Clinical trial NCT01027949
Conditions: Pulmonary Arterial Hypertension
Sponsor: United Therapeutics
Start date: 2007-01-16; Completion date: 2020-02-12
Enrollment: 894 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study provided/continued to provide oral treprostinil (UT-15C SR; treprostinil diethanolamine) to eligible subjects who participated in Studies TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, and TDE-PH-308. The study assessed the long term safety of oral treprostinil and the effect of continued treatment with oral treprostinil on exercise capacity after 1 year of treatment.

Detailed description:
This was an international, multicenter, open-label study designed to provide oral treprostinil for eligible subjects who participated in Studies TDE-PH-301, TDE-PH-302, TDE-PH-308, TDE-PH-202, TDE PH 203, and TDE-PH-205. Subjects randomly allocated to receive oral treprostinil in Studies TDE-PH-301, TDE-PH-302, or TDE-PH-308 and enrolled in this open-label study completed visits at Months 6, 12, 24, 36, and yearly visits thereafter. Subjects randomly allocated to receive placebo in Studies TDE-PH-301, TDE-PH-302, or TDE-PH-308 completed visits at Months 3, 6, 12, 24, 36, and yearly visits thereafter. Subjects that transitioned from Studies TDE-PH-202, TDE-PH-203, and TDE-PH-205 (that had an open-label study design) followed the regimen for subjects receiving oral treprostinil. A 6-Minute Walk Test (6MWT) and Borg dyspnea score were conducted at the visit which occurred 12 months after the subject's first exposure to oral treprostinil.

Adverse events (AEs) were reported continuously throughout the study; any AEs ongoing at the time of discharge from Studies TDE PH-301, TDE PH-302, TDE-PH-308, TDE-PH-202, TDE-PH-203, and TDE-PH-205 were recorded as AEs and marked as "ongoing from previous study" in the subject's electronic Case Report Form (eCRF). Study drug dosing and pulmonary arterial hypertension (PAH) concomitant medication usage were assessed at each scheduled study visit and recorded in the subject's eCRF.

Arms: arm 1: Subjects from previous studies TDE-PH-202 (NCT01104870), TDE-PH-203 (NCT01477333), and TDE-PH-205 (NCT01588405), TDE-PH-301 (NCT00325442), TDE-PH-302 (NCT00325403), or TDE PH-308 (NCT00887978). Subjects were instructed to take the appropriate amount of 0.125, 0.25, 0.5, 1, and/or 2.5 mg tablets based upon their prescribed dose. Investigators were instructed to increase the dose of oral treprostinil in the absence of dose limiting drug-related AEs to ensure each subject received the optimal clinical dose throughout the study
Interventions: intervention 1: Oral Treprostinil
Intervention descriptions: intervention 1: Oral sustained release tablet, twice or thrice daily. Open label study with active drug, no other intervention arms.

Protocol documents:
Prot_000.pdf: 
Protocol Number TDE-PH-304 Amendment 5 
 
Confidential 
United Therapeutics Corporation 
Final Version Dated 20 March 2013 
1 
 
 
 
Protocol TDE-PH-304 
 
 
An Open-Label Extension Trial of UT-15C SR in Subjects with 
Pulmonary Arterial Hypertension 
 
 
IND# 71,537 
 
EudraCT# 2006-000804-18 
 
 
CONFIDENTIAL 
 
 
UNITED THERAPEUTICS CORPORATION 
 
 
55 T.W. Alexander Dr. 
 
 
 
United Therapeutics Europe Limited 
P. O. Box 14186 
 
 
 
 
 
Research Triangle Park, NC 27709 
 
 
United Sates of America   
 
 
United Kingdom 
Phone: 
  
 
 
Phone: 
 
Fax: 
 
 
 
 
Fax: 
 
 
 
Protocol Date:  
 
18 January 2006 
Amendment 1 Date:   
14 February 2007 
Amendment 2 Date:  
13 December 2007 
Amendment 3 Date:  
28 April 2008 
Amendment 4 Date:  
2 March 2009 
Amendment 5 Date:  
20 March 2013 
 
 
Confidentiality Statement: 
 
This document is a confidential, proprietary communication of United Therapeutics 
Corporation and may not be disclosed to parties not associated with the clinical 
investigation or used for any purpose without the prior written consent of © 2013 United 
Therapeutics Corporation. 


Protocol Number TDE-PH-304 Amendment 5 
 
Confidential 
United Therapeutics Corporation 
Final Version Dated 20 March 2013 
2 
LIST OF CONTACTS FOR STUDY 
Study Sponsor: 
United Therapeutics Corp. 
55 T.W. Alexander Drive 
Research Triangle Park, NC  
27709 
USA 
 
 
 
 
 
 
 
 
 
 
 
United Therapeutics Europe 
 
 
 
 
United Kingdom  
 
 
 
 
 
 
 
Contract Research 
Organization: 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
  
 
 
SAE Reporting 
 
 
 
   
 
   
 
 
 
 
 
Clinical Laboratory 
Covance Central Laboratories 
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Number TDE-PH-304 Amendment 5 
 
Confidential 
United Therapeutics Corporation 
Final Version Dated 20 March 2013 
3 
INVESTIGATOR AGREEMENT 
 
I have read the attached protocol entitled “An Open-Label Extension Trial of UT-15C SR in Subjects with 
Pulmonary Arterial Hypertension”, Amendment 5 dated 20 March 2013 and agree to abide by all 
provisions set forth therein. This protocol has been received for information only and must not be 
implemented before all necessary regulatory agency and ethics approval documents have been obtained. 
 
I agree to comply with the International Conference on Harmonisation (ICH) Guideline for Good Clinical 
Practice and applicable Food and Drug Administration regulations/guidelines set forth in 21 Code of 
Federal Regulations Parts 50, 54, 56 and 312 and any local regulations per country. 
 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the conduct of the clinical investigation without the prior written consent of United 
Therapeutics Corporation.  
 
I also have read the current Clinical Investigators’ Brochure for UT-15C (treprostinil diethanolamine) and 
acknowledge that review of the information contained in the Clinical Investigators’ Brochure is a 
requirement for investigators before using UT-15C in a clinical trial.   
 
________________________________                       _______________________________ 
Signature of Principal Investigator                                 Date 
 
 
________________________________                                              
Printed Name of Principal Investigator                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Number TDE-PH-304 Amendment 5 
 
Confidential 
United Therapeutics Corporation 
Final Version Dated 20 March 2013 
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PROTOCOL SUMMARY 
 
Protocol Number: 
 
TDE-PH-304 
 
Protocol Title: 
An Open-Label Extension Trial of UT-15C SR in Subjects with 
Pulmonary Arterial Hypertension 
 
Study Phase: 
 
 
3 
 
Name of Drug:  
 
UT-15C SR (treprostinil diethanolamine) 
 
Indication: 
 
 
Pulmonary Arterial Hypertension (PAH) 
 
Study Objectives: 
To provide, or continue to provide, UT-15C SR for eligible subjects who 
participated in protocols TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-
PH-301, TDE-PH-302, TDE-PH-308, or any additional UT-15C SR 
clinical protocols evaluating subjects with PAH.  
 
To assess the long-term safety of UT-15C SR in these subjects through 
assessment of adverse events and laboratory parameters.  
 
To assess the effect of continued therapy with UT-15C SR on exercise 
capacity after one year of treatment. 
 
Study Design: 
This is a multi-center, open-label study for eligible patients who 
participated in Protocol TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-
PH-301, TDE-PH-302, TDE-PH-308, or any additional UT-15C SR 
clinical protocols evaluating subjects with PAH. 
 
Sample Size: 
Approximately 900 subjects from protocols TDE-PH-202, TDE-PH-203, 
TDE-PH-205, TDE-PH-301, TDE-PH-302, and TDE-PH-308 plus 
additional subjects from any additional UT-15C SR clinical protocols 
evaluating subjects with PAH. 
 
Summary of Subject  
Eligibility Criteria: 
Participation in study TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-
301, TDE-PH-302, TDE-PH-308 or any additional UT-15C SR clinical 
protocol is required.  Subjects must complete all assessments in one of 
these studies to be eligible. 
 
Drug Dosage and 
Formulation: 
UT-15C Sustained Release Tablets will be provided as 0.25, 0.5, 1, and 
2.5 mg tablet strengths.  UT-15C SR tablets may also be provided as a 
0.125 mg strength, if available.     
 
 
 
For subjects on placebo at the end of the TDE-PH-301, TDE-PH-302, 
and TDE-PH-308 protocols, treatment will be initiated at 0.25 mg twice 
daily (every 12 hours +/- 1 hour) with dose escalation of an additional 
0.25 to 0.5 mg twice daily every 3 days if clinically indicated based upon 
adverse events and signs and symptoms of PAH.  The 0.125 mg 
strength, if available, may be used throughout the study if a 0.25 mg 
dose increase is not tolerated and an intermediate dose is required.  
Doses should be optimized throughout the study.  For subjects on active 
therapy in TDE-PH-202, TDE-PH-203, TDE-PH-205 TDE-PH-301, TDE-
PH-302, and TDE-PH-308 the initial dose of the open-label study will be 


Protocol Number TDE-PH-304 Amendment 5 
 
Confidential 
United Therapeutics Corporation 
Final Version Dated 20 March 2013 
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based upon their ending dose in the previous study, and dose 
modification will be based on adverse events and signs and symptoms of 
PAH.  Twice daily(BID) dosing should occur (every 12 hours +/- 1 hour) 
with dose escalation of an additional 0.25 to 0.5 mg twice daily every 3 
days if clinically indicated based upon adverse events and signs and 
symptoms of PAH. Three times (TID) daily dosing for subjects enrolled 
from the TDE-PH-205 study or those subjects transitioning from BID to 
TID dosing, study drug should be taken every 6-8 hours with dose 
escalation of an additional 0.125 to 0.25 mg twice daily every 3 days if 
clinically indicated based upon adverse events and signs and symptoms 
of PAH.  All study drug should be administered immediately following 
(~10 minutes) breakfast and dinner for BID dosing and with food for TID 
dosing. 
 
Route of Administration:  
Oral 
 
Study Visit Schedule: 
Study visits will be timed to occur 3, 6, 12, 24, 36 months after each 
subject’s first exposure to UT-15C SR.  The study will continue with 
yearly visits beyond 36 months until either UT-15C SR is approved by 
the appropriate regulatory authorities or the study is discontinued by the 
sponsor.  Subjects receiving placebo in the previous study (TDE-PH-301, 
TDE-PH-302, or TDE-PH-308) and subjects enrolled from the TDE-PH-
202 study who were in Dose Groups 1 or 2 and permanently 
discontinued treatment must be contacted weekly by telephone during 
the first 12 weeks of the open-label study.  Subjects transitioning from 
BID to TID dosing should be contacted weekly for the first four weeks 
after transitioning. Monthly telephone calls must be conducted for all 
subjects actively participating in TDE-PH-304, regardless of study drug 
allocation (UT-15C SR or placebo) in the previous study.  In addition to 
the scheduled study visits, all subjects must be seen in the clinic no less 
than once every six months for routine standard of care medical 
evaluation.    
 
Efficacy Assessment: 
A 6-Minute Walk Test with Borg Dyspnea Score will be conducted at the 
study visit occurring 1 year after the subject first received UT-15C SR. 
 
Safety Assessments: 
Adverse events and clinical laboratory parameters will be assessed 
throughout the study. 
 
 
Statistical Considerations: 
All data will be summarized in tables and listings. 
 
Sponsor: 
United Therapeutics Corporation 
55 T.W. Alexander Dr. 
 
P.O. Box 14186 
 
Research Triangle Park, NC 27709 
United States of America 
 
 
 
 
 
 


Protocol Number TDE-PH-304 Amendment 5 
 
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Final Version Dated 20 March 2013 
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TABLE OF CONTENTS 
 
LIST OF CONTACTS FOR STUDY .......................................................................................... 2 
INVESTIGATOR AGREEMENT ................................................................................................ 3 
PROTOCOL SUMMARY............................................................................................................. 4 
TABLE OF CONTENTS .............................................................................................................. 6 
LIST OF ABBREVIATIONS ........................................................................................................ 8 
1 
BACKGROUND AND RATIONALE................................................................................... 9 
1.1 Pulmonary Arterial Hypertension:  Definition of Clinical Problem ............................ 9 
1.2 Treprostinil Background .................................................................................................. 9 
1.2.1 UT-15C SR Nonclinical ........................................................................................... 9 
1.2.2 UT-15C SR Clinical Pharmacology ..................................................................... 11 
1.2.3 Remodulin Experience .......................................................................................... 13 
1.3 Rationale for Development of Study Drug in Disease/Condition ............................ 13 
1.4 Clinical Hypothesis ......................................................................................................... 14 
2 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 14 
2.1   Study Objectives............................................................................................................. 14 
2.2 Study Endpoints ............................................................................................................. 14 
3 
EXPERIMENTAL PLAN .................................................................................................... 14 
3.1   Study Design ................................................................................................................... 14 
3.2 Overall Schedule of Times and Events ...................................................................... 15 
3.3 Clinical Assessments ..................................................................................................... 16 
3.3.1 Efficacy..................................................................................................................... 16 
3.3.2 Safety ....................................................................................................................... 16 
3.4 Number of Centers ......................................................................................................... 17 
3.5 Number of Subjects ....................................................................................................... 17 
3.6 Estimated Study Duration ............................................................................................. 17 
4 
SUBJECT ELIGIBILITY ..................................................................................................... 18 
4.1 Subject Inclusion Criteria .............................................................................................. 18 
5 
SUBJECT ENROLLMENT ................................................................................................ 19 
5.1 Treatment Assignment .................................................................................................. 19 
5.2 Randomization ................................................................................................................ 19 
5.3 Blinding ............................................................................................................................ 19 
6 
DRUGS AND DOSING ...................................................................................................... 19 
6.1 Drug Dosage, Administration and Schedule .............................................................. 19 
6.1.1 Twice Daily Dosing Regimen ................................................................................. 19 
6.1.2 Transition from Twice to Three Times daily Dosing ........................................... 20 
6.1.3 Three Times (TID) Daily Dosing Regimen ........................................................... 20 
6.1.4 Dosing of Study Medication in Relation to Meals ................................................ 21 
6.2 Compliance ..................................................................................................................... 21 
7 
EXPERIMENTAL PROCEDURES .................................................................................. 21 
7.1 Open-Label Phase ......................................................................................................... 21 
8 
STUDY TERMINATION .................................................................................................... 23 
8.1 Subject Discontinuation ................................................................................................. 23 
8.2 Study Discontinuation .................................................................................................... 23 
8.3 Site Discontinuation ....................................................................................................... 23 


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9 
ADVERSE EVENT REPORTING .................................................................................... 24 
9.1 Definitions ......................................................................................................................... 24 
9.1.1 Adverse Event .......................................................................................................... 24 
9.1.2 Serious Adverse Event ............................................................................................ 24 
9.1.3 Expected Adverse Event ......................................................................................... 24 
9.2 Documentation of Adverse Events ............................................................................... 25 
9.3 Reporting Responsibilities of the Investigator ............................................................. 25 
9.4 Safety Reports ................................................................................................................. 25 
9.5 Pregnancy ......................................................................................................................... 25 
10 DATA MANGEMENT AND STATISTICS ................................................................... 26 
11 PACKAGING AND FORMULATION ............................................................................... 26 
11.1 Study Drug Content ....................................................................................................... 26 
11.2 Study Drug Labeling ...................................................................................................... 26 
11.3 Study Drug Storage and Handling ............................................................................... 26 
11.4 Study Drug Supply and Return .................................................................................... 26 
11.5 Study Drug Accountability ............................................................................................. 27 
12 REGULATORY AND ETHICAL OBLIGATION .............................................................. 27 
12.1 Regulatory Requirements ............................................................................................. 27 
12.2 Informed Consent Requirements ................................................................................. 27 
12.3 Institutional Review Board/Independent Ethics Committee Approval .................... 27 
12.4 Prestudy Documentation Requirements ..................................................................... 27 
12.5 Subject Confidentiality ................................................................................................... 28 
12.6 Reporting of Clinical Trial Results ............................................................................... 28 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ......................................................... 28 
13.1 Protocol Amendments and Study Termination .......................................................... 28 
13.2 Study Documentation and Storage ............................................................................. 28 
13.3 Study Monitoring and Data Collection ........................................................................ 29 
14 REFERENCES ................................................................................................................... 30 
15 APPENDICES ..................................................................................................................... 31 
APPENDIX A: Procedure for 6-Minute Walk Exercise Test and Borg Dyspnea Score
 
31 
APPENDIX B:  Clinical Laboratory Parameters ................................................................ 33 
APPENDIX C: Guidelines and Definitions for Recording Adverse Events .................. 34 
APPENDIX D:  Expected Adverse Events Listing for UT-15C SR Clinical Studies .. 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS  
 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BID 
Twice Daily 
ºC 
Degrees Celsius 
CRF 
Case Report Form 
EC 
Ethics Committee 
ERA 
Endothelin Receptor Antagonist 
FDA 
Food and Drug Administration 
ºF 
Degrees Fahrenheit  
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
ICH 
International Conference on Harmonisation 
iMTD 
Individual Maximum Tolerated Dose 
IRB 
Independent/Institutional Review Board 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter  
PAH 
Pulmonary Arterial Hypertension 
PDE5 
Phosphodiesterase 5 
PGI2 
Prostacyclin 
SAE 
Serious Adverse Event 
SR 
Sustained Release 
TID 
Three Times Daily 
UT-15C SR 
Treprostinil Diethanolamine 
 
 
 
 
 
 
 


Protocol Number TDE-PH-304 Amendment 5 
 
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1 
BACKGROUND AND RATIONALE 
1.1 
Pulmonary Arterial Hypertension:  Definition of Clinical Problem 
Pulmonary arterial hypertension (PAH), which is defined as an elevation in pulmonary arterial pressure 
and pulmonary vascular resistance, is a severe hemodynamic abnormality associated with a variety of 
diseases and syndromes.  Elevation in pulmonary arterial pressure causes an increase in right ventricular 
afterload, impairing right ventricular function and ultimately leading to inactivity and death.   
 
There are three major factors thought to contribute to the increased pulmonary vascular resistance seen 
in this disease: vasoconstriction, remodeling of the blood vessel wall, and thrombosis. There are a 
number of metabolic pathways implicated as contributing to these changes including vasoactive 
mediators such as the vasodilators nitric oxide and prostacyclin, the vasoconstrictor endothelin-1, and the 
phosphodiesterase type-5 mediated vasodilation.  These substances affect not only vascular tone but 
also effect vascular remodeling and represent current pharmacologic targets.1  
 
Approved pharmacotherapies for PAH include: (1)   intravenous prostacyclin (epoprostenol sodium or 
Flolan®)2,3, (2) the prostacyclin analogues, subcutaneous (SC),  intravenous (IV), and inhaled treprostinil 
sodium (Remodulin®; Tyvaso®)   and inhaled iloprost (Ventavis®), (3) the oral phosphodiesterase-5 
inhibitors (PDE5-I), tadalafil (Adcirca®) and sildenafil (Revatio®); and (4) the oral  endothelin receptor 
antagonists (ERA)9, 10 , bosentan (Tracleer®) and ambrisentan (Letairis®, Volibris®).11,12    
1.2 
Treprostinil Background 
1.2.1 
UT-15C SR Nonclinical 
UT-15C is a novel salt form of Remodulin® (treprostinil) Injection and Tyvaso® (treprostinil) Inhalation 
Solution, which are approved in the United States and other countries for the treatment of patients with 
PAH. The active pharmaceutical ingredient, treprostinil, exists as the sodium salt in the drug product of 
Remodulin and Tyvaso. Given that the only change to the drug substance synthesis route for UT-15C is 
the diethanolamine addition step, and treprostinil is not altered, the bioactive form of treprostinil 
diethanolamine and treprostinil sodium is predicted to be identical.  Therefore, in addition to the 
nonclinical studies conducted with UT-15C, an extensive amount of pharmacology, pharmacokinetic, and 
toxicology information on treprostinil sodium is available from Remodulin and Tyvaso development. 
During the development of Remodulin, treprostinil sodium was administered SC and / or IV in acute 
toxicity studies, repeat-dose toxicity studies, reproductive toxicity studies, and genotoxicity studies, and 
has a well defined clinical safety profile.  Treprostinil sodium was administered via continuous infusion to 
both rats and dogs in toxicity studies for up to 6-months, which supported the chronic administration of 
Remodulin to patients. 
In addition to the extensive toxicology data with treprostinil sodium, the toxicity and toxicokinetic profiles 
of UT-15C have been evaluated in acute and repeat dose oral toxicity studies of up to 13 weeks in 
duration in rodents and up to 9 months duration in dogs.  UT-15C has also been evaluated in 
reproductive-developmental toxicity studies in pregnant rats and rabbits and in an in vivo rat micronucleus 
assay.  
 
Nonclinical findings from 13 week toxicology studies with UT-15C have included dose dependent, yet 
transient decreases in mean body weight gain and food consumption in both rats and dogs and soft / 
mucoid stools, diarrhea, and vomitus in dogs.  Many of these findings have been seen previously during 
development of Remodulin and are consistent with prostacyclin induced effects.  In addition, post-mortem 
findings in rats administered UT-15C included changes in organ weight data and histological findings 
related to the adrenal gland, heart, spleen, thymus and bone marrow; some of which were not seen with 
Remodulin.  The majority of these findings were reversible following a 4-week recovery period.  Data from 
a 9-month dog study provides additional toxicology information following chronic dosing.  UT-15C was 
reasonably well-tolerated following daily oral administration at dose levels up to 35 mg/dog/day for 9 
months.  The primary adverse effect was judged to be gastrointestinal disturbance, evidenced by 
increased incidence of soft stools, mucoid stools and diarrhea.  By the end of the study, all dogs were in 


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good condition.  No systemic adverse effects were detected as judged by ophthalmology, ECG, clinical 
pathology and histopathological examination. 
 
In vitro genotoxicity studies with UT-15C have not been conducted; however, data are available for such 
studies using high doses of Remodulin (treprostinil sodium).  Remodulin (treprostinil sodium) was non-
mutagenic in bacterial reverse mutation assays (Ames assay) at concentrations up to 5,000 mcg/plate 
with and without S9 metabolic activation, and in the mouse lymphoma assay at concentrations up to 400 
mcg/mL without S9 metabolic activation and up to 300 mcg/mL in the presence of S9. 
UT-15C was tested in vivo in the rat micronucleus assay, which aimed to evaluate the potential of UT-15C 
to increase the incidence of micronucleated polychromatic erythrocytes in bone marrow of rats.  The 
results of the assay indicated that oral administration of UT-15C at total doses up to and including a dose 
of 50 mg treprostinil (equivalent to 63.4 mg UT-15C/kg) did not induce a significant increase in the 
incidence of micronucleated polychromatic erythrocytes in either male or female SD rats.  Mortality 
observed at the high dose indicates systemic exposure of animals to the test article.  Based upon these 
findings, treprostinil diethanolamine (UT-15C) was concluded to be negative in the rat micronucleus 
assay. 
 
Segment I (rat) and Segment II (rat and rabbit) reproductive and developmental toxicology studies have 
also been conducted. No adverse effects for fetal viability / growth and fetal development (teratogenicity) 
were seen in rats at or below 20 mg/kg/day or rabbits at or below 0.5 mg/kg/day.  At high doses, there 
were teratogenic effects of UT-15C observed when administered to rabbits.  Findings included increased 
fetal incidence of external, soft tissue, and skeletal malformations.  Additionally, a Segment III 
reproductive and developmental toxicology study has been conducted in female rats.  F0 female rats 
receiving 10 mg/kg/day had decreased food consumption and body weights during gestation, increased 
duration of gestation, had slight decreases in the viability and number of pups per litter, and pups with 
decreased mean neonatal body weights.  F1 pups of females that received 20 mg/kg/day had 
abnormalities in physical development (developmental landmarks), reflex development, exploratory 
behavior, learning and memory, and sexual maturation. 
 
A six month carcinogenicity study in hemizygous Tg.rasH2 mice administered UT-15C at daily oral doses 
of 3, 7.5, 15 mg/kg and 5, 10, 20 mg/kg in females and males, respectively, for 26-weeks did not increase 
the incidence of neoplastic lesions.  A two year rat carcinogenicity study is ongoing. 
 
Studies have been conducted by the United States National Toxicology Program (NTP) to determine 
whether diethanolamine by itself (without treprostinil or any other drug) causes cancer.  Two years of 
topical administration of diethanolamine to mice produced an increased incidence (compared to a control 
group) of malignant liver tumors in males and females, as well as an increased incidence of malignant 
kidney tumors in males.  Doses used in this study were approximately 720 to 2,900 times higher (based 
on mg/m2 dosing) than the proposed starting doses for the UT-15C clinical studies.  However, in 
transgenic mice and rats, topical administration of diethanolamine for twenty weeks and two years, 
respectively, was not associated with the development of any cancers.  The relevance of the mouse 
tumor findings to humans is currently unknown.  Diethanolamine is listed on the FDA database of inactive 
ingredients for a number of approved drug products with no apparent safety concerns. 
 
A GLP cardiovascular safety pharmacology study (Study 1259DU16.003) to evaluate diethanolamine 
effects, independent of treprostinil, on cardiovascular function in telemetered dogs has been conducted.  
Since there are 0.269 grams of diethanolamine per each gram of treprostinil in UT-15C, for this study, 
doses of diethanolamine were selected that were similar or higher than the amount of diethanolamine 
contained in the doses of UT-15C assessed in the UT-15C cardiovascular safety pharmacology study 
(Study 1259DU16.002).  Doses of 0, 2, 3 and 4 mg/kg/day of diethanolamine (equivalent to the amount of 
diethanolamine administered with 7, 11, and 15 mg/kg/day of treprostinil, the free acid of UT-15C), were 
selected to be administered to each of one group of four telemetered male dogs.  Oral administration of 
diethanolamine at doses up to 2 mg/kg/dose twice daily (4 mg/kg/day) to male beagle dogs was not 
associated with any definitive changes in arterial pressure, heart rate or electrocardiogram parameters.  
In addition, no abnormal clinical signs were noted in the animals dosed with the vehicle or with any of the 
doses of diethanolamine. 


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1.2.2 
UT-15C SR Clinical Pharmacology 
In solution, both treprostinil sodium and treprostinil diethanolamine are disassociated from their respective 
salt counter-ions and exist as the freely ionized form of treprostinil.  As a result, the bioactive form present 
in the bloodstream is identical irrespective of the selection of the counter-ion. Given this premise, the 
development of this new diethanolamine salt of treprostinil is expected to retain the bioactivity and safety 
profile of treprostinil sodium. 
 
The most frequent AEs associated with Remodulin in clinical trials of patients 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 patient population, 
was consistent with the profile noted in the controlled trials.  To date, well over 10,000 subjects and 
patients have been exposed to Remodulin.  This number includes patients who have received single 
administration, to patients receiving continuous infusion for greater than 10 years. 
 
UT-15C has been administered to approximately 1,600 subjects in phase I-III clinical trials.  UT-15C 
doses of up to 3 mg twice daily (BID) have been administered to healthy volunteers and patients with 
PAH have received up to 22 mg BID in the ongoing phase III development program. The longest 
individual exposure is now greater than five years. 
 
The absolute bioavailability of the UT-15C 1 mg tablet is 17% compared with IV Remodulin.  Following 
administration, treprostinil diethanolamine is widely distributed.  Treprostinil is approximately 96% protein 
bound with no effect on warfarin or digoxin displacement.  Pharmacokinetic data (area under the curve; 
AUC) indicate that Day 1 pharmacokinetic data are predictive of Day 13 and linearity was observed in 
plasma exposure comparing 1 mg and 2 mg doses in healthy volunteers.  Food, particularly a high calorie 
meal, has been observed to increase absorption and prolong the systemic exposure to treprostinil, 
contributing to the desired pharmacokinetic profile.  Consistent with in vitro studies, clinical studies 
assessing the impact of induction and inhibition of the cytochrome P450 (CYP) 2C8 and CYP 2C9 
metabolic pathways on treprostinil diethanolamine indicate that CYP 2C8 appears to be of major 
importance and CYP 2C9 of minor importance to in vivo metabolism of UT-15C in humans. 
A comprehensive description of UT-15C (treprostinil diethanolamine), including the pharmacology, 
toxicology, and clinical studies completed to date may be found in the most recent Investigators’ 
Brochure. 
 
To date, the majority of UT-15C clinical studies have been conducted with twice daily dosing.  In an 
attempt to understand the pharmacokinetics of three times daily dosing (TID) a study was conducted in 
healthy volunteers.  In this open-label, single-center study 19 healthy subjects received 0.5 mg TID for 7 
days.  On the morning of Day 1 subjects received a single 0.5 mg dose, on Days 2-7 the subjects 
received TID dosing of 0.5 mg (approximately 8AM, 2PM, and 8PM) administered immediately following a 
meal. On the morning of Day 8, the subjects received a final dose of 0.5 mg. 
 
Intensive 24 hour PK sampling occurred following the 8AM doses on Days 1, 7 and 8. Trough samples 
were collected prior to the morning (8 AM) and evening (8PM) doses on Days 4, 5 and 6.   
Nineteen subjects (9F: 10M) with a mean age of 35.2 years (range: 20-54) were enrolled.  On Day 1 the 
mean (+/- SD) maximum plasma concentration (Cmax) of treprostinil was 0.574 +/- 0.22 ng/mL, occurring 
at a median time of 4 hours (range: 2-6 hrs).  In comparison, the Day 8 mean (+/- SD)  Cmax was 0.615 
+/- 0.32 ng/mL, occurring at a median time of 4 hours (range: 1-6 hrs). [Figure 1]    




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1.2.3 
Remodulin Experience 
Remodulin (treprostinil sodium) Injection is a sterile solution of treprostinil sodium formulated for 
subcutaneous or intravenous administration using an ambulatory infusion pump.  The toxicity profile of 
treprostinil delivered by continuous subcutaneous infusion has been extensively evaluated.  The studies 
conducted include the complete International Conference on Harmonisation (ICH) battery of genetic 
toxicology studies; acute, single-dose, intravenous and oral toxicity studies in rats and mice; acute, 
single-dose, subcutaneous toxicity studies in rats and dogs; repeat dose, continuous subcutaneous 
infusion toxicity studies up to 6 months in duration in rats and dogs; and reproductive toxicity studies in 
rats (fertility, teratology and pre/postnatal) and rabbits (teratology). 
 
 
The clinical development of subcutaneous Remodulin included two international, placebo-controlled, 
pivotal studies (13 countries, 40 centers).  These two studies were identical in design and together 
enrolled 470 patients with PAH.  Patients receiving Remodulin had clinically significant improvements in 
exercise tolerance (both distance walked and associated dyspnea), symptoms of PAH, physician-based 
dyspnea-fatigue rating, hemodynamic variables, and quality of life (physical domain) compared to patients 
receiving placebo treatment.  Open-label efficacy data collected by the clinical centers indicate that the 
clinical benefits of Remodulin are maintained with long-term treatment. 
 
The most frequent adverse events (AEs) associated with Remodulin therapy were related to the 
pharmacological properties of Remodulin and were generally not serious.  These prostacyclin-related AEs 
fell into two categories: those related to the local prostaglandin action at the subcutaneous infusion site 
(e.g., infusion site pain and reaction), and those related to systemic effects that are characteristic of 
prostacyclin (e.g., diarrhea, headache, nausea).  Localized subcutaneous infusion site pain and reaction 
were common (85% of Remodulin-treated patients), but were generally manageable, typically resulted in 
withdrawal of treatment in a low percentage of patients (10-15%), did not limit increases in dose, and 
tended to improve with time on therapy.  Remodulin was not 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 patient population, was consistent with 
the profile noted in the controlled trials.  Thus, Remodulin was shown to be a safe and effective treatment 
option for patients with PAH. 
 
To date, well over 10,000 patients/subjects have been exposed to Remodulin from single administration 
to patients receiving continuous infusion of Remodulin for greater than 10 years.  The Remodulin 
(treprostinil sodium) Injection approved product label should be reviewed for additional details on the 
results of studies undertaken during the development of Remodulin. 
 
Although Remodulin is an effective agent given by subcutaneous or intravenous delivery, these forms of 
administration have patient convenience limitations, including the need for an ambulatory infusion device 
and pain at the site of infusion associated with subcutaneous delivery.  Thus, an orally available 
formulation of treprostinil would be of tremendous benefit.  However, the sodium salt of treprostinil (i.e., 
Remodulin) is not an appropriate candidate to develop as a solid-dose oral compound.  A more desirable 
salt of treprostinil (diethanolamine) is therefore being investigated. 
1.3 
Rationale for Development of Study Drug in Disease/Condition 
Prostacyclin (PGI2) is a potent vasodilator and inhibitor of platelet aggregation that is produced by 
vascular endothelium.  A synthetic salt of prostacyclin (i.e.Flolan®) was developed and has demonstrated 
the clinical utility of prostacyclin in the treatment of pulmonary hypertension and other vascular diseases.  
Unfortunately, due to its very short half-life and chemical instability, Flolan must be continuously infused 
by intravenous delivery.  Various analogues have been developed that have overcome some of these 
limitations, but the few orally active agents have remained limited by their short half-life and poor 
solubility.  Remodulin (treprostinil sodium) is a chemically stable, longer acting analogue that has shown 
clinical effectiveness when administered by the continuous subcutaneous and intravenous routes. Recent 
data indicate that a new salt form of treprostinil, diethanolamine, may be delivered by the oral route.  It is 
expected that an oral formulation of treprostinil will not only allow patients suffering from PAH to benefit 


Protocol Number TDE-PH-304 Amendment 5 
 
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from the simplicity of an oral dosage form but may also facilitate the treatment of either previously 
untreated conditions or improve the treatment of conditions that are not adequately controlled with current 
therapies. 
  
1.4 
Clinical Hypothesis 
 
This open-label study will evaluate the safety of continued therapy with UT-15C SR in subjects who 
completed assessments in Protocol TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-
302, TDE-PH-308, or any other study evaluating UT-15C SR in patients with PAH.  The study will also 
provide information about long-term dosing patterns.  Finally, a 6-Minute Walk Test with Borg Dyspnea 
Score to be conducted after subjects have completed one year of treatment with UT-15C SR will provide 
information about the efficacy of long-term treatment. 
 
With Amendment 5, subjects will have the option of modifying their dosing regimen from BID to TID. The 
intention of the dosing modification from BID to TID is to deliver a more sustained plasma concentration 
of treprostinil thereby providing systemic exposure to drug that resembles the approved parenteral 
product, Remodulin, while reducing the occurrence and/or severity of prostacyclin-related adverse events 
previously associated with the twice daily regimen.   
 
The transition from BID to TID dosing should be made at the discretion of the investigator taking into 
account the subjects current disease state and tolerability of UT-15C. 
 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1   
Study Objectives 
The objectives of this study are to: 
• 
Provide, or continue to provide, UT-15C SR for eligible subjects who participated in protocols TDE-
PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, TDE-PH-308 or additional UT-15C 
SR clinical protocols.  
• 
Assess the long-term safety of UT-15C SR in these subjects through assessment of adverse events 
and laboratory parameters.  
• 
Assess the effect of continued therapy with UT-15C SR on exercise capacity after one year of 
treatment. 
2.2 
Study Endpoints 
The safety endpoints are as follows: 
• 
Adverse events 
• 
Clinical laboratory parameters 
PAH concomitant medications also will be documented. 
Efficacy will be assessed by a 6-Minute Walk Test and Borg Dyspnea Score to be conducted after each 
subject has completed one year of therapy with UT-15C SR. 
3 
EXPERIMENTAL PLAN 
3.1   
Study Design 
 


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This is an open-label study.  Each subject’s visit schedule will allow assessments after defined periods of 
exposure to UT-15C SR (3, 6, 12, 24 and 36 months total exposure).  The study will continue with yearly 
visits beyond 36 months until either UT-15C SR is approved by the appropriate regulatory authorities or 
the study is discontinued by the sponsor.  Therefore, the actual date of each visit will be determined by 
the date on which the subject first received UT-15C SR (e.g., the date of study drug initiation in TDE-PH-
301, TDE-PH-302, or TDE-PH-308 for subjects who were randomized to active therapy in those trials, 
and the date of UT-15C SR initiation in this study for subjects who were randomized to placebo in the 
previous controlled trial). Note that the TDE-PH-202, TDE-PH-203, TDE-PH-205 studies are open-label 
design and therefore will follow the regimen for subjects receiving UT-15C SR.  
 
Subjects enrolled from the TDE-PH-202 study who were in Dose Groups 1 or 2 and permanently 
discontinued treatment may enter the study if they undergo all premature termination assessments prior 
to discontinuing study drug and complete all remaining scheduled study visits and assessments (with the 
exception of the hemodynamic measurements) through Week 12. These subjects should follow the same 
procedures as subjects who received placebo in the previous study and will begin on a dose of 0.25mg 
BID. 
 
Subjects randomized to UT-15C SR in Protocol TDE-PH-301, TDE-PH-302, or TDE-PH-308 will complete 
visits 2-5 and yearly visits thereafter, while subjects randomized to placebo in Protocol TDE-PH-301, 
TDE-PH-302, or TDE-PH-308 will complete visits 1-5 and yearly visits thereafter.  A 6-Minute Walk test 
and Borg Dyspnea Score will be conducted at the visit occurring 12 months after the subject’s initial 
exposure to UT-15C SR. 
 
3.2 
Overall Schedule of Times and Events 
 
The overall schedule of Time and Events is shown in Table 3.2.  Note that the timing of each visit 
depends upon when the subject first received UT-15C SR (e.g. whether the subject was assigned to 
active or placebo treatment in Protocol TDE-PH-301, TDE-PH-302, or TDE-PH-308).  Subjects receiving 
placebo in the previous study, or subjects enrolled from the TDE-PH-202 study who are beginning a dose 
of 0.25mg BID, must be contacted weekly by telephone (at a minimum) during the first 12 weeks of the 
open-label study to ensure subject safety.  More specifically, these calls should assess study drug dose 
titration needs, potential adverse events, concomitant medication usage and PAH signs and symptoms.  
Monthly telephone calls (at a minimum) must be conducted for all subjects actively participating in TDE-
PH-304, regardless of study drug allocation (UT-15C SR or placebo) in the previous study, to assess 
dose titration needs, potential adverse events, concomitant medication usage and PAH signs and 
symptoms.  In addition to the scheduled study visits, all subjects must be seen in the clinic no less than 
once every six months for routine standard of care medical evaluation.  
 
Subjects enrolling from the TDE-PH-203 and TDE-PH-205 studies will transition on the same dose they 
were receiving at the end of the study. Study visits for the TDE-PH-304 protocol will be based on the date 
the subject first received active UT-15C in their respective preceding study.  


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Table 3.2.  Time and Events 
 
Visit 4,5,6,7 
Assessment 
Visit 0-1 
(Weeks 1-12) 3 
1 
2 
3 
4 
5+8 
EXIT9  
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
PAH Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
6-Minute Walk Test/Borg Dyspnea Score 1 
 
 
 
X 
 
 
 
Clinical Laboratory Parameters 2 
 
X 
X 
X 
X 
X 
X 
Drug Accountability/Compliance 
X 
X 
X 
X 
X 
X 
X 
1 6-Minute Walk Test/Borg Dyspnea Score as described in Appendix A. conducted 3 to 6 hours after the 
morning dose of UT-15C SR. 
2 Laboratories to be collected are described in Appendix B. 
3 Weekly telephone calls (at a minimum) required during Weeks 1-12 for subjects randomized to placebo in 
TDE-PH-301, 302, or 308 to assess dose titration needs, potential adverse events, concomitant medication 
usage and PAH signs and symptoms. Also applies to subjects enrolled from the TDE-PH-202 study who are 
beginning a dose of 0.25mg BID.  
4 Visit windows are ± 1 month from the scheduled number of months from first exposure to UT-15C SR, 
except for Visit 1, which is ± 2 weeks. 
5 VISIT 1 – Only for subjects randomized to placebo in TDE-PH-301, 302, or 308; 3 months after subject’s first 
exposure to UT-15C.  Also applies to subjects enrolled from the TDE-PH-202 study who are beginning a 
dose of 0.25mg BID. 
VISIT 2 – 6 months after subject’s first exposure to UT-15C SR. 
VISIT 3 – 12 months after subject’s first exposure to UT-15C SR. 
VISIT 4 – 24 months after subject’s first exposure to UT-15C SR. 
VISIT 5 – 36 months after subject’s first exposure to UT-15C SR. 
6 Weekly telephone call required for 4 weeks for all subjects who transition from a BID to TID regimen to 
assess dose titration needs, potential adverse events, concomitant medication usage and PAH signs and 
symptoms. 
7 Monthly telephone calls (at a minimum) required for all subjects participating in TDE-PH-304 to assess 
dose titration needs, potential adverse events, concomitant medication usage and PAH signs and 
symptoms. 
8 Visits beyond Visit 5 will occur yearly until either the drug receives regulatory approval in a particular 
region or the sponsor discontinues the study.  Assessments after visit 5 will include adverse events, PAH 
concomitant medications, concomitant medications, clinical laboratories, and compliance/drug 
accountability. 
9  EXIT – If the subject discontinues from the study between scheduled visits, every effort should be made to 
obtain the exit assessments just prior to termination from the study. 
3.3 
Clinical Assessments 
3.3.1 
Efficacy 
A 6-Minute Walk Test with Borg Dyspnea Score (described in Appendix A) will be conducted at Visit 3, 12 
months from the subject’s first exposure to UT-15C SR.  The 6-Minute Walk Test should be conducted 
approximately 3 to 6 hours after the morning dose of UT-15C SR. 
3.3.2 
Safety 
3.3.2.1 Clinical Laboratory Assessments 
Clinical laboratory parameters will be assessed at each study visit.  Laboratories to be assessed at the 
study visits are listed in Appendix B. 
3.3.2.2  Adverse Event Assessment 


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Adverse event reporting instructions for protocols TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-
301, TDE-PH-302, and TDE-PH-308 will be followed in the open-label study.  Adverse events will be 
reported continuously, as in protocols TDE-PH-202, TDE-PH-301, TDE-PH-302, and TDE-PH-308 and 
documented on the Case Report Form (CRF).  Any AEs that were ongoing at the time of discharge from 
protocols TDE-PH-202, TDE-PH-203, TDE-PH-205,TDE-PH-301, TDE-PH-302, or TDE-PH-308 should 
be recorded as a part of the medical history in the open-label study.  Section 9 and Appendix C provide 
the guidelines and definitions for recording of AEs. 
 
For subjects transitioning from a BID to TID regimen, additional adverse event information will be 
collected via weekly phone contact for at least four weeks from the date of transition.  
 
3.3.2.3. Concomitant Medications 
 
In this open-label study, there are no restrictions on concomitant medications, with the exception of the 
addition of prostanoid therapy. If chronic parenteral prostanoid therapy is added for the treatment of 
worsening PAH, the subject will be discontinued from the study. Short term, parenteral prostanoid therapy 
may be initiated if required (e.g., the patient is temporarily unable to take oral medications). If prostanoid 
therapy is initiated for any other reason than worsening PAH, eligibility for continued participation in this 
study will need to be reviewed by the Medical Monitor on a case by case basis. For subjects enrolling into 
TDE-PH-304 from the TDE-PH-203 study continued chronic use of inhaled treprostinil (Tyvaso®) is 
acceptable.  
 
ERAs and PDE-5 inhibitors may be added or withdrawn at any time. Concomitant PDE-5 inhibitors, ERAs, 
and other medications related to the subject’s treatment will be collected at each study visit and recorded 
in the CRF. 
 
 
3.4 
Number of Centers 
The study will be an international, multi-center study with approximately 118 centers participating.  All 
centers participating in protocols TDE-PH-202, TDE-PH-301, TDE-PH-302, and/or TDE-PH-308 or other 
UT-15C SR clinical protocols will participate in this open-label study. 
3.5 
Number of Subjects 
Approximately 900 subjects will be enrolled across all sites participating in either TDE-PH-202, TDE-PH-
203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE-PH-308.  Additional subjects may be enrolled from 
other clinical protocols evaluating UT-15C SR in subjects with PAH.  All subjects successfully completing 
all assessments in either protocol TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, 
TDE-PH-308 or other UT-15C SR clinical protocols are eligible for participation.   
 
Subjects randomized into Dose Group 1 or Dose Group 2 in the TDE-PH-202 study who permanently 
discontinue study drug during the 12-week Treatment Phase due to clinical worsening are eligible for 
entry into the TDE-PH-304 if they undergo all premature termination assessments prior to discontinuing 
study drug and complete all remaining scheduled study visits and assessments (with the exception of the 
hemodynamic measurements) through Week 12.  Such subjects should start treatment with UT-15C in 
the open-label study at 0.25 mg BID.   
3.6 
Estimated Study Duration 
The estimated study duration for each subject is at least 36 months from the point of transition from 
protocol TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE-PH-308 to the 
end of the open-label study.  The study will continue until either UT-15C SR receives regulatory approval 
in a region or the study is discontinued by the sponsor. 


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4 
SUBJECT ELIGIBILITY 
4.1 
Subject Inclusion Criteria 
A subject is eligible for inclusion in this study if all of the following criteria apply: 
1. 
The subject has remained on study drug and completed all assessments during the Treatment 
Phase of the previous study (TDE-PH-202, TDE-PH-203, TDE-PH-205,TDE-PH-301, TDE-PH-
302, or TDE-PH-308 (or other studies evaluating PAH))  
OR 
 
The subject permanently discontinued study drug during the Treatment Phase of the previous 
study (TDE-PH-301, TDE-PH-302, or TDE-PH-308) due to clinical worsening, completed 
premature termination assessments prior to discontinuing study drug, completed all remaining 
scheduled study visits AND received placebo during the Treatment Phase of the previous study 
(TDE-PH-301, TDE-PH-302, or TDE-PH-308).  
OR 
The subject was randomized into Dose Group 1 or Dose Group 2 in the TDE-PH-202, 
permanently discontinued study drug during the 12-week Treatment Phase due to clinical 
worsening, completed all premature termination assessments prior to discontinuing study drug 
and completed all remaining scheduled study visits and assessments (with the exception of the 
hemodynamic measurements) through Week 12.  Such subjects should start treatment with UT-
15C in the open-label study at 0.25 mg BID.   
 
2.   
The subject voluntarily gives informed consent to participate in the study. 
 
3.  
Women of child bearing potential include any female who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or 
bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea for at least 12 
consecutive months].  Sexually active women of childbearing potential must use two effective 
forms of contraception during the length of the study. Medically acceptable forms of effective 
contraception include:  (1) approved hormonal contraceptives (such as birth control pills), (2) 
barrier methods (such as a condom or diaphragm) used with a spermicide, (3) an intrauterine 
device (IUD), (4) partner vasectomy, or (5) abstinence. Males participating in the study must use 
a condom during the length of the study, and for at least 48 hours after discontinuing study 
medication. 
 
4.2 
Subject Exclusion Criteria 
 
1. 
The subject permanently discontinued study drug during the previous study (TDE-PH-202, TDE-
PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE-PH-308) due to treatment related 
adverse events. 
 
2. 
The subject permanently discontinued study drug during the Treatment Phase of the previous 
study (TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE-PH-308) 
due to clinical worsening (as defined in those study protocols) and did not undergo premature 
termination assessments prior to discontinuing study drug, and/or did not complete all remaining 
study visits through the final scheduled visit. 
 
3. 
The subject permanently discontinued study drug during the Treatment Phase of the previous 
study (TDE-PH-301, TDE-PH-302, or TDE-PH-308) due to clinical worsening, completed 
premature termination assessments prior to discontinuing study drug, completed all remaining 
scheduled study visits AND received UT-15C SR during the Treatment Phase of the previous 
study (TDE-PH-301, TDE-PH-302, or TDE-PH-308). 
 
Subjects enrolled in the TDE-PH-202 study who were randomized into the iMTD group who 
clinically worsen may not participate.  Subjects who permanently discontinue study drug during 


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the 12-week Treatment Phase due to treatment related adverse events are not eligible even if 
they complete all remaining scheduled study visits.  Subjects who permanently discontinue study 
drug during the 12-week Treatment Phase and do not undergo premature termination 
assessments prior to discontinuing study drug and/or who do not complete all remaining study 
visits through the Week 12 visit are also not eligible.   
 
 
4. 
The subject must not have developed any concurrent illness or condition during the conduct of 
the previous study, including but not restricted to, sleep apnea, chronic renal insufficiency, 
anemia, uncontrolled systemic hypertension or left sided heart disease, unless their physician 
feels that entry into this study would not be detrimental to their overall health. 
5 
SUBJECT ENROLLMENT 
5.1 
Treatment Assignment 
All subjects will receive UT-15C SR during the open-label study. 
5.2 
Randomization 
This study is not randomized. 
5.3 
Blinding 
This study is not blinded. 
6 
DRUGS AND DOSING 
6.1 
Drug Dosage, Administration and Schedule 
UT-15C SR tablets will be provided as 0.25, 0.5, 1, and 2.5 mg tablet strengths.  They may also be 
provided as 0.125 mg strength, if available.  The 0.125, 0.25, 0.5, 1, and 2.5 mg tablets are colored blue, 
green, white, yellow, and pink, respectively. 
 
For subjects who were randomized to placebo in protocols TDE-PH-301, TDE-PH-302, or TDE-PH-308, 
dosing of UT-15C SR will be initiated and optimized as in the previous protocol, including all safety 
monitoring including periodic telephone contacts.  That is, the first dose of UT-15C SR (0.25 mg) should 
be taken by the subject immediately following (~ 10 minutes) a meal while at the study site.  The subject 
should remain close to the study site for approximately 3 to 6 hours for periodic observation and 
monitoring of possible AEs.   
 
Subjects who were randomized to UT-15C SR, or were receiving active therapy in the previous trial will 
begin open-label therapy at the same dose and regimen (e.g. BID or TID) they were receiving at the final 
visit in the previous trial, and subsequent dose adjustments will be made based on symptoms of PAH and 
AEs. 
 
With Amendment 5, subjects may now receive UT-15C either twice (BID) or three (TID) time daily. The 
decision to transition subjects from BID to TID is up to the discretion of the principal investigator, and not 
a requirement of the protocol.  
 
The dose of UT-15C SR at the time the subject is discharged from each study visit should be recorded on 
the CRF. 
 
6.1.1   Twice Daily Dosing Regimen 
 


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The next dose of study drug should be taken the following morning.  At this time oral dosing of UT-15C 
SR will be initiated at 0.25 mg twice daily (every 12 hours +/- 1 hour) immediately following (~10 minutes) 
breakfast and dinner.  Subjects must be instructed to take the appropriate amount of 0.25, 0.5, 1, and/or 
2.5 mg tablets based upon their given dose.  In general, the dose of study drug should be increased in 
0.25 to 0.5 mg increments every 3 days, in the absence of dose-limiting drug-related side effects, to 
ensure the subject receives the optimum clinical dose throughout the study.  The 0.125 mg strength, if 
available, may be used throughout the study if a 0.25 mg dose increase is not tolerated and an 
intermediate dose is required.  Dose changes should be conducted under appropriate medical 
supervision in consultation with the study site. 
 
6.1.2   Transition from Twice to Three Times daily Dosing  
 
For subjects enrolled in the TDE-PH-304 study who are receiving UT-15C twice daily, dosing frequency 
may be transitioned from BID to TID.  For applicable subjects, it is recommended to reduce the total daily 
dose administered during BID dosing by approximately 25% and divide the total daily dose into a TID 
regimen using the appropriate tablet strength(s).  Please see Table 6-1 below for examples of 
transitioning from BID dosing to TID dosing.   However, dose modification should occur in accordance 
with investigator judgment. 
Table 6-1  Example Transition from Twice Daily to Three Times Daily Dosing of 
UT-15C 
BID Dosing Regimen 
Total Daily 
Dose with BID 
Dosing 
Total Daily 
Dose with 
BID Dosing 
Reduced by 
25% 
TID Dosing 
Regimen 
Total Daily 
Dose with 
TID Dosing 
3 mg BID 
6 mg 
4.5 mg 
1.5 mg TID 
4.5 mg 
5 mg qAM; 5.25 mg qPM 
10.25 mg 
7.6875 mg 
2.5 mg TID 
7.5 mg 
6 mg BID 
12 mg 
9 mg 
3 mg TID 
9 mg 
6.5 mg qAM; 6.625 mg qPM 
13.125 mg 
9.844 mg 
3.25 mg TID 
9.75 mg 
10 mg BID 
20 mg 
15 mg 
5 mg TID 
15 mg 
11 mg qAM; 11.5 mg qPM 
22.5 mg 
16.875 mg 
5.5 mg TID 
16.5 mg 
13 mg BID 
26 mg 
19.5 mg 
6.5 mg TID 
19.5 mg 
17.125 mg qAM; 17.25 mg qPM  
34.375 mg 
25.781 mg 
8.5 mg TID 
25.5 mg 
 
Dose changes should be conducted under appropriate medical supervision in consultation with the study 
site.  If dose titration is considered appropriate, site personnel will instruct the subject to modify their 
dose; dose changes will be recorded in source documentation and CRF by site personnel.   
 
6.1.3   Three Times (TID) Daily Dosing Regimen 
 
For subjects entering the TDE-PH-304 study receiving a TID dosing regimen (e.g. TDE-PH-205), or for 
those subjects transitioning from BID to TID dosing, the dosing regimen should be managed as follows: 
• 
TID (every 6-8 hours) with food 
• 
Increases should occur in increments of 0.125 or 0.25 mg TID every 3 days.  
 
In general, the dose of study drug should be increased in 0.125 to 0.25 mg increments every 3 days, in 
the absence of dose-limiting drug-related side effects, to ensure the subject receives the optimum clinical 
dose throughout the study.  The 0.125 mg strength, if available, may be used throughout the study if a 


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0.25 mg dose increase is not tolerated and an intermediate dose is required.  Dose changes should be 
conducted under appropriate medical supervision in consultation with the study site. 
6.1.4   Dosing of Study Medication in Relation to Meals 
Subjects should take study drug approximately every 12 hours (+/- 1 hour) for BID dosing and every 6 – 8 
hours for TID dosing, with approximately 240 mL (8 ounces) of water or other beverage (e.g. juice, milk, 
soda, etc.) immediately after (~ 10 minutes) consuming food (approximately 250 calories). 
Subjects should be instructed to be careful not to break, chew, or disrupt the integrity of the tablet as this 
will result in inappropriate delivery of the active ingredient.  If the tablet is inadvertently damaged during 
administration, the subject should contact site personnel in order to be monitored for the onset of 
symptoms due to possible overdose. 
6.2 
Compliance 
At each visit, the Investigator or designee will evaluate the amount of UT-15C SR provided to each 
subject and any returned medication (as required for drug accountability purposes), and compare this 
accounting with the subject’s dosing pattern to obtain an estimate of overall compliance.  Each subject 
will also be asked at each visit whether he or she is in compliance with dosing instructions.  If it is 
determined that a subject is not compliant with study drug then site personnel should re-educate the 
subject on proper dosing compliance.  Continued non-compliance may lead to discontinuation of the 
subject, after consultation between the Investigator and sponsor. 
7 
EXPERIMENTAL PROCEDURES 
7.1 
Open-Label Phase 
All values collected at the subject’s respective final visit in protocol TDE-PH-202 TDE-PH-203, TDE-PH-
205, TDE-PH-301 or TDE-PH-308 and TDE-PH-302 will serve as the baseline assessments for the open-
label study.   
 
Subjects receiving placebo in the previous study must be contacted weekly by telephone (at a minimum)  
during the first 12 weeks of the open-label study and, if necessary, brought in for clinic visits in the first 
several months of the study to ensure subject safety.  This also applies to subjects enrolled from the 
TDE-PH-202 study (Dose Groups 1 or 2) who are beginning a dose of 0.25mg BID. 
 
Monthly telephone calls (at a minimum) must be conducted for all subjects actively participating in the 
open-label study, regardless of study drug allocation (UT-15C SR or placebo) in the previous study.  
 
In addition to the scheduled study visits, as listed below, all subjects must be seen in the clinic no less 
than once every six months for routine standard of care medical evaluation.  
 
Weekly telephone calls (required Weeks 1-12; only for subjects randomized to placebo in previous study). 
This also applies to subjects enrolled from the TDE-PH-202 study (Dose Groups 1 or 2) who are 
beginning a dose of 0.25mg BID. 
• 
Adverse events 
• 
PAH concomitant medications 
• 
Concomitant medications 
Drug accountability / compliance  
Weekly telephone calls (required for 4 weeks for subjects who transition from BID to TID dosing) 
• 
Adverse Events 
• 
PAH concomitant medications 
• 
Concomitant medications 
• 
Drug accountability/compliance 
 


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Monthly telephone calls (required for all subjects participating in open-label study) 
• 
Adverse events 
• 
PAH concomitant medications 
• 
Concomitant medications 
• 
Drug accountability / compliance 
 
Visit 1 (three months after first dose of UT-15C SR; only for subjects randomized to placebo in previous 
study). This also applies to subjects enrolled from the TDE-PH-202 study (Dose Groups 1 or 2) who are 
beginning a dose of 0.25mg BID. 
• 
Adverse events 
• 
PAH concomitant medications 
• 
Concomitant medications 
• 
Clinical laboratories 
• 
Drug accountability/compliance 
 
Visit 2 (six months after first dose of UT-15C SR) 
• 
Adverse events 
• 
PAH concomitant medications 
• 
Concomitant medications 
• 
Clinical laboratories 
• 
Drug accountability/compliance 
 
Visit 3 (12 months after first dose of UT-15C SR) 
• 
Adverse events 
• 
PAH concomitant medications 
• 
Concomitant medications 
• 
Clinical laboratories 
• 
Drug accountability/compliance 
• 
6-Minute walk test/borg dyspnea score 
 
Visit 4 (24 months after first dose of UT-15C SR) 
• 
Adverse events 
• 
PAH concomitant medications 
• 
Concomitant medications 
• 
Clinical laboratories 
• 
Drug accountability/compliance 
 
Visit 5 (36 months after first dose of UT-15C SR) 
• 
Adverse events 
• 
PAH concomitant medications 
• 
Concomitant medications 
• 
Clinical laboratories 
• 
Drug accountability/compliance 
 
Yearly visits beyond 36 months  
• 
Adverse events 
• 
PAH concomitant medications 
• 
Concomitant medications 
• 
Clinical laboratories 
• 
Drug accountability/compliance 
 
Exit (premature discontinuation)  
• 
Adverse events 
• 
PAH concomitant medications 


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• 
Concomitant medications 
• 
Clinical laboratories 
• 
Drug accountability/compliance 
8 
STUDY TERMINATION 
8.1 
Subject Discontinuation 
A subject may voluntarily withdraw or be withdrawn from the study 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 deviated from the protocol. 
• The subject’s behavior is likely to undermine the validity of his/her results.  
• The subject becomes pregnant 
If a subject is discontinued prematurely, the Investigator must provide an explanation in the CRF 
(Investigator’s Comment Log) and complete the End of Study Record for that subject.  If study drug has 
been administered, the Investigator should make every effort to perform all scheduled evaluations prior to 
discharge.  In the event that a subject discontinues prematurely due to an AE, the subject will be followed 
until the Investigator determines the AE has resolved, the AE is no longer considered clinically significant, 
the subject is lost to follow-up, or for 30 days following discontinuation of UT-15C. 
8.2 
Study Discontinuation 
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 adverse events or adverse events that are unacceptable in 
nature, severity, or frequency.  The sponsor reserves the right to discontinue the study for any reason at 
any time. In the event the sponsor discontinues the study, an EXIT visit for each subject should be 
scheduled. 
8.3 
Site Discontinuation 
The study may also be terminated at a given center if: 
• 
The Principal Investigator elects to discontinue the study 
• 
The Sponsor elects to discontinue the study at the site 
• 
U.S. FDA, European, or national regulations are not observed 
• 
The protocol is violated 
• 
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 experience occurring to a subject during a clinical trial whether or not it is 
related to the study drug.  An AE may include an intercurrent illness, injury, or any other concomitant 
impairment of the subject’s health, as well as abnormal laboratory findings if deemed to have clinical 
significance.  AEs may also include worsening of an existing symptom or condition or post-treatment 
events that occur as a result of protocol-mandated procedures. 
9.1.2 Serious Adverse Event  
A serious adverse event (SAE) is an AE occurring at any dose that results in any of the following 
outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
o 
Planned hospitalizations (e.g., admission for elective surgery or right heart catheterization) do 
not qualify as SAE’s 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
In addition, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and require medical/surgical intervention to prevent one of the outcomes listed 
above.  Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in hospitalization, or 
the development of drug dependency or drug abuse.   
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of death 
from the event as it occurred.  It does not mean that the event, had it occurred in a more severe form, 
might have caused death. 
9.1.3 Expected Adverse Event  
Adverse events associated with progression of PAH: 
An expected event that is related to the progression of a subject’s PAH is defined in Appendix D, Part A.  
All events that occur during the course of the study that are included on this list and felt to be related to 
progression of disease by the Investigator should NOT be recorded as AEs in the CRF as the most 
relevant PAH symptoms will be evaluated and recorded as an efficacy endpoint and all other events will 
be captured as disease related events.  If the event is either serious or unusual with respect to intensity, 
frequency, or duration, OR there is a reasonable possibility that it may have been caused by study drug, it 
must be recorded as an AE in the CRF. 
Adverse events known to be associated with treprostinil therapy: 
An expected AE for UT-15C is defined as any AE that is defined in terms of nature, severity, or frequency 
in the current Investigators’ Brochure and in Appendix D, Part B.  When an adverse event may be 
attributed to the progression of pulmonary hypertension or UT-15C SR (e.g., listed in both Parts A and B) 
it must be recorded as an AE in the CRF if the event is either serious or unusual with respect to intensity, 
frequency, or duration, OR there is a reasonable possibility that it may have been caused by study drug.  


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Expected events attributable to UT-15C (e.g., listed in Part B only) must always be recorded as AEs in 
the CRF. 
If an event listed in Appendix D Part A or B occurs during the conduct of the trial, it will not give rise to 
submission of an expedited safety report despite being considered serious and possibly attributable to the 
study drug, unless the United Therapeutics Medical Monitor, responsible for assessing the case 
considers it to be unusual (e.g., more severe than expected) and therefore reportable.  The data 
regarding such events will always be recorded in the clinical study database, regardless of reportability. 
9.2 Documentation of Adverse Events 
An AE or SAE occurring during the study must be documented in the subject’s source documents and on 
the appropriate CRF page.  Information relating to the AE such as onset and cessation date and times, 
intensity, seriousness, relationship to study drug, and outcome will also be documented in the CRF (see 
Appendix C 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 CRF page, not the individual signs and 
symptoms. 
All adverse events should be followed until resolution (or return to normal or baseline values), until they 
are judged by the Investigator to no longer be clinically significant, or for 30 days following discontinuation 
of UT-15C.  All SAEs that occur during the study will be followed until resolution, death, or the subject is 
lost to follow-up.  Supplemental measurements and/or evaluations may be necessary to fully investigate 
the nature and/or causality of an AE or SAE.  This may include additional laboratory tests, diagnostic 
procedures, or consultation with other healthcare professionals.  CRF pages should be updated with any 
new or additional information as appropriate. 
9.3 Reporting Responsibilities of the Investigator 
All SAEs, regardless of expectedness or causality, must be reported to the Sponsor by fax or email 
 
 
 within 24 hours of awareness.  A completed SAE report form along with any 
relevant hospital records and autopsy reports should be faxed to the Drug Safety Department at United 
Therapeutics Corporation.  A follow-up SAE report form should be forwarded to the Drug Safety 
Department at United Therapeutics Corporation within 48 hours of the receipt of any new/updated 
information.  The Investigator must also promptly notify the Investigational Review Board (IRB) or Ethics 
Committee (EC) of the SAE, including any follow-up information according to the guidelines set forth by 
the IRB or EC.   
9.4 Safety Reports 
In accordance with FDA, European, and national regulations, 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.  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.  If an event listed in Appendix D Part A or B occurs during the conduct of the trial, it will not give rise 
to submission of an expedited safety report despite being considered serious and possibly attributable to 
the study drug, unless the United Therapeutics Medical Monitor, responsible for assessing the case 
considers it to be unusual (e.g., more severe than expected) and therefore reportable.  The data 
regarding such events will always be recorded in the clinical study database, regardless of reportability. 
9.5 Pregnancy 
If a study subject becomes pregnant during participation in this clinical study, site staff must notify the 
sponsor within 24 hours of learning of the pregnancy by completing the Pregnancy Report Form and 
either faxing or emailing this form to 
  Subjects who 


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become pregnant during the trial will be withdrawn from active participation in the trial and will discontinue 
study drug after an appropriate period of down-titration.   
 
United Therapeutics Global Drug Safety will follow up with the Investigator each trimester to ensure 
appropriate data are provided regarding the outcome of the pregnancy, and to ask the Investigator to 
update the Pregnancy Report Form.  Pregnancy only becomes an AE / SAE if there is an abnormal 
outcome, a spontaneous abortion, a termination for medical reasons other than PAH, or a congenital 
anomaly in the offspring. 
 
10 
DATA MANGEMENT AND STATISTICS 
Completed CRFs will be forwarded to United Therapeutics or its designee for processing.  A quality-
assured computerized database will be constructed. Data will be listed and also will be summarized either 
in tabular and/or graphical presentations. 
The safety of UT-15C SR will be assessed using laboratory assessments and reports of adverse events.  
All reported adverse events will be assigned MedDRA terms which will be listed and summarized 
according to intensity, seriousness and causality. 
Efficacy assessments (6-Minute Walk/Borg Dyspnea Score) may be compared to assessments in 
Protocols TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, TDE-PH-308, or TDE-
PH-304, as appropriate.  Doses of UT-15C SR will be listed, summarized and analyzed for trends over 
time. 
11 
PACKAGING AND FORMULATION 
11.1 
Study Drug Content    
United Therapeutics will supply UT-15C SR for administration in the study.  UT-15C SR tablets will be 
provided as 0.25, 0.5, 1, and 2.5 mg strengths and may also be provided as a 0.125 mg strength, if 
available. UT-15C SR 0.125 mg (blue), 0.25 mg (green), 0.5 mg (white), 1 mg (yellow), and 2.5 mg (pink) 
tablets will be provided in child resistant bottles each containing 100 tablets, or in other appropriate 
packaging configurations as may be required as more experience with long-term dosing requirements is 
obtained.   
11.2 
Study Drug Labeling 
Each bottle and/or other packaging (e.g., kits/cartons) for UT-15C SR will be labeled with at least the 
following information:  study drug, strength, quantity, manufacture date, lot number, sponsor name and 
address, and storage conditions.   
11.3 
Study Drug Storage and Handling 
All study drug will be stored in accordance with label specified storage conditions.  UT-15C SR should not 
be frozen or exposed to heat.   
Subjects should be instructed to return all study drug, including empty bottles or other containers, to the 
appropriate study personnel for drug accountability and compliance assessments, as appropriate. 
11.4 
Study Drug Supply and Return 
Study sites will be supplied with a sufficient quantity of UT-15C SR to begin enrollment in the study.  
Appropriate arrangements will be made for resupply with respect to each subject’s visit schedule. All 
unused study drug dispensed to the subject should be returned to the study site (including empty and 
unopened bottles).   


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11.5 
Study Drug Accountability 
The Investigator is responsible for study drug accountability and reconciliation overall and on a per 
subject basis.  Drug accountability records are to be maintained during the study and these records 
include:  the amount of study drug received from the Sponsor, the amount dispensed to each subject, and 
the amount of unused drug.  At each visit, site personnel should assess drug dispensed, drug returned, 
and dosing information to confirm drug accountability and compliance. Once a representative from the 
Sponsor is able to confirm drug accountability for that subject, study drug will be returned to a Sponsor 
designated location for destruction. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
Regulatory Requirements 
The study will be conducted in accordance with ICH and GCP guidelines and all applicable national 
regulations.  The Sponsor will obtain the required approval from each national regulatory authority to 
conduct the study.  During the conduct of the study an annual safety report will be compiled by the 
Sponsor for submission to those regulatory authorities and IRBs/ECs that require it.  Any additional 
national reporting requirements as specified by the applicable regulations, regulatory authorities, or 
IRB/EC will also be fulfilled during the conduct of the study. 
12.2 
Informed Consent Requirements 
Before a subject is enrolled in the study, the Investigator or his/her designees must explain the purpose 
and nature of the study, including potential benefits and risks and all study procedures to the subject.  
The subject must sign and date an IRB/EC-approved informed consent form prior to the conduct of any 
study-related activities.  A copy of the signed consent form will be given to the subject and the original will 
be retained in the study site’s records. 
12.3 
Institutional Review Board/Independent Ethics Committee Approval 
Prior to study initiation at each site, the Investigator will obtain approval for the study from an appropriate 
IRB/EC and provide the Sponsor with a copy of the approval letter.  The IRB/EC must also review and 
approve the study site’s informed consent form 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 
informed consent form 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 informed consent form, 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 trial, the following documents will be provided to the site:  
Investigator’s Brochure, Protocol, Informed Consent Form, Budget Agreement, and Case Report Form. 
 
The site will be required to provide the following documents to United Therapeutics Corporation or 
designee prior to study start:  Signature page of the protocol, Form FDA 1572, IRB/EC Composition and 


Protocol Number TDE-PH-304 Amendment 5 
 
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Roster, IRB/EC approval letters for protocol and informed consent, and Curriculum Vitae of study staff 
listed on the 1572. 
12.5 
Subject Confidentiality 
 
Every effort will be made to keep medical information confidential.  United Therapeutics Corporation, the 
FDA or other regulatory bodies, and the IRB/EC governing this study may inspect the medical records of 
any subject involved in this study.  The Investigator may release the subject’s medical records to 
employees or agents of the Sponsor, the IRB/EC or the FDA or appropriate local regulatory agencies for 
purposes of checking the accuracy of the data.  A number will be assigned to all subjects and any report 
published will not identify the subject’s name. 
12.6   
Reporting of Clinical Trial Results 
  
The timely communication of scientifically valid results, positive and negative, from this clinical trial will 
occur.  Avenues for such public communications may include the following:  peer-reviewed publications of 
original research and scientific, nonpromotional summaries on a publicly accessible registry (i.e., a Web 
site).  A committee of principal investigators participating in the clinical trial and enrolling the highest 
number of subjects will oversee the publication of study results. 
  
The guidelines such as the Good Publication Practice (GPP) guidelines for pharmaceutical companies 
(gpp-guidelines.org), and guidelines sponsored by the International Committee of Medical Journal Editors 
and the Pharmaceutical Manufacturers Association (PhRMA) will be endorsed.  In addition, an attempt 
will be made to fulfill any country specific regulatory requirements for publication of clinical trials 
conducted within that country. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
Protocol Amendments and Study Termination 
Protocol amendments that could potentially adversely affect the safety of participating subjects or that 
alter the scope of the investigation, the scientific quality of the study, the experimental design, dosages, 
duration of therapy, assessment variables, the number of subjects treated, or subject selection criteria 
may be made only after consultation between United Therapeutics Corporation or its designee and the 
Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory authorities 
and IRB/Ethics Committee 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, and GCP guidelines, the Investigator must retain 
study records for at least 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational product. For 
investigators in the European Economic Area (EEA), the study records should be maintained for at least 
15 years after study discontinuation.  The Investigator must notify United Therapeutics Corporation before 
any disposal or change in location of study records. 


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13.3 
Study Monitoring and Data Collection 
In accordance with federal/national regulations, ICH, and GCP guidelines, monitors for United 
Therapeutics Corporation or its designee will periodically contact the site and conduct on-site visits.  
During these visits, the monitor will at a minimum:  confirm ethical treatment of subjects, assess study 
progress, review data collected, conduct source document verification, verify drug accountability 
periodically, and identify any issues requiring resolution.   
The Investigator agrees to allow the monitor direct access to all relevant documents and to allocate 
his/her time and his/her staff to the monitor to discuss any findings or any relevant issues.  


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14 
REFERENCES 
1. Farber H. & Loscalzo J.  Mechanisms of disease:  Pulmonary arterial hypertension.  New Engl J Med 
2004; 3511(16):1655-1665.   
2. Barst RJ, Rubin LJ, Long WA, et al.  A comparison of continuous intravenous epoprostenol 
(prostacyclin) with conventional therapy for primary pulmonary hypertension. New Engl J Med 1996; 
334:296-301. 
3. Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, Rich S, Barst RJ, Barrett 
PS, Kral KM, Jobsis MM, Loyd JE, Murali S, Frost A, Girgis R, Bourge RC, Ralph DD, Elliott CG, Hill 
NS, Langleben D, Schilz RJ, McLaughlin VV, Robbins IM, Groves BM, Shapiro S, Medsger TA Jr. 
Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of 
disease. A randomized, controlled trial. Ann Intern Med. 2000; Mar 21; 132(6):425-34. 
4. Simmoneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, 
Blackburn SD, Crow JW, Rubin J.  Continuous subcutaneous infusion of treprostinil, a prostacyclin 
analogue, in subjects with pulmonary arterial hypertension: a double-blind, randomized, placebo-
controlled trial.  Am J. Resp. Crit Care Med. 2002; 165 (6):  800-804. 
5. McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and Safety of Treprostinil: An Epoprostenol 
Analogue for Primary Pulmonary Hypertension.  J. Cardiovascular. Pharm. 2003; 41(2):293-9. 
6. Tapson VF, Gomberg-Maitland M, Horn E, Rich S, Krichman A, Ward G, Widlitz PA, Tomsa L, Barst 
R.  Safety and Efficacy of Chronic Intravenous Treprostinil in Subjects with Pulmonary Arterial 
Hypertension – De Novo and Epoprostenol Transition.  Presented at American Thoracic Society, 
Orlando, FL, May 23, 2004.  
7. Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M.  Pharmacokinetics and Steady-State 
Bioequivalence of Treprostinil Sodium (Remodulin®) Administered by the Intravenous and 
Subcutaneous Route to Healthy Volunteers.  Journal of Cardiovascular Pharmacology. 
2004;44(2):209-214. 
8. Ventavis Package Information.  Co Therix Inc., 2005; South San Francisco, CA 
9. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, 
Landzberg M, Simmoneau G.  Bosentan therapy for pulmonary arterial hypertension.  N Engl J Med. 
2002 Mar 21; 346(12):896-903. 
10. Cohen H., Chahine C., Hui A., Mukherji R.  Bosentan therapy for pulmonary arterial hypertension.  
American Journal of Health Systems Pharmacists, 2004; 61:1107-19. 
11. Ghofrani H., Voswinckel R., Reichenberger F., Olschewski H., Haredza P., Karadas B., Schermuly 
R., Weissman N., Seeger W., Grimminger F.  Differences in hemodynamic and oxygenation 
responses to three different phosphodiesterase-5 inhibitors in subjects with pulmonary arterial 
hypertension.  A randomized prospective study.  Journal of the American College of Cardiology, 
2004;44(7):1488-96. 
12. Sastry B., Narahimhan C., Reddy N., Raju B.  Clinical efficacy of sildenafil in primary pulmonary 
hypertension:  a randomized, placebo-controlled, double-blind, crossover study.  Journal of the 
American College of Cardiology 2004;43:1149-53. 
13. Remodulin U.S. Package Insert.  Research Triangle Park, NC:  United Therapeutics Corporation.  
2011. 

SAP_001.pdf: 
United Therapeutics Corp. 
TDE-PH-304 Statistical Analysis Plan 
 
Oral Treprostinil 
Page 1 of 17 
Document Type: 
Statistical Analysis Plan Protocol / Study No.: 
TDE-PH-304 
Final Date: 
 
2-MAR-2016 
Total Number of Pages 
including Appendices: 
 
17 
Classification: 
Confidential 
 
 
Title: 
An Open-Label Extension Trial of UT-15C SR in Subjects with 
Pulmonary Arterial Hypertension 
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. © 2016 
United Therapeutics Corporation 


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TDE-PH-304 Statistical Analysis Plan 
 
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FINAL: 2MAR2016 
CONFIDENTIAL 
Page 2 of 17 
TABLE OF CONTENTS 
TABLE OF CONTENTS 
........................................................................................................ 2 
ABBREVIATIONS AND DEFINITIONS 
............................................................................ 3 
1 PREFACE 
.......................................................................................................................... 4 
2 STUDY OBJECTIVES AND ENDPOINTS 
................................................................... 4 
2.1 Objectives 
...................................................................................................................... 4 
2.2 Endpoints ...................................................................................................................... 4 
3 STUDY DESIGN 
............................................................................................................... 4 
4 RANDOMIZATION 
......................................................................................................... 5 
5 SEQUENCE OF PLANNED ANALYSES ..................................................................... 5 
6 SAMPLE SIZE CONSIDERATIONS ............................................................................ 5 
7 ANALYSIS POPULATIONS 
........................................................................................... 5 
8 GENERAL CONSIDERATIONS FOR DATA ANALYSES ....................................... 6 
8.1 Examination of Subgroups 
.......................................................................................... 6 
8.2 Premature Discontinuation and Missing Data .......................................................... 6 
8.3 Multiple Comparisons and Multiplicity 
..................................................................... 7 
9 STUDY POPULATION ................................................................................................... 7 
9.1 Subject Accountability 
................................................................................................. 7 
9.2 Eligibility Criteria 
........................................................................................................ 7 
9.3 Other Descriptions of Study Population .................................................................... 7 
9.3.1 
Demographics .......................................................................................................... 7 
9.3.2 
PAH History 
............................................................................................................. 7 
9.3.3 
PAH Therapy 
........................................................................................................... 8 
9.3.4 
Concomitant Therapy 
............................................................................................. 8 
10 EFFICACY ANALYSES 
.................................................................................................. 8 
10.1 Six Minute Walk Test .................................................................................................. 8 
10.2 Clinical Events 
.............................................................................................................. 9 
11 SAFETY ANALYSES 
....................................................................................................... 9 
11.1 Extent of Exposure 
....................................................................................................... 9 
11.2 Adverse Events ........................................................................................................... 10 
11.3 Disease Related Events 
............................................................................................... 10 
11.4 Deaths 
.......................................................................................................................... 11 
11.5 Clinical Laboratory Tests 
.......................................................................................... 11 
12 APPENDICES 
................................................................................................................. 12 
12.1 Inclusion and Exclusion Criteria 
.............................................................................. 12 
12.2 List of Tables 
............................................................................................................... 14 
12.3 List of Listings ............................................................................................................ 16 
12.4 List of Figures 
............................................................................................................. 17 
 


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FINAL: 2MAR2016 
CONFIDENTIAL 
Page 3 of 17 
ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
6MWD 
Six minute walk distance 
AE 
Adverse event 
BID 
Twice daily 
CRF 
Case report form 
CSR 
Clinical study report 
ERA 
Endothelin receptor antagonist 
K-M 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
OL 
Open-label 
PAH 
Pulmonary arterial hypertension 
PDE-5i 
Phosphodiesterase type 5 inhibitor 
PT 
Preferred term 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
SR 
Sustained release 
TID 
Three times daily 
WHO 
World Health Organization 
 
 


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TDE-PH-304 Statistical Analysis Plan 
 
Oral Treprostinil 
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1 
PREFACE 
This statistical analysis plan (SAP) provides further details of the planned analyses for the 
TDE-PH-304 study.  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 conclusions regarding the study objectives and 
the completion of the Clinical Study Report (CSR).  Additional post-hoc or unplanned 
analyses, which are not defined in this SAP, may be performed to support the clinical 
development program.  Such analyses will be documented in the CSR. 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 OBJECTIVES 
The objectives of this study are to: 
• Provide, or continue to provide, UT-15C sustained release (SR) for eligible subjects 
who participated in protocols TDE-PH-202, TDE-PH-203, TDE-PH-205, 
TDE-PH-301, TDE-PH-302, TDE-PH-308, or additional UT-15C SR clinical 
protocols. 
• Assess the long-term safety of UT-15C SR in these subjects through assessment of 
adverse events and laboratory parameters. 
• Assess the effect of continued therapy with UT-15C SR on exercise capacity after one 
year of treatment. 
2.2 ENDPOINTS 
The safety endpoints are as follows: 
• Adverse events (AEs) 
• Clinical laboratory parameters 
Pulmonary arterial hypertension (PAH) concomitant medications also will be documented. 
Efficacy will be assessed by a 6-Minute Walk Test and Borg Dyspnea Score to be conducted 
after each subject has completed one year of therapy with UT-15C SR. 
3 
STUDY DESIGN 
This is an open-label (OL) study.  Each subject’s visit schedule will allow assessments after 
defined periods of exposure to UT-15C SR (3, 6, 12, 24, and 36 months total exposure).  The 
study will continue with yearly visits beyond 36 months until either UT-15C SR is approved 
by the appropriate regulatory authorities or the study is discontinued by the sponsor.  
Therefore, the actual date of each visit will be determined by the date on which the subject 
first received UT-15C SR (e.g., the date of study drug initiation in TDE-PH-301, 
TDE-PH-302, or TDE-PH-308 for subjects who were randomized to active therapy in those 
studies, and the date of UT-15C SR initiation in this study for subjects who were randomized 
to placebo in the previous controlled study).  Note that the TDE-PH-202, TDE-PH-203, and 


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TDE-PH-205 studies are OL in design and therefore will follow the regimen for subjects 
receiving UT-15C SR. 
Subjects enrolled from the TDE-PH-202 study who were in Dose Groups 1 or 2 and 
permanently discontinued treatment may enter the study if they undergo all premature 
termination assessments prior to discontinuing study drug and complete all remaining 
scheduled study visits and assessments (with the exception of the hemodynamic 
measurements) through Week 12.  These subjects should follow the same procedures as 
subjects who received placebo in the previous study and will begin on a dose of 0.25mg twice 
daily (BID). 
Subjects randomized to UT-15C SR in Protocol TDE-PH-301, TDE-PH-302, or TDE-PH-308 
will complete visits 2-5 and yearly visits thereafter, while subjects randomized to placebo in 
Protocol TDE-PH-301, TDE-PH-302, or TDE-PH-308 will complete visits 1-5 and yearly 
visits thereafter.  A 6-Minute Walk Test and Borg Dyspnea Score will be conducted at the 
visit occurring 12 months after the subject’s initial exposure to UT-15C SR. 
Monthly telephone calls must be conducted for all subjects actively participating in 
TDE-PH-304, regardless of study drug allocation in the previous study.  In addition to the 
scheduled study visits, all subjects must be seen in the clinic no less than once every six 
months for routine standard of care medical evaluation. 
4 
RANDOMIZATION 
This study is not randomized.  All subjects will receive UT-15C SR during the OL study. 
5 
SEQUENCE OF PLANNED ANALYSES 
Interim analyses will occur to support regulatory submissions (e.g., NDA, 120-day safety 
updates, etc.) and as frequently as yearly in order to continuously monitor the long-term 
safety of oral treprostinil in this ongoing study.  For each interim analysis, the data currently 
in the database will be soft locked by Data Management and provided to Statistics and 
Programming for creation of output as described in this analysis plan. 
6 
SAMPLE SIZE CONSIDERATIONS 
The sample size for this study was not derived through a power calculation, but rather an 
assumption about the number of subjects who would enroll in this OL study after completion 
of their UT-15C SR clinical protocol.  The sample size is expected to be approximately 
900 subjects from protocols TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, 
TDE-PH-302, and TDE-PH-308, plus additional subjects from any additional UT-15C SR 
clinical protocols evaluating subjects with PAH.   
7 
ANALYSIS POPULATIONS 
All available data from all subjects enrolled in the TDE-PH-304 study will be used as detailed 
in this analysis plan.  Additionally, subjects who were treated with active drug during the 
parent study and who enrolled in the TDE-PH-304 study will have the data from the parent 
study included in the data analyses and listings for this study, as detailed in this SAP.  


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Subjects who were treated with placebo during the parent study and who enrolled in the 
TDE-PH-304 study will have baseline data only from the parent study included in the data 
analyses and listings for this study, as detailed in this SAP.       
8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All available data for subjects enrolled in TDE-PH-304 (regardless of treatment with active 
drug) will be included in each soft lock and will be listed.  All available data for enrolled 
subjects who were treated with active drug in study TDE-PH-304 will be summarized, as 
detailed in this SAP.  Subjects from the 200 series studies (TDE-PH-202, TDE-PH-203, and 
TDE-PH-205) that enrolled into the TDE-PH-304 study will be pooled for summarization 
purposes with the two de novo subjects previously enrolled in the TDE-PH-301 study.  These 
two de novo subjects were initially enrolled in TDE-PH-301, but were later withdrawn from 
that study following a temporary drug recall in June 2006 and were subsequently directly 
enrolled in the TDE-PH-304 OL study.  Likewise, subjects from studies TDE-PH-301 and 
TDE-PH-308 will be pooled for summarization purposes. 
In general, listings will be sorted by subject number and scheduled assessment (if applicable).  
Listings will include assessment date, assessment time (if available), and study day.  For data 
collected on a fixed schedule, the assessment identifier will also be included on the listing.   
In general, the data will be summarized by scheduled assessment (if applicable).  For 
continuous variables, the summary statistics will include the mean, standard deviation, 
standard error, median, lower quartile, upper quartile, minimum, and maximum.  Minimums 
and maximums will be expressed using the level of precision in which the variable was 
collected.  All other statistics will be rounded, using an additional decimal point.  For discrete 
variables, summaries will include the frequency and percent in each category.  Percentages 
will be rounded to a whole number.  Whenever practical, categories of discrete variables will 
be ordered and labeled as they appear in the case report form (CRF), and all categories 
represented on the CRF will be included in summaries, even when they do not apply to any 
subjects in the study. 
8.1 EXAMINATION OF SUBGROUPS 
All summaries will be provided by previous study and overall to allow examination of impact 
from previous study.  Other exploratory subgroup analyses will be performed as data permit.   
8.2 PREMATURE DISCONTINUATION AND MISSING DATA 
A subject may voluntarily withdraw or be withdrawn from the study 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 deviated from the protocol. 
• The subject’s behavior is likely to undermine the validity of his/her results. 
• The subject becomes pregnant 


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8.3 MULTIPLE COMPARISONS AND MULTIPLICITY 
No multiple comparison adjustments are planned for analysis of this study. 
9 
STUDY POPULATION 
9.1 SUBJECT ACCOUNTABILITY 
A listing of subject disposition and study drug exposure will include subject number, previous 
study number, first and last active drug dose dates, data cutoff date, study drug exposure 
(weeks), discontinuation status, reason for discontinuation, and any details regarding 
discontinuation status.  Study drug exposure will account for all active drug exposure, 
including time on active drug during the parent study, where applicable.  A comprehensive 
listing will be generated containing subject number and previous study number.  The 
summary of subject accountability will include the number (percent) of subjects in each 
double-blind study treatment group, who consented prior to study assessments, who 
discontinued the study prematurely, who reached each visit as their maximum visit, and each 
reason for discontinuation.  These summaries will be provided by previous study and overall. 
9.2 ELIGIBILITY CRITERIA 
The listing of admission criteria will include each subject’s status regarding meeting all 
admission criteria for the TDE-PH-304 study as well as any details noted in the CRF.  The 
listing of admission criteria violations will include only those subjects who did not meet all 
admission criteria and any details regarding their criteria evaluation.  The summary of 
admission criteria violations will include a categorical summary of the CRF question “Did the 
subject meet all entry criteria,” with possible choices of no, yes, and missing, by previous 
study and overall. 
9.3 OTHER DESCRIPTIONS OF STUDY POPULATION 
9.3.1 
Demographics 
The listing of subject demographics will include subject, previous study number, age (years), 
sex, ethnicity, and race.  Age is calculated as the age at the time of the first dose of active drug 
(active drug dosing occurred either during the parent study or during the OL study, depending 
on whether subjects were treated with active or placebo in the parent study, respectively).  
The summary of demographics will include descriptive statistics for age (years) and 
categorical summaries for age (<18, 18-64, >64 years), sex, ethnicity, and race.  Each 
categorical summary will include a row for missing, as applicable, in order to sum to 100% of 
subjects.  These summaries will be provide by previous study and overall. 
9.3.2 
PAH History 
The listing of PAH history will include the number of years since PAH diagnosis, etiology, 
WHO functional class at baseline, background PAH therapy (none, endothelin receptor 
antagonist [ERA], phosphodiesterase type 5 inhibitor [PDE-5i], and ERA+PDE-5i), 
background ERA, and background PDE-5i.  The number of years since PAH diagnosis is 
calculated as the time from diagnosis to first dose of active drug.  The summary of PAH 
history will include descriptive statistics for years since PAH diagnosis, six minute walk 


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distance at baseline, and Borg Dyspnea Score at baseline.  The summary will also include 
categorical summaries for etiology, background PAH therapy, background ERA, background 
PDE-5i, and WHO functional class at baseline. 
9.3.3 
PAH Therapy 
The listing of PAH Concomitant Medications will include subject, previous study, and all 
concomitant PAH medications that were denoted as either ongoing at the start of the 
TDE-PH-304 study or added during the TDE-PH-304 study (start date of medication is on or 
after start date of study enrollment), with appropriate designation.  The correspondence of raw 
concomitant medication names to coded generic terms will be listed.  The summaries of PAH 
concomitant medications will be separated by those ongoing at the start of the TDE-PH-304 
study and those added during the TDE-PH-304 study.  These summaries will be provided by 
previous study and overall, and will include the number (percent) of subjects reporting each 
WHO Drug Dictionary medication name, as well as the number of records for each 
medication name.  The PAH medications that were added during the TDE-PH-304 study will 
also be categorically summarized by PAH therapy class (ERA, PDE-5i, oral/inhaled 
prostacyclin, parenteral prostacyclin, and none) within each previous study and overall. 
9.3.4 
Concomitant Therapy 
The listing of Other Concomitant Medications will include subject, previous study, and all 
concomitant medications that were reported during the study (start date of medication is on or 
after start date of study enrollment).  The summary will be provided by previous study and 
overall and will include the number (percent) of subjects reporting each medication category 
(as specified on the CRF), as well as the number of records for each medication category, at 
each scheduled visit. 
10 
EFFICACY ANALYSES 
10.1 SIX MINUTE WALK TEST 
The listing of six minute walk distance (6MWD) will include subject, previous study, and all 
reported 6MWDs, and their associated Borg Dyspnea Scores.  The summaries of 6MWD at 
Month 12 will be provided by previous study and overall, treatment assignment in previous 
study (active/placebo), PAH medication use (no new therapy added/new PAH therapy added), 
PAH etiology (idiopathic/familial, collagen vascular disease, other), baseline WHO functional 
class, and dosing quartiles and tertiles.  The summaries will include a categorical summary of 
current status, as well as descriptive statistics for baseline 6MWD, 6MWD at Month 12, and 
the change in 6MWD from baseline to Month 12.   
Achievement of a walk distance of at least 380 meters at Month 12 will be summarized by 
previous study and overall.  Achievers and non-achievers will then be summarized based on 
their baseline walk (≤380 meters vs. >380 meters) by previous study and overall.   
Note that all six-minute walk test summaries will exclude subjects from study TDE-PH-205 
since the goal of that study was to maintain six-minute walk test performance after transition; 
thus, no improvements were expected.  All associated listings, however, will include the 
subjects from TDE-PH-205. 


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The summaries of the Borg Dyspnea Score at Month 12 will be provided by previous study 
and overall, previous study treatment assignment, and PAH medication use.  The summaries 
will include a categorical summary of current status, as well as descriptive statistics for 
baseline Borg Dyspnea Score, Borg Dyspnea Score at Month 12, and the change in Borg 
Dyspnea Score from baseline to Month 12.  Note that the Borg Dyspnea Score summaries will 
exclude subjects from study TDE-PH-205 since the goal of that study was to maintain 
six-minute walk test performance after transition; thus, no improvements were expected. 
10.2 CLINICAL EVENTS 
Clinical events, including death, study discontinuation for any reason, addition of PAH 
therapy, and addition of parenteral PAH therapy, will be listed, including date of each event, 
if applicable, as well as the subject’s previous background therapy status (naïve, single 
background therapy, or double background therapy).  Note that events may have occurred 
during the parent study for those subjects treated with active drug during the parent study, 
thus event data from the parent study will be included in these data analyses.  The following 
combinations of clinical events will be utilized for summarization and plotting purposes, 
separately: 
• Study discontinuation for any reason 
• Death or discontinuation due to disease progression 
• Death, discontinuation due to disease progression or addition of PAH therapy 
• Death, discontinuation due to disease progression or addition of parenteral PAH 
therapy 
• Death 
Summary tables will be produced by previous study and overall and will display the number 
(percent) of subjects who experienced each event combination detailed above.  Kaplan-Meier 
(K-M) curves for the above combinations of clinical events will be provided separately.  Each 
K-M plot will include a time to clinical event curve for each of the previous studies overlaid 
on the same plot. 
11 
SAFETY ANALYSES 
11.1 EXTENT OF EXPOSURE 
Study drug exposure will be listed, including subject number, previous study, concomitant 
medication use, BID to three times daily (TID) transition, exposure (weeks), and categorical 
exposure (by visit).  Exposure is calculated as the time exposed to active study drug.  For 
subjects treated with active drug during the parent study, exposure calculations will include 
their exposure during the parent study.  For subjects treated with placebo during the parent 
study, exposure calculations will include only the exposure to active drug during the OL 
study.  The summary of disposition and study drug exposure will detail the number (percent) 
of subjects who died during the study, as well as the study drug exposure both by categorical 
visits (≥3 months, ≥6 months, etc.) and using descriptive statistics.  The total study drug 
exposure (pt-years) will also be displayed.   


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Study drug dosing will be summarized at each visit by previous study and overall.  The 
summary will include a categorical summary of current status (in study, death, progression of 
PAH, AE, consent withdrawn, lost to follow-up, discontinued for other reasons, etc.) and 
study drug dose (<1 mg, 1-<2.5 mg, 2.5-<5 mg, 5-<10 mg, 10-<20 mg, 20-<30 mg BID/TID), 
as well as a descriptive statistics summary of study drug dose (mg BID/TID).  
Study drug dosing will also be summarized at each visit by PAH background medication use, 
grouping subjects into monotherapy and combination therapy groups.  The summary table 
will mimic that presented in the summary of study drug dosing by previous study, but will 
produce a separate summary table for each PAH background medication use group. 
The summary of BID to TID transition will detail the number (percent) of subjects who 
completed this transition and who had to transition back to BID (if applicable), and 
descriptive statistics on the doses both before and after the transition by previous study and 
overall.  All of these summaries will be provided by previous study and overall. 
11.2 ADVERSE EVENTS 
Adverse event summaries will include treatment emergent AEs.  Treatment emergent AEs 
include those reported during the parent study for those subjects who were treated with active 
drug during the parent study.  For subjects treated with placebo during the parent study, only 
those AEs reported during the TDE-PH-304 study are considered treatment emergent.   
The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and all summaries will utilize the preferred term (PT) and/or System Organ Class (SOC).  The 
correspondence of raw AE terms to PTs and SOCs will be listed.  All AEs and serious AEs 
will be listed by subject, including onset date/day, cessation date/day, verbatim term, PT, 
SOC, seriousness, severity, relationship to study drug, frequency, and action taken with study 
drug.  The summaries of AEs will be provided by previous study and overall.  The summaries 
of AEs, serious AEs, severe AEs, AEs reasonably or possibly related to study drug, and AEs 
leading to permanent discontinuation of study drug will include the number of subjects 
(percent of subjects) and number of events for each reported PT.  The summary of AEs by 
body system will include the same statistics, but will group the PTs by their respective SOCs.   
The summary of AEs by exposure will include the number of subjects (percent of subjects) 
and number of events for each reported PT, as well as the number of events per patient year of 
exposure.  Note that only those subjects with calculated exposure will have AEs contributing 
to this summary. 
11.3 DISEASE RELATED EVENTS 
The disease-related events reported during the TDE-PH-304 study will be listed, including 
subject number, previous study, and symptom.  The summary will include the number 
(percent) of subjects who reported each symptom by previous study and overall. 


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11.4 DEATHS 
All deaths occurring within 30 days of study TDE-PH-304 participation will be listed by 
subject, including previous study, first dose, last dose, discontinuation date, reason for 
discontinuation, date of death, day of death, and cause of death.  The summary of deaths will 
be presented by previous study and overall and will include the number (percent) of subjects 
who died within 30 days of study participation and their causes of death. 
11.5 CLINICAL LABORATORY TESTS 
All clinical laboratory data from the parent studies and from study TDE-PH-304 will be 
incorporated in these laboratory listings and summaries.  The laboratory data will be listed by 
subject and previous study, including all hematology and clinical chemistry parameters by 
scheduled time point.  Each parameter will include its respective normal range in the row 
label.  A designation for low (L) and high (H) will be included for those laboratory values that 
are outside the normal range.  The listing of urinalysis will also be presented by subject and 
previous study and will include each scheduled and unscheduled urinalysis assessment.  The 
date/time, study day, and window will be provided for each assessment as well as the result of 
the test. 
Plots will be generated for both hematology and clinical chemistry shifts from baseline.  For 
each parameter, two plots will be generated displaying baseline values on the x-axis and 
minimum/maximum values on the y-axis, respectively.  The plots will be scatter plots that 
utilize a different plotting symbol for each previous study denotion.  A line of unity will be 
overlaid on the plot to aid in understanding the shift from baseline for each parameter. 
 


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12 
APPENDICES 
12.1 INCLUSION AND EXCLUSION CRITERIA 
A subject is eligible for inclusion in this study if all of the following criteria apply: 
1. 
The subject has remained on study drug and completed all assessments during the 
Treatment Phase of the previous study (TDE-PH-202, TDE-PH-203, 
TDE-PH-205,TDE-PH-301, TDE-PH-302, or TDE-PH-308 [or other studies 
evaluating PAH]) 
OR 
The subject permanently discontinued study drug during the Treatment Phase of the 
previous study (TDE-PH-301, TDE-PH-302, or TDE-PH-308) due to clinical 
worsening, completed premature termination assessments prior to discontinuing study 
drug, completed all remaining scheduled study visits, AND received placebo during 
the Treatment Phase of the previous study (TDE-PH-301, TDE-PH-302, or 
TDE-PH-308). 
OR 
The subject was randomized into Dose Group 1 or Dose Group 2 in the TDE-PH-202, 
permanently discontinued study drug during the 12-week Treatment Phase due to 
clinical worsening, completed all premature termination assessments prior to 
discontinuing study drug, and completed all remaining scheduled study visits and 
assessments (with the exception of the hemodynamic measurements) through 
Week 12.  Such subjects should start treatment with UT-15C in the open-label study at 
0.25 mg BID. 
2. 
The subject voluntarily gives informed consent to participate in the study.  
3. 
Women of child bearing potential include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as 
amenorrhea for at least 12 consecutive months).  Sexually active women of 
childbearing potential must use two effective forms of contraception during the length 
of the study.  Medically acceptable forms of effective contraception include: (1) 
approved hormonal contraceptives (such as birth control pills), (2) barrier methods 
(such as a condom or diaphragm) used with a spermicide, (3) an intrauterine device 
(IUD), (4) partner vasectomy, or (5) abstinence.  Males participating in the study must 
use a condom during the length of the study, and for at least 48 hours after 
discontinuing study medication. 
 
A subject is ineligible for inclusion in this study if any of the following criteria apply: 
1. 
The subject permanently discontinued study drug during the previous study 
(TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or 
TDE-PH-308) due to treatment related adverse events. 


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2. 
The subject permanently discontinued study drug during the Treatment Phase of the 
previous study (TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, 
TDE-PH-302, or TDE-PH-308) due to clinical worsening (as defined in those study 
protocols) and did not undergo premature termination assessments prior to 
discontinuing study drug, and/or did not complete all remaining study visits through 
the final scheduled visit. 
3. 
The subject permanently discontinued study drug during the Treatment Phase of the 
previous study (TDE-PH-301, TDE-PH-302, or TDE-PH-308) due to clinical 
worsening, completed premature termination assessments prior to discontinuing study 
drug, completed all remaining scheduled study visits AND received UT-15C SR 
during the Treatment Phase of the previous study (TDE-PH-301, TDE-PH-302, or 
TDE-PH-308). 
Subjects enrolled in the TDE-PH-202 study who were randomized into the iMTD 
group who clinically worsen may not participate.  Subjects who permanently 
discontinue study drug during the 12-week Treatment Phase due to treatment related 
adverse events are not eligible even if they complete all remaining scheduled study 
visits.  Subjects who permanently discontinue study drug during the 12-week 
Treatment Phase and do not undergo premature termination assessments prior to 
discontinuing study drug and/or who do not complete all remaining study visits 
through the Week 12 visit are also not eligible. 
4. 
The subject must not have developed any concurrent illness or condition during the 
conduct of the previous study, including but not restricted to, sleep apnea, chronic 
renal insufficiency, anemia, uncontrolled systemic hypertension or left sided heart 
disease, unless their physician feels that entry into this study would not be detrimental 
to their overall health. 


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12.2 LIST OF TABLES 
Table titles suggested here may be altered or edited as appropriate by the clinical data 
programmers while maintaining the original intent of the summary. 
Table Number Table Title 
14.1.1 
Summary of Subject Accountability 
14.1.2 
Summary of Disposition and Study Drug Exposure 
14.1.3 
Summary of Demographics  
14.1.4 
Summary of PAH History 
14.1.5 
Summary of Admission Criteria Violations 
14.1.6.1 
Summary of Study Drug Dosing by Previous Study and Overall 
14.1.6.2 
Summary of Study Drug Dosing by PAH Background Medication Use 
14.1.6.3 
Summary of BID to TID Transition 
14.1.7.1 
Summary of PAH Concomitant Medications Ongoing at Start of 
TDE-PH-304 Study 
14.1.7.2 
Summary of PAH Concomitant Medications Added During the 
TDE-PH-304 Study 
14.1.7.3 
Summary of PAH Medication Use by Class 
14.1.7.4 
Summary of Other Concomitant Medications 
14.2.1.1 
Summary of Six-Minute Walk Distance at Month 12 by Previous Study 
14.2.1.2 
Summary of Borg Dyspnea Score at Month 12 by Previous Study 
14.2.1.3 
Summary of Six-Minute Walk Distance at Month 12 by Treatment 
Assignment in Previous Study 
14.2.1.4 
Summary of Borg Dyspnea Score at Month 12 by Treatment 
Assignment in Previous Study 
14.2.1.5 
Summary of Six-Minute Walk Distance by PAH Medication Use 
14.2.1.6 
Summary of Borg Dyspnea Score by PAH Medication Use 
14.2.1.7 
Summary of Six-Minute Walk Distance by PAH Etiology 
14.2.1.8 
Summary of Six-Minute Walk Distance by Baseline WHO Functional 
Class 
14.2.1.9 
Summary of Six-Minute Walk Distance by Dosing Quartiles/ Tertiles 
14.2.1.10 
Summary of Six-Minute Walk Distance Achievement at Month 12 
14.2.1.11 
Summary of Six-Minute Walk Distance at Baseline by Achievement of 
At Least 380 Meters at Month 12 


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Table Number Table Title 
14.2.1.12 
Summary of Clinical Events 
14.3.1.1 
Summary of Adverse Events 
14.3.1.2 
Summary of Adverse Events by System Organ Class 
14.3.1.3 
Summary of Serious Adverse Events 
14.3.1.4 
Summary of Serious Adverse Events Reasonably or Possibly Related to 
Study Drug 
14.3.1.5 
Summary of Adverse Events Reasonably or Possibly Related to Study 
Drug 
14.3.1.6 
Summary of Severe Adverse Events 
14.3.1.7 
Summary of Adverse Events Leading to Permanent Discontinuation of 
Study Drug 
14.3.1.8 
Summary of Disease Related Events 
14.3.1.9 
Summary of Adverse Events by UT-15C Exposure Time  
14.3.2.1 
Listing of Deaths 
14.3.2.2 
Summary of Deaths 
14.3.2.3 
Listing of Serious Adverse Events 
14.3.4.1 
Summary of Hematology Data 
14.3.4.2 
Summary of Hematology Shifts from Baseline 
14.3.4.3 
Summary of Clinical Chemistry Data 
14.3.4.4 
Summary of Clinical Chemistry Shifts from Baseline 
14.3.4.5 
Summary of Urinalysis Data 
 


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12.3 LIST OF LISTINGS 
Listing titles suggested here may be altered or edited as appropriate by the clinical data 
programmers while maintaining the original intent of the listing. 
Appendix Number Listing Title 
16.2.1 
Listing of Subject Disposition and Study Drug Exposure 
16.2.2.1 
Listing of Admission Criteria for All Subjects 
16.2.2.2 
Listing of Admission Criteria Violations 
16.2.4.1 
Listing of All Subjects 
16.2.4.2 
Listing of Subject Accountability 
16.2.4.3 
Listing of Demographic Information 
16.2.4.4 
Listing of PAH History  
16.2.4.5 
Listing of Correspondence of Raw Concomitant Medication Names 
to Coded Generic Terms 
16.2.4.6 
Listing of PAH Concomitant Medications  
16.2.4.7 
Listing of Other Concomitant Medications 
16.2.5 
Listing of Study Drug Dosing 
16.2.6.1 
Listing of Six-Minute Walk Test Information 
16.2.6.2 
Listing of Clinical Events 
16.2.7.1 
Listing of Adverse Events 
16.2.7.2 
Listing of Correspondence of Raw Adverse Event Terms to 
Preferred Terms and Body Systems 
16.2.7.3 
Listing of Disease Related Events 
16.2.8.1 
Listing of Laboratory Data 
16.2.8.2 
Listing of Urinalysis Data 
 


United Therapeutics Corp. 
TDE-PH-304 Statistical Analysis Plan 
 
Oral Treprostinil 
FINAL: 2MAR2016 
CONFIDENTIAL 
Page 17 of 17 
12.4 LIST OF FIGURES 
Figure titles suggested here may be altered or edited as appropriate by the clinical data 
programmers while maintaining the original intent of the figure. 
Figure Number 
Figure Title 
14.2.1.7.1 
Kaplan-Meier Plot of Study Discontinuation for Any Reason 
14.2.1.7.2 
Kaplan-Meier Plot of Death or Discontinuation Due to Disease 
Progression 
14.2.1.7.3 
Kaplan-Meier Plot of Death, Discontinuation Due to Disease 
Progression or Addition of PAH Therapy 
14.2.1.7.4 
Kaplan-Meier Plot of Death, Discontinuation Due to Disease 
Progression or Addition of Parenteral PAH Therapy 
14.2.1.7.5 
Kaplan-Meier Plot of Death 
14.3.4.1 
Hematology Shifts from Baseline 
14.3.4.2 
Clinical Chemistry Shifts from Baseline