Clinical trial NCT03037580
Conditions: Pulmonary Hypertension Heart Failure With Preserved Ejection Fraction
Keywords: Pulmonary Hypertension 6-Minute Walk Test HFpEF Oral Treprostinil
Sponsor: United Therapeutics
Start date: 2017-08-15; Completion date: 2019-12-03
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multicenter, randomized (1:1; oral treprostinil to placebo), double-blind, placebo-controlled study in subjects with World Health Organization (WHO) Group 2 pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF). Once randomized, subjects took the initial dose of study drug at the study site on the day of randomization. Subjects returned to the study site for visits scheduled at Weeks 6, 12, 18, and 24. The duration of study participation was approximately 28 weeks from Screening until study completion (includes a 30-day Screening Phase and 24-week Treatment Phase).

The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment. As only a small portion of the anticipated total subjects had been enrolled, with many terminating early due to the study termination, there was a limited ability to explore the effect of oral treprostinil in this indication in this study.

Detailed description:
Study TDE-HF-301 was a multicenter, randomized, double-blind, placebo-controlled study designed to investigate the effect of oral treprostinil compared with placebo on exercise capacity in subjects with WHO Group 2 PH associated with HFpEF.

Once randomized, subjects were dispensed study drug and took an initial dose (0.125 mg) at the study site on the day of randomization. Dosing of study drug continued at 0.125 mg 3 times daily (TID; every 6 to 8 hours) with food. Dose increases could occur in 0.125-mg increments every 72 hours at the discretion of the Investigator up to a maximum allowable dose of 6 mg TID. Subjects received oral treprostinil as 0.125, 0.25, 1.0, or 2.5 mg sustained-release osmotic tablets (maximum dose 6 mg TID) or matching placebo. Doses of study drug were to be increased in the absence of dose-limiting drug-related adverse events (AEs) to ensure that each subject received the optimal dose throughout the study. Subjects returned for visits at Weeks 6, 12, 18, and 24. Subjects who terminated study drug early were asked to complete all remaining study visits. The study had an adaptive design where the maximum allowable dose was 2 mg until the Data Monitoring Committee had confirmed a satisfactory safety profile. After this confirmation, the maximum allowable dose was increased to 4 mg TID. This occurred after 45 subjects had been enrolled. A subsequent Data Monitoring Committee meeting, which occurred after 75 subjects had been enrolled, increased the maximum allowable dose to 6 mg TID.

Efficacy assessments consisted of 6-Minute Walk Distance (6MWD), blood collection for N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, clinical worsening, WHO Functional Class (FC), Borg dyspnea score, glycated hemoglobin (HbA1c), and Kansas City Cardiomyopathy Questionnaire (KCCQ).

Safety assessments consisted of AEs, physical examinations, vital signs, 12-lead electrocardiograms (ECGs), echocardiograms (ECHOs), heart failure signs and symptoms, pregnancy testing, clinical laboratory tests, hospitalizations due to cardiopulmonary indication, and worsening heart failure as demonstrated by outpatient administration of intravenous (IV) diuretics. Subjects could have optionally provided samples for the evaluation of biomarkers and pharmacogenomics.

Subjects that completed the 24-week treatment period on study drug were permitted to enter the open-label extension study (Study TDE-HF-302).

The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment. As only a small portion of the anticipated total subjects had been enrolled, with many terminating early due to the study termination, there was a limited ability to explore the effect of oral treprostinil in this indication in this study.

Arms: arm 1: Sustained-release oral tablets for TID administration arm 2: Placebo (sugar pill) for TID oral administration
Interventions: intervention 1: Oral treprostinil intervention 2: Placebo
Intervention descriptions: intervention 1: Sustained-release oral tablets for TID administration intervention 2: Placebo (sugar pill) for TID oral administration

Protocol documents:
Prot_000.pdf: 
United Therapeutics Corp. 
TDE-HF-301 Protocol Amendment 3 
 
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. © 2019 United Therapeutics Corporation 
 
Page 1 
 
 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Safety and Efficacy of Oral Treprostinil in 
Subjects with Pulmonary Hypertension (PH) in Heart Failure 
with Preserved Ejection Fraction (HFpEF) 
IND Number 133,962 
Protocol TDE-HF-301 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
28 December 2016 
Amendment 1 
15 September 2017 
Amendment 2 
01 February 2018 
Amendment 3 
Amendment 4 
20 February 2019 
12 August 2019 


United Therapeutics Corp. 
TDE-HF-301 Protocol Amendment 4 
 
Oral Treprostinil 
Version Date 12 August 2019 
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LIST OF CONTACTS FOR STUDY 
Contract Research 
Organization 
 
 
Study Sponsor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Clinical 
Laboratories 
 
 
 


United Therapeutics Corp. 
TDE-HF-301 Protocol Amendment 4 
 
Oral Treprostinil 
Version Date 12 August 2019 
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INVESTIGATOR’S AGREEMENT 
I have read the attached Protocol Amendment 4 entitled “A Multicenter, Randomized, 
Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Oral 
Treprostinil in Subjects with Pulmonary Hypertension (PH) in Heart Failure with Preserved 
Ejection Fraction (HFpEF)” dated 12 August 2019 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 (FDA) 
regulations/guidelines set forth in 21 Code of Federal Regulations Parts 50, 54, 56, and 312 
and any local regulations per country. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of United Therapeutics Corp. 
I also have read the current Investigator’s Brochure for oral treprostinil (treprostinil 
diethanolamine) and acknowledge that review of the information contained in the 
Investigator’s Brochure is a requirement for Investigators before using oral treprostinil in a 
clinical study. 
This protocol has been received for information only and must not be implemented before all 
necessary regulatory agency and Ethics Committee/Institutional Review Board approval 
documents have been obtained. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 


United Therapeutics Corp. 
TDE-HF-301 Protocol Amendment 4 
 
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Version Date 12 August 2019 
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PROTOCOL SYNOPSIS 
Title  
A Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Safety and 
Efficacy of Oral Treprostinil in Subjects with Pulmonary 
Hypertension (PH) in Heart Failure with Preserved Ejection 
Fraction (HFpEF) 
Study Phase 
3 
Indication 
Pulmonary hypertension (PH) associated with left-sided 
heart failure and preserved ejection fraction 
Primary Objective 
The primary objective of this study is to assess the effect of 
oral treprostinil compared with placebo on change in 
exercise capacity as measured by change in 6-Minute Walk 
Distance (6MWD) from Baseline to Week 24 in subjects 
with PH associated with HFpEF. 
Secondary Objectives 
To assess the effect of oral treprostinil compared with 
placebo on the following: 
 Change in N-terminal pro-brain natriuretic peptide 
(NT-proBNP) levels from Baseline to Week 24 
 Time to the first clinical worsening event where 
clinical worsening is defined by at least 1 of the 
following: 
o Hospitalization due to a cardiopulmonary 
indication (a non-elective hospitalization 
lasting at least 24 hours in duration caused 
by clinical conditions directly related to PH 
and/or heart failure) 
o Outpatient administration of intravenous 
(IV) diuretics 
o Decrease in 6MWD >15% from Baseline (or 
the subject is too ill to walk, and the cause is 
directly related to the disease under study) at 
2 consecutive visits on different days (except 
at Week 24)  
o Death (all causes) 
 Change in World Health Organization (WHO) 
Functional Class from Baseline to Week 24 
Exploratory Objectives 
To assess the effect of oral treprostinil compared with 
placebo on the following: 
 Change in 6MWD from Baseline to Weeks 6, 12, 
and 18 
 Change in Borg dyspnea score from Baseline to 
Weeks 6, 12, 18, and 24 


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 Change in WHO Functional Class from Baseline to 
Weeks 6, 12, and 18 
 Change in NT-proBNP levels from Baseline to 
Week 12 
 Change in glycated hemoglobin (HbA1c) from 
Baseline to Week 24 
 Change in Kansas City Cardiomyopathy 
Questionnaire (KCCQ) from Baseline to Week 24 
 Optional evaluation of biomarkers (specific targets 
to be determined) from Baseline to Week 24 
 Optional evaluation of pharmacogenomics 
Study Design 
A multicenter, randomized, double-blind, 
placebo-controlled, 24-week, parallel-group study 
Sample Size 
Approximately 310 subjects will be enrolled and randomly 
allocated (1:1) to receive oral treprostinil or placebo, 
stratified by Baseline 6MWD.  Using an allocation ratio of 
1:1 between oral treprostinil and placebo, a sample size of 
263 subjects would provide 90% power at a significance 
level of 0.05 (2-sided hypothesis) to detect a 30-meter 
between-treatment difference in the change from Baseline 
to Week 24 in 6MWD assuming a standard deviation of 
75 meters.  The total sample size will be approximately 
310 subjects to account for a discontinuation rate of 
approximately 15%. 
Summary of Subject 
Eligibility Criteria 
Eligible subjects must be between 18 and 85 years of age  
at the time of signing informed consent, have a primary 
diagnosis of WHO Group 2 PH, and have the following 
documented by right heart catheterization (RHC): a 
pulmonary artery pressure mean (PAPm) of ≥25 mmHg, a 
pulmonary capillary wedge pressure (PCWP) of >15 mmHg 
but ≤30 mmHg, and a pulmonary vascular resistance (PVR) 
of ≥3.0 Wood units (≥240 dynes*s/cm5).  Subjects can also 
qualify if they have a positive fluid challenge during the 
RHC that is used to determine eligibility.  In cases where a 
PCWP is not available or deemed unreliable, a left 
ventricular end-diastolic pressure may be used to determine 
eligibility.  In addition, subjects must have a left ventricular 
ejection fraction by echocardiogram (ECHO) obtained 
during Screening (prior to randomization) of at least 45%.  
Subjects must have pulmonary function tests conducted 
within 6 months of Screening or during the Screening phase 
to confirm that total lung capacity is at least 60% of the 
predicted value, forced expiratory volume at 1 second is at 
least 50% of the predicted value, and diffusing capacity of 


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the lungs for carbon monoxide (DLCO) is at least 40% of 
the predicted value (unadjusted, or adjusted for alveolar 
volume).  The Baseline 6MWD must be at least 150 meters 
and subjects must not have received PAH therapies within 
30 days of randomization.  The only exception to this is that 
subjects can be taking chronic doses of an approved 
phosphodiesterase type 5 inhibitor (PDE5-I) as long as they 
have been on a stable dose for at least 90 days prior to 
randomization and have had an RHC that establishes 
eligibility at least 30 days after being on a stable dose of 
their PDE5-I inhibitor.  If the Investigator does not intend 
to keep a subject on their PDE5-I therapy, it must be 
stopped at least 30 days prior to randomization.  Subjects on 
a chronic medication for heart failure must be on a stable 
dose for ≥30 days prior to randomization.  The exception is 
with changes of anticoagulants and/or diuretics; these 
medications should not be newly started or stopped within 
30 days of randomization and no healthcare provider 
prescribed dose change should occur within 7 days of 
randomization.  Eligible subjects will have a body mass 
index of ≤45 kg/m2. 
Drug Dosage  
and Formulation 
Subjects will receive oral treprostinil sustained-release 
tablets or matching placebo.  Study drug will be provided in 
0.125-, 0.25-, 1-, and 2.5-mg sustained-release tablets to be 
administered 3 times daily (TID).  Following 
randomization, the first dose of study drug (0.125 mg) 
should be taken by the subject within 10 minutes of 
consuming food at the Baseline Visit at the study site.  Oral 
dosing of study drug will then continue at 0.125 mg TID 
(every 6 to 8 hours) with food.  Dose escalation should 
occur no more frequently than every 72 hours 
(9 consecutive doses) using only 0.125-mg increments as 
tolerated.  The initial maximum dose allowed will be 2 mg 
TID.  The maximum dose may be increased to 4 mg and 
then to 6 mg TID, if approved by the independent Data 
Monitoring Committee (DMC).  The DMC will meet after 
approximately 10, 30, 60, 100, and 200 subjects have been 
enrolled in the study, or on an ad hoc basis per request of 
the independent DMC, as necessary.  Enrollment will not 
be stopped during the DMC reviews; however, subjects 
may not progress to the next highest maximum dose level 
until the DMC provides their review of the data.  Any 
decision impacting the maximum dose will be relayed to 
study sites following the DMC meeting.  Note that sudden 
dose escalations or reductions may lead to intolerable 


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adverse events (AEs) or worsening of PH, and gradual dose 
escalations or reductions are recommended to reduce risk to 
subjects.  Placebo will be identical in size, shape, and color 
to the respective oral treprostinil tablets. 
Control Group 
Placebo 
Route of  
Administration 
Oral 
Procedures 
Study Visit Schedule:  Subjects will be assessed during 
Screening (up to 30 days) and Baseline to determine 
eligibility for the study.  Once randomized, subjects will be 
dispensed study drug and will take the initial dose of study 
drug at the study site on the day of randomization.  The 
subject will return to the study site for visits scheduled at 
Weeks 6, 12, 18, and 24, and the Study Drug Termination 
Visit (if applicable).  Subjects that complete the 24-week 
treatment period and remain on study drug for the duration 
will be permitted to enter the open-label extension study.  If 
a subject permanently discontinues study drug prior to 
Week 24, that subject will be asked to complete a Study 
Drug Termination Visit and remain in the study through 
Week 24 and complete study assessments off treatment, but 
will not be permitted to enter the open-label extension 
study. 
 
The following efficacy and safety assessments will occur 
during the course of the study: 
 
Efficacy Assessments: exercise capacity (6MWD and Borg 
dyspnea score) measured within 3 to 6 hours following the 
most recent dose of study drug, clinical worsening, WHO 
Functional Class of PH, NT-proBNP, and KCCQ. 
 
Safety Assessments: medical history, physical examination, 
assessment of heart failure signs and symptoms with vital 
signs, AEs, clinical laboratory parameters, ECHOs, 
pregnancy testing, and electrocardiograms (ECGs). 
Statistical Considerations The primary hypothesis is that oral treprostinil will increase 
the distance traversed in the 6-Minute Walk Test (6MWT) 
at Week 24 over placebo in subjects with PH associated 
with HFpEF.  The effect of oral treprostinil versus placebo 
on change from Baseline to Week 24 in 6MWD will be 
analyzed using an analysis of covariance (ANCOVA) with 
Baseline 6MWD as the covariate. 


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The effect of treatment will be formally tested on the 
following secondary efficacy endpoints: 
 Time to the first clinical worsening event 
 Change in NT-proBNP levels from Baseline to 
Week 24 
 Change in WHO Functional Class from Baseline to 
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. 
 
Exploratory endpoints will be summarized and analyzed to 
assess the treatment effect without adjustment for 
multiplicity. 
Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive 
P.O. Box 14186 
Research Triangle Park, NC 27709 
United States of America 
 
 
 


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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY .................................................................................... 2 
INVESTIGATOR’S AGREEMENT ..................................................................................... 3 
PROTOCOL SYNOPSIS ....................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................ 9 
Table of In-Text Tables ........................................................................................................ 12 
LIST OF ABBREVIATIONS .............................................................................................. 13 
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 .......................................................................................... 18 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN PULMONARY 
HYPERTENSION ASSOCIATED WITH HEART FAILURE WITH 
PRESERVED EJECTION FRACTION .................................................................. 20 
1.4 
CLINICAL HYPOTHESIS ....................................................................................... 23 
2 OBJECTIVES ................................................................................................................. 23 
2.1 
PRIMARY OBJECTIVES ........................................................................................ 23 
2.2 
SECONDARY OBJECTIVES .................................................................................. 23 
2.3 
EXPLORATORY OBJECTIVES ............................................................................ 24 
2.4 
SAFETY ENDPOINTS .............................................................................................. 24 
3 EXPERIMENTAL PLAN .............................................................................................. 24 
3.1 
STUDY DESIGN ........................................................................................................ 24 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ............................................ 27 
3.3 
CLINICAL ASSESSMENTS .................................................................................... 30 
3.3.1 
Efficacy ................................................................................................................... 30 
3.3.1.1 
6-Minute Walk Test ........................................................................................... 30 
3.3.1.2 
Borg Dyspnea Score ........................................................................................... 32 
3.3.1.3 
WHO Functional Class ...................................................................................... 32 
3.3.1.4 
Kansas City Cardiomyopathy Questionnaire ................................................. 32 
3.3.1.5 
Clinical Worsening............................................................................................. 33 
3.3.1.6 
N-Terminal Pro-brain Natriuretic Peptide ..................................................... 33 
3.3.2 
Safety ...................................................................................................................... 34 
3.3.2.1 
Medical History and Physical Examinations ................................................... 34 
3.3.2.2 
Clinical Laboratory Tests.................................................................................. 34 
3.3.2.3 
Adverse Events ................................................................................................... 34 
3.3.2.4 
12-Lead Electrocardiogram .............................................................................. 35 
3.3.2.5 
Echocardiogram ................................................................................................. 35 
3.3.2.6 
Pregnancy Testing .............................................................................................. 36 


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3.3.2.7 
Assessment of Heart Failure Signs and Symptoms with Vital Signs ............ 36 
3.3.3 
Pharmacogenomics ................................................................................................ 37 
3.3.4 
Biomarkers ............................................................................................................. 37 
3.4 
NUMBER OF CENTERS .......................................................................................... 37 
3.5 
NUMBER OF SUBJECTS ........................................................................................ 38 
3.6 
ESTIMATED STUDY DURATION ......................................................................... 38 
4 SUBJECT ELIGIBILITY .............................................................................................. 38 
4.1 
INCLUSION CRITERIA .......................................................................................... 38 
4.2 
EXCLUSION CRITERIA ......................................................................................... 40 
4.3 
PRESCRIBED THERAPY ........................................................................................ 41 
4.3.1 
Concomitant Medications ..................................................................................... 41 
5 SUBJECT ENROLLMENT ........................................................................................... 42 
5.1 
TREATMENT ASSIGNMENT ................................................................................ 42 
5.2 
RANDOMIZATION .................................................................................................. 43 
5.3 
BLINDING .................................................................................................................. 43 
6 DRUGS AND DOSING (OR TREATMENT PROCEDURES) ................................. 43 
6.1 
DRUG DOSAGE, ADMINISTRATION, AND SCHEDULE ................................ 43 
6.1.1 
Dosing of Study Drug in Relation to Meals ......................................................... 47 
6.1.2 
Dosing and Administration of Concomitant Medications ................................. 47 
6.1.3 
Prohibited Medications ......................................................................................... 48 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT ..................................... 48 
6.3 
COMPLIANCE .......................................................................................................... 49 
7 EXPERIMENTAL PROCEDURES ............................................................................. 50 
7.1 
SCREENING PHASE ................................................................................................ 50 
7.2 
BASELINE PHASE AND RANDOMIZATION ..................................................... 51 
7.3 
TREATMENT PHASE .............................................................................................. 52 
7.3.1 
Weeks 6, 12, and 18 Assessments ......................................................................... 52 
7.3.2 
Study Drug Termination Assessments ................................................................. 53 
7.3.3 
Week 24 Assessments ............................................................................................ 54 
8 STUDY TERMINATION ............................................................................................... 55 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ....................................................... 55 
8.2 
CRITERIA FOR TERMINATING THE STUDY .................................................. 55 
8.3 
CRITERIA FOR DISCONTINUING THE STUDY SITE .................................... 55 
9 ADVERSE EVENT REPORTING ................................................................................ 56 
9.1 
DEFINITIONS ........................................................................................................... 56 
9.1.1 
Adverse Event ........................................................................................................ 56 
9.1.2 
Serious Adverse Event .......................................................................................... 57 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ..................................................... 57 
9.3 
PREGNANCY ............................................................................................................ 58 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ....................... 58 


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9.5 
SAFETY REPORTS .................................................................................................. 59 
10 STATISTICAL CONSIDERATIONS .......................................................................... 59 
10.1 DATA PROCESSING ................................................................................................ 59 
10.2 SAMPLE SIZE ........................................................................................................... 60 
10.3 ANALYSIS PLAN ...................................................................................................... 60 
10.3.1 
Primary Efficacy Endpoint ................................................................................... 60 
10.3.2 
Secondary Efficacy Endpoints .............................................................................. 61 
10.3.3 
Exploratory Efficacy Endpoints ........................................................................... 61 
10.3.4 
Efficacy Analyses ................................................................................................... 62 
10.3.4.1 
Time to Clinical Worsening .............................................................................. 62 
10.3.4.2 
N-Terminal Pro-brain Natriuretic Peptide ..................................................... 62 
10.3.4.3 
WHO Functional Class ...................................................................................... 62 
10.3.4.4 
6-Minute Walk Distance .................................................................................... 62 
10.3.4.5 
Borg Dyspnea Score ........................................................................................... 62 
10.3.4.6 
Kansas City Cardiomyopathy Questionnaire ................................................. 62 
10.3.5 
Safety Analyses ...................................................................................................... 63 
10.4 INTERIM ANALYSIS ............................................................................................... 63 
10.5 OTHER ANALYSES ................................................................................................. 64 
10.6 DATA LISTINGS AND SUMMARIES ................................................................... 64 
10.7 DATA MONITORING COMMITTEE ................................................................... 64 
11 PACKAGING AND FORMULATION ........................................................................ 64 
11.1 CONTENTS OF STUDY DRUG .............................................................................. 64 
11.2 LABELING ................................................................................................................. 65 
11.3 STORAGE AND HANDLING OF CLINICAL STUDY MATERIAL ................. 65 
11.4 SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL .......................... 66 
11.5 DRUG ACCOUNTABILITY .................................................................................... 66 
12 REGULATORY AND ETHICAL OBLIGATION ...................................................... 66 
12.1 US FDA OR APPLICABLE REGULATORY REQUIREMENTS ...................... 66 
12.2 INFORMED CONSENT REQUIREMENTS ......................................................... 67 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ....................................................................................................................... 67 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ......................................... 68 
12.5 SUBJECT CONFIDENTIALITY ............................................................................. 68 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 68 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .......................... 68 
13.2 STUDY DOCUMENTATION AND STORAGE .................................................... 69 
13.3 STUDY MONITORING AND DATA COLLECTION .......................................... 69 
14 REFERENCES ................................................................................................................ 70 
15 APPENDICES ................................................................................................................. 73 


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15.1 PROCEDURES FOR 6-MINUTE WALK TEST AND BORG DYSPNEA 
SCALE ......................................................................................................................... 73 
15.2 WHO FUNCTIONAL CLASSIFICATION FOR PULMONARY 
HYPERTENSION ...................................................................................................... 75 
15.3 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE 
EVENTS ...................................................................................................................... 76 
15.4 CLINICAL LABORATORY PARAMETERS ....................................................... 80 
15.5 CHILD-PUGH SCORE ............................................................................................. 81 
15.6 KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE ............................... 82 
15.7 EVALUATION OF SIGNS/SYMPTOMS OF HEART FAILURE AND 
VITAL SIGNS ............................................................................................................ 86 
 
Table of In-Text Tables 
Table 3-1 
Overall Schedule of Time and Events ............................................................. 27 
Table 3-2 
Expected Events Attributable to the Progression of the Disease Under 
Study ............................................................................................................... 35 
Table 6-1 
Anticipated Maximum Dose Ranges Based on DMC Review and 
Approval .......................................................................................................... 44 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
ARB 
Angiotensin-receptor blockers 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BID 
Twice daily 
Cmax 
Maximal drug concentration 
CYP 
Cytochrome P450 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram(s) 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
ERA 
Endothelin receptor antagonist 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume at 1 second 
GCP 
Good Clinical Practices 
GDS 
Global Drug Safety 
GLP 
Good Laboratory Practices 
HbA1c 
Glycated hemoglobin 
HF 
Heart failure 
HFpEF 
Heart failure with preserved ejection fraction 
HFrEF 
Heart failure with reduced ejection fraction 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous(ly) 
IVRS/IWRS 
Interactive voice or web response system 


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Abbreviation 
Definition 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LV 
Left ventricular 
LVEDP 
Left ventricular end-diastolic pressure 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-proBNP 
N-Terminal pro-brain natriuretic peptide 
PAH 
Pulmonary arterial hypertension 
PAPm 
Pulmonary artery pressure mean 
PASP 
Pulmonary artery systolic pressure 
PCWP 
Pulmonary capillary wedge pressure 
PDE5-I 
Phosphodiesterase type 5 inhibitor 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic(s) 
PVR 
Pulmonary vascular resistance 
RHC 
Right heart catheterization 
RV 
Right ventricle 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
SD 
Standard deviation 
SR 
Sustained release 
TID 
3 times daily 
US 
United States 
UT-15C 
Treprostinil diolamine or treprostinil diethanolamine; oral treprostinil 
WHO 
World Health Organization 
WOCBP  
Women of childbearing potential 


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1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
Pulmonary hypertension (PH) is defined as an elevation in pulmonary arterial pressure and 
pulmonary vascular resistance.  The World Health Organization (WHO) classifies PH due to 
left heart disease as WHO Group 2 PH.  This classification includes PH due to left ventricular 
systolic and diastolic dysfunction, valvular heart disease, inflow/outflow tract obstruction, and 
congenital cardiomyopathies (Simonneau 2013).  WHO Group 2 PH accounts for 65% to 80% 
of all PH cases, making it the most common form of PH (Rosenkranz 2016). 
Heart failure with preserved ejection fraction (HFpEF) refers to heart failure with left 
ventricular diastolic dysfunction in the presence of normal systolic function.  Diastolic 
dysfunction occurs due to increased left ventricular (LV) stiffness and impaired relaxation, 
resulting in inadequate LV filling.  In order to achieve adequate filling during diastole, the 
pressure within the left atrium increases.  PH can result from increased pressures in the 
pulmonary circulation as a direct consequence of increased left atrium pressure, often referred 
to as ‘postcapillary’ PH due to left heart disease.  Chronic elevations in left-sided pressures 
can also trigger endothelial dysfunction and subsequent vascular remodeling, similar to WHO 
Group 1 pulmonary arterial hypertension (PAH), which is termed ‘precapillary’ PH (Hussain 
2016).  Increased levels of endothelin and decreased levels of nitric oxide have been found in 
subjects with LV dysfunction, and both can contribute to vascular remodeling by causing 
smooth muscle cell proliferation and hypertrophy (Moraes 2000).  HFpEF subjects often have 
some elements of pre- and postcapillary PH (Hussain 2016). 
Heart failure affects 1% to 2% of the adult population in developed countries, and HFpEF 
represents up to 73% of those cases (Ponikowski 2016).  The incidence of PH has recently 
been reported in up to 80% of HFpEF subjects and is associated with increased morbidity and 
mortality (Guazzi 2015a). 
There are no approved treatments for PH in subjects with left heart disease; however, the 
efficacy of therapies in WHO Group 1 PAH, along with lack of evidence-based therapies 
available for the treatment of HFpEF, have stimulated further investigation in this indication 
(Guazzi 2015b, Hussain 2016, Rosenkranz 2016). 


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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 
prostacyclin. 
The pharmacology of treprostinil has been extensively characterized in well-established 
models, all confirming the suitability of the drug to treat PAH following the subcutaneous 
(SC), intravenous (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-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 prostacyclins in the treatment of PAH.  The mechanism of action is 
therefore likely to be multifactorial. 
Treprostinil diethanolamine (UT-15C sustained release [SR]), hereinafter referred to as oral 
treprostinil, was selected from a series of treprostinil salts based on critical physicochemical 
characteristics (eg, solubility, hygroscopicity, melting point) with a goal of delivering 
treprostinil by the oral route as an 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. 


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Additional nonclinical studies have shown that the observed pharmacological profile of oral 
treprostinil 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 
Oral treprostinil is a novel salt form of Remodulin® (treprostinil) Injection and Tyvaso® 
(treprostinil) Inhalation Solution, which are approved in the United States (US) to treat 
subjects with PAH.  In addition to the nonclinical studies conducted with oral treprostinil, 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 rats and dogs in toxicity studies for up to 6 months, 
which supported the chronic administration of Remodulin to subjects. 
In addition to the extensive toxicology data with treprostinil sodium, the toxicity and 
toxicokinetic profiles of oral treprostinil 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.  
Oral treprostinil has also been evaluated in reproductive developmental toxicity studies in 
pregnant rats and rabbits and in an in vivo rat micronucleus assay. 
Nonclinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeat-dose toxicity, and genotoxicity.  A comprehensive description of oral 
treprostinil, including the pharmacology, toxicology, and clinical studies completed to date, 
may be found in the current Investigator’s Brochure. 
Segment I, II, and III studies have been completed in rats, and a Segment II study has been 
completed in rabbits.  No adverse effects for fetal viability/growth and fetal development 
(teratogenicity) were seen in rats at or below 20 mg/kg/day or in rabbits at or below 
0.5 mg/kg/day.  At high doses, teratogenic effects of oral treprostinil were observed in rabbits.  


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Findings included increased fetal incidence of external, soft tissue, and skeletal 
malformations.  Initial parent generation female rats receiving 10 mg/kg/day had decreased 
food consumption and body weights during gestation, increased duration of gestation, slight 
decreases in the viability and number of pups per litter, and pups with decreased mean 
neonatal body weights. 
A 6-month carcinogenicity study in mice with oral treprostinil administered at daily oral doses 
of 3, 7.5, and 15 mg/kg in females and 5, 10, and 20 mg/kg in males for 26 weeks did not 
demonstrate increases in the incidence of neoplastic lesions.  A 2-year rat carcinogenicity 
study demonstrated that daily administration of oral treprostinil does not have carcinogenic 
potential. 
A Good Laboratory Practices (GLP) cardiovascular safety pharmacology study to evaluate 
diethanolamine effects, independent of treprostinil, on cardiovascular function in telemetered 
dogs was conducted.  Data support that oral administration of diethanolamine at doses up to 
2 mg/kg/dose twice daily (4 mg/kg/day) to male beagle dogs was not associated with any 
definitive changes in arterial pressure, heart rate, or electrocardiogram (ECG) 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 
The most frequent adverse events (AEs) associated with Remodulin in clinical studies of 
subjects with PAH were related to the pharmacological properties of Remodulin and were 
generally not serious.  These prostacyclin-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 durations of exposure and a larger, more diverse subject population, was 
consistent with the profile noted in the controlled studies.  To date, over 17,000 subjects have 
been exposed to Remodulin.  This number includes subjects who have received single 
administration to subjects receiving continuous infusion for greater than 15 years. 


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Oral treprostinil has been administered to approximately 2100 subjects in Phase 1 to 3 clinical 
studies.  Oral treprostinil doses of up to 3 mg twice daily (BID) have been administered to 
healthy volunteers, and subjects with PAH have received up to 27.5 mg 3 times daily (TID) in 
the ongoing Phase 2 to 3 development program.  The average exposure is approximately 
2 years; the longest exposure is approximately 8 years. 
The absolute bioavailability of the oral treprostinil 1-mg tablet is 17.6%.  Following 
administration, treprostinil diethanolamine is widely distributed.  Treprostinil is 
approximately 96% protein bound, with no effect on warfarin or digoxin displacement.  
Pharmacokinetic (PK) data (area under the plasma concentration-time curve [AUC]) indicate 
that Day 1 PK 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 fat, high 
calorie meal, has been observed to increase absorption and prolong the systemic exposure to 
treprostinil, contributing to the desired PK 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 oral treprostinil indicate that CYP 2C8 appears to be of 
major importance and CYP 2C9 of minor importance to in vivo metabolism of oral 
treprostinil in humans. 
To date, the majority of oral treprostinil studies have been conducted with BID dosing.  In an 
attempt to understand the PK 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. 
Nineteen subjects (10 females and 9 males) with a mean age of 35.2 years (range: 20 to 
54 years) were enrolled.  On Day 1 the mean maximal drug concentration (Cmax) (±standard 
deviation [SD]) of treprostinil was 0.574±0.22 ng/mL, which occurred at a median time of 
4 hours (range: 2 to 6 hours).  In comparison, the Day 8 mean Cmax (±SD) was 
0.615±0.32 ng/mL and occurred at a median time of 4 hours (range: 1 to 6 hours). 
On Day 7, the mean Cmax (±SD) was 0.810±0.491 ng/mL and occurred at a median time of 
14 hours (range: 6 to 20 hours) following the morning dose.  This indicated that maximum 
concentration during a daily interval at steady state occurs after the evening (or third) dose of 


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the day.  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. 
Sixteen AEs occurred in 7 subjects and primarily included known prostacyclin class-effect 
related AEs (eg, headache, diarrhea, and jaw pain). 
A comprehensive description of oral treprostinil, including the pharmacology, toxicology, and 
clinical studies completed to date can be found in the current Investigator’s Brochure. 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN PULMONARY 
HYPERTENSION ASSOCIATED WITH HEART FAILURE WITH 
PRESERVED EJECTION FRACTION 
Oral treprostinil has shown clinical improvements in exercise capacity after 12 weeks of 
therapy in subjects with WHO Group 1 PH (Jing 2013).  It has been hypothesized that the 
vasodilatory effects of prostanoids may also benefit WHO Group 2 PH subjects because of 
the precapillary component of PH due to left heart disease, which has been demonstrated in 
clinical studies (Hussain 2016).  A study with 44 subjects with PH associated with HFpEF 
given sildenafil or placebo for 12 months found an increase in pulmonary arteriolar resistance 
(+0.69 Wood units, p<0.01) with stable pulmonary capillary wedge pressure (PCWP) in the 
placebo group, suggesting that changes in pulmonary pressure are also due to vascular 
dysfunction and not solely the transmission of backward pressures caused by LV diastolic 
dysfunction (Guazzi 2011).  Another study followed 244 HFpEF subjects over 3 years to 
assess the severity of PH in HFpEF subjects versus hypertension subjects without heart 
failure.  The study found increases in pulmonary artery systolic pressure (PASP) and PCWP 
in both the HFpEF and control groups (p<0.007 for both); however, after adjusting for PCWP, 
PASP was still higher in the HFpEF group compared with control (p<0.001), suggestive of a 
precapillary component of PH in these subjects (Lam 2009). 
There are limited data on the use of prostacyclin therapy in subjects with WHO Group 2 PH.  
An open-label pilot study with 33 subjects with heart failure with reduced ejection fraction 
(HFrEF; left ventricular ejection fraction [LVEF] ≤30%) found that epoprostenol plus 


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conventional therapy resulted in improvements in 6-Minute Walk Distance (6MWD) after 
12 weeks when compared with conventional therapy alone (+72 meters in epoprostenol 
versus -39 meters in the control, p=0.033) (Sueta 1995).  However, the larger scale mortality 
study (the FIRST study) was terminated early due to a trend toward increased mortality in 
subjects treated with epoprostenol.  It is important to note that subjects enrolled in this study 
were New York Heart Association Class IIIB to IV and severely symptomatic at maximum 
dosages of conventional heart failure therapies.  Additionally, subjects in the epoprostenol 
group had a higher baseline PCWP compared with the control group, thus it is unknown if the 
mortality trend was a result of the study drug itself or due to increased severity and 
progression of heart disease.  Despite the mortality trend, epoprostenol did produce a 
significant decrease in pulmonary artery pressure mean (PAPm), PCWP, and pulmonary 
vascular resistance (PVR) (p<0.01) (Califf 1997).  The results of other small studies in HFrEF 
subjects have been positive.  A small observational study with 45 subjects with HFrEF 
(LVEF ≤35%) and PH showed improvements in PAPm (57.7 to 40.8 mmHg; p<0.001) and a 
trend towards increased survival (72.7% with prostaglandin E1 versus 56% in the control) 
after 36 months of intermittent infusions with prostaglandin E1 compared with conventional 
heart failure therapy (Serra 2011).  When considering HFpEF subjects specifically, 1 
prospective case study in HFpEF (LVEF >50%) subjects with PH showed a reduction in 
PAPm after both the first (-7.0 mmHg; p=0.005) and second doses (-4.7 mmHg; p=0.021) of 
inhaled iloprost (Grossman 2015). 
There has also been positive data for the use of other vasodilators in WHO Group 2 PH 
subjects.  A randomized, placebo-controlled study with sildenafil (a phosphodiesterase type 5 
inhibitor) in HFpEF subjects (LVEF ≥50%) showed improvements in PAPm (20.8 mmHg in 
sildenafil versus 39.6 mmHg in placebo, p<0.01), PCWP (17.8 versus 22.2 mmHg, 
respectively; p<0.01), and quality of life after 12 months (Guazzi 2011).  Sildenafil has also 
shown benefit in HFrEF (LVEF <40%) subjects.  In another randomized, placebo-controlled 
study, treatment with sildenafil for 12 weeks resulted in improvements in exercise capacity 
(change in 6MWD 29 meters greater in sildenafil group; p=0.047) and quality of life (Lewis 
2007).  A meta-analysis including studies with HFrEF subjects found that sildenafil reduced 


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PAPm (p<0.05) and PVR (p<0.00001), increased exercise capacity measured as peak 
maximal oxygen consumption (p<0.00001), and improved quality of life (Wu 2014). 
The guanylate cyclase stimulator, riociguat, has also been shown to be well tolerated in WHO 
Group 2 PH subjects and improves some hemodynamic measurements; however, riociguat 
has not shown reductions in PAPm.  A randomized, double-blind, placebo-controlled study in 
HFrEF (LVEF ≤40%) subjects showed improvements in cardiac index (+0.4 L/min/m2, 
p=0.0001), stroke volume index (+5.2 mL/m2; p=0.0018), quality of life (p=0.0002), and 
reductions in PVR (p=0.03) with riociguat (Bonderman 2013).  Similarly, riociguat was well 
tolerated and increased stroke volume (+9 mL, p=0.04) in HFpEF subjects (LVEF >50%) 
when compared with placebo (Bonderman 2014). 
When considering endothelin receptor antagonists (ERAs), studies with bosentan have failed 
to show benefit in subjects with HFrEF (Packer 2005, Kalra 2002, Kaluski 2008).  Studies are 
ongoing to investigate the potential benefit of macitentan and bosentan in HFpEF subjects 
(NCT02070991 and NCT00820352, respectively).  These studies hypothesize that ERAs will 
improve exercise tolerance, hemodynamics, and quality of life. 
While there are positive data for vasodilators in subjects with HFrEF associated with PH, 
1 potential risk of this treatment is pulmonary edema.  This has been established in 2 studies 
with HFrEF subjects where the decreased afterload on the right ventricle (RV) and 
corresponding increase in RV output with inhaled nitric oxide resulted in increased LV filling 
pressures, PCWP, and subsequent pulmonary edema (Loh 1994, Bocchi 1994).  It is possible 
that pulmonary vasodilation in combination with the impaired ability of HFrEF subjects to 
unload the LV may have played a role in the mortality trend in the FIRST study (Califf 1997).  
Aside from 1 reported subject case (Boilson 2010), PH studies with vasodilators have not 
observed pulmonary edema in HFpEF subjects (Bonderman 2014).  Unlike HFrEF subjects, 
HFpEF subjects have preserved systolic function and the ability to increase cardiac output in 
response to increases in blood volume.  This pathophysiologic response, along with recent 
data, suggest that treprostinil can be safely administered in subjects with WHO Group 2 
HFpEF. 


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Additionally, HFrEF has been extensively studied and the treatment guidelines are well 
established given the availability of multiple therapies with proven survival benefit.  
Conversely, no therapies have shown a reduction in mortality in HFpEF subjects, and very 
few have shown clinical improvement.  Given that the prevalence of HFpEF is increasing and 
its outcome is similar to that of HFrEF, new therapies are needed to treat this disease 
(Ponikowski 2016).  Studies have established a precapillary component of PH associated with 
HFpEF; thus, modulation of endothelial dysfunction via the prostacyclin pathway represents a 
therapeutic target with potential clinical benefit (Guazzi 2011, Lam 2009). 
1.4 
CLINICAL HYPOTHESIS 
This study hypothesizes that oral treprostinil will improve exercise capacity after 24 weeks of 
therapy as compared with placebo when administered to subjects with PH associated with 
HFpEF. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective of this study is to assess the effect of oral treprostinil compared with 
placebo on change in exercise capacity as measured by change in 6MWD from Baseline to 
Week 24 in subjects with PH associated with HFpEF. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are to assess the effect of oral treprostinil compared 
with placebo on the following: 
 Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels from Baseline 
to Week 24 
 Time to the first clinical worsening event where clinical worsening is defined by at 
least 1 of the following: 
 Hospitalization due to a cardiopulmonary indication (a non-elective hospitalization 
lasting at least 24 hours in duration caused by clinical conditions directly related to 
PH and/or heart failure) 
 Outpatient administration of IV diuretics 
 Decrease in 6MWD >15% from Baseline (or the subject is too ill to walk, and the 
cause is directly related to the disease under study) at 2 consecutive visits on 
different days (except at Week 24) 


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 Death (all causes) 
 Change in WHO Functional Class from Baseline to Week 24 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are to assess the effect of oral treprostinil compared 
with placebo on the following: 
 Change in 6MWD from Baseline to Weeks 6, 12, and 18 
 Change in Borg dyspnea score from Baseline to Weeks 6, 12, 18, and 24 
 Change in NT-proBNP levels from Baseline to Week 12 
 Change in glycated hemoglobin (HbA1c) from Baseline to Week 24 
 Change in WHO Functional Class from Baseline to Weeks 6, 12, and 18 
 Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) from Baseline to 
Week 24 
 Optional evaluation of biomarkers (specific targets to be determined) from Baseline to 
Week 24 
 Optional evaluation of pharmacogenomics 
2.4 
SAFETY ENDPOINTS 
To evaluate the effect of oral treprostinil on the following parameters: 
 AEs 
 Clinical laboratory parameters 
 Physical examinations 
 Assessment of heart failure signs and symptoms with vital signs 
 ECGs 
 Echocardiograms (ECHOs) 
 Hospitalizations due to cardiopulmonary indication  
 Worsening heart failure as demonstrated by outpatient administration of IV diuretics 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled study in subjects with 
WHO Group 2 PH associated with HFpEF.  Subjects will be assessed during Screening to 
determine eligibility for the study.  Confirmation of eligibility criteria in Section 4 will be 


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confirmed during the Baseline Visit prior to randomization.  Once randomized, subjects will 
be dispensed study drug and will take the initial dose of study drug at the study site on the day 
of randomization.  The subject will return to the study site for visits scheduled at Weeks 6, 12, 
18, and 24, and the Study Drug Termination Visit (if applicable; see Table 3-1).  If a subject 
completes the 24-week treatment period on study drug, they will be permitted to enter the 
open-label extension study (Study TDE-HF-302).  If a subject prematurely discontinues the 
study for any reason, has the study blind broken, or permanently discontinues study drug, they 
will not be permitted to enter the open-label extension study. 
At each scheduled visit after randomization, subjects will undergo the following efficacy 
assessments: exercise capacity as measured by the 6-Minute Walk Test (6MWT) and Borg 
dyspnea score, clinical worsening, and WHO Functional Class.  At every scheduled protocol 
visit following randomization, measurement of exercise capacity via the 6MWT will occur 3 
to 6 hours after the most recent dose of study drug.  This 3 to 6 hour time window does not 
apply to subjects who have permanently discontinued study drug and have remained in the 
study, or those that are currently on a prescribed zero dose from the Investigator.  Serum 
samples will also be collected for measurement of NT-proBNP at Baseline, Week 12, and 
Week 24, and the Study Drug Termination Visit (if applicable).  The KCCQ will be collected 
at Baseline and Week 24, and the Study Drug Termination Visit (if applicable).  See Table 
3-1 for the overall schedule of time and events. 
Safety will be assessed by vital signs, physical examination, assessment of heart failure signs 
and symptoms, pregnancy testing, AEs, and clinical laboratory parameters.  Subjects will 
undergo a 12-lead ECG at Baseline and Week 24, and the Study Drug Termination Visit (if 
applicable); and an ECHO during Screening (prior to randomization) and Week 24, and the 
Study Drug Termination Visit (if applicable). 
Subjects on a chronic medication for heart failure (eg, angiotensin-converting enzyme [ACE] 
inhibitors, angiotensin-receptor blockers [ARBs], and beta blockers) must be on a stable dose 
for ≥30 days prior to randomization.  The exception is with changes of anticoagulants and/or 
diuretics; these medications should not be newly started or stopped within 30 days of 
randomization and no healthcare provider prescribed dose change should occur within 7 days 


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of randomization, with the exception of the withholding of doses of anticoagulants for the 
conduct of the right heart catheterization (RHC) when required. 
Subjects will receive their first dose of study drug (0.125 mg) at the study site on the day of 
randomization.  Dosing of study drug will be continued at 0.125 mg TID (every 6 to 8 hours) 
with food, up to an initial maximum dose of 2 mg TID.  Based on the approval by the 
independent Data Monitoring Committee (DMC), the dose will be slowly titrated throughout 
the study up to a maximum of 4 mg and then 6 mg TID, as safety data permit, in an effort to 
reach a tolerated dose that provides clinical benefit. 


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3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
Table 3-1 
Overall Schedule of Time and Events 
Study Procedures 
Screening 
Phasea 
Baselinea 
Combined 
Screening and 
Baseline Visita 
Treatment Phase 
Study Week 
 
 
 
Week 6b 
Week 12b Week 18b 
Study Drug 
Termination (if 
applicable) 
Week 24b 
Study day 
-30 to -1 
1 
1 
43 
85 
127 
 
169 
Informed consent 
X 
 
X 
 
 
 
 
 
Subject eligibilityc 
X 
X 
X 
 
 
 
 
 
Medical history with PH history, HF 
history, and demographics 
X 
 
X 
 
 
 
 
 
KCCQ 
 
X 
X 
 
 
 
X 
X 
Physical examination 
X 
 
X 
 
 
 
X 
X 
Assessment of heart failure signs and 
symptoms with vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
X 
X 
 
 
 
X 
X 
ECHOe 
X--- 
---X 
X 
 
 
 
X 
X 
WHO Functional Class 
 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory assessments 
X 
X 
X 
 
X 
 
X 
X 
NT-proBNPf 
 
X 
X 
 
X 
 
X 
X 
HbA1c 
 
X 
X 
 
 
 
X 
X 
Urine pregnancy testg 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-Baseline Review Form 
X 
 
X 
 
 
 
 
 
6MWT and Borg dyspnea scoreh 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
X 
 
 
 
 
 
Dosing instructions/ 
dosing/accountability 
 
Xl 
Xl 
X 
X 
X 
X 
X 


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Study Procedures 
Screening 
Phasea 
Baselinea 
Combined 
Screening and 
Baseline Visita 
Treatment Phase 
Study Week 
 
 
 
Week 6b 
Week 12b Week 18b 
Study Drug 
Termination (if 
applicable) 
Week 24b 
Weekly telephone/email contacti 
 
X-- 
X-- 
--X-- 
--X-- 
--X-- 
--X 
--X 
Adverse eventsj 
X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X 
--X 
Concomitant medications  
X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X 
--X 
Assessment of clinical worseningk 
 
X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X 
--X 
Survival status 
 
 
 
 
 
 
Xm 
Xm 
Blood sample for biomarker 
evaluation (Optional)n 
 
X 
X 
 
 
 
Xp 
Xp 
Urine sample for biomarker 
evaluation (Optional)n 
 
X 
X 
 
 
 
Xp 
Xp 
Pharmacogenomic Sample 
(Optional)o 
 
X 
X 
 
 
 
Xp 
Xp 
Abbreviations: 6MWD, 6-Minute Walk Distance; 6MWT, 6-Minute Walk Test; AE, adverse event; ECG, electrocardiogram; ECHO, echocardiogram; eCRF, electronic 
case report form; HF, heart failure; IV, intravenous(ly); KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro-brain natriuretic peptide; PH, 
pulmonary hypertension; SAE, serious adverse event; TID, 3 times daily; WHO, World Health Organization 
a Screening Visit assessments can occur up to 30 days prior to randomization and after informed consent has been obtained.  Baseline assessments can occur up to 
48 hours prior to the first dose of study drug to allow for scheduling of all activities; however, the Baseline 6MWT must be performed prior to, but on the same day as, 
the first dose of study drug.  Screening and Baseline assessments may be combined if all entry criteria are satisfied within 48 hours prior to the first dose of study drug.   
b The visit window is ±5 days from the projected visit date. 
c For the Screening and Baseline visits, the subject must be evaluated for and meet all inclusion criteria and not meet any exclusion criteria. 
d Refer to Appendix 15.7 for the assessments of heart failure signs and symptoms to be completed.  Vital signs must be collected after 5 minutes of rest (seated); no other 
measurements or procedures should be performed during this 5-minute period.  When possible, vital signs should be collected prior to the 6MWT.  If vital signs cannot 
be obtained prior to the 6MWT, then they should be obtained after a minimum 30-minute recovery from the 6MWT. 
e ECHO must be completed during Screening (prior to randomization) and assessed locally for LVEF.  It should also be conducted in accordance with the manual 
provided by the ECHO core lab and uploaded to the central imaging center. 
f Blood for NT-proBNP assessments must be drawn prior to conducting the 6MWT and will occur prior to the first dose of study drug at Baseline (or as part of the 
Baseline Visit assessment if the Screening and Baseline visits are combined). 
g For females of childbearing potential.  Urine pregnancy test at Screening and Baseline to be completed prior to randomization. 
h If the subject has not previously undergone a 6MWT at the study site on the study-designated course, a practice test must be conducted at the Screening Visit and must 
precede the Baseline 6MWT by at least 1 day.  The Baseline 6MWT must be performed on the same day as and precede the first dose of study drug.  All 6MWTs 


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following randomization must be conducted 3 to 6 hours after the most recent dose of study drug.  Prior to the start of each 6MWT, the subject should rest (seated) for 
at least 10 minutes.  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.  The supplemental oxygen flow rate must be recorded at each study visit, as applicable.  The Borg dyspnea score should be conducted 
immediately following the 6MWT. 
i At least weekly telephone contact is required throughout the study to monitor study drug compliance, AEs, use of concomitant medications, occurrence of clinical 
worsening, signs and symptoms of disease, and to make decisions regarding dose titration (may be replaced by a face-to-face interaction on the weeks where study 
visits occur and the information can be obtained during the visit).  Subjects may be contacted via email in lieu of a telephone call.  A copy of the emails and/or 
telephone contact sheets must be documented in the subject’s source documentation.  Email should not replace direct follow-up by phone or at the study site for 
clinically significant AEs or other emergent issues. 
j  All AEs will be documented from the time of informed consent until the time screen failure is documented, or until the subject is either discontinued from the study or 
all Week 24 study assessments have been completed, and 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 at least 30 days if the AE extends beyond the final study visit. 
k Clinical worsening will be assessed continuously from randomization to Week 24 or Study Drug Termination until any of the following criteria are met: hospitalization 
due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to PH and/or heart 
failure), administration of outpatient IV diuretics, decrease in 6MWD >15% from Baseline (or the subject is too ill to walk, and the cause is directly related to the 
disease under study) at 2 consecutive visits on different days (except Week 24), or death (all causes).  Assessment for clinical worsening should continue for 7 days 
after the final dose of study drug if a subject permanently discontinues study drug during the treatment phase.   
l Once all entry criteria have been met and all Baseline assessments completed, the first dose of study drug (0.125 mg) will be administered at the study site.  Study drug 
dosing will continue at 0.125 mg TID (every 6 to 8 hours) with food, up to an initial maximum dose of 2 mg TID. 
m Subjects who discontinue the study and do not enter Study TDE-HF-302 will be contacted approximately 30 days (±5 days) after study drug discontinuation to confirm 
their survival status. 
n For subjects consenting to the optional biomarker samples. 
o For subjects consenting to the optional pharmacogenomic samples. 
p Subjects who consent to the optional pharmacogenomic and/or biomarker samples and discontinue study drug prior to Week 24 should provide samples at the 
Study Drug Termination Visit and the Week 24 Visit. 
 


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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
3.3.1.1 
6-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 described in Appendix 15.1 (ATS 
2002, Holland 2014).  Prior to the start of each 6MWT, the subject should rest (seated) for at 
least 10 minutes.  The 6MWT instructions provided in Appendix 15.1 apply to the practice 
walk (if applicable), the walks conducted at Baseline, Weeks 6, 12, 18, and 24, and any repeat 
6MWT done for the purpose of this study. 
3.3.1.1.1 
Practice 6-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 
on the study-designated course, a practice 6MWT must be conducted at the Screening Visit 
and must precede the Baseline 6MWT by at least 1 day for applicable subjects. 
3.3.1.1.2 
Baseline 6-Minute Walk Test 
A Baseline 6MWT must be performed prior to initiation of study drug and should be 
conducted no more than 48 hours prior to randomization.  After the Baseline 6MWT has been 
conducted and the subject is ready for randomization, the study site will enter the subject’s 
6MWD into an interactive voice or web response system (IVRS/IWRS).  The IVRS/IWRS 
will confirm to study site personnel the subject’s eligibility to participate in the study based on 
6MWD, and if the subject is eligible, randomize them into a treatment group and allocate 
appropriate study drug. 
The Baseline 6MWT must be conducted free of any unusual or extenuating circumstances 
(eg, intercurrent illness other than that under study, ankle or knee sprains, unusual pain 
affecting the lower limbs, respiratory infection, etc).  If there is any unusual or extenuating 
circumstance at Baseline, the visit should be postponed to allow adequate time for the 
recovery of the subject.  If the 30-day Screening phase is exceeded by allowing the subject to 


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recover, the subject can be re-screened at a later time when the unusual or extenuating 
circumstance is adequately resolved so as to not impact the results of the Baseline 6MWT. 
NOTE:  The Baseline 6MWT (not the practice 6MWT) will determine the subject’s eligibility 
to participate in the study. 
3.3.1.1.3 
Treatment 6-Minute Walk Tests 
The 6MWTs will be conducted at Weeks 6, 12, 18, and 24, and the Study Drug Termination 
Visit (if applicable).  The 6MWT should be conducted 3 to 6 hours following the most recent 
dose of study drug.  This 3 to 6 hour time window does not apply to subjects who have 
permanently discontinued study drug and have remained in the study, or those that are 
currently on a prescribed zero dose from the Investigator.  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 electronic Case Report Form (eCRF).  In addition, 
subjects receiving pulmonary or cardiac rehabilitation prior to study entry should continue on 
the same schedule up to and including Week 24.  Pulmonary or cardiac rehabilitation may not 
be added to, or discontinued from, a subject’s regimen between 4 weeks before randomization 
and Week 24.  Subjects utilizing a walker or cane for stability must also use a walker or cane 
at every 6MWT during the study.  Additional 6MWTs may be conducted as appropriate 
throughout the course of the study for the purposes of evaluating the clinical worsening status. 
Each 6MWT conducted after randomization should be documented and compared with the 
subject’s Baseline 6MWD.  If a subject has a decrease of more than 15% in 6MWD compared 
with Baseline (or the subject is too ill to walk, and the cause is directly related to the disease 
under study), a second confirmatory 6MWT should be performed on a different day to assess 
for clinical worsening.  Note that the first 6MWT distance should be counted as the one 
determining the clinical worsening event, rather than the confirmatory 6MWT.  Confirmatory 
6MWTs are required for every visit except the Week 24 Visit where a decrease of more than 
15% (or the subject is too ill to walk, and the cause is directly related to the disease under 
study) in 6MWD would be considered a clinical worsening event.  Confirmatory 6MWTs 
must be consecutive and should be conducted within 30 days of the initial qualifying decrease 


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in 6MWD; however, confirmatory 6MWTs occurring outside of this window will still be 
considered to have met the definition of clinical worsening.  If the second consecutive 6MWT 
also shows more than a 15% decrease in 6MWD as compared with Baseline (or the subject is 
too ill to walk, and the cause is directly related to the disease under study), the subject will 
meet the definition of clinical worsening.  The subject will remain in the study and continue 
dosing with study drug until the Week 24 Visit, even if clinical worsening has been met.  
Details regarding the conduct of the 6MWT are described in Appendix 15.1. 
3.3.1.2 
Borg Dyspnea Score 
The Borg dyspnea score will be assessed immediately following each 6MWT.  The Borg 
dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the 
6MWT (Appendix 15.1).  Scores range from 0 (for the best condition) to 10 (for the worst 
condition). 
3.3.1.3 
WHO Functional Class 
The subject’s WHO Functional Class (Appendix 15.2) will be assessed at Baseline prior to 
starting study drug and at Weeks 6, 12, 18, and 24, and the Study Drug Termination Visit (if 
applicable). 
3.3.1.4 
Kansas City Cardiomyopathy Questionnaire 
The KCCQ is a 23-question, self-administered, health-related quality of life survey validated 
for heart failure that assesses physical function, symptoms (frequency, severity, and recent 
change), social function, self-efficacy and knowledge, and quality of life.  Responses are 
arrayed on an adjectival (Likert) scale with clinically meaningful graduations between 
categories.  It is scored by assigning each response an ordinal value, beginning with 1 for the 
response that implies the lowest level of functioning, and summing items within each domain 
(Green 2000).  This assessment will be conducted at Baseline (prior to starting study drug) 
and Week 24, and the Study Drug Termination Visit (if applicable).  The KCCQ 
questionnaire is available for this study in English (US and Canada), French (Canada), and 
Spanish (US and Mexico).  Subjects whose primary language is not English, Canadian 
French, or Spanish should not complete the KCCQ.  Additional detail is provided in Section 
10.3.4.6, and an example of the KCCQ is provided in Appendix 15.6. 


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3.3.1.5 
Clinical Worsening 
Clinical worsening will be assessed continuously from randomization until Week 24, or the 
Study Drug Termination Visit (if applicable).  Assessment for clinical worsening should 
continue for 7 days after the final dose of study drug if a subject permanently discontinues 
study drug during the Treatment Phase.  A subject may experience multiple clinical 
worsening events based on the 4 categories below.  The first occurrence within each category 
will be recorded in the eCRF if multiple events are experienced by a subject (eg, if a subject 
receives outpatient IV diuretics on 4 different occasions throughout the study, only the first 
occurrence should be recorded in the eCRF.  If the subject is hospitalized due to a 
cardiopulmonary indication, that would also be recorded as a clinical worsening event).  All 
clinical worsening events will be reviewed by the Sponsor’s Medical Monitors as part of their 
review of clinical data sets.  Clinical worsening is defined as the occurrence of any of the 
following: 
 Hospitalization due to a cardiopulmonary indication (a non-elective hospitalization 
lasting at least 24 hours in duration caused by clinical conditions directly related to PH 
and/or heart failure) 
 Outpatient administration of IV diuretics 
 Decrease in 6MWD >15% from Baseline (or the subject is too ill to walk, and the 
cause is directly related to the disease under study) at 2 consecutive visits on different 
days.  Confirmatory 6MWTs are required for every visit except the Week 24 Visit 
where a decrease of more than 15% (or the subject is too ill to walk and the cause is 
directly related to the disease under study) in 6MWD would be considered a clinical 
worsening event. 
 Death (all causes) 
3.3.1.6 
N-Terminal Pro-brain Natriuretic Peptide 
NT-proBNP concentration is a useful biomarker 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, and Week 24, and the Study Drug 
Termination Visit (if applicable). 


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3.3.2 
Safety 
3.3.2.1 
Medical History and Physical Examinations 
A complete medical history, demographics, PH history, and physical examination will be 
conducted during the Screening phase.  Clinically significant past or present illnesses, current 
prescription and nonprescription medications (including vitamins and herbal products), and a 
history of allergies or idiosyncratic responses to drugs should be noted in the eCRF, as 
required.  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 also be conducted at Week 24, and the Study Drug 
Termination Visit (if applicable). 
3.3.2.2 
Clinical Laboratory Tests 
A central clinical laboratory will be used to standardize test results.  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 
combined screening and baseline procedures are completed and all eligibility criteria are 
confirmed within 48 hours prior to randomization.  Central laboratory data are ultimately used 
to qualify subjects for the study.  For subjects who are well known to the Investigator and 
who are clinically stable, the Investigator may choose not to delay randomization at a 
combined Screening/Baseline Visit and may utilize local laboratory values to confirm 
eligibility while waiting for central laboratory confirmation.  Clinical laboratory assessments 
will also be assessed at Weeks 12 and 24, and the Study Drug Termination Visit (if 
applicable).  Clinical laboratory assessments and a Visit Test Schedule are displayed in 
Appendix 15.4. 
3.3.2.3 
Adverse Events 
The AEs will be captured from the time the Informed Consent Form (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 at least 30 days if 
the AE extends beyond the final study visit.  All serious adverse events (SAEs) should be 
followed until resolution, death, or the subject is lost to follow-up, even if they are ongoing 


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more than 30 days after completion of the final study visit.  Sections 9.1.1 and 9.1.2 and 
Appendix 15.3 provide the guidelines and definitions for recording AEs and SAEs. 
Events attributable to the progression of the disease under study should only be recorded as an 
AE or SAE if the event is unusual with respect to intensity, frequency, duration as compared 
with symptoms in the subject’s medical history, or if there is a reasonable possibility that the 
event was caused by the study drug (Table 3-2). 
Table 3-2 
Expected Events Attributable to the Progression of the Disease Under 
Study 
Abdominal pain 
Palpitations 
Anorexia  
Paroxysmal nocturnal dyspnea 
Chest pain 
Peripheral edema/generalized edema 
Dizziness 
Presyncope 
Dyspnea/dyspnea on exertion 
Pulmonary hypertension, exacerbation of 
Exercise tolerance decreased  
Left heart failure/left ventricular failure 
Fatigue 
Right heart failure/right ventricular failure 
Hypoxia 
Sudden death 
Lethargy 
Syncope 
Loss of consciousness 
Weight loss 
Orthopnea 
Weight gain 
Note: Symptoms of right ventricular failure/right heart failure can include, but are not limited to, ascites, cyanosis, 
tachycardia, and other cardiac arrhythmias.  The effects of pulmonary hypertension and right ventricular 
failure/right heart failure can include cardiac arrest and death. 
3.3.2.4 
12-Lead Electrocardiogram 
Twelve-lead ECGs will be recorded after at least 5 minutes rest in the semi-recumbent 
position at Baseline and Week 24, and the Study Drug Termination Visit (if applicable).  
Recordings should include Lead II as a rhythm strip and contain at least 5 QRS complexes.  
The ECG parameters collected include heart rate, PR interval, QT interval, QRS duration, and 
any clinically significant abnormalities. 
3.3.2.5 
Echocardiogram 
Two-dimensional transthoracic ECHO examinations will be performed during Screening 
(prior to randomization) and Week 24, and the Study Drug Termination Visit (if applicable).  
The ECHO results will be uploaded and stored in a central repository.  The ECHO 
examination performed prior to randomization will be assessed locally to ensure inclusion 


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criterion 4 is met.  All ECHO examinations will be conducted in accordance with the manual 
provided by the ECHO core lab facility and uploaded to the central imaging center.  The 
following echocardiographic parameters will be measured: 
 RV fractional area change 
 Tricuspid annular plane systolic excursion 
 The maximal tricuspid regurgitant jet velocity 
 Right atrial area 
 Right atrial pressure (estimated by inferior vena cava) 
 LV ejection fraction 
 Left atrial volume index 
 Mitral E velocity 
 Mitral A velocity 
 Mitral septal e’ velocity 
 Mitral lateral e’ velocity 
Additional exploratory parameters may be assessed. 
3.3.2.6 
Pregnancy Testing 
All women of childbearing potential (WOCBP) will undergo a urine pregnancy test at 
Screening and Baseline prior to randomization, and at Weeks 6, 12, 18, and 24, and the Study 
Drug Termination Visit (if applicable).  A positive pregnancy test will exclude the subject 
from further participation in the study.  Subjects who become pregnant during the study are to 
be discontinued from the study. 
3.3.2.7 
Assessment of Heart Failure Signs and Symptoms with Vital Signs 
Signs and symptoms of heart failure (Appendix 15.7) will be assessed at Screening, Baseline 
(prior to starting study drug), and during the Treatment Phase at Weeks 6, 12, 18, and 24, and 
the Study Drug Termination Visit (if applicable).  Data from the review of the heart failure 
signs and symptoms will not be included in the eCRF; however, if there are clinically 
significant changes in the opinion of the Investigator relative to Baseline, they should be 
recorded as AEs.  When possible, vital signs should be collected prior to the 6MWT.  If vital 
signs cannot be obtained prior to the 6MWT, then they should be obtained after a minimum 
30-minute recovery from the 6MWT.  Vital signs must be collected after 5 minutes of rest 


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(seated); no other measurements or procedures should be performed during this 5-minute 
period.  Vital signs include blood pressure, peripheral (radial/brachial artery) heart rate, 
weight, and respiration rate.  Height will be collected at the Baseline Visit only. 
3.3.3 
Pharmacogenomics 
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations allow, a blood sample will be collected for pharmacogenomic analyses.  
Participation in the pharmacogenomic sampling is optional and samples will be collected at 
Baseline, the Study Drug Termination Visit (if appropriate), and Week 24 as noted in the 
Overall Schedule of Time and Events (see Table 3-1). 
Samples will be stored, and analyses may be performed on genetic variants or gene expression 
patterns thought to play a role in pulmonary hypertension to evaluate their association with 
observed response to prostacyclin therapy including oral treprostinil. 
3.3.4 
Biomarkers 
Samples will be collected for potential biomarker research where local regulations allow.  
Samples may be used for research on the drug target, disease process, pathways associated 
with pulmonary hypertension, mechanism of action of oral treprostinil, and/or research 
method or in validating diagnostic tools or assay(s) related to pulmonary hypertension.  
Participation in the biomarker sampling is optional and serum and urine samples will be 
collected at Baseline, the Study Drug Termination Visit (if appropriate), and Week 24 as 
noted in the Overall Schedule of Time and Events (see Table 3-1). 
3.4 
NUMBER OF CENTERS 
This is a multicenter study with approximately 100 study sites in the US, Canada, and Mexico 
participating. 


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3.5 
NUMBER OF SUBJECTS 
Approximately 310 subjects will be randomized (1:1 oral treprostinil to placebo) across all 
study sites.  
3.6 
ESTIMATED STUDY DURATION 
The maximum length of participation is approximately 28 weeks.  This includes an up to 
30-day Screening phase and the 24 weeks of treatment.  Subjects who permanently 
discontinue study drug (eg, due to an AE) prior to Week 24 will be asked to complete a Study 
Drug Termination Visit and remain in the study through Week 24 and complete study 
assessments off treatment.  The study will enroll until approximately 310 subjects are 
randomized.  Subjects who permanently discontinue study drug and do not enter 
Study TDE-HF-302 will be contacted approximately 30 days (±5 days) after study drug 
discontinuation 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 for additional details). 
4 
SUBJECT ELIGIBILITY 
Inclusion and exclusion criteria are to be assessed during the Screening phase and 
reconfirmed at the Baseline Visit prior to randomization.  If necessary, certain procedures 
may be conducted during the Screening phase after obtaining informed consent to determine 
subject eligibility for the study. 
4.1 
INCLUSION CRITERIA 
1. The subject voluntarily gives informed consent to participate in the study. 
2. The subject is 18 to 85 years of age (inclusive) at Screening (ie, date of providing 
written informed consent). 
3. A subject can qualify if they have undergone a RHC within 180 days of Baseline and 
either of the following conditions (regular criterion or fluid challenge criterion) are 
met: 
Regular criterion: 
a. A PAPm ≥25 mmHg  
b. A PCWP >15 mmHg but ≤30 mmHg.  In cases where a PCWP is not available or 
deemed unreliable, a left ventricular end-diastolic pressure (LVEDP) obtained 
within the 180-day window may be used.  Note that a subject would be eligible to 


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participate in the trial if they have a PAPm >25 mmHg, a PVR >3 wood units, and 
a PCWP <15 mmHg from a RHC conducted during the Screening period if they 
had a PCWP >15 mmHg (with no upper limit) associated with a diagnosis of 
HFpEF on the preceding RHC (done within 180 days of Baseline). 
c. A PVR of ≥3.0 Wood units (≥240 dynes*s/cm5) calculated using thermodilution or 
Fick technique. 
Fluid challenge criterion: 
a. A PAPm ≥25 mmHg  
b. A positive fluid challenge, namely a PCWP ≥16 mmHg after ~500 ml saline 
infused via IV over approximately 5 minutes. 
c. A PVR of ≥3.0 Wood units (≥240 dynes*s/cm5) calculated using thermodilution or 
Fick technique  
d. 3 or more of the following risk factors for PH associated with HFpEF: 
i. 
Hypertension 
ii. 
Type 2 diabetes mellitus 
iii. 
Hyperlipidemia  
iv. 
Atrial fibrillation 
v. 
Age >65 years old 
vi. 
Sleep apnea  
vii. 
Left atrial volume index >32 ml/m2 (transthoracic echocardiogram) 
viii. 
Body mass index >30 kg/m2 
4. The subject has a diagnosis of heart failure with a LVEF ≥45% by ECHO completed 
during Screening (prior to randomization). 
5. The subject’s baseline 6MWD must be at least 150 meters. 
6. The subject has pulmonary function tests conducted within 6 months of Screening or 
during the Screening phase to confirm the following: 
a. Total lung capacity is ≥ 60% of the predicted value. 
b. Forced expiratory volume at 1 second (FEV1) is ≥50% of the predicted value. 
c. Diffusing capacity of the lungs for carbon monoxide (DLCO) is ≥40% of the 
predicted value (unadjusted, or adjusted for alveolar volume). 
7. Subjects on a chronic medication for heart failure (eg, ACE inhibitors, ARBs, and beta 
blockers) must be on a stable dose for ≥30 days prior to randomization.  The exception 
is with changes of anticoagulants and/or diuretics; these medications should not be 
newly started or stopped within 30 days of randomization and no healthcare provider 
prescribed dose change should occur within 7 days of randomization, with the 
exception of the withholding of doses of anticoagulants for the conduct of the RHC 
when required. 
8. In the opinion of the 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. 


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9. 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).  WOCBP 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 drug.  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, or (4) partner vasectomy.  For WOCBP, a negative urine pregnancy test is 
required at Screening and Baseline prior to initiating study drug.  Male subjects with a 
partner of childbearing potential must use a condom during the length of the study, 
and for at least 48 hours after discontinuing study drug. 
10. Subjects on chronic medications (eg, inhaled corticosteroids, long-acting 
beta2-adrenergic agonist, long-acting muscarinic antagonists, combination inhaled 
drugs, anti-inflammatory drugs, oral/parenteral corticosteroids, or biologic agents) for 
any underlying respiratory condition must be on a stable dose for ≥30 days prior to 
randomization. 
4.2 
EXCLUSION CRITERIA 
1. The subject is pregnant or lactating. 
2. In the opinion of the Principal Investigator, the subject has a primary diagnosis of PH 
other than WHO Group 2 PH.   
3. The subject has shown intolerance or significant lack of efficacy to a prostacyclin or 
prostacyclin analogue that resulted in discontinuation of therapy or inability to 
effectively titrate that therapy. 
4. The subject has received PAH therapies, including prostacyclin therapy (ie, 
epoprostenol, treprostinil, iloprost, or beraprost; except for acute vasoreactivity 
testing), nonprostanoid IP receptor agonist (selexipag), ERA, or soluble guanylate 
cyclase stimulator, within 30 days of randomization.  Chronic use of an approved 
phosphodiesterase type 5 inhibitor (PDE5-I) is allowed as long as the subject has been 
on a stable dose for at least 90 days prior to randomization and has had an RHC 
confirming the parameters necessary for inclusion in the study after being on a stable 
PDE5-I dose for at least 30 days.  If the Investigator does not intend to keep a subject 
on their PDE5-I therapy, it must be stopped at least 30 days prior to randomization.  
Intermittent use of a PDE5-I (≤3 times per week) to treat erectile dysfunction is 
permitted. 
5. The subject has been hospitalized for a cardiopulmonary indication within 30 days of 
randomization. 
6. The subject had a myocardial infarction within 90 days of randomization. 
7. The subject had cardiac resynchronization therapy within 90 days of randomization or 
anticipated resynchronization therapy during the study treatment period. 


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8. The subject has liver function tests (aspartate aminotransferase [AST] or alanine 
aminotransferase [ALT]) greater than 3 times the upper limit of normal at Screening, 
clinically significant liver disease/dysfunction per Investigator’s clinical judgement, 
known Child-Pugh Class C hepatic disease (see Appendix 15.5), or noncirrhotic portal 
hypertension. 
9. The subject has uncontrolled systemic hypertension, defined as a systolic blood 
pressure >160 mmHg or a diastolic blood pressure >110 mmHg at Baseline. 
10. The subject has a systolic blood pressure <100 mmHg at Baseline. 
11. The subject has a resting heart rate >100 beats per minute at Baseline. 
12. The subject has known genetic hypertrophic cardiomyopathy. 
13. The subject has sarcoidosis or cardiac amyloidosis. 
14. The subject has a known history of any LVEF less than 40% by ECHO within 3 years 
of randomization.  Note: a transient decline in LVEF below 40% that occurred and 
recovered more than 6 months before the start of Screening and was associated with 
an acute intercurrent condition (eg, atrial fibrillation) is allowed. 
15. The subject has hemodynamically significant valvular heart disease as determined by 
the Investigator, including: 
 Greater than mild aortic and/or mitral stenosis 
 Severe mitral and/or aortic regurgitation (>Grade 3) 
16. The subject has a body mass index >45 kg/m2. 
17. The subject has any musculoskeletal disorder (eg, arthritis affecting the lower limbs, 
recent hip or knee joint replacement, artificial leg), or has any other condition that 
would likely be the primary limit to ambulation as opposed to the disease under study. 
18. The subject has end-stage renal disease requiring/receiving dialysis. 
19. The subject has used any investigational drug/device, or participated in any 
investigational study, within 30 days prior to the first dose of study drug. 
4.3 
PRESCRIBED THERAPY 
4.3.1 
Concomitant Medications 
All subjects on a chronic medication for heart failure (eg, ACE inhibitors, ARBs, and beta 
blockers) must be on a stable dose for ≥30 days prior to randomization.  The exception is with 
changes of anticoagulants and/or diuretics; these medications should not be newly started or 
stopped within 30 days of randomization and no healthcare provider prescribed dose change 
should occur within 7 days of randomization, with the exception of the withholding of doses 
of anticoagulants for the conduct of the RHC when required.  After randomization, additions, 
deletions, and dose changes of any heart failure therapy may occur if the Investigator 
determines it is medically necessary; however, every attempt should be made to minimize 


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changes to background heart failure (HF) therapy.  If changes to conventional heart failure 
therapies are made, study drug should be continued as per protocol. 
Subjects who are chronically using an approved PDE5-I prior to entry into the study must 
have been on a stable dose for at least 90 days prior to randomization and should remain on a 
stable dose throughout the study.  If the Investigator does not intend to keep a subject on their 
PDE5-I therapy, it must be stopped at least 30 days prior to randomization.  If a subject is on 
intermittent doses of a PDE5-I to treat erectile dysfunction, they cannot take more than 
3 doses per week. 
All subjects receiving chronic medications (eg, inhaled corticosteroids, long-acting 
beta2-adrenergic agonist, long-acting muscarinic antagonists, combination inhaled drugs, 
anti-inflammatory drugs, oral/parenteral corticosteroids, or biologic agents) for any 
underlying respiratory condition must be on a stable dose for at least 30 days prior to 
randomization. 
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.  Conversely, if the subject was assessed at Baseline without 
oxygen therapy, then all future 6MWTs during the study should be conducted without oxygen 
therapy unless it would represent a safety risk to the subject.  Any changes to oxygen therapy 
relative to Baseline when conducting the 6MWT will be considered an unusual circumstance 
for eCRF completion purposes. 
All concomitant medications taken during the conduct of the study, including those taken for 
AEs or other medical events, should be recorded in the subject’s source documents and 
transcribed to the eCRF. 
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
Eligible subjects will be randomly allocated 1:1 to receive either oral treprostinil or placebo at 
randomization.  During the Screening phase, a screening number will be assigned using an 


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electronic data capture 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 oral treprostinil to placebo.  All subjects will be randomly 
allocated to receive oral treprostinil or placebo through the IVRS/IWRS using a centrally 
administered randomization.  The randomization will be stratified by Baseline 6MWD (less 
than or equal to 350 meters and greater than 350 meters). 
Prior to randomization, study site personnel should complete a Pre-Baseline Review Form for 
review and approval by the Sponsor’s Medical Monitor. 
5.3 
BLINDING 
The Investigator, study site personnel, subject, and Sponsor will not be aware of the treatment 
allocation.  All clinical study material 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 (Study TDE-HF-302). 
6 
DRUGS AND DOSING (OR TREATMENT PROCEDURES) 
6.1 
DRUG DOSAGE, ADMINISTRATION, AND SCHEDULE 
The oral treprostinil tablets are SR osmotic tablets.  Active treatment is oral treprostinil tablets 
provided as 0.125-, 0.25-, 1-, and 2.5-mg strengths.  The 0.125-, 0.25-, 1-, and 2.5-mg tablets 
are colored blue, green, yellow, and pink, respectively.  The formulation contains 
pharmaceutically acceptable excipients used in other approved drug products.  Placebo tablets 
are identical in size, shape, and color to the respective oral treprostinil tablets. 
Once all entry criteria have been met and treatment randomly assigned by IVRS/IWRS, the 
first dose of study drug (0.125 mg) should be taken by the subject immediately after 
(approximately 10 minutes) consuming food at the study site on the day of randomization.  
Oral dosing of study drug will be continued at 0.125 mg TID (every 6 to 8 hours) immediately 
after (approximately 10 minutes) the subject consumes food.  Subjects must be instructed to 


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take the appropriate number of tablets based upon their prescribed dose.  Each dose of study 
drug can be upwardly adjusted by a maximum of 0.125-mg increments as clinically indicated 
and tolerated.  Throughout the course of the study, dose increases can occur in 0.125-mg 
increments every 72 hours (9 consecutive doses) as indicated at the discretion of the 
Investigator up to an initial maximum allowable dose of 2 mg TID.  If necessary, dose 
titration can occur less frequently than every 9 doses.  The anticipated maximum allowed dose 
during the study will be 6 mg TID based on recommendations from the independent DMC.  
The DMC will meet after approximately 10, 30, 60, 100, and 200 subjects have been enrolled 
in the study, or on an ad hoc basis per request of the independent DMC, as necessary.  
Enrollment will not be stopped during the DMC reviews; however, subjects may not progress 
to the next highest maximum dose level until the DMC provides their review of the data.  Any 
decision impacting the maximum dose will be relayed to study sites following the DMC 
meeting.  Note that sudden dose escalations or reductions may lead to intolerable AEs or 
worsening of PH, and gradual dose escalations or reductions are recommended to reduce risk 
to subjects. 
Doses of study drug should continue to be increased in the absence of dose-limiting drug-
related AEs to ensure that each subject receives the optimal clinical dose throughout the 
study.  Table 6-1 provides an anticipated maximum dose of study drug that can be obtained 
based on DMC review and approval, notwithstanding any AEs that limit dose escalation. 
Table 6-1 
Anticipated Maximum Dose Ranges Based on DMC Review and Approval 
Approximate Number of Subjects 
Maximum Dose 
1 to 10 
2 mg TID 
11 to 30 
4 mg TID 
31 and above 
6 mg TID 
DMC, Data Monitoring Committee; TID, 3 times daily 
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 in the morning, 1.125 mg in the afternoon, and 1.25 mg in the 
evening, are acceptable during titration.  The maximal difference between the lowest dose and 
the highest doses cannot exceed 0.125mg. 


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Weekly telephone calls or emails between scheduled visits (eg, Weeks 1, 2, 3, 4, and 5 
between randomization and Week 6) up to Week 24, and the Study Drug Termination Visit (if 
applicable) are to be made between study site personnel and the subject to monitor study drug 
compliance, AEs, signs and symptoms of disease, use of concomitant medications, occurrence 
of clinical worsening, and to make decisions regarding dose titration.  More 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, study site 
personnel will instruct the subject to modify their dose.  A copy of the emails and/or 
telephone contact sheets must be documented in the subject’s source documentation.  Email 
should not replace direct follow-up by phone or at the study site for clinically significant AEs 
or other emergent issues. 
Study drug dose should be recorded at each study visit 6MWT between Week 6 and Week 24.  
Dose changes between Baseline and Week 24 will be recorded in source documentation and 
the subject’s eCRF by study site personnel.  If it becomes necessary for a subject to modify 
their dose (eg, due to an AE) without prior instructions from study site personnel, the subject 
should be instructed to contact the study site as soon as possible and report any dose changes 
to study site personnel for updating in source documentation and the eCRF, as appropriate.  
Subjects must not make-up or double-up on missed doses of study drug.  If dosing is 
interrupted for longer than 24 hours, consideration should be given to gradually retitrate the 
subject’s dose to the last dose administered prior to the dose interruption.  In the event of a 
planned, short-term interruption for subjects unable to take oral medications during the study, 
study sites should contact the United Therapeutics Medical Monitor to discuss dosing options. 
In the event a subject is required to be permanently discontinued from study drug (eg, adverse 
event, requirement for the addition of a prohibited medication, or the subject wishes to 
withdraw from further participation in the study), the Investigator should conduct the 
Study Drug Termination Visit assessments (see Table 3-1) 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.  Subjects who terminate study 


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drug early will be asked to complete all remaining study visits in addition to the Study Drug 
Termination Visit. 
Throughout the course of the study, the dose of study drug can be increased at the discretion 
of the Investigator up to an initial maximum allowable dose of 2 mg TID prior to a 
DMC-approved dose escalation.  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, further 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- or 0.25-mg increments every 12 to 24 hours.  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 
restarted 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 PH occurs, so long as the maximum allowable 
dose determined by the DMC is not surpassed. 
Subjects that complete through Week 24 on study drug and do not roll over to the TDE-HF-
302 study shall be provided enough study drug for down-titration and discontinuation of 
dosing from either their remaining study drug supply that was provided at Week 18 and/or via 
an unscheduled call to the IVRS/IWRS during Week 24 (prior to the study completion call).  
Subjects should not down-titrate their dose of study drug until after the Week 24 Visit has 
been completed.  Following completion of the Week 24 Visit, subjects should down-titrate 
until a zero dose is achieved.  As needed, site personnel should maintain at least weekly 


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contact via phone or email until a zero dose is achieved and ensure the return of all unused 
study drug to the study site. 
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 (eg, juice, milk, etc) immediately after (approximately 
10 minutes) consuming food. 
Subjects should be instructed to be careful not to break, chew, crush, or disrupt the integrity of 
the tablets, as this will result in inappropriate delivery of the active ingredient.  If the tablet is 
inadvertently damaged during administration, the subject should contact study site personnel 
in order to be monitored for the onset of symptoms due to possible overdose.  Any tablet 
damaged during handling 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 Concomitant Medications 
All subjects on a chronic medication for heart failure (eg, ACE inhibitors, ARBs, and beta 
blockers) must be on a stable dose for ≥30 days prior to randomization (see Section 4.3.1).  
The exception is with changes of anticoagulants and/or diuretics; these medications should 
not be newly started or stopped within 30 days of randomization and no healthcare 
practitioner prescribed dose change should occur within 7 days of randomization with the 
exception of the withholding of doses of anticoagulants for the conduct of the RHC when 
required.  After randomization, additions, deletions, and dose changes of any background 
therapy as above may occur if the Investigator determines it is medically necessary; however, 
every attempt should be made to minimize changes to background therapies.  If changes to 
background medications are made, study drug should be continued as per protocol. 


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6.1.3 
Prohibited Medications 
Subjects must not be receiving PAH therapies, including prostacyclin therapy 
(ie, epoprostenol, treprostinil, iloprost, or beraprost; except for acute vasoreactivity testing), 
nonprostanoid IP receptor agonist (selexipag), ERA, or soluble guanylate cyclase stimulator 
within 30 days of randomization through the permanent discontinuation of study drug or study 
termination.  The exception is that intermittent use of a PDE5-I (≤3 times per week) to treat 
erectile dysfunction is permitted, as well as chronic use of an approved PDE5-I that was 
initiated at least 90 days prior to randomization.  PDE5-I therapy is not to be initiated within 
90 days of randomization or after randomization through the permanent discontinuation of 
study drug or study termination.  If the Investigator feels that starting an approved PAH 
therapy is clinically necessary during the course of the study, a Study Drug Termination Visit 
should be scheduled and the subject should be withdrawn from study drug by gradual down-
titration. 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
During the study, neither the Investigator, study site personnel, subject, nor Sponsor (with the 
exception of the clinical supply colleagues responsible for the IVRS/IWRS and study drug 
management) should be unblinded to the treatment assignment of any subject for any reason 
except in the event of a medical emergency (eg, a life threatening event) or regulatory 
reporting requirement, if and when knowledge of the treatment assignment is considered 
necessary to determine the optimal medical management.  Appropriate communications 
should take place between the study 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 unblinding, the IVRS/IWRS may be accessed by the Investigator to 
obtain treatment assignment information.  In the event of a premature unblinding prior to 
Week 24, subjects will be discontinued from the study drug and should complete all 
remaining study visits. 
Subjects who remain on study drug and complete the required study assessments through 
Week 24 will be eligible for an open-label study (Study TDE-HF-302).  Following 
completion of the Week 24 assessments and entry of required data into the IVRS/IWRS, the 


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study site personnel will be unblinded to that subject’s treatment assignment to determine the 
initial dose for the open-label study (Study TDE-HF-302).  If the subject received oral 
treprostinil 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 oral treprostinil in the open-label study in accordance 
with that protocol. 
Subjects who permanently discontinue study drug for any reason prior to Week 24 are not 
eligible for entry into the open-label study.  The study site personnel will not be unblinded to 
the treatment assignment of these subjects unless required for safety reasons. 
6.3 
COMPLIANCE 
The Investigator or other study site personnel under the direction of the Investigator will be 
responsible for dose titration of study drug and recording dosing information in source 
documents.  During weekly telephone calls/emails, study site personnel will record the current 
dose of study drug and determine if the subject is taking study drug as prescribed. 
Each subject will be provided with a dosing diary at each scheduled visit in order to record 
dosing information from randomization until Week 24.  At scheduled study visits, subjects 
should be instructed to return all study drug (including empty and unused bottles) and their 
dosing diary to the study site.  Upon return of study drug and the dosing diary at the Week 6, 
12, 18, and 24 visits, the study coordinator or pharmacist must document the number of 
returned tablets of each strength on the subject’s study drug accountability log 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.  If it is determined that a subject is not compliant with study drug, then study site 
personnel must re-educate the subject on proper dosing compliance and its importance.  
Continued noncompliance 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 (eg, Weeks 6, 12, 18, 
and 24, and the Study Drug Termination Visit [if applicable]), all bottles of study drug will be 


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collected.  Study drug returned at scheduled study visits will not be re-dispensed to the 
subject.  Study 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 
Study sites may conduct pre-Screening activities prior to a subject signing an ICF.  
Pre-Screening activities may include review of the study site’s database to identify potential 
subjects 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 signing of 
informed consent will begin the 30-day window.  The Screening and Baseline assessments 
may be conducted in 1 visit if all assessments are performed and all entry criteria are satisfied 
within the 48 hours prior to randomization and dosing with study drug. 
The list of Screening assessments is displayed below: 
 Informed consent 
 Inclusion/exclusion criteria 
 If necessary, the following procedures may be performed during the 30-day Screening 
phase if required to satisfy inclusion/exclusion criteria:  
 RHC 
 Pulmonary function tests 
 ECHO 
Medical records documenting eligibility criteria may also be used provided they document 
subject eligibility within the protocol-mandated timelines, as applicable.  Results from the 
most recent RHC, including waveforms, and ECHO studies used in determining subject 
eligibility will be uploaded and stored in a central repository. 
 Demographics 
 PH history 
 HF history  
 Medical history 


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 Assessment of HF signs and symptoms (see Appendix 15.7) and vital signs (following 
at least 5 minutes of rest [seated]) 
 Physical examination 
 Practice 6MWT/Borg dyspnea score (optional; serves as a practice test if the subject 
has not previously performed this test at the study site on the study-designated course; 
6MWT is to be conducted following at least 10 minutes of rest [seated], and the Borg 
dyspnea score is 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 
If a subject does not initially meet all entry criteria, they may be re-screened at a later date 
when any unusual or extenuating circumstances are adequately resolved.  The Sponsor should 
be contacted prior to starting any re-screening assessments.  Within the Screening Period, 
retests will be allowed if the results of any procedures or assessments are thought to be 
spurious, or if the underlying cause has been corrected.  This would include, but is not limited 
to, laboratory-related entry criteria (eg, liver function parameters, renal function parameters, 
and hemoglobin values), the 6MWT, or pulmonary function tests. 
7.2 
BASELINE PHASE AND RANDOMIZATION 
Baseline assessments can occur up to 48 hours prior to the first dose of study drug to allow for 
scheduling of all activities.  The list of the Baseline Visit assessments is displayed below. 
 Confirmation of remaining inclusion/exclusion criteria 
 Assessment of HF signs and symptoms with vital signs (following at least 5 minutes 
of rest [seated]) 
 WHO Functional Class 
 KCCQ 
 Height and weight (body mass index) 
 AE assessment 
 Concomitant medications 
 12-lead ECG (following at least 5 minutes rest in the semi-recumbent position) 
 ECHO (if not done previously during Screening) 


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 Clinical laboratory tests/NT-proBNP (NT-proBNP samples must be taken prior to the 
6MWT and prior to the first dose of study drug) 
 Collection of blood and urine samples for evaluation of biomarkers (optional) 
 Collection of blood sample for evaluation of pharmacogenomics (optional) 
 6MWT/Borg dyspnea score (6MWT to be conducted prior to the first dose and 
following at least 10 minutes of rest [seated]; Borg dyspnea score to be conducted 
immediately following 6MWT) 
 Clinical worsening assessment 
 Urine pregnancy test for WOCBP (prior to randomization) 
 Randomization via IVRS/IWRS (to be performed after all other Baseline assessments 
are completed and the Pre-Baseline Review Form has been approved by the Medical 
Monitor) 
 First administration of study drug immediately (approximately 10 minutes) after 
consuming food 
 Dosing instructions/dosing/accountability  
 At least weekly telephone/email contact to begin following initiation of study drug up 
to Week 24 of treatment to monitor study drug compliance, AEs, signs and symptoms 
of disease, use of concomitant medications, occurrence of clinical worsening, and to 
make decisions regarding dose titration 
7.3 
TREATMENT PHASE 
7.3.1 
Weeks 6, 12, and 18 Assessments 
The following assessments will be conducted at Weeks 6, 12, and 18 (the visit window is 
±5 days from the projected visit date): 
 Assessment for HF signs and symptoms with vital signs (following at least 5 minutes 
of rest [seated]) 
 WHO Functional Class 
 AE assessment 
 Dosing instructions/dosing/accountability 
 Concomitant medications 
 Clinical laboratory tests/NT-proBNP (Week 12 Visit only; NT-proBNP samples must 
be taken prior to the 6MWT) 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after the most recent 
dose of study drug and following at least 10 minutes of rest [seated]; Borg dyspnea 
score to be conducted immediately following 6MWT) 
 Clinical worsening assessment 
 Urine pregnancy test for WOCBP 


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 Continue administration of study drug and dose titration 
 Continue at least weekly telephone/email contact 
7.3.2 
Study Drug Termination Assessments 
The assessments below will be conducted at the Study Drug Termination Visit.  The Study 
Termination Visit is only applicable if a subject permanently discontinues study drug prior to 
Week 24.  Subjects should not down-titrate their dose of study drug until after the Study Drug 
Termination Visit has been completed. 
 Physical exam 
 Assessment for HF signs and symptoms with vital signs (following at least 5 minutes 
of rest [seated]) 
 WHO Functional Class 
 KCCQ 
 AE assessment 
 Dosing instructions/dosing/accountability  
 12-lead ECG (following at least 5 minutes rest in the semi-recumbent position) 
 ECHO 
 Concomitant medications 
 Clinical laboratory tests/NT-proBNP (NT-proBNP samples must be taken prior to the 
6MWT) 
 Collection of blood and urine samples for evaluation of biomarkers (optional) 
 Collection of blood sample for evaluation of pharmacogenomics (optional) 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after the most recent 
dose of study drug and following at least 10 minutes of rest [seated]; Borg dyspnea 
score to be conducted immediately following 6MWT) 
 Clinical worsening assessment (to continue for 7 days after the final dose of study 
drug if a subject permanently discontinues study drug during the Treatment Phase) 
 Survival status (assessed 30 days [±5 days] after study drug discontinuation) 
 Urine pregnancy test for WOCBP 
 Telephone/email contact 


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7.3.3 
Week 24 Assessments 
The following assessments will be conducted at Week 24 (the visit window is ±5 days from 
the projected visit date; as needed, the completion of these assessments can occur over the 
visit window, but all assessments must be completed within window and prior to rollover into 
TDE-HF-302): 
 Physical exam 
 Assessment for HF signs and symptoms with vital signs (following at least 5 minutes 
of rest [seated]) 
 WHO Functional Class 
 KCCQ 
 AE assessment 
 Drug accountability 
 12-lead ECG (following at least 5 minutes rest in the semi-recumbent position) 
 ECHO 
 Concomitant medications 
 Clinical laboratory tests/NT-proBNP (NT-proBNP samples must be taken prior to the 
6MWT) 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after the most recent 
dose of study drug and following at least 10 minutes of rest [seated]; Borg dyspnea 
score to be conducted immediately following 6MWT) 
 Clinical worsening assessment 
 Survival status (assessed 30 days [±5 days] after study drug discontinuation) 
 Urine pregnancy test for WOCBP 
 Telephone/email contact 
 Collection of blood and urine samples for evaluation of biomarkers (optional) 
 Collection of blood sample for evaluation of pharmacogenomics (optional) 


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8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A subject may voluntarily withdraw or 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 significantly deviates from the protocol. 
 The subject’s behavior is likely to undermine the validity of his/her results. 
 The subject becomes pregnant. 
If a subject is discontinued from the study prematurely, the Investigator must provide an 
explanation in the eCRF (eg, Investigator’s Comment Log or other appropriate eCRF pages to 
provide an explanation of the reason) and complete the End of Study Record for that subject.  
If study drug has been administered, the Investigator should make every effort to perform all 
scheduled evaluations prior to discharge.   
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. 
8.3 
CRITERIA FOR DISCONTINUING THE STUDY SITE 
The study may also be terminated at a given center if any of the following occur: 
 The Investigator elects to discontinue the study 
 The Sponsor elects to discontinue the study at the study site 
 Violation of US Food and Drug Administration (FDA) regulations, International 
Council for Harmonisation (ICH) Good Clinical Practices (GCP) guidelines, or 
national 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 


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9 
ADVERSE EVENT REPORTING  
All AEs/SAEs that occur while the subject is participating in the study will be recorded as 
instructed in this protocol (Section 9.2). 
9.1 
DEFINITIONS 
9.1.1 
Adverse Event  
An AE is any untoward medical occurrence in a subject administered study drug, which does 
not necessarily have to have a causal relationship with this treatment.  An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding for example), 
symptom, or disease temporally associated with the use of study drug, whether or not related 
to the use of the study drug.  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.  The Investigator is responsible for recording all AEs that occur during the study 
beginning at Screening. 
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. 
 Worsening of an existing symptom or condition or post-treatment events that occur as 
a result of protocol-mandated procedures (eg, exacerbation of a pre-existing illness 
following the start of the study or an increase in the frequency or intensity of a 
pre-existing episodic event or condition). 
Thus, no causal relationship with the study drug is implied by the use of the term “adverse 
event.” 
An AE does not include the following: 
 Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
however, the condition for which the surgery is required may be an AE. 
 Planned surgical measures permitted by the study protocol and the condition(s) 
leading to these measures are not AEs. 
 Day to day fluctuations of pre-existing disease or conditions present or detected at the 
start of the study that do not worsen. 


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 Situations where an untoward medical occurrence has not occurred (eg, 
hospitalizations for cosmetic elective surgery, social and/or convenience admissions). 
Events attributable to the progression of the disease under study should only be recorded as an 
AE or SAE if the event is unusual with respect to intensity, frequency, duration as compared 
with symptoms in the subject’s medical history, or if there is a reasonable possibility that the 
event was caused by the study drug (see Table 3-2). 
9.1.2 
Serious Adverse Event  
An SAE is an AE which results in any of the following: 
 Death 
 Life-threatening 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 Results in a medically important event or reaction 
Life-threatening in this context refers to a reaction in which the subject was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered SAEs, such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization, but might jeopardize the subject or might 
require intervention to prevent 1 of the other outcomes listed above.  Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization or development of dependency 
or abuse. 
9.2 
DOCUMENTATION OF ADVERSE EVENTS 
An AE or SAE occurring during the study 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, 


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is also to be documented in the eCRF (see Appendix 15.3).  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, not the individual signs and symptoms. 
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 meaningful, or for at least 
30 days if the AE extends beyond the final study 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 study 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. 
9.3 
PREGNANCY 
If a subject becomes pregnant during participation in this clinical study, study site staff must 
notify the Sponsor within 24 hours of learning of the pregnancy by completing the Pregnancy 
Notification Form and submitting via email or fax to United Therapeutics Global Drug Safety 
(GDS; email:___; fax:__).  Subjects who become pregnant during the study will be withdrawn 
from active participation in the study and will discontinue study drug after an appropriate 
period of down-titration.  These subjects will be transitioned to an alternate therapy at the 
discretion of the Investigator.  United Therapeutics GDS will follow-up with the Investigator 
to ensure appropriate data are provided regarding the outcome of the pregnancy.  Pregnancy 
only becomes an AE/SAE if there is an abnormal outcome, a spontaneous abortion, an 
elective termination for medical reasons, or a congenital anomaly in the offspring. 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
All SAEs, regardless of expectedness or causality, must be reported to United Therapeutics 
GDS by email or fax (email: ___; fax: ___) within 24 hours of awareness.  A completed SAE 
Notification Form, along with any relevant hospital records and autopsy reports should be 
sent to United Therapeutics GDS.  A follow-up SAE Notification Form must be forwarded to 


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United Therapeutics GDS within 24 hours of the receipt of any new/updated information.  
The Investigator must also promptly notify their Institutional Review Board (IRB) or Ethics 
Committee (EC) of the SAE, including any follow-up information, in accordance with 
applicable national regulations and guidelines set forth by the IRB or EC.  Events attributable 
to the progression of the disease under study (see Table 3-2 and Section 3.3.2.3) are not to be 
reported to United Therapeutics as SAEs unless the event is unusual with respect to intensity, 
frequency, duration as compared with symptoms in the subject’s medical history, or if there is 
a reasonable possibility that the event was caused by the study drug. 
9.5 
SAFETY REPORTS 
In accordance with the US FDA, the Sponsor will notify the US FDA, other competent 
authorities, and all participating Investigators of any AE that is considered to be possibly 
attributable to study drug and is both serious and unexpected.  The Investigator must report 
these AEs to their IRB or EC in accordance with applicable national regulations and 
guidelines set forth by the IRB or EC. The Investigator must report these AEs 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 
The results of all assessments will be transcribed into an eCRF by the appropriate study site 
personnel for each subject who signs an ICF until study completion or study discontinuation 
for any reason.  A representative from the Sponsor will verify eCRF data fields against source 
documentation.  All data transmitted from the study site will be reviewed and entered into a 
quality assured computerized database.  Data clarifications will be generated and the database 
will be edited as appropriate.  The eCRF data for each subject are to be reviewed by the 
Investigator for completeness and accuracy.  The Investigator must electronically sign each 
subject’s eCRF to signify their approval of the data.  The Investigator will be required to 
re-sign an eCRF if changes are made to a subject’s eCRF by the study site after the 
Investigator has applied his/her signature.  The database will be considered final when all 


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outstanding queries have been resolved and all data management quality assurance procedures 
are complete. 
10.2 
SAMPLE SIZE 
Approximately 310 subjects will be enrolled and randomly allocated to receive oral 
treprostinil or placebo.  Using an allocation ratio of 1:1 between oral treprostinil and placebo, 
a sample size of 263 subjects would provide 90% power at a significance level of 
0.05 (2-sided hypothesis) to detect a 30-meter between-treatment difference in the change 
from Baseline to Week 24 in 6MWD, assuming a SD of 75 meters.  The total sample size will 
be approximately 310 subjects to account for a discontinuation rate of approximately 15%.  
To ensure a final analysis population contains only subjects who were afforded the 
opportunity to reach their maximum tolerated dose, additional subjects may need to be 
enrolled up to an additional 15% overage, for a total maximum enrollment of 356 subjects. 
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.  
Additionally, a statistical analysis plan detailing the safety analyses for use at the DMC 
meetings will be generated to guide the independent statistical consultant tasked with 
performing these analyses.  All statistical calculations will be done using SAS version 9.4 or 
above (SAS Institute Inc., Cary, NC, USA). 
The Intent-to-Treat (ITT) Population will be defined as all subjects randomized into the study 
that receive at least 1 dose of study drug; all subjects will be counted 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 the detailed statistical analysis plan. 
10.3.1 
Primary Efficacy Endpoint 
The primary hypothesis is that oral treprostinil will increase the distance traversed in the 
6MWT at Week 24 over placebo in subjects with PH associated with HFpEF.  The effect of 
oral treprostinil versus placebo on change from Baseline to Week 24 in 6MWD will be 


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analyzed using an analysis of covariance (ANCOVA) with Baseline 6MWD as the covariate 
(if the assumptions for ANCOVA do not hold, the nonparametric analysis of variance 
[ANOVA] may be used).  For subjects who discontinue from the study early, the last 
observation carried forward method will be used to impute the 6MWD at Week 24; the 
exception being subjects who die.  For subjects who die prior to Week 24, a 6MWD of 
0 meters will be imputed at Week 24.  For subjects who discontinue study drug prior to 
Week 24, but remain in the study for the duration of the treatment period, their last on-drug 
6MWD will be carried forward to Week 24 for analysis.  The worst case imputation and other 
imputation techniques will be employed to investigate the impact of the missing data.   
10.3.2 
Secondary Efficacy Endpoints 
The effect of treatment will be formally tested on the following secondary efficacy endpoints: 
1. Change in NT-proBNP levels from Baseline to Week 24 
2. Time to the first clinical worsening event 
3. Change in WHO Functional Class from Baseline to 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 change in NT-proBNP levels from 
Baseline to Week 24 will be tested at a 2-sided Type 1 error rate of 0.05.  The subsequent 
tests for other secondary efficacy endpoints will be tested only if the preceding test is 
statistically significant. 
10.3.3 
Exploratory Efficacy Endpoints 
The following exploratory endpoints will be summarized and analyzed to assess the treatment 
effect without adjustment for multiplicity: 
1. Change in 6MWD from Baseline to Weeks 6, 12, and 18 
2. Change in Borg dyspnea score from Baseline to Weeks 6, 12, 18, and 24 
3. Change in NT-proBNP levels from Baseline to Week 12 
4. Change in WHO Functional Class from Baseline to Weeks 6, 12, and 18 
5. Change in HbA1c from Baseline to Week 24  
6. Change in KCCQ from Baseline to Week 24 


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10.3.4 
Efficacy Analyses 
10.3.4.1 
Time to Clinical Worsening 
Clinical worsening is defined in Section 2.2.  The time from the first dose of study drug until 
to the first clinical worsening event will be summarized using Kaplan-Meier estimates, and 
compared between treatment groups using the log-rank test.  The incidence of clinical 
worsening events will be summarized and compared between treatment groups using Fisher’s 
exact test. 
10.3.4.2 
N-Terminal Pro-brain Natriuretic Peptide 
Changes from Baseline to each follow-up assessment in plasma NT-proBNP will be 
summarized and analyzed using an ANCOVA, using baseline NT-proBNP values as the 
covariate. 
10.3.4.3 
WHO Functional Class 
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.  The 
number and percentage of subjects with WHO Functional Class improvement, no change, and 
worsening will be summarized by treatment group. 
10.3.4.4 
6-Minute Walk Distance 
The effect of oral treprostinil versus placebo on change from Baseline to Week 24 in 6MWD 
will be analyzed as described above for the primary endpoint.  Descriptive statistics will be 
used to summarize the 6MWD data at Baseline and Weeks 6, 12, and 18. 
10.3.4.5 
Borg Dyspnea Score 
Changes from Baseline to each follow-up assessment in Borg dyspnea score will be 
summarized and compared between treatment groups using the Wilcoxon rank-sum test. 
10.3.4.6 
Kansas City Cardiomyopathy Questionnaire 
Responses to the KCCQ will be summarized utilizing the published scoring algorithms to 
provide an overall summary score and individual scores within the following specific health 
domains pertaining to heart failure: physical function, symptoms (frequency, severity, and 
recent change), social function, self-efficacy and knowledge, and quality of life.  Values for 


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each domain range from 0 to 100; higher scores indicate lower symptom burden and better 
quality of life.  Changes from Baseline to Week 24 in domain and overall scores for the 
KCCQ will be summarized and compared between treatment groups using an ANCOVA 
method. 
10.3.5 
Safety Analyses 
The Safety Population will be defined as all subjects in the study that receive study drug 
(regardless of randomization status), and all subjects will be counted in the group 
corresponding to the treatment that they actually received.  If a subject received oral 
treprostinil at any point during the study, he/she will be counted in the oral treprostinil 
treatment group within the Safety Population.  All safety analyses will be performed on the 
Safety Population. 
The safety of oral treprostinil will be evaluated through comparisons of AEs, assessment of 
heart failure signs and symptoms with vital signs, clinical laboratory parameters, ECGs, and 
ECHOs between treatment groups.  All AEs as recorded by the Investigators will be assigned 
Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms by the Sponsor for 
reporting purposes.  For all safety endpoints, tabular summaries will be provided. 
10.4 
INTERIM ANALYSIS 
No formal interim analysis for efficacy data will be performed.  Analyses of safety data for 
review by the independent DMC will be performed after approximately 10, 30, 60, 100, and 
200 subjects have been enrolled in the study, or on an ad hoc basis per request of the 
independent DMC, as necessary.  Enrollment will not be stopped during the DMC reviews; 
however, subjects may not progress to the next highest maximum dose level until the DMC 
provides their review of the data.  All interim analyses will be performed by a statistical 
consultant independent and external to the Sponsor.  This statistical consultant will have 
access to the unblinded study data and will prepare the necessary output for review by the 
DMC as defined in the DMC charter.  The Sponsor will only have access to blinded study 
data during these interim analyses. 


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10.5 
OTHER ANALYSES 
Other 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 final 
clinical study report.  In general, listings will be sorted by subject and scheduled assessment 
(if applicable).  For summary tables, in general, the data will be summarized by scheduled 
assessment.  For continuous variables, descriptive statistics will include the number of 
observations, mean, SD, median, minimum, and maximum.  For categorical variables, 
descriptive statistics will include the frequency and percent in each category. 
10.7 
DATA MONITORING COMMITTEE 
An independent DMC will be established for the study, composed of a minimum of 
3 independent members, 1 physician knowledgeable in the treatment of PH, 1 physician 
knowledgeable in the treatment of HF, and 1 statistician.  Throughout the course of the study, 
the DMC will meet on a regular basis to monitor the safety of the study and make changes to 
maximum dosages of study drug to be used in accordance with the DMC Charter.  The 
frequency of meetings will depend on the rate of enrollment and the rate of occurrence of 
SAEs, as outlined in the DMC Charter.  The DMC will be masked to individual subject 
treatment allocation during the review process.  Analyses of safety data will be performed 
after approximately 10, 30, 60, 100, and 200 subjects have been enrolled in the study, or on an 
ad hoc basis per request of the independent DMC, as necessary.  Enrollment will not be 
stopped during the DMC reviews; however, subjects may not progress to the next highest 
maximum dose level until the DMC provides their review of the data.  The analyses will be 
prepared by an independent external statistical 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. 
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG  
United Therapeutics Corporation will supply study drug (oral treprostinil and placebo) for 
administration during the study.  The oral treprostinil tablets are SR osmotic tablets.  Active 


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treatment will be oral treprostinil tablets provided as 0.125-, 0.25-, 1-, and 2.5-mg strengths 
for the study.  Each tablet contains either 0.125 mg treprostinil (equivalent to 0.159 mg 
treprostinil diethanolamine), 0.25 mg treprostinil (equivalent to 0.317 mg treprostinil 
diethanolamine), 1 mg treprostinil (equivalent to 1.27 mg treprostinil diethanolamine), 2.5 mg 
treprostinil (equivalent to 3.17 mg treprostinil diethanolamine), or no treprostinil (placebo).  
The 0.125-, 0.25-, 1-, and 2.5-mg tablets are colored blue, green, yellow, and pink, 
respectively.  Oral treprostinil 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, study 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 study 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 CLINICAL STUDY MATERIAL 
All study drug will be stored at room temperature (25°C [77°F]) with excursions permitted to 
15°C to 30°C (59°F to 86°F).  Study drug should not be frozen, refrigerated, or exposed to 
heat.  Study site personnel should refer to study drug labeling or regulatory submissions for 
specific requirements by country or region in accordance with local regulations or guidance. 
Study drug at the study 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. 
The pharmacist or appropriate personnel at the study 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. 


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11.4 
SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL 
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 study site personnel to 
randomize each subject and assign the appropriate study drug bottles for the first 6-week 
treatment interval.  At subsequent visits to the study site, the IVRS/IWRS will be utilized by 
study 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 returned or destroyed.  At each 
visit, study 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 can be returned to a 
Sponsor-designated location for destruction. 
Study drug may be destroyed on site provided the institution has written policies and/or 
procedures in place describing their process and maintains all documentation related to on-site 
destruction.  Prior to proceeding with on-site destruction, the site should notify the Sponsor 
for review of their policies and/or procedures.  For sites that perform on-site destruction of 
study drug, accountability by the Sponsor may not be performed prior to destruction. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
US FDA OR APPLICABLE REGULATORY REQUIREMENTS 
The study will be conducted in accordance with the ICH GCP guidelines and all applicable 
national regulations.  The study will be conducted in Canada, Mexico, and the US.  The 
Sponsor will obtain the required approval from each national regulatory authority to conduct 


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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 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 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 study 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 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 standard procedures. 


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12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical study, the following documents will be provided to 
the study site: Investigator’s Brochure, Protocol, ICF, Budget Agreement, and eCRF. 
The study site will be required to provide the following documents 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, and Curriculum Vitae of study staff listed on the Form FDA 1572. 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  United Therapeutics 
Corporation, the US FDA or other 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 
the US FDA or appropriate local regulatory agencies for purposes of checking the accuracy of 
the data.  A number will be assigned to all subjects, and any report published will not identify 
the subject’s name. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially 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 study report will be provided to the local 
regulatory agencies. 
13.2 
STUDY DOCUMENTATION AND STORAGE 
In accordance with federal/national regulations, ICH, and GCP guidelines, the Investigator 
must retain study records for at least 2 years after the last approval of a marketing application 
in an ICH region, and until there are no pending or contemplated marketing applications in an 
ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  The Investigator must notify 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, and GCP guidelines, monitors for 
United Therapeutics Corporation or its designee will periodically contact the study 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 agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and his/her staff to the monitor to discuss any findings or any relevant 
issues. 


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14 
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2002;166(1):111-117. 
Bocchi EA, Bacal F, Auler Júnior JO, et al.  Inhaled nitric oxide leading to pulmonary edema 
in stable severe heart failure.  Am J Cardiol.  1994;74(1):70-72. 
Boilson BA, Schirger JA, Borlaug BA.  Caveat medicus!  Pulmonary hypertension in the 
elderly: a word of caution.  Eur J Heart Fail.  2010;12(1):89-93. 
Bonderman D, Ghio S, Felix SB, et al.  Riociguat for patients with pulmonary hypertension 
caused by systolic left ventricular dysfunction.  Circulation.  2013;128(5):502-511. 
Bonderman D, Pretsch I, Steringer-Mascherbauer R, et al.  Acute hemodynamic effects of 
riociguat in patients with pulmonary hypertension associated with diastolic heart failure 
(DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study.  Chest.  
2014;146(5):1274-1285. 
Califf RM, Adams KF, McKenna WJ, et al.  A randomized controlled trial of epoprostenol 
therapy for severe congestive heart failure: The Flolan International Randomized Survival 
Trial (FIRST).  Am Heart J.  1997;134(1):44-54. 
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(5):1313-1321. 
Green CP, Porter CB, Bresnahan DR, et al.  Development and evaluation of the Kansas City 
Cardiomyopathy Questionnaire: a new health status measure for heart failure.  J Am Coll 
Cardiol.  2000; 35(5):1245-1255. 
Grossman NL, Fiack CA, Weinberg JM, et al.  Pulmonary hypertension associated with heart 
failure and preserved ejection fraction: acute hemodynamic effects of inhaled iloprost.  Pulm 
Circ.  2015;5(1):198-203. 
Guazzi M, Vicenzi M, Arena R, et al.  Pulmonary hypertension in heart failure with preserved 
ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study.  Circulation.  
2011;124(2):164-174. 
Guazzi M, Gomberg-Maitland M, Arena R, et al.  Pulmonary hypertension in heart failure 
with preserved ejection fraction.  J Heart Lung Transplant.  2015a;34(3):273-281. 
Guazzi M, Gomberg-Maitland M, Naeije R.  Impact of pharmacologic interventions--treating 
endothelial dysfunction and group 2 pulmonary hypertension.  Prog Cardiovasc Dis.  
2015b;57(5):473-479. 


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Holland AE, Spruit MA, Troosters T, et al.  An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease.  Eur Respir J.  2014;44(6):1428-1446. 
Hussain N, Charalampopoulos A, Ramjug S, et al.  Pulmonary hypertension in patients with 
heart failure and preserved ejection fraction: differential diagnosis and management.  Pulm 
Circ.  2016;6(1):3-14. 
Jing ZC, Parikh K, Pulido T, et al.  Efficacy and safety of oral treprostinil monotherapy for 
the treatment of pulmonary arterial hypertension: A randomized, controlled trial.  Circulation.  
2013;127(5):624-633. 
Kalra PR, Moon JCC, Coats AJS.  Do results of the ENABLE (Endothelin Antagonist 
Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective 
endothelin antagonism in heart failure?  Int J Cardiol.  2002;85(2-3):195-197. 
Kaluski E, Cotter G, Leitman M, et al.  Clinical and hemodynamic effects of bosentan dose 
optimization in symptomatic heart failure patients with severe systolic dysfunction, associated 
with secondary pulmonary hypertension – a multi-center randomized study.  Cardiology.  
2008;109(4):273-280. 
Lam CS, Roger VL, Rodeheffer RJ, et al.  Pulmonary hypertension in heart failure with 
preserved ejection fraction: a community-based study.  J Am Coll Cardiol.  
2009;53(13):1119-1126. 
Lewis GD, Shah R, Shahzad K, et al.  Sildenafil improves exercise capacity and quality of life 
in patients with systolic heart failure and secondary pulmonary hypertension.  Circulation.  
2007;116(14):1555-1562. 
Loh E, Stamler JS, Hare JM, et al.  Cardiovascular effects of nitric oxide in patients with left 
ventricular dysfunction.  Circulation.  1994;90(6):2780-2785. 
Moraes DL, Colucci WS, Givertz MM.  Secondary pulmonary hypertension in chronic heart 
failure: the role of endothelium in pathophysiology and management.  Circulation.  
2000;102(14):1718-1723. 
Packer M, McMurray J, Massie BM, et al.  Clinical effects of endothelin receptor antagonism 
with bosentan in patients with severe chronic heart failure: results of a pilot study.  J Card 
Fail.  2005;11(1):12-20. 
Ponikowski P, Voors AA, Anker SD, et al.  2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of 
acute and chronic heart failure of the European Society of Cardiology (ESC).  Developed with 
the special contribution of the Heart Failure Association (HFA) of the ESC.  Eur J Heart Fail.  
2016;18(8):891-975. 


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Rosenkranz S, Gibbs JS, Wachter R, et al.  Left ventricular heart failure and pulmonary 
hypertension.  Eur Heart J.  2016;37(12):942-954. 
Serra W, Musiari L, Ardissino D, et al.  Benefit of prostaglandin infusion in severe heart 
failure: preliminary clinical experience of repetitive administration.  Int J Cardiol.  
2011;146(1):e10-e15. 
Simonneau G, Gartzoulis MA, Adatia I, et al.  Updated clinical classification of pulmonary 
hypertension.  J Am Coll Cardiol.  2013;62(25 Suppl):D34-D41. 
Sueta CA, Gheorghiade M, Adams KF Jr, et al.  Safety and efficacy of epoprostenol in 
patients with severe congestive heart failure.  Epoprostenol Multicenter Research Group.  Am 
J Cardiol.  1995;75(3):34A-43A. 
Wu X, Yang T, Zhou Q, et al.  Additional use of a phosphodiesterase 5 inhibitor in subjects 
with pulmonary hypertension secondary to chronic systolic heart failure: a meta-analysis.  Eur 
J Heart Fail.  2014;16(4):444-453. 


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15 
APPENDICES 
15.1 
PROCEDURES FOR 6-MINUTE WALK TEST AND BORG DYSPNEA 
SCALE 
General Procedures 
The 6MWT should be administered by the same tester at each study site throughout the study.  
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 study 
site.  If the subject was assessed at Baseline using oxygen therapy, then all 6MWTs during the 
study should be conducted with the same oxygen flow rate and mode of administration.  
Similarly, if the Baseline assessment was conducted without oxygen therapy, then subsequent 
assessments should also be conducted without oxygen therapy.  Before each 6MWT, the 
subject should rest (seated) for at least 10 minutes. 
The area used for the 6MWT should be premeasured at approximately 30 meters in length 
(but no shorter than 15 meters [16 yards or 50 feet] in length) and approximately 2 to 3 meters 
in width.  There must be no turns or significant curves to the 6MWT area.  The length should 
be marked with gradations 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 where you are” while simultaneously stopping the 
watch, and then measure the distance walked. 
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 6 minutes.  You will start 
from this point and follow the hallway to the marker (eg, 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 


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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 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?” 
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 each minute by saying: 
“You have 5 minutes to go.” 
“You have 4 minutes to go.” 
“You have 3 minutes to go.” 
“You have 2 minutes to go.” 
“You have 1 minutes to go.” 
At 6 minutes, the person administering the test will tell the subject:  
“Stop where you are.” 
No other instruction or encouragement will be given during the test.  Eye contact with the 
subject should be avoided during the test. 
Borg Dyspnea Score 
Immediately after the walk, the person administering the test will obtain a rating of dyspnea 
using the Borg dyspnea scale.  The person will use the following dialogue: 
“I would like to use the following scale to describe how out of breath you are (indicate the 
scale).  This scale uses 0 for no shortness of breath at all and 10 is the worst shortness of 
breath you have ever had.  Please point to a number that tells me how short of breath you 
feel right now.” 


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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 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Investigator or a designated member of his/her staff will probe each subject for any AEs 
that may have occurred.  The Investigator should always ask the same question when 
conducting the verbal probe in order to ensure uniformity between subjects.  The Investigator 
should ask: 
 
“How are you doing (feeling)?” 
Based on the subject’s response to this question, the Investigator should ask additional 
questions relevant to the specific complaint such as: 
 
“How severe is/was the symptom?” 
 
“How often did the symptom occur?” 
 
“How long did the symptom last?” 
It is the Investigator’s responsibility to review the results of all diagnostic and laboratory tests 
as they become available and ascertain if there is a clinically significant change from 
Baseline.  If the results are determined to be a clinically significant change from Baseline, this 
should be reported as an AE.  The Investigator may repeat the diagnostic procedure or 
laboratory test or request additional tests to verify the results of the original tests.  When 
possible, a diagnosis associated with the abnormality should be used as the reported AE. 
Using provided definitions, the Investigator will then: 
(1) rate the intensity and seriousness of the AE, (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.   


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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 an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition). 
*Hospitalizations that would not be considered SAEs include those for: 
 Routine treatment or monitoring of the study indication not associated with any 
deterioration in condition (eg, hospitalization for a routine RHC). 
 Treatment which was elective or preplanned, for a pre-existing condition not 
associated with any deterioration in condition (eg, preplanned operation which does 
not lead to further complications etc). 
 Treatment of an emergency, in an outpatient setting for an event not fulfilling any of 
the definitions of serious as given above and not resulting in hospital admission. 
CAUSALITY 
An estimate of causality between a specified AE and the study drug is made by the 
Investigator.  Several factors should be considered when determining causality.  These factors 
include temporal relationship and response to withdrawal or reintroduction of the study drug.   
Definitions of the causality categories are as follows: 
 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, or any of the following: 
 An event that precedes the first administration of study drug 
 An event for which the cause is clearly related to an external event 
 Temporal relationship to study drug is atypical 
 Is readily explained by an intercurrent illness AND has an expected level of severity, 
duration and resolution 
 An alternative explanation (concomitant drug, intercurrent illness) is likely 


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 POSSIBLE – There is a reasonable causal relationship between the study drug and the 
SAE.  Dechallenge information is lacking or unclear, study drug administration was 
not modified in response to the SAE, or any of the following: 
 Has a reasonable temporal relationship to study drug 
 The event has a plausible biological link to the activity of the study drug 
 Is unlikely to be related to an intercurrent illness or has an unexpected degree of 
severity, duration, or complication 
 PROBABLE – There is a reasonable causal relationship between the study drug and 
the SAE.  The event responds to dechallenge—the event resolves or improves with 
modification of study drug administration.  Rechallenge (the original study drug was 
restarted) is not required, or any of the following: 
 Has a reasonable temporal relationship to study drug 
 The event has a plausible biologic link to the activity of the study drug 
 Not readily explained by an intercurrent illness 
 Not readily explained by external event 
 Improves on discontinuation of study drug 
 If study drug has been discontinued, may recur or reintroduction of study drug 
ACTION TAKEN 
STUDY DRUG DOSE MODIFICATION 
 Dose Not Changed – The dose or regimen of the study drug was not changed. 
 Dose Increased – The dose or regimen of study drug was increased  
 Dose Reduced – The dose or regimen of study drug was reduced  
 Drug Interrupted – Administration of the study drug was stopped temporarily 
 Drug Withdrawn – Administration of the study drug was stopped permanently and not 
restarted 
 Not Applicable 
 Unknown – Changes to the administration of the study drug cannot be determined 
NOTE:  Only the last study drug action should be recorded in the eCRF.  For example, if the 
study drug is withdrawn and then the decision is made to restart, the dose modification of 
“Drug interrupted” should be reported on the SAE form. 


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OUTCOME 
 Fatal – The study subject died. 
 Not Recovered/Not Resolved – The AE was ongoing at the time of death or at the time 
the subject was lost to follow up. 
 Recovered/Resolved – The AE resolved. 
 Recovered/Resolved with Sequelae – The AE is considered resolved; however, there 
is residual sequelae.  Some events do not return to baseline, such as metastasis or 
progression of disease; however, once these events are determined by the Investigator 
to be stable or chronic, the Investigator may consider the event to be resolved or 
resolved with sequelae. 
 Recovering/Resolving – The AE is improving but is not yet completely 
recovered/resolved. 
 Unknown – The outcome of the AE cannot be determined. 


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15.4 
CLINICAL LABORATORY PARAMETERS 
Blood Chemistries 
Hematology 
Other 
Sodium 
Red blood cell count 
N-terminal pro-brain natriuretic 
peptide (NT-proBNP)  
Potassium 
Hemoglobin 
Urine pregnancy testa 
Chloride 
Hematocrit 
 
Bicarbonate/CO2 
Platelet count 
 
Albumin 
White blood cell count 
 
Blood urea nitrogen/urea 
Glycated hemoglobin (HbA1c) 
 
Total bilirubin 
 
 
Indirect bilirubin 
 
 
Direct bilirubin 
 
 
Alkaline phosphatase 
 
 
Alanine aminotransferase (ALT) 
 
 
Aspartate aminotransferase (AST) 
 
 
Gamma-glutamyl transferase (GGT) 
 
 
Creatinine 
 
 
a Urine pregnancy test for women of childbearing potential 
Visit Test Schedule 
Visit 
Labs Collected 
Screenb 
Chemistries, Hematology, urine pregnancya 
Baselineb 
Chemistries, Hematology, NT-proBNP, urine pregnancya 
Week 6 
Urine pregnancya 
Week 12 
Chemistries, Hematology, NT-proBNP, urine pregnancya 
Week 18 
Urine pregnancya 
Study Drug Termination 
Chemistries, Hematology, NT-proBNP, urine pregnancya 
Week 24 
Chemistries, Hematology, NT-proBNP, urine pregnancya 
NT-proBNP, N-terminal pro-brain natriuretic peptide 
a Urine pregnancy tests for women of childbearing potential only 
b If combining Screening and Baseline visits, utilize Baseline laboratory kit type 


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


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15.6 
KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE 
 


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15.7 
EVALUATION OF SIGNS/SYMPTOMS OF HEART FAILURE AND VITAL 
SIGNS 
Vital signs should be collected prior to the 6MWT (following at least 5 minutes of rest 
[seated]; no other measurements or procedures should be performed during this 5-minute 
period).  If vital signs cannot be obtained prior to the 6MWT, then they should be obtained 
after a minimum 30-minute recovery from the 6MWT.  The following vital signs and heart 
failure signs and symptoms should be evaluated at each study visit. 
Vital Signs 
1. Blood pressure-peripheral (radial/brachial artery) 
2. Heart rate 
3. Respiratory rate 
4. Weight 
5. Height (collected at the Baseline Visit only) 
Heart Failure Signs and Symptoms 
1. Peripheral edema (none, trace, 1+, 2+, 3+) 
2. Jugular venous pressure (present, absent) 
3. Breath sounds: clear, diminished, rhonchi, wheezes, rales (present/absent) 
4. Ascites (present/absent) 
5. Dyspnea (at rest, minimal activity, exertional activity, none, or with vigorous activity 
only) 
6. Orthopnea (present/absent)  
7. Paroxysmal nocturnal dyspnea (present/absent) 
8. Decreased appetite/bloating/early satiety compared with Baseline (present/absent) 
9. Syncope (present/absent) 
10. Chest pain (present/absent) 
11. Fatigue (none, mild, moderate, severe) 

SAP_001.pdf: 
United Therapeutics Corp. 
 
TDE-HF-301 and -302 DMC SAP 
Oral Treprostinil 
Document Type: 
Statistical Analysis Plan for 
DMC Meeting Deliverables 
Protocol/Study No.:  
TDE-HF-301 and 
TDE-HF-302 
Final Date: 
 
18 September 2017 
Total Number of 
Pages including 
Appendices: 
 
15 
Classification: 
Confidential 
 
 
Title: 
Protocol TDE-HF-301:  A Multicenter, Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Safety and Efficacy of Oral Treprostinil in 
Subjects with Pulmonary Hypertension (PH) in Heart Failure with Preserved 
Ejection Fraction (HFpEF) 
 
Protocol TDE-HF-302:  An Open-label Extension Study of Oral Treprostinil in 
Subjects with Pulmonary Hypertension (PH) Associated with Heart Failure 
with Preserved Ejection Fraction (HFpEF)- A Long-term Follow-up to Study 
TDE-HF-301 
 
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. © 2017 United Therapeutics 
Corporation 


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TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ........................................................................................................2 
TABLE OF IN-TEXT TABLES .............................................................................................3 
ABBREVIATIONS AND DEFINITIONS .............................................................................4 
1  PREFACE ...........................................................................................................................5 
2  STUDY OBJECTIVES ......................................................................................................5 
3  STUDY DESIGN(S) ...........................................................................................................6 
4  RANDOMIZATION ..........................................................................................................6 
5  SEQUENCE OF PLANNED ANALYSES ......................................................................6 
6  ANALYSIS POPULATION ..............................................................................................7 
7  GENERAL CONSIDERATIONS FOR DATA ANALYSES ........................................7 
7.1 
Premature Discontinuation and Missing Data ....................................................7 
8  STUDY POPULATION ....................................................................................................8 
8.1 
Subject Disposition.................................................................................................8 
8.2 
Demographics and Baseline Characteristics .......................................................8 
9  EFFICACY ANALYSES ..................................................................................................8 
9.1 
Six-Minute Walk Test ............................................................................................8 
9.2 
WHO Functional Class ..........................................................................................8 
9.3 
Clinical Worsening.................................................................................................9 
10  SAFETY ANALYSES .......................................................................................................9 
10.1  Study Drug Dosing .................................................................................................9 
10.2  Diuretic Dosing .....................................................................................................10 
10.3  Adverse Events .....................................................................................................10 
10.4  Deaths ....................................................................................................................10 
10.5  Vital Signs .............................................................................................................11 
10.6  Laboratory Assessments ......................................................................................11 
11  APPENDICES ..................................................................................................................12 
11.1  List of Tables ........................................................................................................12 
11.2  List of Listings ......................................................................................................13 
11.3  List of Figures .......................................................................................................14 


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TABLE OF IN-TEXT TABLES 
Table 10-1 
Laboratory Parameters .............................................................................. 11 
 
 


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ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
HFpEF 
Heart failure with preserved ejection fraction 
HR 
Heart rate 
IV 
Intravenous 
IVRS/IWRS 
Interactive voice or web response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-proBNP 
N-Terminal pro-brain natriuretic peptide 
PH 
Pulmonary hypertension 
PT 
Preferred Term 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOC 
System Organ Class 
TID 
3 Times daily 
WHO 
World Health Organization 
 


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1 
PREFACE 
This statistical analysis plan (SAP) provides further details of the planned interim deliverables 
for each Data Monitoring Committee (DMC) meeting for the TDE-HF-301 and TDE-HF-302 
studies.  The purpose of this SAP is to ensure that the statistical methodologies that will be 
used, and the data listings, summary tables, and figures which will be produced, are 
appropriate and complete to support valid interim safety reviews.   
2 
STUDY OBJECTIVES  
The primary objective of the TDE-HF-301 study is to assess the effect of oral treprostinil 
compared with placebo on change in exercise capacity as measured by change in 6-Minute 
Walk Distance (6MWD) from Baseline to Week 24 in subjects with pulmonary hypertension 
(PH) associated with heart failure with preserved ejection fraction (HFpEF). 
The secondary objectives of this study are to assess the effect of oral treprostinil compared 
with placebo on the following: 
 Time to clinical worsening defined by at least 1 of the following: 
o Hospitalization due to a cardiopulmonary indication 
o Outpatient administration of intravenous (IV) diuretics 
o Decrease in 6MWD >15% from Baseline (or too ill to walk) directly related to 
disease under study at 2 consecutive visits on different days 
o Death (all causes) 
 Change in N-Terminal pro-brain natriuretic peptide (NT-proBNP) levels from 
Baseline to Week 24 
 Change in World Health Organization (WHO) Functional Class from Baseline to 
Week 24 
The exploratory objectives of the TDE-HF-301 study are to assess the effect of oral 
treprostinil compared with placebo on the following: 
 Change in 6MWD from Baseline to Weeks 6, 12, and 18 
 Change in Borg dyspnea score from Baseline to Weeks 6, 12, 18, and 24 
 Change in NT-proBNP levels from Baseline to Week 12 
 Change in WHO Functional Class from Baseline to Weeks 6, 12, and 18 
 Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) from Baseline to 
Week 24 
 Optional evaluation of biomarkers (specific targets to be determined) from Baseline to 
Week 24 
 Optional evaluation of pharmacogenomics 
The primary objective of the TDE-HF-302 study is to evaluate the long-term safety of oral 
treprostinil in subjects with PH associated with HFpEF who completed Study TDE-HF-301. 
The secondary objective of the TDE-HF-302 study is to assess the effect of continued long-
term therapy with oral treprostinil on the following: 
 6MWD  
 Borg dyspnea score  
 WHO Functional Class 


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 NT-proBNP at Weeks 24 and 48 
 
3 
STUDY DESIGN(S) 
Study TDE-HF-301 is a multi-center, randomized, double-blind, placebo-controlled study in 
subjects with WHO Group 2 PH associated with HFpEF.  Once randomized, subjects will 
return to the site for study visits every 6 weeks for a 24-week treatment period.  If a subject 
completes the 24-week treatment period on study drug, they will be permitted to enter the 
open-label extension study (Study TDE-HF-302).  If a subject prematurely discontinues the 
study for any reason, or discontinues study drug prematurely, they will not be permitted to 
enter Study TDE-HF-302. 
Subjects will receive their first dose of study drug (0.125 mg) in the clinic on the day of 
randomization.  Dosing of study drug will be continued at 0.125 mg 3 times daily (TID; every 
6 to 8 hours) with food, up to an initial maximum dose of 2 mg TID.  Based on the approval 
by the DMC, the dose will be slowly titrated throughout the study up to a maximum of 4 mg 
TID and then 6 mg TID, as safety data permit, in an effort to reach a tolerated dose that 
provides clinical benefit. 
Study TDE-HF-302 is a multi-center, open-label study for eligible patients who completed 
Study TDE-HF-301.  Once enrolled, subjects will return to the site for study visits at Weeks 6, 
12, 18, 24, and every 12 weeks thereafter. 
4 
RANDOMIZATION 
Study TDE-HF-301 will be randomized 1:1 oral treprostinil to placebo.  All subjects will be 
randomly allocated to receive oral treprostinil or placebo through the interactive voice or web 
response system (IVRS/IWRS) using a centrally administered randomization.  The 
randomization will be stratified by Baseline 6MWD (less than or equal to 350 meters and 
greater than 350 meters). 
Study TDE-HF-302 is an open-label study of oral treprostinil.  All subjects will receive oral 
treprostinil. 
5 
SEQUENCE OF PLANNED ANALYSES 
Throughout the course of the TDE-HF-301 study, the DMC will meet on a regular basis to 
monitor the safety of the studies and make changes to maximum dosages of study drug to be 
used in accordance with the DMC charter.  The DMC will meet for formal safety reviews 
after approximately 10, 30, 60, 100, and 200 subjects have been enrolled in the TDE-HF-301 
study.  Ad hoc meetings may be scheduled at additional enrollment milestones or in response 
to events related to the safety of study treatment.  
For the TDE-HF-301 study, the DMC will review subject disposition, demographics and 
baseline characteristics, 6-Minute Walk Test (6MWT), WHO Functional Class, clinical 
worsening, diuretic dosing, selected clinical laboratory parameters, vital signs, study drug 
dosing, and safety data, including adverse events (AEs), serious adverse events (SAEs), and 
deaths for the safety population using all available data.  Pertinent vital sign parameters, 
dosing, and clinical laboratory parameters will be plotted. 


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For the TDE-HF-302 study, the DMC will review subject disposition and safety data, 
including AEs, SAEs, and deaths.     
Data to be reviewed for the TDE-HF-301 and TDE-HF-302 studies will include by-subject 
listings as well as tabular summaries of the above noted data.  Any additional information 
deemed necessary to evaluate the continued safety of all enrolled subjects will also be 
provided. 
6 
ANALYSIS POPULATION 
The safety population for Study TDE-HF-301 will be defined as all subjects who receive at 
least 1 dose of study drug (regardless of randomization status); all subjects will be counted in 
the group corresponding to the treatment that they actually received.   
The safety population for Study TDE-HF-302 will be defined as all subjects who receive at 
least 1 dose of open-label study drug; all subjects will be counted in the oral treprostinil 
group.   
The safety population will be utilized to produce all data listings, summaries, and figures for 
discussion at the DMC meetings for the TDE-HF-301 and TDE-HF-302 studies. 
7 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All available data will be presented in a semi-unblinded (masked) fashion with no imputation 
for any missing data.  Treatment groups will be labeled A or B for summarization purposes; 
however, the DMC may request the full unblinding information in the closed session.   
Subjects will contribute the data available up to the point of study completion or study 
discontinuation for any reason for both studies.  For continuous variables, the summary 
statistics will include the mean, standard deviation, median, minimum, and maximum.  
Minimums and maximums will be expressed using the level of precision to which the variable 
was collected.  All other statistics will be rounded, using an additional decimal point.  For 
discrete variables, summaries will include the frequency and percent in each category.  
Percentages will be rounded to 1 decimal point.  Whenever practical, categories of discrete 
variables will be ordered and labeled as they appear in the electronic case report form (eCRF), 
and all categories represented on the eCRF will be included in summaries, even when they do 
not apply to any subjects in the study. 
7.1 
PREMATURE DISCONTINUATION AND MISSING DATA 
Subjects may voluntarily withdraw or 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 significantly deviates from the protocol. 
 The subject becomes pregnant. 


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 The subject’s behavior is likely to undermine the validity of his/her results. 
All available data from all treated subjects will be used as detailed in this analysis plan.  No 
imputation for missing data will be performed. 
8 
STUDY POPULATION 
8.1 
SUBJECT DISPOSITION 
For the TDE-HF-301 study, the listing of subject disposition will include subject number, date 
of enrollment, date of randomization, date study drug initiated, date study drug discontinued, 
reason for study drug discontinuation, date completed/discontinued from study, and reason for 
study termination.  The number of subjects enrolled, randomized, dosed with study drug 
(safety population), who discontinued study drug, and who discontinued from the study will 
be summarized by treatment and overall, as well as the reasons for study drug discontinuation 
and study discontinuation, and the descriptive statistics for weeks on study drug. 
For the TDE-HF-302 study, the listing of subject disposition will include subject number, date 
of enrollment, date completed/discontinued from study, and reason for discontinuation.  The 
number of subjects enrolled, dosed with study drug (safety population), who discontinued 
from the study, and the reasons for discontinuation will be summarized overall. 
8.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
The listing of subject demographics and baseline characteristics for Study TDE-HF-301 will 
include subject number, date of birth, age at randomization (years), sex, race, ethnicity, 
HFpEF diagnosis, and etiology.  Age at randomization, sex, race, ethnicity, and etiology will 
be summarized by masked treatment group and overall. 
9 
EFFICACY ANALYSES 
Efficacy parameters will be assessed as a surrogate for safety issues.  The efficacy parameters 
to be included are the 6MWT, WHO Functional Class, and reports of clinical worsening. 
9.1 
SIX-MINUTE WALK TEST 
The listing of the 6MWT data for Study TDE-HF-301 will include subject number, nominal 
time point, assessment date/time, date/time of last study drug dose, last study drug dose (mg), 
total distance walked (m), Borg dyspnea score, oxygen receipt (yes/no), amount of oxygen 
(L/min), unusual circumstances, and reason walk not attempted (if applicable) for each 
treatment arm.  The total distance walked (m) and Borg dyspnea score will be summarized by 
masked treatment group at Baseline, Weeks 6, 12, 18, and 24/Early Termination, including 
changes from Baseline. 
9.2 
WHO FUNCTIONAL CLASS 
The listing of WHO Functional Class for Study TDE-HF-301 will include subject number, 
nominal time point, assessment date, and WHO Functional Class (I, II, III, or IV) for each 
treatment arm.  The WHO Functional Class will be summarized by masked treatment group 


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and overall at Baseline, Weeks 6, 12, 18, and 24/Early Termination, including shifts from 
Baseline. 
9.3 
CLINICAL WORSENING 
Clinical worsening will be assessed continuously from randomization until 1 of the following 
criteria are met: 
 Hospitalization due to a cardiopulmonary indication 
 Outpatient administration of IV diuretics 
 Decrease in 6MWD >15% from Baseline (or too ill to walk) directly related to 
the disease under study at 2 consecutive visits on different days 
 Death (all causes) 
A listing of clinical worsening data for Study TDE-HF-301 will include subject number, 
clinical worsening (yes/no), date of clinical worsening event, and type of clinical worsening 
event for each treatment arm.  The number (percent) of subjects who experienced clinical 
worsening and the clinical worsening event types will be summarized by masked treatment 
group. 
10 SAFETY ANALYSES 
Safety will be assessed by treatment-emergent changes in physical examination findings, vital 
signs, assessment of heart failure signs and symptoms, clinical laboratory tests, and the 
development of AEs after treatment.  Treatment emergence is defined as the time points on or 
after the first dose of study drug. 
Treatment-emergent changes in vital signs, incidence of treatment-emergent AEs, and 
treatment-emergent changes in laboratory parameters will be evaluated.  Statistical summaries 
of safety data will be descriptive and exploratory in nature, focusing on the incidence of 
adverse experiences.  The vital signs, AEs, deaths, and clinical laboratory parameters 
collected in Study TDE-HF-301 will be listed and summarized.  The safety data analysis for 
Study TDE-HF-302 will list and summarize the AEs SAEs, and deaths.  No inferential 
statistical analyses are planned for safety data.     
10.1 STUDY DRUG DOSING 
The listing of study drug dosing for Study TDE-HF-301 will include the subject number, date 
of study drug dose, first study drug dose (mg), and the dates/times of any new doses, along 
with the new dose (mg).  The summary of study drug dose will include the first study drug 
dose (mg) and the study drug doses (mg) at Weeks 6, 12, 18, and 24/Early Termination by 
masked treatment group.  For summarization purposes, the study drug dose (mg) will be 
calculated as the sum of the doses administered during the study day that corresponds to each 
nominal time point divided by the number of doses administered on that given day.  Study 
drug dosing will be plotted across time.  For the first 2 DMC meetings, given the low number 
of subjects, the dosing figures will include a line for each individual subject (spaghetti plot), 
using a different line type for each masked treatment group.  After the second DMC meeting, 
the number of subjects will be too great for a spaghetti plot to be informative, thus mean plots 


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will be generated across time with each treatment group being represented by its own unique 
line.  
10.2 DIURETIC DOSING 
The listing of diuretic dosing will include the subject number, name of generic drug, total 
daily dose, indication that drug was onging at randomization (yes/no), start date, end date, and 
indication that drug was onging at the end of study for each treatment arm (yes/no). 
10.3 ADVERSE EVENTS 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
according to System Organ Class (SOC) and Preferred Term (PT).  The listings of all AEs and 
SAEs, separately, will include the subject number, reported AE/SAE term (verbatim term and 
MedDRA coded PT), start and stop dates/time or ongoing, treatment emergent status (yes/no), 
seriousness (reason for seriousness/no), date event became serious, frequency 
(once/intermittent/continuous), severity (mild/moderate/severe), action taken with study drug, 
Investigator’s assessment of relationship to study drug (not related/possible/probable), and 
outcome.  The listings will be sorted by subject number and then in chronological order of 
start date of AEs/SAEs, with the masked treatment arm represented at the page level for Study 
TDE-HF-301.  The listings for Study TDE-HF-302 will also be sorted by subject number and 
then in chronological order of start date of AEs/SAEs, but all subjects will be included in the 
same listing since there is 1 treatment group in this open-label study. 
Adverse event/SAE summaries will be limited to include only treatment-emergent AEs/SAEs.  
Treatment-emergent AEs/SAEs are those that were not present prior to receiving study drug 
or those that increased in seriousness or intensity after receiving study drug.  The summaries 
of treatment-emergent AEs/SAEs will include the number and percent of subjects 
experiencing each type of event (by PT) and the total number of each type of event by masked 
treatment group for Study TDE-HF-301.  For Study TDE-HF-302, the summaries of 
treatment-emergent AEs/SAEs will include the number and percent of subjects experiencing 
each type of event (by PT) and the total number of each type of event overall.  The order of 
AEs/SAEs by PT will be in decreasing frequency within the overall column.  The first row on 
these 4 tables will present the data for “Any Adverse Event” or “Any Serious Adverse Event,” 
respectively. 
10.4 DEATHS 
The listing of deaths for studies TDE-HF-301 and TDE-HF-302 will include subject number, 
date of death, and cause of death for all deaths occurring between first study drug dose and 
the end of study, or within 4 weeks after last study drug dose, if the subject prematurely 
terminates.  The summary of deaths for Study TDE-HF-301 will include the number 
(percentage) of deaths, as well as causes of death by masked treatment group.  The summary 
of deaths for Study TDE-HF-302 will include the number (percentage) of deaths, as well as 
causes of death overall. 


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10.5 VITAL SIGNS 
The listing of vital signs for Study TDE-HF-301 will include subject number, nominal time 
point, date/time, diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate 
(HR), respiratory rate (RR), and weight for each treatment arm.  All time points will be 
ordered chronologically by subject.  Vital signs (excluding height) and their respective 
changes from Baseline will be summarized by masked treatment group at Baseline, Weeks 6, 
12, 18, and Week 24/Early Termination.  Vital signs, with the exception of height, will be 
plotted across time.  For the first 2 DMC meetings, given the low number of subjects, the vital 
sign figures will include a line for each individual subject (spaghetti plot).  After the second 
DMC meeting, the number of subjects will be too great for a spaghetti plot to be informative, 
thus mean plots will be generated across time with each treatment group being represented by 
its own unique line. 
10.6 LABORATORY ASSESSMENTS 
The listing of laboratory parameters for Study TDE-HF-301 will include subject number, 
nominal time point, date/time, and the laboratory parameters specified for each type, as shown 
in 10-1. 
Table 10-1 
Laboratory Parameters 
Clinical Chemistry  
Hematology 
Sodium 
Red blood cell count 
Potassium 
Hemoglobin 
Chloride 
Hematocrit 
Bicarbonate/CO2 
Platelet 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 
 
These laboratory parameters will be summarized along with change from Baseline by masked 
treatment group at Baseline, Week 12, and Week 24/Early Termination.  The laboratory 
parameters will be plotted across time.  For the first 2 DMC meetings, given the low number 
of subjects, the laboratory figures will include a line for each individual subject (spaghetti 
plot) with 2 different line colors used to delineate the 2 treatment groups.  After the second 
DMC meeting, the number of subjects will be too great for a spaghetti plot to be informative, 
thus mean plots will be generated across time with each treatment group being represented by 
its own unique line. 


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11 APPENDICES 
Table, listing, and figure titles suggested here may be altered or edited as appropriate by the 
clinical data programmers while maintaining the original intent of the output. 
11.1 LIST OF TABLES 
Table Number 
Table Title 
1 
Summary of Subject Disposition for Study TDE-HF-301 
2 
Summary of Demographics and Baseline Characteristics for Study TDE-HF-301 
3 
Summary of Six-Minute Walk Test for Study TDE-HF-301 
4 
Summary of WHO Functional Class for Study TDE-HF-301 
5 
Summary of Clinical Worsening for Study TDE-HF-301 
6 
Summary of Study Drug Dosing for Study TDE-HF-301 
7 
Summary of Treatment-Emergent Adverse Events for Study TDE-HF-301 
8 
Summary of Treatment-Emergent Serious Adverse Events for Study TDE-HF-301 
9 
Summary of Deaths for Study TDE-HF-301 
10 
Summary of Vital Signs for Study TDE-HF-301 
11 
Summary of Laboratory Parameters for Study TDE-HF-301 
12 
Summary of Subject Disposition for Study TDE-HF-302 
13 
Summary of Treatment-Emergent Adverse Events for Study TDE-HF-302 
14 
Summary of Treatment-Emergent Serious Adverse Events for Study TDE-HF-302 
15 
Summary of Deaths for Study TDE-HF-302 


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11.2 LIST OF LISTINGS 
Listing Number 
Listing Title 
1 
Listing of Subject Disposition for Study TDE-HF-301 
2 
Listing of Demographics and Baseline Characteristics for Study 
TDE-HF-301 
3 
Listing of Six-Minute Walk Test Data for Study TDE-HF-301 
4 
Listing of WHO Functional Class for Study TDE-HF-301 
5 
Listing of Clinical Worsening for Study TDE-HF-301 
6 
Listing of Study Drug Dose for Study TDE-HF-301 
7 
Listing of Diuretic Dosing for Study TDE-HF-301 
8 
Listing of Adverse Events for Study TDE-HF-301 
9 
Listing of Serious Adverse Events for Study TDE-HF-301 
10 
Listing of Deaths for Study TDE-HF-301 
11 
Listing of Vital Signs for Study TDE-HF-301 
12 
Listing of Laboratory Parameters for Study TDE-HF-301 
13 
Listing of Subject Disposition for Study TDE-HF-302 
14 
Listing of Adverse Events for Study TDE-HF-302 
15 
Listing of Serious Adverse Events for Study TDE-HF-302 
16 
Listing of Deaths for Study TDE-HF-302 
 
 
 


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11.3 LIST OF FIGURES 
Figure Number 
Figure Title 
1 
Plot of Study Drug Dosing for Study TDE-HF-301 
2 
Plot of Blood Pressure for Study TDE-HF-301 
3 
Plot of Heart Rate for Study TDE-HF-301 
4 
Plot of Respiratory Rate for Study TDE-HF-301 
5 
Plot of Weight for Study TDE-HF-301 
6 
Plot of Sodium for Study TDE-HF-301 
7 
Plot of Potassium for Study TDE-HF-301 
8 
Plot of Chloride for Study TDE-HF-301 
9 
Plot of Bicarbonate/CO2 for Study TDE-HF-301 
10 
Plot of Albumin for Study TDE-HF-301 
11 
Plot of Blood Urea Nitrogen/Urea for Study TDE-HF-301 
12 
Plot of Total Bilirubin for Study TDE-HF-301 
13 
Plot of Indirect Bilirubin for Study TDE-HF-301 
14 
Plot of Direct Bilirubin for Study TDE-HF-301 
15 
Plot of Alkaline Phosphatase for Study TDE-HF-301 
16 
Plot of Alanine Aminotransferase for Study TDE-HF-301 
17 
Plot of Aspartate Aminotransferase for Study TDE-HF-301 
18 
Plot of Gamma-glutamyl Transferase for Study TDE-HF-301 
19 
Plot of Creatinine for Study TDE-HF-301 
20 
Plot of Red Blood Cell Count for Study TDE-HF-301 
21 
Plot of Hemoglobin for Study TDE-HF-301 
22 
Plot of Hematocrit for Study TDE-HF-301 


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Figure Number 
Figure Title 
23 
Plot of Platelet Count for Study TDE-HF-301 
24 
Plot of White Blood Cell Count for Study TDE-HF-301