrew early due to death or a clinical worsening event 
without WHO FC measurement at visits up to Week 48, the WHO FC is set to the worst class 
value of IV; for all other withdrawals without WHO FC measurement, the LOCF method is 
used for imputation. 
10.3.4 
NT-proBNP 
NT-proBNP at weeks 12 and 36 will be analysed in the same way as described in 
Section 10.2.2.  In addition, NT-proBNP at weeks 12, 24, and 36 will also be analysed with 
LOCF imputation for missing data.  NT-proBNP at other timepoints will only be summarized.  
10.3.5 
Hemodynamic Parameters 
Values of all hemodynamic parameters obtained as part of the optional hemodynamic study 
(heart rate, systemic arterial pressure systolic [SAPs], systemic arterial pressure diastolic 
[SAPd], systemic arterial pressure mean [SAPm], pulmonary artery pressure systolic [PAPs], 
pulmonary artery pressure diastolic [PAPd], pulmonary artery pressure mean [PAPm], right 
atrial pressure mean [RAPm], pulmonary capillary wedge pressure mean [PCWPm], systemic 
arterial oxygen saturation [SaO2], mixed venous oxygen saturation [SvO2], CO 
Thermodilution, CO Fick, and BSA) will be listed for all subjects with hemodynamic 
measures.  Additional hemodynamic parameters, including cardiac index, SVR, SVRI, PVR, 
and PVRI, will be derived according to the formulas described in Section 8.5. 


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The values and their respective changes from Baseline to Week 24 will be summarized by 
treatment group for each hemodynamic parameter.  The difference between treatment groups 
for the change from Baseline to Week 24 will be tested using analysis of covariance, with 
change from Baseline as the dependent variable, treatment as the fixed effect, and Baseline 
measure as the covariate.  The results from the non-parametric Wilcoxon rank-sum test will 
also be provided.  The analyses will be based on the observed cases, and no imputation will be 
performed for the missing values.  
10.4 
EXPLORATORY ANALYSIS 
10.4.1 
The low risk-profile analysis 
Risk categories will be defined and the shift in risk categories will be analyzed according to 
the method defined in Weatherald et al (Weatherald 2018).  The number and percentage of 
subjects with a low risk profile at Week 24 or other time points will be calculated and a 
treatment group comparison will be performed.  
10.4.2 
Optional Evaluation of Biomarkers 
The optional evaluation of biomarkers will be specified in a separate document and not 
covered in this SAP. 
10.4.3 
Optional Evaluation of Pharmacogenomics 
The optional evaluation of pharmacogenomics will be specified in a separate document and 
not covered in this SAP. 
11 
HEALTH OUTCOMES 
11.1 
QUALITY OF LIFE MEASURES 
Quality of life was not assessed during this study. 
11.2 
RESOURCE UTILIZATION MEASURES 
All details for all hospitalizations will be listed.  Number of hospitalizations, number of 
hospitalizations for PAH, total duration of hospitalization, and total duration of hospitalization 
for PAH will be summarized for each treatment group. 


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12 
SAFETY ANALYSES 
All safety analyses will be performed only on the Safety Population (see Section 6). 
12.1 
EXTENT OF EXPOSURE 
All study drug dosing will be listed for all subjects.  The listing will include initial dose and 
date of this initial dose, dose and date of each change, and whether each change applied to the 
morning, afternoon, or evening doses.  Dosing at Weeks 4, 8, 12, 24, and every 12-week 
follow-up assessment will be summarized for subjects still receiving study drug at each of 
these assessments.  A summary by treatment group of maximum study drug dose and overall 
duration of exposure will be included. The study drug dosing and exposure by the use of 
background PAH therapy will be provided in a separate summary. 
In addition, a summary table will be provided for study drug treatment compliance for the 
first 24 weeks by treatment group.  The summary will include the number and percent of days 
subjects are dosed and total study drug consumed for first 24 weeks. 
12.2 
ADVERSE EVENTS 
All AEs will be coded using MedDRA and will be listed by treatment group, including all the 
details on the eCRF page plus an indicator of whether the event was treatment emergent.  The 
AE listings will include the AE verbatim term and its corresponding PT and SOC. 
The AE summary tables will be limited to include only treatment-emergent AEs and will be 
summarized for each treatment group.  Treatment-emergent AEs are those AEs with an onset 
date equal to or after the start date of the study drug.  The non-treatment emergent AEs (the 
AEs that occur after signing the informed consent form, but before receiving study drug, will 
be listed but will not be included in summary tables. 
All summaries will include the number and percentage of subjects experiencing each type of 
event based on PT and the total number of each type of event, in order of overall frequency 
and/or SOC.  Serious AEs and non-serious AEs will be summarized by PT. 
Maximum level of seriousness and intensity occurring during the treatment phase for each AE 
will be summarized separately and by causality (probable or possible versus not related). 


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Considering the potential imbalance in treatment exposure, the total number of AEs and the 
AE rate will be calculated and summarized.  The AE rate will be calculated as the total 
number of AEs divided by the total patient years per treatment group. 
Separate listings and summary tables will be provided for all serious adverse events (SAEs), 
AEs leading to the discontinuation of the study drug, and all deaths during the study. 
12.3 
DEATHS 
Information for all subjects who die during the study period from randomization to the end of 
study (including 30 days after the last study drug dosing) will be listed.  The number and 
percent of subjects who die will be summarized by treatment group. 
In addition, the information for vital status, including alive/death, last known date subject is 
alive, or date of death at the study closure, will also be listed. 
Death information is also analysed as an efficacy endpoint as described in Sections 10.1.1.2 
and 10.1.1.3. 
12.4 
PREGNANCIES  
Pregnancy test results for female subjects will be listed. 
12.5 
CLINICAL LABORATORY EVALUATIONS 
Blood samples will be taken at Baseline; Weeks 12, 24, 36; and every 24 weeks thereafter 
during the study.  All samples will be sent to a central laboratory for evaluation of clinical 
chemistry and hematology.  Urine samples collected at screening and study drug termination 
visit will be collected and sent to a central laboratory for urinalysis. 
12.5.1 
Clinical Chemistry 
The following clinical chemistry parameters will be evaluated by the central laboratory: 
Parameter 
Units 
Sodium 
mmol/L 
Potassium 
mmol/L 
Chloride 
mmol/L 
Bicarbonate 
mmol/L 


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Parameter 
Units 
Albumin 
g/L 
Blood urea nitrogen (BUN) 
mmol/dL 
Total bilirubin 
umol/dL 
Indirect bilirubin 
umol/dL 
Direct bilirubin 
umol/dL 
Alkaline phosphatase 
U/L 
Alanine aminotrasferase (ALT/SGPT) 
U/L 
Aspartate aminotransferase (AST/SGOT) 
U/L 
Gamma-glutamyl transferase (GGT) 
U/L 
Creatinine 
umol/L 
Thyroid stimulating hormone (TSH) 
mIU/L 
Thyroxine (T4; free) 
pmol/L 
 
Values that are “high” or “low” with respect to the reference range provided by the central 
laboratory will be flagged with an “H” or an “L.”  All parameters will be listed for all subjects 
and assessments, along with their respective “high/low” flags. 
Values of these parameters at each assessment and their corresponding changes from Baseline 
will be descriptively summarized by treatment group. 
For each parameter, the frequency and percentage of subjects within each treatment group 
who had “low,” “normal,” or “high” Baseline values, then subsequently had “low,” “normal,” 
or “high” follow-up values at each assessment will be presented in a shift summary. 
12.5.2 
Hematology 
The following hematology parameters will be evaluated by the central laboratory: 
Parameter 
Units 
Red blood cell (RBC) count 
106/uL 
Hemoglobin 
g/dL 
Hematocrit 
% 
Platelet count 
103/uL 
White blood cell (WBC) count 
103/uL 
 


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Values that are “high” or “low” with respect to the reference range provided by the central 
laboratory will be flagged with an “H” or an “L.”  All parameters will be listed for all subjects 
and assessments, along with their respective “high/low” flags. 
Values of these parameters at each assessment, and their corresponding changes from 
Baseline will be descriptively summarized by treatment group. 
For each parameter, the frequency and percentage of subjects within each treatment group 
who had “low,” “normal,” or “high” Baseline values, then subsequently had “low,” “normal,” 
or “high” follow-up values at each assessment will be presented in a shift summary. 
12.5.3 
Urinalysis 
All urinalysis information will be listed for all subjects and assessments.  The presence of 
protein and blood in the urine will be categorically summarized by treatment group. 
12.6 
ELECTROCARDIOGRAMS 
All ECG assessments will be listed for all subjects.  This listing will include the heart rate, QT 
interval, QTc interval (calculated using formulas by both Bazett and Fridericia as described in 
Section 8.5), PR interval, QRS duration, whether there were clinically significant changes 
from Screening visit, whether abnormalities were present, and details and comments on any 
abnormalities.  The ECG results at each assessment and changes at Week 24 will be 
descriptively summarized by treatment group.  In addition, for QTc interval calculated using 
both the Bazett and Fridericia methods, the number and percent of subjects with values ≥500 
msec and the number and percent of subjects with changes of <30 msec, 30 to <60 msec, and 
≥60 msec will be presented by treatment group. 
12.7 
VITAL SIGNS 
All vital sign assessments will be listed for all subjects.  This listing will include weight, heart 
rate, systolic and diastolic blood pressure, and respiration rate.  The vital sign results at each 
assessment and changes for each post-Baseline assessment will be descriptively summarized 
by treatment group. 


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12.8 
DISEASE-RELATED EVENTS 
All disease-related events occurring during the study will be listed for all subjects.  Overall 
frequency of each type of event will be summarized by treatment group. 
13 
PHARMACOKINETICS 
No pharmacokinetic measures will be assessed in this study. 


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14 
REFERENCES 
Koch GG, Carr GJ, Amara IA, Stokes ME, and Uryniak TJ.  Categorical data analysis.  In: 
Berry DA ed. Statistical Methodology in the Pharmaceutical Sciences.  New York, NY: 
Marcel Dekker Inc.; 1990:391-475. 
Koch GG, Tangen CM, Jung JW, Amara IA.  Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them.  Stat Med.  1998;17(15-16):1863-1892. 
Stokes ME, Davis CS, Koch GG.  Categorical Data Analysis Using the SAS System.  2nd 
Edition.  Cary, NC: SAS Institute Inc.; 2000. 
SAS Institute Inc.  SAS/Stat® 14.1 User’s Guide.  Cary, NC: SAS Institute Inc.; 2015.  
Weatherald J, Boucly A, Sahay S, et al. The low-risk profile in pulmonary arterial 
hypertension time for a paradigm shift to goal-oriented clinical trial endpoints?  Am J Respir 
Crit Care Med.  2018;197(7):860-868 


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15 
APPENDICES 
15.1 
INCLUSION AND EXCLUSION CRITERIA 
A subject is eligible for inclusion in this study if all of the following criteria apply: 
1. The subject voluntarily gives informed consent to participate in the study. 
2. The subject is 18 to 75 years of age (inclusive) at Screening (ie, date of providing 
written informed consent). 
3. Women of childbearing potential (WOCBP) include any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as 
amenorrhea for at least 12 consecutive months).  Women of childbearing potential 
must practice true abstinence from intercourse when it is in line with their preferred 
and usual lifestyle, or use 2 different forms of highly effective contraception for the 
duration of the study and for at least 30 days after discontinuing study medication.  
Medically acceptable forms of effective contraception include:  (1) approved 
hormonal contraceptives (such as birth control pills), (2) barrier methods (such as a 
condom or diaphragm) used with a spermicide, (3) an intrauterine device (IUD), or 
(4) partner vasectomy.  For women of childbearing potential, a negative urine 
pregnancy test is required at Screening and Baseline prior to initiating study 
medication.   
4. The subject, if male, must use a condom during the length of the study, and for at least 
48 hours after discontinuing study medication. 
5. The subject has a diagnosis of symptomatic idiopathic or heritable PAH, PAH 
associated with connective tissue disorder (CTD), PAH associated with human 
immunodeficience virus (HIV) infection, PAH associated with repaired congenital 
systemic-to-pulmonary shunt (at least 1 year since repair with respect to the date of 
providing informed consent), or PAH associated with appetite suppressant or toxin 
use. 
6. The subject, if known to be positive for HIV infection, has a CD4 lymphocyte count of 
at least 200 cells/mm3 assessed at Screening and is receiving current standard of care 
anti-retroviral or other effective medication for treatment of HIV infection. 
7. The subject must have a Baseline 6MWD greater than or equal to 150 meters, in the 
absence of a concurrent injury, illness (other than PAH or a PAH related condition), or 
other confounding factor including, but not limited to, use of an aid for ambulation 
(eg, use of a cane or walker) or connection to a non-portable machine, that would 
prevent the accurate assessment of the subject’s exercise capacity. 
8. The subject must be optimally treated with conventional pulmonary hypertension 
therapy (eg, oral vasodilators, oxygen, digoxin, diuretics, anticoagulants as deemed 
appropriate by the Investigator) with no additions, discontinuations, or dose changes 
for a minimum of 10 days prior to randomization.  The exceptions are the 
discontinuation or dose changes of anticoagulants and/or dose change of diuretics. 


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9. The subject must have been receiving a PAH-approved oral monotherapy at a 
minimum dose that complies with the approved prescribing information for the 
product for at least 30 days prior to randomization and must have been receiving a 
stable dose for at least 10 days prior to randomization.  The subject who previously 
received 2 PAH-approved oral therapies at the same time (specifically, a PDE5-I, an 
ERA, or an sGC stimulator) will be eligible provided they received these medications 
concomitantly for less than or equal to 90 days cumulatively.  The subject must have 
taken only 1 PAH-approved therapy for at least 30 days prior to randomization and 
must have been receiving a stable dose for at least 10 days prior to randomization. 
10. The subject has previously undergone a cardiac catheterization within 3 years prior to 
the start of Screening, or during the Screening period, and the most recent assessment 
has documented a PAPm of at least 25 mmHg, a PCWP (or in the event a PCWP 
cannot be reliably obtained, a left ventricular end-diastolic pressure [LVEDP]) less 
than or equal to 15 mmHg, and absence of unrepaired congenital heart disease (other 
than patent foramen ovale [PFO]).  In the event that a reliable PCWP or LVEDP is 
unobtainable during cardiac catheterization, subjects with clinically normal left heart 
function and absence of clinically relevant mitral valve disease on echocardiography 
are eligible for enrollment. 
11. The subject has undergone echocardiography with evidence of clinically normal left 
systolic and diastolic ventricular function and absence of any clinically significant left 
sided heart disease (eg, mitral valve disease).  Subjects with clinically insignificant left 
ventricular diastolic dysfunction due to the effects of right ventricular overload (ie, 
right ventricular hypertrophy and/or dilatation) are eligible. 
12. The subject has a previous ventilation perfusion lung scan, and/or high resolution 
computerized tomography scan of the chest, and/or pulmonary angiography that are 
consistent with the diagnosis of PAH (eg, low probability of pulmonary embolism; 
absence of major perfusion defects). 
13. The subject has pulmonary function tests conducted within 6 months before Screening 
or during the Screening period to confirm the following: 
a. Total lung capacity (TLC) is at least 60% (predicted value) assessed by either 
whole body plethysmography or helium dilution or nitrogen washout technique  
b. Forced expiratory volume at 1 second (FEV1) of at least 50% (predicted value) 
14. In the opinion of the Principal Investigator, the subject is able to communicate 
effectively with study personnel, and is considered reliable, willing, and likely to be 
cooperative with protocol requirements, including attending all study visits.  
A subject is not eligible for inclusion in this study if any of the following criteria apply: 
1. The subject is pregnant or lactating. 
2. The subject has previously received UT-15C. 
3. The subject has received a prostacyclin (except if used during acute vasoreactivity 
testing) within 30 days prior to randomization or had previous intolerance or 


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significant lack of efficacy to any prostacyclin or prostacyclin analogue that resulted 
in discontinuation or inability to titrate that therapy effectively. 
4. The subject has had any background conventional therapies for PAH added, removed, 
or dose adjusted (including but not limited to oxygen, vasodilators, diuretics, digoxin, 
anticoagulants) within 10 days prior to randomization.  The exceptions are removal or 
dose adjustments of anticoagulants and/or dose adjustments of diuretics. 
5. The subject has received their first dose of a PAH-approved therapy less than 30 days 
prior to randomization, has had their PAH-approved oral monotherapy dose changed 
within 10 days prior to randomization, the subject discontinued any PAH-approved 
therapy within 30 days prior to Screening, or the subject previously received 2 PAH 
approved oral therapies (specifically, a PDE5-I, an ERA, or an sGC stimulator) 
concomitantly for more than 90 days cumulatively. 
6. The subject has any disease associated with PAH other than CTD, HIV infection, 
repaired (for at least 1 year) congenital systemic-to-pulmonary shunt, PAH associated 
with appetite suppressant/toxin use (eg, portal hypertension, chronic thromboembolic 
disease, pulmonary veno-occlusive disease, etc), or has had an atrial septostomy. 
7. The subject has a current diagnosis of uncontrolled sleep apnea as defined by their 
physician. 
8. The subject has a history of ischemic heart disease, including a previous myocardial 
infarction or symptomatic coronary artery disease within 6 months prior to Screening 
or a history of left sided myocardial disease as evidenced by a mean PCWP (or a 
LVEDP) greater than 15 mmHg or left ventricular ejection fraction less than 40%, as 
assessed by either multigated angiogram (MUGA), angiography, or echocardiography. 
9. The subject has uncontrolled systemic hypertension, as evidenced by systolic blood 
pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg. 
10. The subject has ALT or AST levels at least greater than 3 times the upper limit of 
normal, clinically significant liver disease/dysfunction, or known Child-Pugh Class C 
hepatic disease at Screening. 
11. The subject has any other disease or condition that would interfere with the 
interpretation of study assessments. 
12. The subject has a musculoskeletal disorder (eg, arthritis affecting the lower limbs, 
recent hip or knee joint replacement, artificial leg), is using a device to assist walking 
(eg, cane or walker), or any disease that is likely to limit ambulation, or is connected 
to a machine that is not portable. 
13. The subject has an unstable psychiatric condition or is mentally incapable of 
understanding the objectives, nature, or consequences of the study, or has any 
condition which in the Investigator’s opinion would constitute an unacceptable risk to 
the subject’s safety. 
14. The subject is receiving an investigational drug, has an investigational device in place, 
or has participated in an investigational drug or device study within 30 days prior to 
Screening. 
15. The subject has chronic renal insufficiency, as defined by either a Screening creatinine 
value greater than 2.5 mg/dL (221 μmol/L) or the requirement for dialysis. 


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16. Subjects must not have 3 or more of the following left ventricular disease/dysfunction 
risk factors: 
i. Body Mass Index (BMI) ≥30 kg/m2 
ii. History of essential hypertension 
iii. Diabetes mellitus (any type) 
iv. Historical evidence of significant coronary disease established by any one of the 
following: history of myocardial infarction or percutaneous coronary intervention 
or angiographic evidence of coronary artery disease (>50% stenosis in at least 
1 coronary artery), positive stress test with imaging, previous coronary artery 
bypass graft, stable angina 


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16 
LIST OF TABLES, LISTINGS, AND FIGURES 
16.1 
LIST OF TABLES 
Table Number 
Table Title 
14.1.1 
Summary of Subject Accountability 
14.1.2 
Summary of Analysis Population Information 
14.1.3 
Summary of Demographic Data 
14.1.4 
Summary of PAH History 
14.1.5 
Summary of Entry Criteria Violations 
14.1.6 
Summary of Protocol Deviations 
14.1.7 
Summary of Randomization Information 
14.1.8 
Summary of Medical History  
14.1.9 
Summary of Concomitant Medications Ongoing at Baseline 
14.1.10 
Summary of Concomitant Medications Added During the Study  
14.1.11 
Summary of Background PAH Therapy Use 
14.1.12 
Summary of Background PAH Therapy with Total Daily Dosage at 
Baseline 
14.1.13 
Summary of Study Drug Dosing and Exposure 
14.1.14 
Summary of Study Drug Dosing and Exposure by Background PAH 
Therapy 
14.1.15 
Summary of Study Drug Treatment Compliance for First 24 Weeks 
14.2.1.1 
Summary and Analysis of Adjudicated Clinical Worsening Events – 
ITT Population 
14.2.1.2 
Summary and Analysis of Adjudicated Clinical Worsening Events – 
Per-Protocol Population 
14.2.1.3 
Summary and Analysis of Clinical Worsening Events with Early 
Termination Treated as Clinical Worsening Event 
14.2.1.4 
Summary and Analysis of Clinical Worsening Events with Early 
Termination due to AEs Treated as Clinical Worsening Event 
14.2.1.5 
Summary and Analysis of Adjudicated Clinical Worsening Events by 
Subgroups 
14.2.1.6 
Summary and Analysis of Investigator Reported Clinical Worsening 
Events  
14.2.1.7 
Summary and Analysis of Investigator Reported Clinical Worsening 
Events 
14.2.1.8  
Summary and Analysis of Death (All Causes) During the Study 
14.2.1.9 
Summary and Analysis of Death (All Causes) at Study Closure 


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Table Number 
Table Title 
14.2.1.10 
Summary and Analysis of Hospitalization Due to Worsening PAH 
14.2.2.1 
Analysis of 6MWD (meter) at Week 24 Using Mixed Model Repeated 
Measurement (MMRM) – ITT Population 
14.2.2.2 
Analysis of 6MWD (meter) at Week 24 Using Mixed Model Repeated 
Measurement (MMRM) – Per-Protocol Population 
14.2.2.3 
Analysis of 6MWD (meter) at Week 24 Using Mixed Model Repeated 
Measurement (MMRM) – for Subjects Who Achieve 9 mg Daily Dose 
14.2.2.4 
Analysis of 6MWD (meter) at Week 48 Using Mixed Model Repeated 
Measurement (MMRM) – ITT Population 
14.2.2.5 
Summary and Analysis of 6MWD (meter) at Week 24 – ITT Populatino 
14.2.2.6 
Summary and Analysis of 6MWD (meter) at Week 24 – Per-Protocol 
Population 
14.2.2.7 
Summary and Analysis of 6MWD (meter) at Week 24 with No 
Imputation for Missing Data 
14.2.2.8 
Summary and Analysis of 6MWD (meter) at Week 24 Including Data 
Collected After Termination of Study Drug  
14.2.2.9 
Summary and Analysis of 6MWD (meter) at Week 24 by Etiology 
14.2.2.10 
Summary and Analysis of 6MWD (meter) at Week 24 by Baseline 
WHO Functional Class 
14.2.2.11 
Summary and Analysis of 6MWD (meter) at Week 24 by Geographic 
Region 
14.2.2.12 
Summary and Analysis of 6MWD (meter) at Week 24 by Sex 
14.2.2.13 
Summary and Analysis of 6MWD (meter) at Week 24 by Age Group 
14.2.2.14 
Summary and Analysis of 6MWD (meter) at Week 24 by Study Drug 
Dose  
14.2.2.15 
Summary and Analysis of 6MWD (meter) at Week 24 by UT-15C Dose 
Quartile at Week 24 
14.2.2.16 
Summary and Analysis of 6MWD (meter) at Week 24 by Background 
PAH Therapy 
14.2.2.17 
Summary and Analysis of 6MWD (meter) at Week 24 by Baseline 
6MWD Category 
14.2.2.18 
Summary and Analysis of 6MWD (meter) at Weeks 4, 8, 12, 36, and 48 
14.2.2.19 
Summary of 6MWD (meter) by Visit with Observed Case 
14.2.3.1 
Summary and Analysis of NT-proBNP (pg/mL) Data at Week 24  
14.2.3.2 
Summary and Analysis of NT-proBNP (pg/mL) Data at Weeks 12 and 
36  


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Table Number 
Table Title 
14.2.3.3 
Summary and Analysis of NT-proBNP (pg/mL) Data at Weeks 12, 24, 
and 36 with LOCF Imputation 
14.2.3.4 
Summary of NT-proBNP (pg/mL) Data by Visit  
14.2.3.5 
Analysis of NT-proBNP (pg/mL) at Week 24 Using Mixed Model 
Repeated Measurement (MMRM) – ITT Population 
14.2.3.6 
Analysis of NT-proBNP (pg/mL) at Week 36 Using Mixed Model 
Repeated Measurement (MMRM) – ITT Population 
14.2.4.1 
Summary and Analysis of Borg Dyspnea Score up to Week 48 
14.2.4.2 
Summary of Borg Dyspnea Score by Visit with Observed Case 
14.2.5.1 
Summary and Analysis of WHO Functional Class up to Week 48 
14.2.5.2 
Summary of WHO Functional Class by Visit with Observed Case 
14.2.6 
Summary and Analysis of Hemodynamic Parameters at Week 24 
14.2.7 
Summary of Hospitalization Information 
14.3.1.1 
Overall Summary of Adverse Events 
14.3.1.2 
Summary of Adverse Events by System Organ Class and Preferred 
Term 
14.3.1.3 
Summary of Adverse Events by System Organ Class  
14.3.1.4 
Summary of Adverse Events by Preferred Term 
14.3.1.5 
Summary of Deaths 
14.3.1.6 
Summary of Serious Adverse Events by Preferred Term 
14.3.1.7 
Summary of Adverse Events Probably or Possibly Related to Study 
Drug by Preferred Term 
14.3.1.8 
Summary of Adverse Events Leading to Permanent Discontinuation of 
Study Drug by Preferred Term 
14.3.1.9 
Summary of Non-serious Adverse Events by Preferred Term 
14.3.1.10 
Summary of Adverse Events by Maximum Seriousness and Causality 
14.3.1.11 
Summary of Adverse Events by Maximum Intensity 
14.3.1.12 
Summary of Adverse Events by Maximum Intensity and Causality 
14.3.1.13 
Summary of Adverse Events by Study Drug Dose at Onset 
14.3.2.1 
List of Deaths 
14.3.2.2 
Listing of Serious Adverse Events 
14.3.2.3 
Listing of Adverse Events Leading to Permanent Discontinuation of 
Study Drug 
14.3.4.1 
Summary of Clinical Chemistry Data 
14.3.4.2 
Summary of Clinical Chemistry Shift from Baseline 


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Table Number 
Table Title 
14.3.4.3 
Summary of Hematology Data 
14.3.4.4 
Summary of Hematology Shift from Baseline 
14.3.4.5 
Summary of Urinalysis Data 
14.3.5 
Summary of Vital Signs 
14.3.6.1 
Summary of Electrocardiogram Parameters 
14.3.6.2 
Summary of Electrocardiogram Categorical Results 
14.3.7 
Summary of Disease Related Events 
 
16.2 
LIST OF LISTINGS 
Listing Number 
Listing Title 
16.2.1.1 
Subject Dispositions 
16.2.1.2 
Subject Accountability 
16.2.2 
Protocol Deviations 
16.2.3.1 
Subject Randomization 
16.2.3.2 
Analysis Population Information 
16.2.3.3 
Entry Criteria 
16.2.4.1 
Demographics 
16.2.4.2 
PAH History 
16.2.4.3 
Medical History 
16.2.4.4 
Concomitant Medications 
16.2.5.1 
Study Drug Dosing 
16.2.5.2 
Compliance for First 24 Weeks of Treatment 
16.2.5.3 
Background PAH Medication History 
16.2.5.4 
Change to ERA, PDE5-I, or sGC Stimulator Dosing 
16.2.6.1 
Clinical Worsening Events 
16.2.6.2 
Time to Clinical Worsening Events 
16.2.6.3 
6MWT and Borg Dyspnea Score Data 
16.2.6.4 
6MWT Information with Imputed Data up to Week 48 
16.2.6.5 
WHO Functional Class for PAH 
16.2.6.6 
WHO Functional Class with Imputed Data up to Week 48 
16.2.6.7 
Plasma NT-proBNP (pmol/L) 
16.2.6.8 
Plasma NT-proBNP (pmol/L) with Imputed Data up to Week 36 
16.2.6.9 
Hemodynamic Measurements 


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Listing Number 
Listing Title 
16.2.6.10 
Hospitalizations 
16.2.6.11 
Death Records 
16.2.6.12 
Disease Related Events 
16.2.7 
Adverse Events 
16.2.8.1 
Laboratory Results – Clinical Chemistry 
16.2.8.2 
Laboratory Results – Hematology 
16.2.8.3 
Laboratory Results – Urinalysis 
16.2.8.4 
Pregnancy Test Results (Female Subjects Only) 
16.2.8.5 
Vital Signs 
16.2.8.6 
Electrocardiogram Results 
 
16.3 
LIST OF FIGURES 
Figure Number 
Figure Title 
14.2.1.1 
Kaplan-Meier Plot of Time to Adjudicated Clinical Worsening Events 
14.2.1.2 
Kaplan-Meier Plot of Time to Investigator Reported Clinical Worsening 
Events 
14.2.1.3 
Kaplan-Meier Plot of Time to Death  
14.2.1.4 
Kaplan-Meier Plot of Time to Death at the Study Closure 
14.2.1.5 
Kaplan-Meier Plot of Hospitalization Due to PAH 
14.2.1.6 
Forest Plot on Subgroup Analyses of Time to Adjudicated Clinical 
Worsening Events 
14.2.2.1 
Plot of 6MWD at Week 24 By UT-15C Drug Dose 
14.2.2.2 
Forest Plot on Subgroup Analyses of 6MWD (meter) at Week 24 
14.2.3 
Plot of the Combined 6MWD and Borg Dyspnea Score Ranks at 
Week 24