Clinical trial NCT03043651
Conditions: Pulmonary Hypertension Associated With HFpEF
Keywords: Pulmonary Hypertension HFpEF 6-Minute Walk Test Oral Treprostinil
Sponsor: United Therapeutics
Start date: 2018-01-30; Completion date: 2020-03-02
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was an open-label study to evaluate the safety of continued therapy with oral treprostinil in subjects who completed Study TDE-HF-301. This study provided long-term, open-label data regarding the effect of continued long-term oral treprostinil therapy for the treatment of pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF). Subject visits occurred at Baseline, Weeks 6, 12, 18, 24, and every 12 weeks thereafter until either oral treprostinil was commercially available to treat PH associated with HFpEF or the study was discontinued by the Sponsor.

The Sponsor terminated Studies TDE-HF-301 and TDE-HF-302 on 14 October 2019 due to slow enrollment. Safety data from the final subject in Study TDE-HF-302 were recorded on 02 March 2020. Due to the lower than expected number of subjects enrolled, the planned secondary efficacy-related endpoints were not analyzed.

Detailed description:
Study TDE-HF-302 was a multicenter, open-label study in subjects participating and completing all required visits for Study TDE-HF-301. This study assessed the long-term safety of oral treprostinil in subjects with PH associated with HFpEF.

Subjects received oral treprostinil as 0.125-, 0.25-, 1-, and 2.5-mg sustained-release tablets. For subjects who were randomly allocated to receive oral treprostinil in Study TDE-HF-301, the initial dose of oral treprostinil was the same as the final dose in Study TDE-HF-301. Subjects randomly allocated to receive placebo in Study TDE-HF-301 were administered the initial dose of oral treprostinil at 0.125 mg 3 times daily (TID). Dose increases could occur in 0.125-mg increments every 72 hours at the discretion of the Investigator up to 6 mg TID, the maximum allowable dose determined by the Data Monitoring Committee during Study TDE-HF-301. 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, and every 12 weeks thereafter. Subjects who terminated the study early were asked to return to the study center for a final evaluation.

Safety assessments consisted of AEs, clinical laboratory parameters, and clinical assessment of heart failure signs and symptoms.

Due to the lower than expected number of subjects enrolled, the planned secondary efficacy-related endpoints were not analyzed.

Arms: arm 1: Sustained-release tablets for TID administration
Interventions: intervention 1: Oral treprostinil
Intervention descriptions: intervention 1: Sustained-release oral tablets for TID administration

Protocol documents:
Prot_000.pdf: 
United Therapeutics Corp. 
TDE-HF-302 Protocol Amendment 2 
 
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 
 
 
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 
IND Number 133,962 
Protocol TDE-HF-302 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
28 December 2016 
Amendment 1 
19 September 2017 
Amendment 2 
11 February 2019 


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LIST OF CONTACTS FOR STUDY 
Contract Research 
Organization 
 
 
Study Sponsor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Clinical 
Laboratory 
3 
 
 


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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “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” 
Amendment 2, dated 11 February 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 (EC)/Institutional Review Board (IRB) 
approval documents have been obtained. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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PROTOCOL SYNOPSIS 
Title  
An 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 
Study Phase 
3 
Indication 
Pulmonary hypertension associated with HFpEF 
Primary Objective 
The primary objective of this study is to evaluate the long-term 
safety of oral treprostinil in subjects with PH associated with 
HFpEF for subjects who completed Study TDE-HF-301. 
Secondary Objective(s) 
To assess the effect of continued long-term therapy with oral 
treprostinil on the following: 
 6-Minute Walk Distance (6MWD) 
 Borg dyspnea score 
 World Health Organization (WHO) Functional Class 
 N-Terminal pro-brain natriuretic peptide (NT-proBNP) 
at Weeks 24 and 48 
Study Design 
Multi-center, open-label study for eligible patients who 
completed Study TDE-HF-301 
Sample Size 
Approximately 310 subjects from Study TDE-HF-301 will be 
enrolled 
Summary of Subject 
Eligibility Criteria 
Participation and completion of required visits from 
Study TDE-HF-301 
Drug Dosage  
and Formulation 
All subjects will receive oral treprostinil sustained release 
tablets.  Study drug will be provided in 0.125-, 0.25-, 1-, and 
2.5-mg sustained release tablets. 
For subjects who were randomly allocated to oral treprostinil 
in Study TDE-HF-301, the initial dose of oral treprostinil will 
be based upon the final dose in Study TDE-HF-301. 
For subjects who were randomly allocated to placebo in 
Study TDE-HF-301, the initial dose of oral treprostinil will be 
initiated at 0.125 mg 3 times daily (TID). 
Control Group 
None 
Route of  
Administration 
Oral 


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Procedures 
Study visits will occur at Baseline, Weeks 6, 12, 18, 24, and 
every 12 weeks thereafter.  Study visits will continue until 
either the subject discontinues the study or until the study is 
discontinued by the Sponsor. 
Study assessments include: 
 6-Minute Walk Test (6MWT)/Borg dyspnea score 
 WHO Functional Class 
 NT-proBNP (Weeks 24 and 48 only) 
 
Safety (assessment of heart failure signs and symptoms 
with vital signs, adverse events (AEs), clinical 
laboratory assessments, concomitant medications 
Statistical Considerations All data will be summarized in tables and listings. 
Sponsor 
United Therapeutics Corp. 
55 TW Alexander Dr. 
P.O. Box 14186 
Research Triangle Park, NC  27709 
USA 


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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY .................................................................................... 2 
INVESTIGATOR’S AGREEMENT ..................................................................................... 3 
PROTOCOL SYNOPSIS ....................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................ 6 
Table of In-Text Tables .......................................................................................................... 8 
LIST OF ABBREVIATIONS ................................................................................................ 9 
1 BACKGROUND AND RATIONALE .......................................................................... 11 
1.1 
DEFINITION OF CLINICAL PROBLEM ............................................................. 11 
1.2 
TREPROSTINIL DIETHANOLAMINE BACKGROUND .................................. 12 
1.2.1 
General Pharmacology .......................................................................................... 12 
1.2.2 
General Toxicology ................................................................................................ 13 
1.2.3 
Clinical Pharmacology .......................................................................................... 14 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION ............................................................................................ 16 
1.4 
CLINICAL HYPOTHESIS ....................................................................................... 19 
2 OBJECTIVES ................................................................................................................. 19 
2.1 
PRIMARY OBJECTIVE .......................................................................................... 19 
2.2 
SECONDARY OBJECTIVES .................................................................................. 19 
2.3 
SAFETY ENDPOINTS .............................................................................................. 20 
3 EXPERIMENTAL PLAN .............................................................................................. 20 
3.1 
STUDY DESIGN ........................................................................................................ 20 
3.2 
SCHEDULE OF TIMES AND EVENTS ................................................................. 21 
3.3 
CLINICAL ASSESSMENTS .................................................................................... 23 
3.3.1 
Efficacy ................................................................................................................... 23 
3.3.1.1 
6-Minute Walk Test ........................................................................................... 23 
3.3.1.2 
Borg Dyspnea Score ........................................................................................... 23 
3.3.1.3 
WHO Functional Class ...................................................................................... 23 
3.3.1.4 
NT-proBNP ......................................................................................................... 23 
3.3.2 
Safety ...................................................................................................................... 23 
3.3.2.1 
Assessment of Heart Failure Signs and Symptoms with Vital Signs ............ 23 
3.3.2.2 
Physical Examination ........................................................................................ 24 
3.3.2.3 
Clinical Laboratory Assessments ..................................................................... 24 
3.3.2.4 
Adverse Event Assessments .............................................................................. 24 
3.3.2.5 
Pregnancy Testing .............................................................................................. 25 
3.3.2.6 
Concomitant Medications ................................................................................. 25 
3.4 
NUMBER OF CENTERS .......................................................................................... 26 
3.5 
NUMBER OF SUBJECTS ........................................................................................ 26 
3.6 
ESTIMATED STUDY DURATION ......................................................................... 26 


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4 SUBJECT ELIGIBILITY .............................................................................................. 26 
4.1 
INCLUSION CRITERIA .......................................................................................... 26 
4.2 
EXCLUSION CRITERIA ......................................................................................... 27 
4.3 
PRESCRIBED THERAPY ........................................................................................ 27 
4.3.1 
Concomitant Medications ..................................................................................... 27 
5 SUBJECT ENROLLMENT ........................................................................................... 27 
5.1 
TREATMENT ASSIGNMENT ................................................................................ 27 
5.2 
RANDOMIZATION .................................................................................................. 27 
5.3 
BLINDING .................................................................................................................. 27 
6 DRUGS AND DOSING (OR TREATMENT PROCEDURES) ................................. 27 
6.1 
DRUG DOSAGE, ADMINISTRATION, AND SCHEDULE ................................ 27 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT ..................................... 30 
6.3 
COMPLIANCE .......................................................................................................... 30 
7 EXPERIMENTAL PROCEDURES ............................................................................. 31 
7.1 
TREATMENT PHASE .............................................................................................. 31 
7.1.1 
Baseline ................................................................................................................... 31 
7.1.2 
Week 6 Visit ........................................................................................................... 32 
7.1.3 
Week 12 Visit ......................................................................................................... 33 
7.1.4 
Week 18 Visit ......................................................................................................... 33 
7.1.5 
Week 24 Visit ......................................................................................................... 33 
7.1.6 
Follow-up Visits (Every 12 Weeks) ...................................................................... 33 
7.1.7 
Study Termination Visit ........................................................................................ 34 
8 STUDY TERMINATION ............................................................................................... 35 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ....................................................... 35 
8.2 
CRITERIA FOR TERMINATING THE STUDY .................................................. 35 
8.3 
CRITERIA FOR DISCONTINUING THE STUDY SITE .................................... 35 
9 ADVERSE EVENT REPORTING ................................................................................ 36 
9.1 
DEFINITIONS ........................................................................................................... 36 
9.1.1 
Adverse Event ........................................................................................................ 36 
9.1.2 
Serious Adverse Event .......................................................................................... 37 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ..................................................... 37 
9.3 
PREGNANCY ............................................................................................................ 38 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ....................... 38 
9.5 
SAFETY REPORTS .................................................................................................. 39 
10 STATISTICAL CONSIDERATIONS .......................................................................... 39 
10.1 DATA PROCESSING ................................................................................................ 39 
10.2 SAMPLE SIZE ........................................................................................................... 40 
10.3 ANALYSIS PLAN ...................................................................................................... 40 
10.4 OTHER ANALYSES ................................................................................................. 40 
11 PACKAGING AND FORMULATION ........................................................................ 40 


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11.1 CONTENTS OF STUDY DRUG .............................................................................. 40 
11.2 LABELING ................................................................................................................. 40 
11.3 STORAGE AND HANDLING OF CLINICAL STUDY MATERIAL ................. 41 
11.4 SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL .......................... 41 
11.5 DRUG ACCOUNTABILITY .................................................................................... 41 
12 REGULATORY AND ETHICAL OBLIGATION ...................................................... 42 
12.1 ICH GCP OR APPLICABLE REGULATORY REQUIREMENTS .................... 42 
12.2 INFORMED CONSENT REQUIREMENTS ......................................................... 42 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ....................................................................................................................... 42 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ......................................... 43 
12.5 SUBJECT CONFIDENTIALITY ............................................................................. 43 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 44 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .......................... 44 
13.2 STUDY DOCUMENTATION AND STORAGE .................................................... 44 
13.3 STUDY MONITORING AND DATA COLLECTION .......................................... 44 
14 REFERENCES ................................................................................................................ 46 
15 APPENDICES ................................................................................................................. 49 
15.1 PROCEDURE FOR 6-MINUTE WALK TEST AND BORG DYSPNEA 
SCORE ........................................................................................................................ 49 
15.2 WHO FUNCTIONAL CLASSIFICATION FOR PULMONARY 
HYPERTENSION ...................................................................................................... 51 
15.3 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE 
EVENTS ...................................................................................................................... 52 
15.4 CLINICAL LABORATORY PARAMETERS ....................................................... 56 
15.5 EVALUATION OF SIGNS/SYMPTOMS OF HEART FAILURE AND 
VITAL SIGNS ............................................................................................................ 57 
 
Table of In-Text Tables 
Table 3-1 
Overall Schedule of Time and Events ............................................................. 21 
Table 3-2 
Expected Events Attributable to the Progression of the Disease Under 
Study ............................................................................................................... 25 
Table 7-1 
Follow-up Visits by Week Beyond Week 24 .................................................. 34 
 


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LIST OF ABBREVIATIONS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
AUC 
Area under the curve 
BID 
Twice daily 
Cmax 
Maximal drug concentration 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ERA 
Endothelin receptor antagonist 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
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 
IV 
Intravenous(ly) 
IVRS/IWRS Interactive voice or web response system 
LV 
Left ventricular 
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 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic(s) 
PVR 
Pulmonary vascular resistance 
RHC 
Right heart catheterization 
RV 
Right ventricle 
SAE 
Serious adverse event 
SC 
Subcutaneous 


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SD 
Standard deviation 
TID 
3 times daily 
US 
United States 
UT 
United Therapeutics 
UT-15C SR 
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 (Simonneau 2013).  This classification includes PH 
due to left ventricular systolic and diastolic dysfunction, valvular heart disease, 
inflow/outflow tract obstruction, and congenital cardiomyopathies.  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 ‘post-capillary’ 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 ‘pre-capillary’ 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 post-capillary PH (Hussain 2016). 
Heart failure affects 1% to 2% of the adult population in developed countries, and HFpEF 
represents up to 70% 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 


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available for the treatment of HFpEF, have stimulated further investigation in this indication 
(Guazzi 2015b, Hussain 2016, Rosenkranz 2016). 
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 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 a sustained-release dosage form.  In solution, both treprostinil sodium and treprostinil 
diethanolamine are disassociated from their respective salt counter-ions and exist as the freely 


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ionized form of treprostinil.  As a result, the bioactive form present in the bloodstream is 
identical irrespective of the selection of the counter-ion. 
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 
patients 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 


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(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.  
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 administered oral treprostinil 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 
increase 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 Practice (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 (BID; 4 mg/kg/day) to male beagle dogs was not associated with 
any definitive changes in arterial pressure, heart rate, or electrocardiogram parameters.  In 
addition, no abnormal clinical signs were noted in the animals dosed with the vehicle or with 
any of the doses of diethanolamine. 
1.2.3 
Clinical Pharmacology 
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 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 curve [AUC]) indicate that Day 1 PK data are 
predictive of Day 13 and linearity was observed in plasma exposure comparing 1- 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.  On 
Day 7, the mean maximal drug concentration (Cmax; ± standard deviation [SD]) was 
0.810±0.491 ng/mL, occurring at a median time of 14 hours (range: 6 to 20 hours) following 
the morning dose.  This indicates that maximum concentration during a daily interval at 
steady state occurs after the evening (or third) dose of the day. 
Nineteen subjects (9 female, 10 male) with a mean age of 35.2 years (range: 20 to 54) were 
enrolled.  On Day 1 the mean (±SD) Cmax of treprostinil was 0.574±0.22 ng/mL, occurring at 
a median time of 4 hours (range: 2 to 6 hours).  In comparison, the Day 8 mean (±SD) Cmax 
was 0.615±0.32 ng/mL, occurring at a median time of 4 hours (range: 1 to 6 hours). 


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On Day 7, the mean Cmax (±SD) was 0.810±0.491 ng/mL, occurring at a median time of 
14 hours (range: 6 to 20 hours) following the morning dose.  This indicates that maximum 
concentration during a daily interval at steady state occurs after the evening (or third) dose of 
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. 
Fifteen 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 Investigator’s Brochure. 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION 
Oral treprostinil has shown clinical improvements in exercise capacity after 12 weeks of 
therapy in subjects with WHO Group I 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 transmission of backward pressures caused by LV diastolic 
dysfunction (Guazzi 2011).  Another study followed 244 HFpEF subjects over 3 years to 
assess the disease severity in subjects with PH associated with HFpEF versus subjects with 
hypertension 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). 


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There is 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 
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 subjects with PH associated with HFpEF (LVEF>50%) 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 


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(change in 6MWD 29 meters greater in sildenafil group; p=0.004) and quality of life 
(Lewis 2007).  A meta-analysis including studies with HFrEF subjects found that sildenafil 
reduced 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, 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 (ERA), 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 is 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 (Redfield 2013, 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, 


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along with recent data, suggest that treprostinil can be safely administered in subjects with 
WHO Group 2 HFpEF. 
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 HFpEF associated 
with PH, 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 open-label study will evaluate the safety of continued therapy with oral treprostinil in 
subjects who have completed Study TDE-HF-301.  This study will provide long-term, 
open-label data regarding the safety and efficacy of oral treprostinil for the treatment of PH 
associated with HFpEF. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the long-term safety of oral treprostinil in 
subjects with PH associated with HFpEF for subjects who completed Study TDE-HF-301. 
2.2 
SECONDARY OBJECTIVES 
Secondary objectives of this study are: 
 To assess the effect of continued long-term therapy with oral treprostinil on the 
following: 
 6MWD 
 Borg dyspnea score 
 WHO Functional Class 
 N-Terminal pro-brain natriuretic peptide (NT-proBNP) at Weeks 24 and 48 


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2.3 
SAFETY ENDPOINTS 
To evaluate the effect of oral treprostinil on the following parameters: 
 AEs 
 Clinical laboratory parameters  
 Physical assessment of heart failure signs and symptoms with vital signs 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is an open-label study.  Subject visits will occur at Baseline, Weeks 6, 12, 18, 24, and 
every 12 weeks thereafter (see Table 3-1).  The study will continue until either oral 
treprostinil becomes commercially available to treat PH associated with HFpEF or the study is 
discontinued by the Sponsor. 


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3.2 
SCHEDULE OF TIMES AND EVENTS 
Table 3-1 
Overall Schedule of Time and Events 
Abbreviations: 6MWT, 6-Minute Walk Test; AE, adverse event; NT-proBNP, N-terminal pro-brain natriuretic peptide; TID, 3 times daily; WHO, World Health Organization 
a   Baseline assessments for this study are those collected at the Week 24 visit from Study TDE-HF-301 and prior to initiation of open-label study drug.  The exceptions to 
this are the Informed Consent Form and inclusion/exclusion criteria specific to this protocol. 
b   The visit window is ±7 days through Week 24 and ±14 days starting with the follow-up visits. 
c   Refer to Appendix 15.5 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. 
d  During the follow-up visits, clinical laboratory samples should be collected every 24 weeks. 
Study Procedures 
 
Treatment Phase 
Study Week 
Baselinea 
(Study Entry) 
Week 6b 
Week 12b 
Week 18b 
Week 24b 
Follow-up Visits 
(Every 12 Weeksb) 
Study 
Termination 
Study day 
1 
43 
85 
127 
169 
 
 
Informed consent 
X 
 
 
 
 
 
 
Subject eligibility 
(inclusion/exclusion criteria) 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
Assessment of heart failure signs 
and symptoms with vital signsc 
X 
X 
X 
X 
X 
X 
X 
WHO Functional Class 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory assessments 
X 
 
X 
 
X 
Xd 
X 
NT-proBNPe 
X 
 
 
 
X 
X 
 
Urine pregnancy testf 
X 
X 
X 
X 
X 
X 
X 
6MWT/Borg dyspnea scoreg 
X 
X 
X 
X 
X 
X 
X 
Dosing instructions/ 
dosing/accountabilityh 
X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X 
Weekly/monthly 
telephone/email contacti 
X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X 
Adverse eventsj 
X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X 
Concomitant medications 
X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X-- 
--X 


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e  Blood for NT-proBNP assessment must be drawn prior to conducting the 6MWT and will occur prior to the first dose of TDE-HF-302 study drug at Baseline (done as part 
of TDE-HF-301 Week 24 assessments).  NT-proBNP will be collected at Baseline, Week 24, and Week 48 (Follow-up Visit 2) only. 
f  For females of childbearing potential only. 
g All 6MWTs 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 by simple face mask at all subsequent 
6MWT assessments.  The supplemental oxygen flow rate must be recorded at each study visit, as applicable. 
h Once all entry criteria have been met, the first dose of study drug will be administered at the study site with food.  The initial dose of study drug will be dependent on the 
treatment assignment from Study TDE-HF-301.  Those subjects who were assigned to placebo will begin dosing at 0.125 mg TID and those subjects who were assigned 
to active will remain on the previous dose of study drug.  Study drug dosing will continue TID (every 6 to 8 hours). 
i  At least weekly telephone/email contact is required through the first 24 weeks of the study and monthly thereafter (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).  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 meaningful AEs or other emergent issues. 
j  All AEs ongoing at the Week 24 visit from Study TDE-HF-301 will be recorded as continuing AEs in this open-label study.  The AEs will be documented from the time of 
informed consent until the subject is discontinued from the study 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. 
 


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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
3.3.1.1 
6-Minute Walk Test 
A 6-Minute Walk Test (6MWT; described in Appendix 15.1) will be conducted at Baseline as 
part of study termination assessments from Study TDE-HF-301, and at Weeks 6, 12, 18, 24, 
every 12 weeks thereafter, and at the study termination visit.  Before each 6MWT, the subject 
should rest (seated) for at least 10 minutes.  The 6MWTs will be conducted by qualified, 
trained personnel in a designated 6MWT area that meets the requirements outlined in 
Appendix 15.1 (ATS 2002, Holland 2014).  The 6MWT should be conducted 3 to 6 hours 
after the most recent dose of oral treprostinil.  This 3- to 6-hour time window does not apply 
to subjects who are currently on a prescribed zero dose. 
3.3.1.2 
Borg Dyspnea Score 
The Borg dyspnea score will be assessed following each 6MWT.  The Borg dyspnea score is a 
10-point scale rating the maximum level of dyspnea experienced during the 6MWT 
(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 for PH (Appendix 15.2) will be assessed at Baseline as 
part of study termination assessments from Study TDE-HF-301, and at Weeks 6, 12, 18, 24, 
every 12 weeks thereafter, and at the study termination visit. 
3.3.1.4 
NT-proBNP 
The NT-proBNP concentration is a useful biomarker associated with changes in right heart 
morphology and function (Fijalkowska 2006).  The NT-proBNP sample collection will occur 
at Baseline as part of study termination assessments from Study TDE-HF-301, Week 24, and 
Week 48 (Follow-up Visit 2). 
3.3.2 
Safety 
3.3.2.1 
Assessment of Heart Failure Signs and Symptoms with Vital Signs 
Symptoms of heart failure (Appendix 15.5) will be assessed at Baseline as part of the study 
termination assessments from Study TDE-HF-301, and at Weeks 6, 12, 18, 24, every 


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12 weeks thereafter, and at the study termination visit.  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.  All vital signs will be collected prior to or at least 30 minutes following the 
corresponding 6MWT to ensure accurate measurement.  Vital signs include blood pressure, 
height, weight, peripheral (radial/brachial artery) heart rate, and respiration rate. 
3.3.2.2 
Physical Examination 
A physical examination will be assessed at Baseline as part of study termination assessments 
from Study TDE-HF-301 and at the study termination visit. 
3.3.2.3 
Clinical Laboratory Assessments 
Clinical laboratory parameters will be assessed at Baseline as part of study termination 
assessments from Study TDE-HF-301.  Clinical laboratory assessments will also be assessed 
at Weeks 12 and 24, at every 24 weeks thereafter, and at the study termination visit.  Clinical 
laboratory parameters to be assessed at the study visits are listed in Appendix 15.4.  A urine 
pregnancy test will be collected for women of childbearing potential (WOCBP) at each study 
visit. 
3.3.2.4 
Adverse Event Assessments 
Any AEs that are ongoing at the study termination visit from Study TDE-HF-301 should be 
recorded as continuing AEs in this open-label study. 
AEs will be captured from the time the Informed Consent Form (ICF) is signed.  All AEs 
should be followed until resolution (or return to normal or baseline values), until they are 
judged by the Investigator to no longer be clinically meaningful, or for up to 30 days if the AE 
extends beyond the final 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 more than 
30 days after completion of the final visit.  Sections 9.1.1 and 9.1.2 and Appendix 15.3 
provide the guidelines and definitions for recording AEs. 
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 


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with symptoms in the subject’s medical history; or 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. 
3.3.2.5 
Pregnancy Testing 
All WOCBP will undergo a urine pregnancy test at Baseline as part of study termination 
assessments from Study TDE-HF-301 and at Weeks 6, 12, 18, 24, every 12 weeks thereafter, 
and at the study termination visit.  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. 
3.3.2.6 
Concomitant Medications 
Concomitant medication may be adjusted as deemed clinically necessary by the Investigator 
during the study.  However, additional prostanoid therapies should not be added.  
Concomitant medications used during the study will be reviewed at each protocol-required 
visit and recorded as they are prescribed in the electronic Case Report Form (eCRF).  
Concomitant medications that were ongoing at the end of Study TDE-HF-301 will be 
recorded in the eCRF for the open-label study. 


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3.4 
NUMBER OF CENTERS 
The study sites who participate in Study TDE-HF-301 (approximately 100) will take part in 
the study. 
3.5 
NUMBER OF SUBJECTS 
Approximately 310 subjects from Study TDE-HF-301 may be eligible to participate in the 
study. 
3.6 
ESTIMATED STUDY DURATION 
It is estimated that the study will continue for 4 years; however, this could last longer.  The 
study may be discontinued at any time if, in the opinion of the Investigators 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.  Subjects that discontinue the study 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 
AEs/SAEs (see Section 9.2 for additional details). 
4 
SUBJECT ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
A subject is eligible to participate in this study if all of the following criteria apply: 
1. The subject voluntarily provides informed consent to participate in the study. 
2. The subject participated in Study TDE-HF-301, remained on study drug, was 
compliant with study procedures and assessments during Study TDE-HF-301, and 
completed through Week 24 of that study. 
3. All WOCBP must have a negative urine pregnancy test at Baseline (completed as part 
of Week 24 assessments from Study TDE-HF-301) prior to initiating Study TDE-HF-
302 study drug. 
The WOCBP includes any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea for at least 
12 consecutive months).  The 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 


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after discontinuing study medication.  Medically acceptable forms of effective 
contraception include: (1) approved hormonal contraceptives (such as birth control 
pills), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, 
(3) an intrauterine device, or (4) partner vasectomy.  Male subjects with a partner of 
child-bearing potential, must use a condom during the length of the study, and for at 
least 48 hours after discontinuing study medication. 
4.2 
EXCLUSION CRITERIA 
A subject is not eligible to participate in this study if any of the following criteria apply: 
1. The subject is pregnant or lactating. 
2. The subject was prematurely discontinued from Study TDE-HF-301 for any reason. 
3. The subject developed a concurrent illness or condition during the conduct of Study 
TDE-HF-301, which, in the opinion of the Investigator, would represent a risk to the 
subject’s overall health if they enrolled in this study. 
4.3 
PRESCRIBED THERAPY 
4.3.1 
Concomitant Medications 
In this open-label study, there are no restrictions on concomitant medications with the 
exception that other prostanoid therapy should not be added. 
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
All subjects will receive oral treprostinil sustained release tablets during this open-label study.  
Subjects will retain the same subject number as assigned for the TDE-HF-301 study. 
5.2 
RANDOMIZATION 
This study is not randomized. 
5.3 
BLINDING 
This study is not blinded. 
6 
DRUGS AND DOSING (OR TREATMENT PROCEDURES) 
6.1 
DRUG DOSAGE, ADMINISTRATION, AND SCHEDULE 
The oral treprostinil tablets are sustained-release 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-, 


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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.   
For subjects who were randomly allocated to receive placebo in Study TDE-HF-301, dosing 
of oral treprostinil will be initiated and optimized as described in the Study TDE-HF-301 
protocol, including all safety monitoring and periodic telephone/email contacts.  That is, the 
first dose of oral treprostinil (0.125 mg) should be taken by the subject at the study site 
immediately after (~10 minutes) consuming food.  Oral dosing of study drug will be 
continued at 0.125 mg TID (every 6 to 8 hours) immediately after (~10 minutes) consuming 
food.  Subjects must be instructed to take the appropriate amount of oral treprostinil 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 maximal difference during each titration between the lowest dose 
and the highest dose cannot exceed 0.125 mg.  The maximum allowed dose will be identical 
to TDE-HF-301.  The anticipated maximum allowed dose during the study will be 6 mg TID.  
The Data Monitoring Committee (DMC) will meet at predetermined intervals during Study 
TDE-HF-301.  Any decision impacting the maximum dose will be relayed to all study sites 
following the DMC meetings. 
Subjects who were randomly allocated to receive oral treprostinil in Study TDE-HF-301 will 
begin the open-label study at the same dose they were receiving at the Week 24 visit in Study 
TDE-HF-301, and subsequent adjustments will be made based on symptoms of PH and 
adverse effects while continuing to observe the maximum study drug dose permitted by the 
DMC. 
All subjects must be instructed to take the appropriate amount of 0.125-, 0.25-, 1-, and/or 
2.5-mg tablets based upon their prescribed dose.  All dose changes should be conducted under 
appropriate medical supervision in consultation with the study site.  Weekly telephone 
calls/emails between study site personnel and the subject should be made during the first 


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24 weeks of the study to monitor AEs and make decisions about dose titration.  After 
Week 24, monthly telephone calls/emails should be made to continue to monitor AEs and 
make decisions regarding appropriate dose titrations.  If dose titration is considered 
appropriate, study site personnel will instruct the subject to modify their dose and the dose 
change will be recorded in source documentation.  If it becomes necessary for a subject to 
modify their dose of oral treprostinil (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 oral 
treprostinil.  If dosing is interrupted for longer than 24 hours, consideration should be given to 
gradually re-titrating the subject’s dose to the last dose administered prior to the dose 
interruption.  In the event of a planned, short-term interruption of study drug for subjects 
unable to take oral medications during the study, study sites should contact the United 
Therapeutics (UT) Medical Monitor to discuss oral treprostinil dosing options. 
In the event a subject requires to be permanently discontinued from study drug (eg, AE or the 
subject wishes to withdraw from further participation in the study), the Investigator should 
conduct the study termination assessments and then gradually down titrate the study drug, 
taking into consideration the subject’s clinical condition, current study drug dosing regimen, 
and previous clinical response to study drug. 
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 


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study drug in affected subjects.  Subjects should be re-started on study drug at a reduced dose 
or at 0.125 mg TID depending on the subject’s clinical condition and 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. 
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. 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
This study is not blinded. 
6.3 
COMPLIANCE 
The Investigator or other study site personnel under the direction of the Investigator will be 
responsible for dose titration of oral treprostinil and recording all dosing information in source 
documents.  During telephone calls/emails, study site personnel will record the current dosing 
regimen of oral treprostinil and determine if the subject is taking oral treprostinil as 
prescribed.  At the discretion of study site personnel, subjects may be provided with an 
optional dosing diary to help with study drug titration and accountability. 
At scheduled study visits, subjects should be instructed to bring all study drug (including 
empty and unused bottles) to the study site.  Upon return of study drug at each required 
protocol visit (eg, Weeks 6, 12, 18, 24, etc), the study coordinator or pharmacist must 
document the number of returned tablets of each strength and determine if the appropriate 
amount of study drug remains based upon the dose of study drug prescribed.  Each subject 
will also be asked at each visit whether he or she has been compliant with dosing.  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 
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Upon return of study drug at all protocol-required on-site study visits (eg, Weeks 6, 12, 18, 
24, etc), all bottles of study drug will be collected.  Study drug returned will not be 
redispensed 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 at unscheduled visits. 
7 
EXPERIMENTAL PROCEDURES 
7.1 
TREATMENT PHASE 
7.1.1 
Baseline 
All data collected at the subject’s study termination visit during Study TDE-HF-301 and prior 
to initiating open-label study drug will serve as Baseline assessments for this study.  
Following completion of all TDE-HF-301 study termination assessments for a subject and 
entry of required data into the interactive voice or web response system (IVRS/IWRS), the 
study site personnel will be unblinded to that subject’s treatment assignment.  Subjects must 
sign an ICF and meet inclusion/exclusion criteria specific to this protocol. 
The list of Baseline assessments are displayed below: 
 Informed consent (prior to any study assessments) 
 Inclusion/exclusion criteria 
 Physical examinationa 
 Assessment of heart failure signs and symptoms with vital signs (following at least 
5 minutes of rest [seated])a 
 WHO Functional Classa 
 AE assessmenta 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after the most recent 
dose of study drug from Study TDE-HF-301; Borg dyspnea score to be conducted 
immediately following 6MWT)a 
 Urine pregnancy test (for WOCBP)a 
 Clinical laboratory assessmentsa 
 Plasma NT-proBNPa 
 
a Assessments conducted during the study termination visit for Study TDE-HF-301 do not need to be repeated 


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 Study drug dosing (for subjects randomized to placebo in TDE-HF-301, the initial 
dose of oral treprostinil in TDE-HF-302 should be taken at the study site) 
 Drug accountability 
 Concomitant medicationsa 
 Weekly telephone calls are highly recommended, especially after any dose changes 
AEs that were ongoing at the end of the TDE-HF-301 study will be recorded as ongoing 
events for this open-label study.  Concomitant medications that were ongoing at the 
TDE-HF-301 study termination visit will be recorded in the eCRF for the open-label study.  
The AEs and concomitant medications will be reported continuously for the duration of the 
study.  Phone calls/emails to the subject must begin within 1 week of the subject receiving the 
first dose of study drug in this follow-up study and continue to be made weekly for the first 
24 weeks of the study.  After 24 weeks, phone calls/emails must be made at least monthly.  
Dose titration should occur as needed in accordance with Section 6.1. 
7.1.2 
Week 6 Visit 
Subjects are to return to the study site at Week 6.  This visit should be conducted within 
7 days of the scheduled visit (as determined by the Baseline visit) and the following 
assessments are to occur: 
 Assessment of heart failure signs and symptoms with vital signs (following at least 
5 minutes of rest [seated]) 
 WHO Functional Class 
 AE assessment 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after the most recent 
dose of oral treprostinil; Borg dyspnea score to be conducted immediately following 
6MWT) 
 Urine pregnancy test (for WOCBP) 
 Oral treprostinil dose titration 
 Dosing instructions/dosing/accountability 
 Concomitant medications 
 Weekly telephone calls/emails are highly recommended, especially after any dose 
changes 


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7.1.3 
Week 12 Visit 
Subjects are to return to the study site at Week 12.  This visit should be conducted within 
7 days of the scheduled visit (as determined by the Baseline visit).  In addition to all 
assessments from the Week 6 visit, clinical laboratory assessments are to be conducted. 
7.1.4 
Week 18 Visit 
Subjects are to return to the study site at Week 18.  This visit should be conducted within 
7 days of the scheduled visit (as determined by the Baseline visit) and all of the Week 6 visit 
assessments are to occur. 
7.1.5 
Week 24 Visit 
Subjects are to return to the study site at Week 24.  This visit should be conducted within 
7 days of the scheduled visit (as determined by the Baseline visit).  In addition to all 
assessments from the Week 6 visit, the following assessments are to be conducted:  
 Clinical laboratory assessments 
 NT-proBNP (NT-proBNP samples must be taken prior to the 6MWT) 
7.1.6 
Follow-up Visits (Every 12 Weeks) 
Subjects should return to the study site every 12 weeks after the Week 24 visit.  Follow-up 
visits are presented with the corresponding study week in Table 7-1.  These visits should be 
conducted within 14 days of the scheduled visit (as determined by the Baseline visit).  
Assessment of AEs, concomitant medications, and dose titration should occur continuously 
between and during study visits.  In addition to all assessments from the Week 6 visit, the 
following assessments are to be conducted: 
 Clinical laboratory assessmentsa 
 NT-proBNPb (Week 48 only [Follow-up Visit 2]; NT-proBNP samples must be taken 
prior to the 6MWT) 
 
a To be assessed every 24 weeks 
b To be assessed at Week 48 only (Follow-up Visit 2) 


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Table 7-1 
Follow-up Visits by Week Beyond Week 24 
Follow-up Visit 
Corresponding  
Study Weeka 
Follow-up Visit 
Corresponding Study 
Weeka 
#1 
36 
#19 
252 
#2 
48 
#20 
264 
#3 
60 
#21 
276 
#4 
72 
#22 
288 
#5 
84 
#23 
300 
#6 
96 
#24 
312 
#7 
108 
#25 
324 
#8 
120 
#26 
336 
#9 
132 
#27 
348 
#10 
144 
#28 
360 
#11 
156 
#29 
372 
#12 
168 
#30 
384 
#13 
180 
#31 
396 
#14 
192 
#32 
408 
#15 
204 
#33 
420 
#16 
216 
#34 
432 
#17 
228 
#35 
444 
#18 
240 
#36 
456 
a Visit window is ±14 days as determined by the Baseline visit. 
7.1.7 
Study Termination Visit 
When subjects discontinue the study, they will complete a study termination visit.  If possible, 
each subject should remain on study drug until they have completed the study termination 
visit.  After the study termination visit is completed, subjects should down titrate the study 
drug over an appropriate period of time in accordance with their clinical condition.  Once the 
study drug has been discontinued, any remaining supplies should be returned to the study site 
for drug accountability.  In addition to all assessments from the Week 6 visit, the following 
assessments are to be conducted at the study termination visit: 
 Physical examination 
 Clinical laboratory assessments 


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8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A subject may voluntarily withdraw or will be withdrawn from the study and/or study drug by 
the Investigator at any time for reasons including, but not limited to, the following: 
 The subject wishes to withdraw from further participation 
 A serious or life-threatening AE occurs or the Investigator considers that it is 
necessary to discontinue study drug to protect the safety of the subject 
 The subject significantly deviated from the protocol 
 The subject’s behavior is likely to undermine the validity of his/her results 
 The subject becomes pregnant 
When a subject is discontinued from the study, the Investigator will complete the study 
termination record and provide an explanation, if needed.  If oral treprostinil has been 
administered, the Investigator should make every effort to perform all study termination 
evaluations prior to termination of oral treprostinil treatment. 
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 or International 
Council for Harmonisation (ICH) Good Clinical Practices (GCP) guidelines 
 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  
9.1 
DEFINITIONS 
9.1.1 
Adverse Event  
An AE is any untoward medical occurrence in a subject administered a 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 a 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 Baseline. 
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. 
 Situations where an untoward medical occurrence has not occurred (eg, 
hospitalizations for cosmetic elective surgery, social and/or convenience admissions). 


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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 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 
AEs will be captured from the time the ICF is signed.  Any AEs that are ongoing at the study 
termination visit from Study TDE-HF-301 should be recorded as continuing AEs in this 
open-label study.  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 


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drug, and outcome is also to be documented in the eCRF (see Appendix 15.3 for definitions).  
Where possible, AEs should be recorded using standard medical terminology.  If several signs 
or symptoms are clearly related to a medically defined diagnosis or syndrome, the diagnosis 
or syndrome should be recorded on the eCRF page, 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 visit.  All SAEs that occur during the study will be 
followed until resolution, death, or the subject is lost to follow-up even if they are ongoing 
more than 30 days after completion of the final visit.  Supplemental measurements and/or 
evaluations may be necessary to investigate fully the nature and/or causality of an AE or SAE.  
This may include additional laboratory tests, diagnostic procedures, or consultation with other 
healthcare professionals.  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 UT 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.  UT 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 UT 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 UT 
GDS.  A follow-up SAE Notification Form must be forwarded to UT GDS within 24 hours of 
the receipt of any new/updated information.  The Investigator must also promptly notify their 


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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 3.3.2.4) are not to be reported to UT 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 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, with the exception of events 
attributable to the progression of the disease under study, which will only be reported if 
assessed as an SAE (see Section 3.3.2.4).  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 or 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 outstanding 
queries have been resolved and all data management quality assurance procedures are 
complete. 


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10.2 
SAMPLE SIZE 
No formal sample size calculation has been conducted.  All eligible subjects from Study 
TDE-HF-301 may enter this study. 
10.3 
ANALYSIS PLAN 
All safety and efficacy data will be summarized in tables and listings and analyzed for trends 
over time.  No formal hypothesis testing is planned. 
The Safety population will be defined as all subjects in the study that received oral treprostinil 
at any time during the course of the study.  All analyses will be performed on the Safety 
population.  All AEs as recorded by the Investigators will be assigned Medical Dictionary for 
Regulatory Activities (MedDRA) preferred terms by the Sponsor for reporting purposes. 
10.4 
OTHER ANALYSES 
Exploratory analyses may be conducted based on available study data. 
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG  
UT will supply oral treprostinil for administration during the study.  Oral treprostinil tablets 
will be provided as 0.125-, 0.25-, 1-, and 2.5-mg strengths for the study.  The oral treprostinil 
tablets are sustained release osmotic tablets.  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 of treprostinil (equivalent to 1.27 mg treprostinil 
diethanolamine), 2.5 mg of treprostinil (equivalent to 3.17 mg treprostinil diethanolamine).  
The 0.125-, 0.25-, 1-, and 2.5-mg tablets are colored blue, green, yellow, and pink, 
respectively.  Oral treprostinil tablets will be provided in child resistant bottles each 
containing 100 tablets. 
11.2 
LABELING  
Each bottle 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 


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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 investigational medicinal product labeling or 
regulatory submissions for specific requirements by country or region in accordance with 
local regulations or guidance. 
Study drug at the 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 bottle 
assigned to the subject at each study visit during the course of the study.  Subjects should be 
instructed to return all study drug, including empty bottles, to the appropriate study personnel 
at every protocol-required visit. 
11.4 
SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL 
Study sites will be supplied with a sufficient quantity of oral treprostinil to begin enrollment 
in the study.  An IVRS/IWRS will be utilized to manage resupply with respect to each 
subject’s visit schedule.  If required, additional study drug may be dispensed to a subject 
between protocol-required visits.  At each protocol required visit, all study drug dispensed to 
the subject should be returned to the study site (including empty and unopened bottles).  A 
new supply of study drug will be dispensed at each protocol-required visit. 
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 


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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 allowing 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 
ICH GCP 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 
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 authorized designees must 
explain the purpose and nature of the study, including potential benefits and risks and all 
study procedures to the subject.  The subject must sign and date an IRB/EC-approved ICF 
prior to the conduct of any study-related activities.  A copy of the signed ICF will be given to 
the subject, and the original will be retained in the study site’s records. 
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
Prior to study initiation at each 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 


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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’s standard procedures. 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical study, the following documents (at minimum) will 
be provided to the study site: Investigator’s Brochure, Protocol, ICF, Budget Agreement, and 
access to an eCRF. 
The study site will be required to provide the following documents (at minimum) to UT or 
designee prior to study start: Signature page of the protocol, Form FDA 1572, IRB/EC 
Composition and Roster, IRB/EC protocol and ICF approval letters, Curriculum Vitae of 
study staff listed on the Form FDA 1572, and authorized clinical study agreement (as 
required). 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  UT, regulatory bodies, 
and the IRB/EC governing this study may inspect the medical records of any subject involved 
in this study.  The Investigator may release the subject’s medical records to employees or 
agents of the Sponsor, the IRB/EC, or appropriate local regulatory agencies for purposes of 


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checking the accuracy of the data.  A unique number will be assigned to all subjects and any 
report published will not identify the subjects by name. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially adversely affect the safety of participating 
subjects or that alter the scope of the investigation, the scientific quality of the study, the 
experimental design, dosages, duration of therapy, assessment variables, the number of 
subjects treated, or subject selection criteria may be made only after consultation between UT 
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. 
At the end of the study, where applicable, a final report will be provided to the local 
regulatory agencies. 
13.2 
STUDY DOCUMENTATION AND STORAGE 
In accordance with federal/national regulations, ICH GCP guidelines, the Investigator must 
retain study records for at least 2 years after the last approval of a marketing application in an 
ICH region, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  The Investigator must notify UT before any 
disposal or change in location of study records. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
In accordance with federal/national regulations, ICH GCP guidelines, monitors for UT 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 


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progress, review data collected, conduct source document verification, verify drug 
accountability periodically, and identify any issues requiring resolution.   
The Investigator must agree to allow the monitor direct access to all relevant documents and 
to allocate his/her time and his/her staff to the monitor to discuss any findings or any relevant 
issues.  In addition, auditors for UT or its designee may periodically contact the study site and 
conduct on-site visits. 


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14 
REFERENCES 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories.  
ATS statement: Guidelines for the Six-Minute Walk Test.  Am J Respir Crit Care Med.  
2002;166(1):111-117. 
Bocchi EA, Bacal F, Auler Júnio 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.  Euro J Heart Failure.  2010;12:89-93. 
Bonderman D, Ghio S, Felix SB, et al.  Riociguat for the left ventricular systolic dynsfunction 
associated with pulmonary hypertension riociguat trial (LEPHT) study group.  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):1274-1211. 
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;29:1313-1321. 
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, 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; 
57:473-479. 
Guazzi M, Vicenzi M, Arena R.  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. 
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. 


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Hussain N, Charalampopoulos A, Ramjug S, et al.  Pulmonary hypertension in patients with 
heart failure and preserved ejection fraction:differential diagnosis and management.  
Pulmonary Circulation.  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; 127:624-633. 
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 dyfunction, associated 
with secondary pulmonary hypertension – a multi-center randomized study.  Cardiology.  
2008;109(4):273-280. 
Lam CSP, Roger VL, Rodeheffer RJ, et al.  Pulmonary hypertension in heart failure with 
preserved ejection fraction: A community-based study.  Am Coll Cardiol.  2009; 
53(13):273-280. 
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;90:2780-2785. 
Moraes DL, Colucci WS, and Givertz MM.  Secondary pulmonary hypertension in chronic 
heart failure: The role of endothelium in pathology 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 Heart J.  
2016; 37(27):2129-200. 
Redfield MM, Chen HH, Borlaug BA, et al.  Effect of phosphodiesterase-5 inhibition on 
exercise capacity and clinical status in heart failure with preserved ejection fraction: a 
randomized clinical trial.  JAMA.  2013;309(12):1268-1277. 


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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):e10-15. 
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 patients 
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 
PROCEDURE FOR 6-MINUTE WALK TEST AND BORG DYSPNEA SCORE 
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 pre-measured 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 stop and rest if you need to.  Just remain where you are until you can go on again.  


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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 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 meaningful change from 
Baseline.  If the results are determined to be a clinically meaningful 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 right heart 
catheterization [RHC]). 
 Treatment which was elective or pre-planned, for a pre-existing condition not 
associated with any deterioration in condition (eg, pre-planned operation which 
does not lead to further complications etc). 
 Treatment of an emergency, in an outpatient setting for an event not fulfilling any 
of the definitions of serious as given above and not resulting in hospital admission. 
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 
 Unknown – Changes to the administration of the study drug cannot be determined 
 Not Applicable  
* 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. 
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. 


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 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 
NT-proBNP (plasma) 
Potassium 
Hemoglobin 
Urine pregnancy testa 
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 
 
 
a Urine pregnancy test for WOCBP 
Visit Test Schedule 
Visit 
Labs Collected 
Baselineb 
Chemistries, Hematology, NT-proBNP, urine pregnancya 
Week 6 
Urine pregnancya 
Week 12 
Chemistries, hematology, urine pregnancya 
Week 18 
Urine pregnancya 
Week 24 
Chemistries, hematology, NT-proBNPc, urine pregnancya 
Follow-up visitsd 
Chemistries, hematology, NT-proBNPe 
Study termination visit 
Chemistries, hematology, urine pregnancya 
Abbreviation: NT-proBNP, N-Terminal pro-brain natriuretic peptide 
a  Urine pregnancy tests for WOCBP only 
b  Baseline clinical laboratory assessments for this study are those collected at Week 24 from study TDE-HF-301 and 
prior to initiation of treatment with open-label oral treprostinil 
c  NT-proBNP at Week 24 only 
d  During follow-up visits, clinical laboratory samples should be collected every 24 weeks 
e  NT-proBNP at Week 48 (Follow-up Visit 2) only 


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15.5 
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, rhonci, 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