Clinical trial NCT02276872
Conditions: PAH
Keywords: pediatric treprostinil transition Remodulin
Sponsor: United Therapeutics
Start date: 2014-12-18; Completion date: 2017-07-20
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multi-center, open-label, safety, tolerability and pharmacokinetic study of oral treprostinil in pediatric subjects with stable PAH aged 7 to 17 years who were (1) transitioning from parenteral Remodulin therapy; (2) transitioning from inhaled prostacyclin therapy; or (3) not currently receiving prostacyclin therapy.

Detailed description:
Study TDE-PH-206 was a multicenter, open-label study designed to investigate the safety, tolerability, and PK of oral treprostinil administered 3 times daily (TID) or 4 times daily (QID), at the discretion of the Investigator, with food in pediatric PAH subjects aged 7 to 17 years of age (1) transitioning from continuous IV/SC Remodulin, (2) transitioning from inhaled prostacyclin, or (3) as add-on to current PAH therapies in de novo prostacyclin subjects. Eligible subjects were assigned to a cohort based upon their background therapy. All subjects received oral treprostinil provided as 0.125, 0.25, 1, or 2.5 mg extended-release tablets. Subjects in Cohort 1 began the transition from IV/SC Remodulin in the hospital with a goal of complete transition to oral treprostinil within 5 days. The initial dose of oral treprostinil for Cohort 1 was calculated from the subject's dose of IV/SC Remodulin and weight. Subjects in Cohorts 2 and 3 were initiated on 0.125 mg TID or QID oral treprostinil with dose escalations possible every 24 hours in increments of 0.125 mg TID or QID at the discretion of the Investigator during the first 4 weeks, and in increments of either 0.125 mg or 0.25 mg every 24 hours thereafter. Cross titration occurred for Cohorts 1 and 2 such that doses of IV/SC Remodulin or inhaled prostacyclin were decreased as subjects were fully transitioned to oral treprostinil.

Arms: arm 1: Transitioned from IV or SC Remodulin to oral treprostinil arm 2: Transitioned from inhaled prostacyclin to oral treprostinil arm 3: Treated with oral treprostinil as a de novo add-on to current PAH therapy
Interventions: intervention 1: oral treprostinil
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_001.pdf: 
 
 
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 
 
A Multicenter, Open-Label, 24-Week, Uncontrolled Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of 
Oral Treprostinil Extended Release Tablets Following 
Transition from Remodulin or Inhaled Prostacyclin Therapy 
or as Add-on to Current PAH Therapy in De Novo 
Prostacyclin Pediatric Subjects Aged 7 to 17 Years with 
Pulmonary Arterial Hypertension  
IND # 71,537 
Protocol TDE-PH-206 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
29 Jul 2014 
Amendment 1 Date: 
28 April 2015 
Amendment 2 Date: 
01 Sep 2016 
 
 
 
 
 


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LIST OF CONTACTS FOR STUDY 
Study Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive  
PO Box 14186 
Research Triangle Park, NC 27709 USA 
 
 
 
 
 
Nicole Leedom, CCRA 
(Clinical Trial Leader) 
Telephone:  +1 919 425 5870 
Fax:  +1 919 485 8352 
Email: Nleedom@unither.com 
 
 
 
Kevin Laliberte, PharmD  
(Program Head) 
Telephone:+1  919 425 5479 
Fax: +1 919 485 8352 
Email: Klaliberte@unither.com 
 
Cynthia Madden, MD, MPH   
(Medical Monitor) 
Telephone:  +1  919 425 5488 
Fax: +1 919 485 8352 
Email: TDE-PH-206medical@unither.com 
 
 
SAE Reporting 
UT Global Drug Safety 
Fax:  + 1 919 313 1297 
Email:  Drugsafety@unither.com 
 
 
Central Clinical 
Laboratory 
Covance Central Laboratories 
Indianapolis 
8211 SciCor Drive 
Indianapolis, IN  46214  USA 
Telephone: +1 317 271-1200 
 
Bioanalytical Laboratory 
–Covance Central Laboratories 
2202 Ellis Road 
Durham, NC 27703 USA 
 
Valerie L. Belcher 
Project Manager 
Phone: +1 919 281 0952 
Fax: +1 919 281 0906 
Valerie.Belchler@covance.com 
 


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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “A Multicenter, Open-Label, 24-Week, 
Uncontrolled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral 
Treprostinil Extended Release Tablets Following Transition from Remodulin or Inhaled 
Prostacyclin Therapy or as Add-on to Current PAH Therapy in De Novo Prostacyclin 
Pediatric Subjects Aged 7 to 17 Years with Pulmonary Arterial Hypertension,” Amendment 2 
(01 Sep 2016) and agree to abide by all provisions set forth therein. 
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 evaluation or conduct of the clinical investigation without the 
prior written consent of United Therapeutics Corp.  
I also have read the current Clinical Investigators’ Brochure for oral treprostinil (UT-15C; 
treprostinil diolamine) and acknowledge that review of the information contained in the 
Clinical Investigators’ Brochure is a requirement for Investigators before using oral 
treprostinil in a clinical trial. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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PROTOCOL SYNOPSIS 
Title  
A Multicenter, Open-Label, 24-Week, Uncontrolled Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral 
Treprostinil Extended Release Tablets Following Transition from 
Remodulin or Inhaled Prostacyclin Therapy or as Add-on to Current 
PAH Therapy in De Novo Prostacyclin Pediatric Subjects Aged 7 to 
17 Years with Pulmonary Arterial Hypertension 
Study Phase 
Phase II 
Indication 
Pulmonary Arterial Hypertension (PAH) 
Primary Objective To assess the safety and tolerability of oral treprostinil extended 
release tablets in three cohorts of pediatric subjects with PAH aged 
7 to 17 years: 
• Cohort 1: Subjects transitioning from intravenous (IV) or 
subcutaneous (SC) Remodulin® 
• Cohort 2: Subjects transitioning from inhaled prostacyclin 
• Cohort 3: As add-on to current PAH therapy in de novo 
prostacyclin subjects 
Secondary 
Objective(s) 
1)  To assess the effect of oral treprostinil on the following (assessed 
in all cohorts): 
• Cardiopulmonary exercise testing (CPET) with progressive 
cycle ergometry  
• Symptoms of PAH 
• Panama functional classification 
• WHO functional classification 
• Six-minute walk distance (6MWD) (with oximetry and heart 
rate [HR] recovery monitoring) 
• Borg dyspnea score 
• Quality of life assessed via the Pediatric Quality of Life 
Inventory (PedsQLTM) questionnaire 
• Plasma N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) 
• Cardiac magnetic resonance imaging (cMRI) 
 
2)  To describe treprostinil pharmacokinetics (PK) in pediatric 
subjects with PAH aged 7 to 17 years. 
Study Design 
Multi-center, open-label, safety, tolerability and PK study of oral 
treprostinil in pediatric subjects with stable PAH aged 7 to 17 years 
who are, (1) transitioning from IV/SC Remodulin therapy; (2) 
transitioning from inhaled prostacyclin therapy; or (3) not currently 
receiving prostacyclin therapy. 
Sample Size 
Up to 40 pediatric subjects aged 7 to 17 years (25 transition [IV/SC 
Remodulin and inhaled] subjects and 15 de novo subjects)  


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Summary of 
Subject Eligibility 
Criteria 
All Cohorts: 
Eligible subjects are between 7 and 17 years of age, inclusive, and 
have a diagnosis of PAH as confirmed by a previous right heart 
catheterization (RHC).  Panama functional classification IIIb and IV 
subjects will be excluded. 
All subjects must be optimally treated (as determined by the 
Investigator) with background PAH therapies (e.g., 
phosphodiesterase type 5 inhibitor [PDE-5i], endothelin receptor 
antagonist [ERA], soluble guanylate cyclase [sGC]) for at least 
90 days and have been on a stable dose without changes (except 
documented weight based adjustments) for at least 30 days prior to 
the first dose of oral treprostinil. 
Cohort 1:  Remodulin to Oral Treprostinil Transition 
Subjects must have been receiving IV/SC Remodulin for at least 
90 days and at a stable dose for at least 30 days prior to the first 
dose of oral treprostinil.  The IV/SC Remodulin dose will be 
between  
25-75 ng/kg/min, inclusive, for the first five subjects enrolled in 
Cohort 1.  Following a safety review by the Data Safety Monitoring 
Board (DSMB) after the first five Cohort 1 subjects have been 
enrolled and transitioned to oral treprostinil (study drug), the dose 
range may be expanded to 25-125 ng/kg/min, inclusive, for the 
remaining subjects. 
Cohort 2:  Inhaled Prostacyclin to Oral Treprostinil Transition 
Subjects must have been receiving inhaled prostacyclin therapy for 
at least 90 days and at a stable dose for at least 30 days prior to the 
first dose of oral treprostinil. 
Cohort 3: Add-On to Current PAH Therapy in De Novo 
Prostacyclin 
Subjects must weigh at least 22 kg.  


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Drug Dosage and 
Formulation 
All Cohorts: 
All subjects will receive study drug (oral treprostinil extended 
release tablets).  The tablets may be provided as 0.125, 0.25, 1, or 
2.5 mg strengths.  Oral treprostinil will be dosed three times daily 
(TID) or four times daily (QID) at the discretion of the Investigator, 
with food.  Dosing will take place approximately every 6 to 8 hours 
for TID dosing, or approximately every 4 to 6 hours for QID dosing, 
with adjustments permitted based on the subject’s lifestyle and 
schedule. Sudden dose escalation or reductions should be avoided as 
they may lead to intolerable adverse events (AEs) or worsening of 
PAH.  Gradual dose titrations are recommended to reduce the risk to 
subjects. 
Cohort 1:  IV/SC Remodulin to Oral Treprostinil Transition 
Dose Transition Schedule: 
Once all entry criteria have been met and Baseline assessments 
completed, subjects will begin transition in the hospital from IV/SC 
Remodulin to oral treprostinil with a goal for complete transition 
off of IV/SC Remodulin within five days of the start of the 
transition.  If possible, Day 5 (or last day of hospital stay, if 
transition occurred in less than 4 days) should be reserved as an 
observational period for subjects successfully transitioned to oral 
treprostinil and no longer receiving IV/SC Remodulin.  Subjects 
will be discharged from the hospital after they have transitioned off 
IV/SC Remodulin, reached their target oral treprostinil dose, or as 
the Investigator feels appropriate.  If necessary or appropriate per 
Investigator discretion, subjects can prolong or complete the 
transition in an outpatient setting for a total transition time of up to 
four weeks.  A cross titration will occur so that the dose of IV/SC 
Remodulin is decreased as the dose of oral treprostinil is increased.  
Once subjects have been transitioned off IV/SC Remodulin, the 
dose of oral treprostinil may continue to be modified/titrated to the 
appropriate optimal dose for that subject throughout the rest of the 
study. 
Cross Titration Dosing Guidelines: 
• IV/SC Remodulin should not be decreased more than 
30 ng/kg/min within a 24 hour period 
• Oral treprostinil should be increased in proportion to 
Remodulin decreases and the subject’s weight 
• IV/SC Remodulin doses should be adjusted (i.e., decreased) 
at the same time oral treprostinil dose is increased 


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Cohort 2:  Inhaled Prostacyclin to Oral Treprostinil Transition 
Dose Transition Schedule: 
Once all entry criteria have been met and Baseline assessments 
completed, dosing of oral treprostinil will be initiated at 0.125 mg 
TID or QID, at the discretion of the Investigator, with food. Dosing 
will take place approximately every 6 to 8 hours for TID dosing, or 
approximately every 4 to 6 hours for QID dosing, with adjustments 
permitted based on the subject’s lifestyle and schedule. The first 
dose of 0.125 mg oral treprostinil should occur at the study site.  
Dose escalations may occur every 24 hours (following three or four 
consecutive doses, depending on TID or QID dosing, respectively) 
and should occur in increments of 0.125 mg TID or QID at the 
discretion of the Investigator during the first four weeks of the study 
as clinically indicated.  Following four weeks of treatment, dose 
escalations may occur in either 0.125 mg or 0.25 mg increments 
every 24 hours, as tolerated.  A cross titration will occur so that the 
doses of inhaled prostacyclin are decreased and the subject is fully 
transitioned off the inhaled prostacyclin by no later than Week 4. 
Cohort 3: Add-On to Current PAH Therapy in De Novo 
Prostacyclin 
Dose Schedule: 
Once all entry criteria have been met and Baseline assessments 
completed, dosing of oral treprostinil will be initiated at 0.125 mg 
TID or QID, at the discretion of the Investigator, with food. Dosing 
will take place approximately every 6 to 8 hours for TID dosing, or 
approximately every 4 to 6 hours for QID dosing, with adjustments 
permitted based on the subject’s lifestyle and schedule. The first 
dose of oral treprostinil should be taken at the study site.  Dose 
escalations may occur every 24 hours (following three or four 
consecutive doses depending on TID or QID dosing, respectively) 
and should occur in increments of 0.125 mg TID or QID at the 
discretion of the Investigator during the first four weeks of the study 
as clinically indicated.  Following four weeks of treatment, dose 
escalations may occur in either 0.125 mg or 0.25 mg increments 
every 24 hours, as tolerated. 
Control Group 
None 
Route of  
Administration 
Oral 
Procedures 
Up to seven study visits will occur during the 24-week study at the 
following time points: Screening, Baseline, Week 0 (Cohort 1 only; 
inpatient hospital stay Days 1-5), Week 3 Week 6, Week 12, and 
Week 24. 


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Screening/Baseline (All Cohorts): 
All subjects will be assessed for eligibility during the 28 day 
screening period.  Baseline assessments can be conducted over five 
days (120 hours) prior to the first dose of oral treprostinil, to allow 
for scheduling of all activities.  The Screening and Baseline visits 
may be combined if all entry criteria are satisfied and all 
assessments are completed within five days (120 hours) prior to the 
first dose of oral treprostinil.  The following assessments will be 
performed:  vital signs, physical examination, six-minute walk test 
(6MWT)/Borg dyspnea score, CPET, 12-lead ECG, Panama and 
WHO functional classification assessments, symptoms of PAH, 
PedsQL, NT-Pro BNP, cMRI, clinical laboratory assessments, and 
safety assessments.  Females of child bearing potential will undergo 
a urine pregnancy test.  In addition, all subjects in Cohort 1will 
undergo an 8-hour PK assessment, which may occur up to seven 
days prior to the first dose of oral treprostinil (study drug).  
Pharmacokinetic assessments at Baseline will not be conducted in 
Cohort 2 or Cohort 3 subjects. 
Transition Phase (Cohort 1): 
Within five days (120 hours) of beginning Baseline assessments 
Cohort 1 subjects will undergo an inpatient hospital stay lasting 
approximately five days (Week 0) to transition from IV/SC 
Remodulin to oral treprostinil.  The target transition goal is no 
longer than five days and for the subject to be completely 
transitioned off IV/SC Remodulin prior to discharge from the 
hospital.  Subjects will be discharged from the hospital after they 
have transitioned off IV/SC Remodulin, reached their target oral 
treprostinil dose, or as the Investigator feels appropriate.  If 
necessary or appropriate per Investigator discretion, subjects can 
prolong or complete the transition in an outpatient setting for a total 
transition time of up to four weeks. 
The maximum time to titrate off IV/SC Remodulin is four weeks 
from the start of the transition; if the subject is not fully transitioned 
by Week 4, they will be removed from the study.  If the subject is in 
the hospital during one of the scheduled study visits, the 
assessments for that visit should be conducted as scheduled during 
the defined visit window. 
Treatment Phase (Cohort 2 and 3): 
Following completion of Baseline assessments, the first dose of 
0.125 mg oral treprostinil should be taken at the study site.  Dosing 
of oral treprostinil will be initiated at 0.125 mg TID or QID, at the 
discretion of the Investigator, with food.  Dosing will take place 


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approximately every 6 to 8 hours for TID dosing, or approximately 
every 4 to 6 hours for QID dosing, with adjustments permitted based 
on the subject’s lifestyle and schedule.   Dose changes should be 
conducted under appropriate medical supervision in consultation 
with the study site. 
Dose Optimization/Evaluation Phase (All Cohorts): 
Weeks 3, 6, and 12:  Subjects will return to clinic for the following 
assessments:  vital signs, 6MWT/Borg dyspnea score, Panama and 
WHO functional classification, symptoms of PAH, and safety 
assessments.  At each visit, females of childbearing potential will 
undergo a urine pregnancy test.  At Week 12, QOL (as measured by 
PedsQL Inventory) and clinical laboratory assessments, including  
NT-pro-BNP, will occur. 
Week 24 (or premature termination):  Subjects will return to the 
clinic for the following assessments:  vital signs, physical 
examination, 6MWT/Borg dyspnea score, CPET, 12-lead ECG, 
Panama and WHO functional class, symptoms of PAH, PedsQL, 
NT-Pro BNP, cMRI, clinical laboratory assessments, and safety 
assessments.  Females of child bearing potential will undergo a 
urine pregnancy test.  In addition, all subjects will undergo an 8-
hour PK assessment. 
Stopping Criteria Stopping Criteria: 
• Unplanned hospitalization as a result of worsening PAH 
• Clinically significant worsening in PAH symptoms or signs, 
which the Investigator feels requires a change of current 
therapy 
If one of these events occur within the four weeks following the first 
dose of oral treprostinil, the subject should be transitioned back to 
IV/SC Remodulin (for Cohort 1 subjects) and tapered off oral 
treprostinil, as appropriate, and discontinued from study.  If any of 
these events occur after the first four weeks of the study, it is not 
required that a subject be removed from the study.  The Investigator 
will determine whether it is safe for the subject to remain in the 
study. 
If two or more of the first five subjects in any cohort meet the 
stopping criteria, the data will be reviewed by the DSMB prior to 
enrolling additional subjects into that cohort. 
Statistical 
Considerations 
The study is not powered to test a null hypothesis.  A sample size of 
40 pediatric PAH subjects aged 7 to 17 years (25 transition [IV/SC 
Remodulin and inhaled] subjects and 15 de novo prostacyclin 
subjects) will enable a descriptive evaluation of the PK and an 


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initial assessment of the safety and tolerability in this subject 
population for (1) transition from moderate to high doses of IV/SC 
Remodulin to oral treprostinil, (2) transition from inhaled 
prostacyclin to oral treprostinil, and (3) initiation of oral treprostinil 
as add-on therapy in de novo prostacyclin subjects. 
The safety and tolerability of transitioning subjects from IV/SC 
Remodulin to oral treprostinil (Cohort 1) or from inhaled 
prostacyclin (Cohort 2) will be based on the percentage of subjects 
successfully transitioning to oral treprostinil.  A successful 
transition is defined as a subject from Cohort 1 or 2 who is receiving 
oral treprostinil and no longer receiving IV/SC Remodulin or 
inhaled prostacyclin, respectively at Week 4 and clinically 
maintained on oral treprostinil treatment through Week 24.  A 
successful initiation of oral treprostinil (Cohort 3) will be defined as 
a subject who has been clinically maintained on oral treprostinil 
through Week 24. 
Analysis of secondary endpoints will be descriptive in nature.  
Numeric endpoints for post-Baseline assessments will be compared 
to Baseline using Wilcoxon signed rank test, and p-values will be 
calculated for descriptive purposes; no formal hypothesis testing is 
planned. 
Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive 
PO Box 14186 
Research Triangle Park, NC  27709 USA 
 
 


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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY ....................................................................................... 2 
INVESTIGATOR’S AGREEMENT ........................................................................................ 3 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................ 11 
Table of In-Text Tables ........................................................................................................... 14 
1 BACKGROUND AND RATIONALE ............................................................................. 15 
1.1 
DEFINITION OF CLINICAL PROBLEM .................................................................. 15 
1.2 
ORAL TREPROSTINIL BACKGROUND ................................................................. 17 
1.2.1 
General Pharmacology .......................................................................................... 17 
1.2.2 
General Toxicology ................................................................................................ 18 
1.2.3 
Clinical Pharmacology .......................................................................................... 18 
1.2.4 
Clinical Trials Experience .................................................................................... 20 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION .............................................................................................. 22 
1.4 
CLINICAL HYPOTHESIS .......................................................................................... 23 
2 OBJECTIVES ................................................................................................................... 24 
2.1 
PRIMARY OBJECTIVE ............................................................................................. 24 
2.2 
SECONDARY OBJECTIVES ..................................................................................... 24 
3 EXPERIMENTAL PLAN ................................................................................................. 25 
3.1 
STUDY DESIGN ......................................................................................................... 25 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ................................................ 27 
3.3 
CLINICAL ASSESSMENTS ...................................................................................... 34 
3.3.1 
Efficacy ................................................................................................................... 34 
3.3.1.1 
Cardiopulmonary Exercise Testing (CPET) ................................................... 34 
3.3.1.2 
Six-Minute Walk Test ........................................................................................ 35 
3.3.1.3 
Borg Dyspnea ..................................................................................................... 36 
3.3.1.4 
PAH Symptoms .................................................................................................. 36 
3.3.1.5 
Functional Classification ................................................................................... 36 
3.3.1.6 
N-terminal pro-BNP .......................................................................................... 36 
3.3.1.7 
Pediatric Quality of Life Inventory (PedsQLTM) ............................................ 37 
3.3.2 
Safety ...................................................................................................................... 37 
3.3.2.1 
Medical History and Physical Examinations ................................................... 37 
3.3.2.2 
Vital Signs ........................................................................................................... 38 
3.3.2.3 
12-Lead ECG ...................................................................................................... 38 
3.3.2.4 
Clinical Laboratory Assessments ..................................................................... 38 
3.3.2.5 
Adverse Events ................................................................................................... 39 
3.3.2.6 
Telephone Contact (All Cohorts) ...................................................................... 40 
3.3.2.7 
Continued Access Plan ...................................................................................... 41 
3.3.3 
Pharmacokinetics or Other Special Study .......................................................... 41 
3.3.3.1 
Pharmacokinetic Sampling ............................................................................... 41 
3.3.3.2 
Cardiac Magnetic Resonance Imaging (cMRI) ............................................... 44 
3.4 
NUMBER OF CENTERS ............................................................................................ 45 
3.5 
NUMBER OF SUBJECTS ........................................................................................... 45 
3.6 
ESTIMATED STUDY DURATION ........................................................................... 45 


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4 SUBJECT ELIGIBILITY ................................................................................................. 46 
4.1 
INCLUSION CRITERIA ............................................................................................. 46 
4.2 
EXCLUSION CRITERIA ............................................................................................ 48 
4.3 
PRESCRIBED THERAPY .......................................................................................... 50 
4.3.1 
Concomitant Medications ..................................................................................... 50 
5 SUBJECT ENROLLMENT .............................................................................................. 51 
5.1 
TREATMENT ASSIGNMENT ................................................................................... 51 
5.2 
RANDOMIZATION .................................................................................................... 51 
5.3 
BLINDING ................................................................................................................... 51 
5.4 
STOPPING CRITERIA ............................................................................................... 52 
6 DRUGS AND DOSING (OR TREATMENT PROCEDURES) ...................................... 52 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE ..................................... 52 
6.1.1 
Cohort 1: IV/SC Remodulin to Oral Treprostinil Transition ........................... 53 
6.1.2 
Cohort 2: Inhaled Prostacyclin to Oral Treprostinil Transition ...................... 56 
6.1.3 
Cohort 3:  Addition of Oral Treprostinil to Background PAH Therapy 
(De Novo Prostacyclin Subjects) .......................................................................... 57 
6.1.4 
Dosing Interruptions ............................................................................................. 58 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT .......................................... 58 
6.3 
COMPLIANCE ............................................................................................................ 58 
7 EXPERIMENTAL PROCEDURES ................................................................................. 59 
7.1 
SCREENING PHASE (ALL COHORTS) ................................................................... 59 
7.2 
BASELINE VISIT (ALL COHORTS) ........................................................................ 60 
7.3 
Combined screening and baseline (all cohorts) ............................................................ 61 
7.4 
TREATMENT PHASE ................................................................................................ 63 
7.4.1 
Week 0/ Study Days 1-5 (Cohort 1 Only:  IV/SC Remodulin to Oral 
Treprostinil Transition) ........................................................................................ 63 
7.4.2 
Week 3 Visit (All Cohorts) .................................................................................... 64 
7.4.3 
Week 6 Visit (All Cohorts) .................................................................................... 64 
7.4.4 
Week 12 Visit (All Cohorts) .................................................................................. 65 
7.4.5 
Week 24 Visit (All Cohorts) .................................................................................. 66 
7.4.6 
Premature Termination (All Cohorts) ................................................................. 67 
7.4.7 
Continued Access Plan .......................................................................................... 68 
8 STUDY TERMINATION ................................................................................................. 68 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ............................................................ 68 
8.1.1 
Lost to Follow-up ................................................................................................... 69 
8.2 
CRITERIA FOR TERMINATING THE STUDY ....................................................... 69 
8.3 
CRITERIA FOR DISCONTINUING THE SITE ........................................................ 69 
9 ADVERSE EVENT REPORTING ................................................................................... 70 
9.1 
DEFINITIONS ............................................................................................................. 70 
9.1.1 
Adverse Event ........................................................................................................ 70 
9.1.2 
Suspected Adverse Reaction ................................................................................. 71 
9.1.3 
Serious Adverse Event .......................................................................................... 71 
9.1.4 
Adverse Events Anticipated for PAH .................................................................. 72 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ......................................................... 74 
9.3 
Follow up of adverse events ......................................................................................... 74 


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9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR .............................. 75 
9.5 
PREGNANCY ............................................................................................................. 75 
9.6 
SAFETY REPORTS .................................................................................................... 75 
10 STATISTICAL CONSIDERATIONS .............................................................................. 76 
10.1 DATA PROCESSING ................................................................................................. 76 
10.2 SAMPLE SIZE ............................................................................................................. 76 
10.3 ANALYSIS PLAN ....................................................................................................... 76 
10.3.1 
Primary Endpoint(s) ............................................................................................. 77 
10.3.2 
Secondary Endpoint(s) .......................................................................................... 77 
10.3.3 
Safety Analyses ...................................................................................................... 77 
10.4 INTERIM ANALYSIS ................................................................................................ 78 
10.5 OTHER ANALYSES ................................................................................................... 79 
10.6 DATA LISTINGS AND SUMMARIES ...................................................................... 79 
11 PACKAGING AND FORMULATION ........................................................................... 79 
11.1 CONTENTS OF STUDY DRUG ................................................................................ 79 
11.2 LABELING .................................................................................................................. 80 
11.3 STORAGE AND HANDLING OF CTM .................................................................... 80 
11.4 SUPPLY AND RETURN OF CTM ............................................................................. 80 
11.5 DRUG ACCOUNTABILITY ...................................................................................... 80 
12 REGULATORY AND ETHICAL OBLIGATION .......................................................... 81 
12.1 U.S. FDA OR APPLICABLE REGULATORY REQUIREMENTS .......................... 81 
12.2 INFORMED CONSENT and ASSENT REQUIREMENTS ....................................... 81 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD ... 81 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ............................................. 82 
12.5 SUBJECT CONFIDENTIALITY ................................................................................ 82 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ..................................................... 83 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION ............................... 83 
13.2 STUDY DOCUMENTATION AND STORAGE ....................................................... 83 
13.3 STUDY MONITORING AND DATA COLLECTION .............................................. 83 
14 REFERENCES .................................................................................................................. 85 
15 APPENDICES .................................................................................................................. 87 
15.1 PROCEDURE FOR SIX-MINUTE WALK EXERCISE TEST AND DYSPNEA 
SCALE ......................................................................................................................... 87 
15.2 FUNCTIONAL CLASSIFICATION ........................................................................... 89 
15.3 PEDIATRIC QUALITY OF LIFE INVENTORY (PEDSQL)   .................................. 91 
15.4 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS ...... 92 
15.5 PHARMACOKINETIC SAMPLE PROCESSING ..................................................... 96 
 


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Table of In-Text Tables 
Table 3-1 Cohort 1 Schedule of Times and Events ............................................................... 28 
Table 3-2 Cohort 2 and Cohort 3 Schedule of Times and Events ......................................... 31 
Table 9-1 Expected Events Attributable to PAH (System Organ Class and 
PREFERRED Term, Ver. 17.1) ............................................................................ 73 
 


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1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
Pulmonary arterial hypertension (PAH) is defined as an elevation in mean pulmonary arterial 
pressure (PAPm) greater than 25 mmHg at rest as measured by right heart catheterization 
(RHC) and is also associated with an increase in pulmonary vascular resistance (PVR).  
Elevation in PVR causes an increase in right ventricular afterload, impairing right ventricular 
function and ultimately leading to heart failure and death. 
The typical etiologies of PAH include idiopathic (IPAH), heritable (FPAH), or associated 
with collagen vascular/connective tissue disease, portal hypertension, infection with the 
human immunodeficiency virus (HIV), history of cocaine or appetite suppressant drug use.  
Estimates of disease incidence have been reported between 2.4 and 7.6 cases per million 
individuals [Peacock 2007; Humbert 2006]. 
There are three major factors thought to contribute to the increased pulmonary vascular 
resistance seen in this disease: vasoconstriction, remodeling of the vessel wall, and 
thrombosis.  There are a number of metabolic pathways which contribute to these changes 
that involve vasoactive mediators such as the vasodilators nitric oxide and prostacyclin, and 
the vasoconstrictor endothelin-1.  These substances affect both vascular tone and remodeling 
leading to their use as pharmacologic targets [Farber, 2004]. 
PAH occurs in both adults and children. Of the etiological subgroups of PAH, congenital 
heart disease (CHD) and IPAH are the most common etiologies in pediatric patients 
[Beghetti, 2008; van Loon, 2011].  For the annual incidence and point prevalence averaged, 
respectively for IPAH and PAH-CHD, has been estimated at 0.7 and 4.4 (IPAH) and 2.2 and 
15.6 (PAH-CHD) cases per million children [van Loon, 2011].  The characteristic pathologic 
processes of pulmonary vasoconstriction, endothelial dysfunction, vascular remodeling, 
inflammation, and thrombosis that characterize PAH in adults are also observed in children 
[Galie, 2009].  Although, more pulmonary vascular medial hypertrophy and a lesser amount 
of intimal fibrosis and formation of plexiform lesions is observed in children compared to 
adults [Barst, 2011].  It has also been observed that the prevalence of acute vasoreactivity is 


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higher in children with IPAH than adults with IPAH, suggesting that vasoconstriction may 
precede vascular remodeling in this subset of PAH patients [Rosenzweig, 2004; Tissot, 2009]. 
Clinical symptoms are similar in children and adults, and include exertional dyspnea, fatigue, 
chest pain and syncope.  Syncope and near-syncope presents more commonly in children than 
adults.  Additionally, children appear to tolerate increased workload on the right heart better 
than in adults, with better preservation of cardiac output and less frequent occurrence of right 
heart failure with edema [Barst, 2011].  Dyspnea is the most common symptom in older 
children, occasionally accompanied with chest pain [Rosenzweig, 2004]. 
Pediatric patients with PAH are currently diagnosed, classified, and treated in the same 
manner as adults.  Treatment efficacy in adults is commonly measured by the change in 
World Health Organization (WHO) classification or exercise capacity, usually measured as 
the change in the six minute walk distance (6MWD).  Unfortunately, the 6MWD can be 
difficult to reliably assess in children and may underestimate a child’s exercise limitations 
[Ivy, 2006; Tissot, 2009; Barst, 2011].  Cardiopulmonary exercise testing (CPET) with gas 
exchange is a complementary non-invasive test to measure functional capacity and better 
reflect functional status, especially in children with a 6MWD of more than 300 meters 
[Ivy, 2006; Adatia, 2013; Barst, 2011]. 
Changes in hemodynamic parameters measured with right heart catheterization can be used to 
measure treatment efficacy; however, there is increased risk as general anesthesia is required 
to perform this procedure in the pediatric population [Carmosino, 2007].  Biomarkers, such as 
brain natriuretic peptide (BNP), have also been positively correlated with disease severity in 
children and can be used to measure treatment efficacy [Bernus, 2009]. 
Children with IPAH have a worse prognosis than adults, with an estimated median survival of 
less than one year.  Children also have a shorter length of time between the onset of 
symptoms and diagnosis [D’Alonzo, 1991; Galie, 2009; Rosenzweig, 2004].  Overall 5-year 
pediatric PAH survival estimates have been reported between 64% and 81%; although one 
study reported survival without transplantation or atrial septostomy as 57% [Yung, 2004; van 
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1.2 
ORAL TREPROSTINIL BACKGROUND 
Prostacyclin is an endogenous substance produced by vascular endothelium with potent 
vasodilating, antiplatelet aggregation, and antiproliferative properties.  Treprostinil 
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-
benz[f]inden-5-yl]oxy]acetic acid) is a tricyclic benzindene analogue of prostacyclin.  
Treprostinil is approved as the inhaled (Tyvaso®), intravenous (IV)/subcutaneous (SC) 
(Remodulin®) and oral (Orenitram®) formulations for the treatment of pulmonary arterial 
hypertension in adults. 
Oral treprostinil is an innovative diolamine salt form of treprostinil formulated as an extended 
release osmotic tablet for oral administration, and exists in the same biologically active form 
in the plasma as the inhaled and parental formulations.  The tablet core is coated with a semi-
permeable membrane and has a laser-drilled aperture through the membrane.  Upon contact 
with water (e.g., after ingestion), the core tablet absorbs water through the semi-permeable 
membrane. The water dissolves the water-soluble treprostinil diolamine and the water-soluble 
osmotic excipients, which creates hydrostatic pressure within the membrane, eventually 
forcing the drug out through the tablet at a controlled rate.  Oral treprostinil was recently 
approved in the United States under the brand name Orenitram for the treatment of pulmonary 
arterial hypertension WHO Group 1 in adults. 
1.2.1 
General Pharmacology 
The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and 
systemic arterial vascular beds and inhibition of platelet aggregation.  In vitro, treprostinil 
induced concentration dependent relaxation of rabbit isolated pre-contracted mesenteric 
arteries and inhibition of adenosine diphosphate (ADP) induced platelet aggregation in human 
and rat platelet rich plasma.  In animals, the vasodilatory effects of treprostinil reduce right 
and left ventricular afterload, also increasing cardiac output and stroke volume.  Prostacyclins 
lower pulmonary artery pressure, increase cardiac output without affecting the heart rate, 
improve systemic oxygen transport as well as possibly reverse pulmonary artery remodeling.  
There is also increasing evidence that the ability to block the proliferation of pulmonary artery 
smooth muscle cells may contribute, along with vasodilation, to the therapeutic effects of 


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prostacyclins in the treatment of PAH.  The mechanism of action is therefore likely to be 
multifactorial. 
1.2.2 
General Toxicology 
Treprostinil diolamine did not demonstrate any carcinogenic effects in mouse or rat 
carcinogenicity studies.  Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 
5, 10 and 20 mg/kg/day in males and 0, 3, 7.5 and 15 mg/kg/day in females daily for 26 weeks 
did not significantly increase the incidence of tumors.  The exposures obtained at the highest 
dose levels used in males and females are about 8- and 17-fold, respectively, the human 
exposure at the mean dose of 3.4 mg BID.  Oral administration of treprostinil diolamine to 
Sprague Dawley rats at 0, 1, 3 and 10 mg/kg/day daily for 104 weeks did not significantly 
increase the incidence of tumors. The exposures obtained at the highest dose levels used in 
males and females are about 25- and 40-fold, respectively, the human exposure at the mean 
dose of 3.4 mg BID. 
In vitro genotoxicity studies with high doses of treprostinil did not demonstrate any mutagenic 
or clastogenic effects.  Treprostinil as the diolamine salt was tested in vivo in a rat 
micronucleus assay and did not induce an increased incidence of micronucleated 
polychromatic erythrocytes. 
No adverse effect doses for fertility, fetal viability/growth, fetal development (teratogenicity), 
and postnatal development were determined in rats.  In pregnant rabbits, external fetal and 
soft tissue malformations and fetal skeletal malformation occurred with the no observed 
adverse effect level for these adverse effects of 0.5 mg/kg/day (five times the human 
exposure). 
1.2.3 
Clinical Pharmacology 
The absolute bioavailability following administration of the oral treprostinil extended release 
tablet is 17% compared with IV Remodulin.  Maximum treprostinil concentrations occur 
between approximately 4 and 6 hours following administration of oral treprostinil in adults. 


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Following administration, oral treprostinil is widely distributed.  Oral treprostinil is 
approximately 96% protein bound with no effect on warfarin or digoxin displacement.  
Pharmacokinetic area under the curve (AUC) data; indicate that Day 1 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 exposure, contributing to the desired pharmacokinetic profile.  The 
relative bioavailability of treprostinil following oral administration of a 1 mg extended release 
tablet was not significantly altered by meal types ranging from 250 to 500 calories in healthy 
adult volunteers. 
Treprostinil is primarily metabolized by cytochrome (CYP) 2C8 and to a lesser extent by 
CYP2C9.  It is unknown if the metabolism of oral treprostinil will be altered in pediatric 
patients. A study evaluating the metabolism of paclitaxel by CYP2C8 using pediatric and 
adult liver microsomes found no age-related differences in metabolism [Blanco, 2000]; 
however, CYP2C9 activity appears to be increased in children.  Clearance is approximately 
twice that of adult values for several drugs predominately metabolized by CYP2C9, including 
warfarin, phenytoin, and celecoxib [Anderson, 2009].  Co-administration of oral treprostinil 
with a strong CYP2C8 inhibitor (e.g., gemfibrozil) has been demonstrated to result in 
significant elevation of treprostinil plasma concentrations.  
In a study conducted in healthy volunteers using [14C] treprostinil, 78.6% and 13.4% of the 
subcutaneous dose was recovered in the urine and feces, respectively, over 10 days.  Only 4% 
was excreted as unchanged treprostinil in the urine.  Five metabolites were detected in the 
urine, ranging from 10.2% to 15.5% and representing 64.4% of the dose administered.  
Metabolites of treprostinil were tested for pharmacologic activity and found to be much less 
hemodynamically active than treprostinil itself.  Specifically, metabolite M388 was 100- to 
1,000-fold less active than treprostinil, metabolites M392 and M566 were 1,000-fold less 
active than treprostinil, and metabolite M334 was at least 10,000-fold less active than 
treprostinil (i.e., did not affect blood pressure or heart rate at the highest dose tested).  
Metabolites M348 and M374 likewise had little cardiovascular activity, having some 


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0.01-0.05% the activity of parent drug.  It is concluded that the metabolites contributed very 
little to pharmacologic activity in this model. 
Initial clinical studies used a twice a day dosing regimen; however, a three times a day dosing 
(TID) regimen has been evaluated and a reduction in the peak-to-trough fluctuations 
observed.  A TID regimen more closely resembles a parental infusion to facilitate the 
achievement of higher doses with greater clinical effect on the signs and symptoms of PAH, 
and reduces the occurrence of prostacyclin-related adverse events previously seen with the 
twice daily regimen.  Successful transition of stable adult PAH subjects from parenteral 
treprostinil (IV or subcutaneous [SC] infusion) to a TID regimen with oral treprostinil without 
a significant decline in exercise capacity or worsening functional classification has been 
demonstrated in a recent clinical trial [White, 2014]. 
1.2.4 
Clinical Trials Experience 
Oral treprostinil has been administered to over 1,800 subjects in phase I-III trials.  Doses of 
up to 3 mg BID have been administered to healthy volunteers and subjects with PAH have 
received up to 28 mg TID in phase III and open-label studies.  As reported as of February 
2014, the average exposure has been approximately two years and the longest exposure 
reported as almost six years. 
Oral treprostinil has been evaluated in studies in subjects with PAH as monotherapy and in 
combination with endothelin receptor antagonist (ERA) and phosphodiesterase type 5 
inhibitor (PDE-5i) therapies. 
In a 12-week, randomized (2:1 oral treprostinil to placebo), double-blind, placebo-controlled, 
international study in subjects with WHO Group 1 PAH not currently receiving PAH therapy, 
subjects receiving oral treprostinil improved their median 6MWD at Week 12 by 
approximately +23 meters (Hodges-Lehmann estimate; p=0.013, non-parametric analysis of 
covariance in accordance with the pre-specified statistical analysis plan in the primary 
analysis population; n=228) as compared to subjects receiving placebo.  The within group 
median change from baseline was +25 meters for oral treprostinil and -5 meters for placebo at 


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Week 12 (n=228).  Mean dose (±SD) in the oral treprostinil group was 2.3 ±1.3, 3.2 ±1.9, and 
3.4 ±1.9 mg BID at Weeks 4, 8, and 12, respectively. 
The study enrolled 349 subjects (overall analysis population) who were not receiving any 
PAH medication.  Subjects were in WHO functional class II (~33%) and class III (~66%) 
with either idiopathic or heritable PAH (~75%), collagen vascular disease associated PAH 
(~19%), or PAH associated with HIV (1%) or congenital heart defect (5%) or other conditions 
(~6%).  The mean baseline 6MWD was approximately 330 meters. 
Subjects were administered oral treprostinil or placebo twice daily, with the doses titrated to 
effect up to a maximum of 12 mg BID based on clinical response and study drug tolerability.  
At the beginning of the study, subjects were dosed with only the 1 mg tablets, with 0.5 and 
0.25 mg tablets introduced at sequentially later dates during the study.  The primary analysis 
population consisted of the 228 subjects who had access to the 0.25 mg tablet at the time of 
randomization.  Discontinuations occurred in 17% of subjects receiving oral treprostinil 
compared to 14% of subjects on placebo in this population. 
Two 16-week, randomized, double-blind, placebo-controlled, international efficacy and safety 
studies of oral treprostinil in subjects with WHO Group 1 PAH already receiving treatment 
with an ERA, PDE-5i or a combination of both have been conducted.  The results did not 
demonstrate a benefit in exercise testing with median 6MWD at Week 16 (11 meters 
[Hodges-Lehmann estimate; p=0.072] and 10 meters [Hodges-Lehmann estimate; p=0.089], 
respectively).  Subjects were in WHO functional classification II (~23%) and III (~77%) with 
either idiopathic or heritable PAH (~66%), collagen vascular disease associated PAH (~29%), 
or PAH associated with HIV (1%) or congenital heart defect (4%).  The mean baseline 
6MWD was approximately 340 meters.  Approximately 40% of enrolled subjects were 
receiving both an ERA and a PDE-5i. 
Over 824 subjects have received oral treprostinil in a long-term, uncontrolled, open-label 
ongoing extension study.  About 70% of subjects continued treatment with oral treprostinil for 
at least a year.  The mean dose was 4.2 mg BID at one year.  The dose of oral treprostinil 
continued to increase over time with doses (mean ± SD) of 3.6 ±2.7, 4.1 ±3.1, and 5 ±3.7 mg 


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BID at 6 (n=649), 12 (n=433), and 24 months (n=238), respectively.  In the 522 subjects that 
completed the 12-month efficacy assessment, their mean 6MWD improved by 24 meters 
compared to baseline (30 meters in subjects not on another PAH therapy and 20 meters when 
oral treprostinil was used in combination with an ERA and/or a PDE-5i).  Of the subjects that 
remained in the study, overall survival was 92%, 87%, and 82% at the end of 1, 2, and 
3-years, respectively, with progression-free survival (progression defined as death, 
discontinuation or addition of a PAH therapy) of 74%, 61%, and 47%.  Reasons for 
discontinuation from the study included adverse event (16%), progression of disease (15%), 
death (13%), and withdrawn consent (7%). 
The most frequent adverse events (AEs) associated with oral treprostinil that occurred more 
frequently than placebo in clinical trials were related to systemic effects that are characteristic 
of prostacyclin (e.g., headache, diarrhea, nausea, flushing, pain in jaw, pain in extremity).  
A comprehensive description of oral treprostinil, including the pharmacology, toxicology, and 
clinical studies completed to date may be found in the Orenitram Package Insert and current 
version of the Investigators’ Brochure. 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION 
Parenteral prostacyclins are considered by many providers as the “gold standard” treatment 
for PAH.  Currently, the complexity and risks associated with approved prostanoid therapy 
including line sepsis, thromboembolism, and rebound hypertensive crisis limit its utility in 
clinical practice, particularly in children [Melnick, 2010].  Because of the risks and limitations 
of continuous parenteral infusion, an alternative route of administration would be desirable for 
adults as well as children. 
Oral treprostinil is a prostacyclin analogue, a class of medication that has long played a 
prominent role in the treatment of PAH [Badesch, 2004].  Prostacyclin, an endogenous 
compound produced by the vascular endothelium, has several activities that are relevant to the 
treatment of pulmonary arterial hypertension.  The similarity between adults and children with 
PAH in underlying pathobiological mechanisms supports the extrapolation that medicinal 


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products that are effective in adults would also be effective in children.  In addition to the data 
in adult patients establishing the safety and efficacy and supporting the regulatory approval of 
parenteral prostacyclin and prostacyclin analogue products, it has been reported that the use of 
IV epoprostenol in children is associated with clinical benefit and improved survival 
[Barst, 1999; Yung, 2004].  In a recent observational study evaluating the efficacy and 
tolerability of SC treprostinil for refractory pediatric pulmonary hypertension, eight children 
aged from 15 months to 10 years old received SC treprostinil therapy at doses ranging from 
37-60 ng/kg/min.  Of the eight children treated, seven showed improvement in functional 
classification, hemodynamic, and/or 6MWD (p<0.05), suggesting treprostinil is effective in 
children with pulmonary hypertension [Levy, 2011].  Additionally, a study in 13 children 
aged 3-17 years with PAH suggested that IV treprostinil is a therapeutic alternative to IV 
epoprostenol, with fewer side effects [Ivy, 2007].  Successful transitions from IV to oral or 
inhaled therapies (PDE-5i, ERA, calcium channel blockers, inhaled iloprost) have been 
previously demonstrated in studies in children aged six years or greater [Ivy, 2004; 
Melnick, 2010].  A retrospective study of 77 pediatric PAH patients receiving epoprostenol 
(n=37), treprostinil (n=20), or were transitioned from epoprostenol to treprostinil (n=20), 
reported a 5-year transplant-free survival of 70% (95% confidence interval, 56%-80%).  
Hemodynamic changes over time on treprostinil were similar to epoprostenol.  There was a 
significant improvement in the pulmonary-to-systemic vascular resistance ratio with 
treprostinil after 2 years of therapy and a trend toward improvement on epoprostenol after 1 to 
2 years of therapy; although, these changes were not sustained over the 4 year follow-up 
period [Siehr, 2013]. 
Given the established beneficial effects of prostanoid therapy in PAH and the limitations of 
existing prostanoid medications, oral treprostinil may provide therapeutic benefit to pediatric 
patients with PAH who are old enough to safely take the medication.  
1.4 
CLINICAL HYPOTHESIS 
This study aims to test the safety and tolerability of oral treprostinil in three cohorts of 
pediatric subjects aged 7 to 17 years: transitioning from IV/SC Remodulin, transitioning from 
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The hypothesis of this study is that stable PAH pediatric subjects can be safely be transitioned 
from IV/SC Remodulin to oral treprostinil therapy while maintaining the clinical benefit of 
the infused therapy.  A recent study in stable, carefully-selected PAH adult subjects receiving 
IV/SC Remodulin demonstrated that subjects can be safely transitioned to oral treprostinil 
three times daily (TID) dosing under close medical observation without a significant decline 
in exercise capacity or worsening functional classification [White, 2014].  After analysis of 
interim pharmacokinetic data from this study, it was determined that a four times daily (QID) 
dosing regimen in select pediatric subjects may achieve a better pharmacokinetic profile than 
a TID regimen, potentially providing a clinical benefit.  Additionally, we hypothesize that 
initiation of oral treprostinil in pediatric subjects following transition from inhaled 
prostacyclin or added to current PAH therapies in de novo prostacyclin subjects will result in 
clinical improvement compared to Baseline. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To assess the safety and tolerability of oral treprostinil extended release tablets in three 
cohorts of pediatric subjects with PAH aged 7 to 17 years:  
• 
Cohort 1: Subjects transitioning from IV/SC Remodulin  
• 
Cohort 2: Subjects transitioning from inhaled prostacyclin 
• 
Cohort 3: As add-on to current PAH therapy in de novo prostacyclin subjects 
2.2 
SECONDARY OBJECTIVES  
1. To assess the effect of oral treprostinil on the following (assessed in all cohorts): 
• CPET with progressive cycle ergometry  
• Symptoms of PAH 
• Panama and WHO functional classification 
• 6MWD  with oximetry and heart rate (HR) recovery monitoring 
• Borg dyspnea score 
• Quality of life (QOL) assessed via the Pediatric Quality of Life Inventory (PedsQL) 
questionnaire  


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• Plasma N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) 
• Cardiac magnetic resonance imaging (cMRI) 
2. To describe treprostinil pharmacokinetics (PK) in pediatric subjects with PAH aged 
7 to 17 years. 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a multi-center, open-label, safety and tolerability study of oral treprostinil (study drug) 
administered TID or QID, at the discretion of the Investigator, with food in pediatric PAH 
subjects aged 7 to 17 years of age (1) transitioning from continuous IV/SC Remodulin; 
(2) transitioning from inhaled prostacyclin; or (3) as add-on to current PAH therapies in de 
novo prostacyclin subjects.  Eligible subjects will be assigned to a cohort based upon their 
background therapy. 
Up to seven study visits will occur during the 24-week study at the following time points; 
Screening, Baseline, Week 0 (Cohort 1 only; inpatient hospital stay Days 1-5), Week 3, 
Week 6, Week 12, and Week 24. 
Cohort 1 Subjects: 
Following completion of Baseline assessments, including an 8-hour PK assessment while 
receiving IV/SC Remodulin within seven days prior to the first dose of oral treprostinil, 
subjects in Cohort 1 will undergo an inpatient hospital stay lasting approximately five days to 
transition from IV/SC Remodulin to oral treprostinil.  The target transition goal is five days 
and for the subject to be completely transitioned off IV/SC Remodulin prior to discharge from 
the hospital.  Subjects will be discharged from the hospital after they have transitioned off 
IV/SC Remodulin, reached their target oral treprostinil dose, or as the Investigator deems 
appropriate.  If necessary or if appropriate per Investigator discretion, subjects can prolong or 
complete the transition in an outpatient setting for a total transition time of up to four weeks. 
The maximum time to titrate off IV/SC Remodulin is four weeks from the start of the 
transition; if the subject is not fully transitioned by Week 4, they will be removed from the 


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study.  If the subject is in the hospital during one of the scheduled study visits, the 
assessments for that visit will be conducted as scheduled during the defined visit window. 
Cohort 2 and 3 Subjects:  
Following completion of Baseline assessments, the first dose of 0.125 mg oral treprostinil 
should be taken at the study site.  Dosing of oral treprostinil will be initiated at 0.125 mg TID 
or QID at the discretion of the investigator, with food.  Dosing will take place approximately 
every 6 to 8 hours for TID dosing, or approximately every 4 to 6 hours for QID dosing, with 
adjustments permitted based on the subject’s lifestyle and schedule.  Dose changes should be 
conducted under appropriate medical supervision in consultation with the study site. 
Dose Optimization/Evaluation Phase (All Cohorts): 
Week 3, Week 6, and Week 12: Subjects will return to clinic for the following assessments:  
vital signs, six-minute walk test (6MWT)/Borg dyspnea score, Panama and WHO functional 
classification, symptoms of PAH, and safety assessments.  At each visit, females of 
childbearing potential will undergo a urine pregnancy test.  At Week 12, QOL (as measured 
by PedsQL) and clinical laboratory assessments, including NT-pro-BNP, will occur. 
Week 24 (or premature termination): Subjects will return to the clinic for the following 
assessments:  vital signs, physical examination, 6MWT/Borg dyspnea score, CPET, Panama 
and WHO functional classification, symptoms of PAH, QOL assessment, NT-Pro BNP, 
cMRI, clinical laboratory assessments, electrocardiogram (ECG), and safety assessments.  
Females of child bearing potential will undergo a urine pregnancy test.  In addition all 
subjects will undergo an 8-hour PK assessment. 
Once the first five subjects have enrolled in Cohort 1 and transitioned from IV/SC Remodulin, 
the safety data will be reviewed by a Data Safety Monitoring Board (DSMB).  The IV/SC 
Remodulin dose will be between 25-75 ng/kg/min, inclusive, for the first five subjects 
enrolled in the cohort.  The dose range may be expanded to 25-125 ng/kg/min, inclusive, for 
the remaining subjects following the safety review. 
Additionally, if two or more of the first five subjects within any cohort meet the pre-specified 
stopping criteria (see Section 5.4) the data from that cohort will be reviewed by the DSMB 


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prior to enrolling additional subjects into that cohort.  If any of these events happen after the 
first four weeks of the study, it is not required that a subject be removed from the study.  The 
Investigator will determine whether it is safe for a subject to remain in the study. 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
No study-related procedures will be performed before a subject and/or their legal guardian has 
provided written informed consent and assent, as per institutional requirements.  All study-
related events and activities including specific instructions, procedures, concomitant 
medications, and descriptions of AEs will be recorded in the appropriate source documents 
and electronic case report forms (eCRFs).  


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Table 3-1 
Cohort 1 Schedule of Times and Events 
 
Screeninga Baselinea 
Treatmentc 
Transition Phase 
Dose Optimization/Evaluation 
Study Visit/Week 
Week 0a 
Week 3b 
Week 4n 
Week 6b 
Week 12b 
Week 24b/  
Premature Terminationc 
Study Day 
-28 to -1 
0/1 
2–5 (daily) 
22 
29 
43 
85 
169 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
PAH History 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
PedsQL Questionnaired 
 
X 
 
 
 
 
X 
X 
Vital Signse 
X 
X 
X 
X 
 
X 
X 
X 
Clinical Laboratory Parameters 
X 
X 
 
 
 
 
X 
X 
NT-pro-BNP 
 
Xf 
 
 
 
 
Xf 
Xf 
Urine Pregnancy Testg 
X 
X 
 
X 
 
X 
X 
X 
12-lead ECG 
 
X 
 
 
 
 
 
X 
Cardiac MRIh 
 
X 
 
 
 
 
 
X 
Panama and WHO Functional 
Classification 
X 
X 
 
X 
 
X 
X 
X 
PAH Symptoms 
 
X 
X 
X 
 
X 
X 
X 
6MWT/Borg Dyspnea Score 
Xi 
Xi 
Xj 
Xk 
 
Xk 
Xk 
Xk 
CPET 
 
Xl 
 
 
 
 
 
Xl 
Pharmacokinetic Evaluation 
 
Xm 
 
 
 
 
 
Xm 
Hospital Stay 
 
X 
X 
 
 
 
 
 
IV/SC Remodulin Weaningn 
 
X 
------- 
------- 
X 
 
 
 
Administration of Oral 
Treprostinil 
 
X 
------- 
------- 
------- 
------- 
------- 
------ 


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Screeninga Baselinea 
Treatmentc 
Transition Phase 
Dose Optimization/Evaluation 
Study Visit/Week 
Week 0a 
Week 3b 
Week 4n 
Week 6b 
Week 12b 
Week 24b/  
Premature Terminationc 
Study Day 
-28 to -1 
0/1 
2–5 (daily) 
22 
29 
43 
85 
169 
Dosing Instructions / Dosing 
Diary 
 
X 
 
X 
 
X 
X 
 
Drug Accountability / 
Compliance 
 
 
 
X 
 
X 
X 
X 
Telephone Contacto 
 
 
X------- 
 
------- 
------- 
------- 
------X 
Adverse Eventsp 
X------- 
------- 
---Xq--- 
-------- 
------- 
------- 
------- 
------X 
Concomitant Medications  
X------- 
------- 
------- 
-------- 
------- 
------- 
------- 
------X 
Pre-Baseline Review Formr 
-------X 
 
 
 
 
 
 
 
a 
The Screening phase can begin up to 28 days prior to Baseline.  Baseline assessments can be conducted over five days (120 hours) prior to the first dose 
of oral treprostinil, to allow for scheduling of all activities.  Screening and Baseline visits may be combined if all assessments are completed and entry 
criteria are satisfied within five days (120 hours) prior to first dose of oral treprostinil.  Baseline PK assessments for subjects enrolled in Cohort 1 can be 
performed up to seven days prior to beginning oral treprostinil.  The subject will begin transitioning from IV/SC Remodulin to oral treprostinil in the 
hospital (Week 0). 
b 
The window for Week 3, 6, 12, and 24 visits is ± five days. 
c 
The Week 24/Premature Termination visit can occur over five days (120 hours) to allow for scheduling of assessments on separate days; however, no 
oral treprostinil dose adjustments are allowed from five days prior to the Week 24 study visit until all Week 24/Premature Termination procedures have 
been completed, unless required to protect subject safety.  If the subject discontinues the study before Week 24, then the Premature Termination visit 
should be conducted.  All assessments should be conducted prior to discontinuation of oral treprostinil or as close as possible to the last dose of study 
drug. 
d 
PedsQL questionnaires must be completed based upon the subject’s age group and in accordance with the questionnaire administration guidelines.  
Must be completed as the first assessment at Baseline (or as part of the Screening visit assessment [after informed consent is obtained] if the Screening 
and Baseline visits are combined), Week 12 and Week 24 /Premature Termination, before the respondents complete any other health data forms, and 
before they see their physician/healthcare provider or have other assessments performed. 
e  
Vital signs must be collected after five minutes of rest (sitting); no other measurements or procedures should be performed during this five-minute 
period.  All vital signs will be collected prior to or after at least 30 minutes following the 6MWT. 
f 
Blood for NT-pro-BNP assessment must be drawn prior to conducting the 6MWT or CPET and will occur prior to the first dose of oral treprostinil at 
Baseline (or as part of the Screening visit assessment if the Screening and Baseline visits are combined). 
g Urine pregnancy test will be conducted for all females of childbearing potential.  If Screening and Baseline assessments are combined, a pregnancy test 
only needs to be conducted once. 


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h 
cMRI is optional for children younger than 10 years of age.  Must be performed prior to 6MWT and CPET if done on the same day.  If subject requires 
anti-anxiety medication (no general anesthesia) during the cMRI (without contrast), then the cMRI should be performed on a separate day from the 
CPET and 6MWT. 
i 
6MWT is only required at Screening if the subject has not previously undergone a 6MWT/Borg dyspnea score at the study site.  In that case, a practice 
test must be conducted and must precede the Baseline 6MWT by at least one day.  The 6MWT at Baseline must be conducted prior to the first dose of 
oral treprostinil.  Screening (if applicable) and Baseline 6MWTs will also include oximetry and HR recovery monitoring. 
j 
6MWT will occur daily during the inpatient hospital stay and should occur within 2-6 hours of the subject’s last dose (i.e., most recent dose) of oral 
treprostinil.  This will include oximetry and HR recovery monitoring. 
k 6MWT should occur within 2-6 hours of the subject’s last dose (i.e., most recent dose) of oral treprostinil and should be performed at least two hours 
before the CPET when they are performed at the same day.  Includes oximetry and HR recovery monitoring. 
l 
CPET should be performed a minimum of two hours after the 6MWT.  At Week 24, the CPET should be performed 2-6 hours after the morning dose of 
oral treprostinil.  It may be waived for subjects less than 130 cm in height, based on equipment available at the center. 
m Baseline PK assessments can be performed up to seven days prior to beginning oral treprostinil.  Administration of the oral treprostinil dose on the day 
of Week 24 PK sampling should occur approximately 8 hours after the prior evening’s last oral treprostinil dose for subjects using the morning dose for 
the PK assessment.  When using the midday dose for the PK assessment, the midday dose of oral treprostinil should occur approximately 4 to 6 hours 
after that day’s morning dose.  No oral treprostinil dose changes are allowed within five days of the Week 24 PK sampling, unless required to protect 
subject safety.  See Section 3.3.3 and Section 15.5. 
n 
The maximum time to titrate off IV/SC Remodulin is four weeks from the start of the transition; if the subject is not fully transitioned by Week 4, they 
will be removed from the study.  Subjects do not need to return to clinic for a visit at Week 4. 
o 
Daily telephone contact (excluding weekends and inpatient hospital stay) is required for the first two weeks of the study.  Weekly telephone contact is 
required from the Week 3 visit until the Week 12 visit and then at least every other week until the Week 24 visit.  Subjects may be contacted via email 
in lieu of a telephone call.  A copy of the emails and/or telephone contact sheets must be documented in the subject’s source documentation.  Email 
should not replace direct follow-up by phone or in clinic for clinical significant AEs or other emergent issues. 
p 
All AEs will be documented from the time of informed consent until the time screen failure is documented, or until the subject is either discontinued 
from the study or all Week 24 study assessments have been completed and should be followed until either resolution (or return to normal or baseline 
values), until they are judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extends beyond the final study 
visit. 
q 
Detailed prostacyclin-related AE collection will occur during the inpatient transition phase. 
r 
A pre-baseline review form must be completed and submitted for Sponsor approval after all screening assessments have been conducted for permission 
to move forward with the Baseline visit assessments. 


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Table 3-2 
Cohort 2 and Cohort 3 Schedule of Times and Events 
 
Screeninga 
Baselinea 
Treatmentc 
Study Visit/Week 
Week 3b 
Week 6b 
Week 12b 
Week 24b /  
Premature Terminationc 
Study Day 
-28 to -1 
0/1 
22 
43 
85 
169 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
PAH History 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
X 
Clinical Laboratory Parameters 
X 
X 
 
 
X 
X 
Urine Pregnancy Testd 
X 
X 
X 
X 
X 
X 
PedsQL Questionnairee 
 
X 
 
 
X 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
X 
 
 
 
X 
Cardiac MRIg 
 
X 
 
 
 
X 
PAH Symptoms 
 
X 
X 
X 
X 
X 
Panama and WHO Functional 
Classification 
X 
X 
X 
X 
X 
X 
NT-pro-BNP 
 
Xh 
 
 
X 
Xh 
6MWT/Borg Dyspnea Score 
Xi 
Xi 
Xj 
Xj 
Xj 
Xj 
CPET 
 
Xk 
 
 
 
Xk 
Pharmacokinetic evaluationl 
 
 
 
 
 
X 
Administration of oral treprostinil 
 
X 
-------- 
-------- 
------- 
------ 
Dosing Instructions / Dosing Diary    
 
X 
X 
X 
X 
 
Drug Accountability  / Compliance 
 
 
X 
X 
X 
 
Telephone Contactm 
 
X---- 
------- 
-------- 
------- 
------X 
Adverse Eventsn 
X------- 
------- 
-------- 
-------- 
------- 
------X 


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Screeninga 
Baselinea 
Treatmentc 
Study Visit/Week 
Week 3b 
Week 6b 
Week 12b 
Week 24b /  
Premature Terminationc 
Study Day 
-28 to -1 
0/1 
22 
43 
85 
169 
Concomitant Medications  
X------- 
------- 
-------- 
-------- 
------- 
------X 
Pre-Baseline Review Formo 
-------X 
 
 
 
 
 
a 
The Screening phase can begin up to 28 days prior to Baseline.  Baseline assessments can be conducted over five days (120 hours) prior to the first 
dose of oral treprostinil, to allow for scheduling of all activities.  Screening and Baseline visits may be combined if all assessments are completed and 
entry criteria are satisfied within five days (120 hours) prior to first dose of oral treprostinil. 
b 
The window for Week 3, 6, 12 and 24 visits is ± five days. 
c 
The Week 24/Premature Termination visit can occur over five days (120 hours) to allow for scheduling of assessments on separate days; however, no 
oral treprostinil dose adjustments are allowed from five days prior to the Week 24 study visit until all Week 24/Premature Termination procedures 
have been completed, unless required to protect subject safety.  If the subject discontinues the study before Week 24, then the Premature Termination 
visit should be conducted.  All assessments should be conducted prior to discontinuation of oral treprostinil or as close as possible to the last dose of 
study drug. 
d 
Urine pregnancy test will be conducted for all females of childbearing potential.  If Screening and Baseline assessments are combined, a pregnancy 
test only needs to be conducted once. 
e 
PedsQL questionnaires must be completed based upon the subject’s age group and in accordance with the questionnaire administration guidelines.  
Must be completed as the first assessment at Baseline (or as part of the Screening visit assessment [after informed consent is obtained] if the 
Screening and Baseline visits are combined), Week 12 and Week 24/Premature Termination, before the respondents complete any other health data 
forms, and before they see their physician/healthcare provider or have other assessments performed. 
f 
Vital signs must be collected after five minutes of rest (sitting); no other measurements or procedures should be performed during this five-minute 
period.  All vital signs will be collected prior to or after at least 30 minutes following the 6MWT. 
g 
cMRI is optional for children younger than 10 years of age.  Must be performed prior to 6MWT and CPET if done on the same day.  If subject 
requires anti-anxiety medication (no general anesthesia) during the cMRI (without contrast), then the cMRI should be performed on a separate day 
from the CPET and 6MWT. 
h 
Blood for NT-pro-BNP assessment must be drawn prior to conducting the 6MWT or CPET and will occur prior to the first dose of oral treprostinil at 
Baseline (or as part of the Screening visit assessment if the Screening and Baseline visits are combined). 
i 
6MWT is only required at Screening if the subject has not previously undergone a 6MWT/Borg dyspnea score at the study site.  In that case, a 
practice test must be conducted and must precede the Baseline 6MWT by at least one day.  The 6MWT at Baseline must be conducted prior to the 
first dose of oral treprostinil.  Screening (if applicable) and Baseline 6MWTs will also include oximetry and HR recovery monitoring. 
j 
6MWT should occur within 2-6 hours of the subject’s last dose (i.e., most recent dose) of oral treprostinil and should be performed at least two hours 
before the CPET when they are performed at the same day.  This will include oximetry and HR recovery monitoring. 
k CPET should be performed a minimum of two hours after the 6MWT.  At Week 24, the CPET should be performed 2-6 hours after the morning dose 
of oral treprostinil.  It may be waived for subjects less than 130 cm in height, based on equipment available at the center. 


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l 
Administration of the oral treprostinil dose on the day of Week 24 PK sampling should  occur approximately 8 hours after the prior evening’s last oral 
treprostinil dose for subjects using the morning dose for the PK assessment.  When using the midday dose for the PK assessment, the midday dose of 
oral treprostinil should occur approximately 4 to 6 hours after that day’s morning dose.  No oral treprostinil dose changes are allowed within five days 
of the Week 24 PK sampling, unless required to protect subject safety.  See Section 3.3.3 and Section 15.5. 
m Daily telephone contact (excluding weekends) is required for the first two weeks of the study.  Weekly telephone contact is required from the Week 3 
visit until the Week 12 visit and then at least every other week until the Week 24 visit.  Subjects may be contacted via email in lieu of a telephone call.  
A copy of the emails and/or telephone contact sheets must be documented in the subject’s source documentation.  Email should not replace direct 
follow-up by phone or in clinic for clinical significant AEs or other emergent issues. 
n 
All AEs will be documented from the time of informed consent until the time screen failure is documented, or until the subject is either discontinued 
from the study or all Week 24 study assessments have been completed and should be followed until either resolution (or return to normal or baseline 
values), until they are judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extends beyond the final study 
visit. 
o 
A pre-baseline review form must be completed and submitted for Sponsor approval after all screening assessments have been conducted for 
permission to move forward with the Baseline visit assessments. 


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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
3.3.1.1 
Cardiopulmonary Exercise Testing (CPET) 
Exercise testing will be performed with progressive cycle ergometry and ventilatory expired 
gas analysis obtained using a metabolic cart at Baseline and Week 24/Premature Termination.  
The CPET may be waived in subjects less than 130 cm in height based on equipment 
available at the center.  Cardiopulmonary exercise testing entails measurements of oxygen 
uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE) and other variables, in 
addition to a 12-lead ECG, blood pressure (BP) monitoring, and pulse oximetry.  Testing 
should be performed a minimum of two hours after the 6MWT when they occur on the same 
visit, and should be conducted 2-6 hours after the morning dose of oral treprostinil (study 
drug) at the Week 24 visit. 
Resting measurements will be made for 1-3 minutes; followed by one minute unloaded (no 
tension/resistance) cycling as a warm-up period.  The workload will then be increased at a 
rate designed to allow reaching maximum work capacity in 8-12 minutes.  Workload will be 
increased in a continuous (ramp) fashion, with 5 Watt/minute for subjects <40 kg, 
10Watt/min for subjects 40 to <70 kg, and 15 Watt/min for subjects ≥70 kg.  Subjects will be 
instructed to maintain a pedaling cadence between 50-60 revolutions per minute (RPM).  
Maximal effort will be defined as the attainment of a Respiratory Quotient (RQ) equal to 1.10 
or greater.  Subjects will be encouraged to put forth a maximal effort on CPET.  Tests will be 
terminated according to published guidelines and institutional standards. 
• Metabolic data will be continuously collected and recorded in the subject’s source 
documentation during baseline, warm up, exercise, and the first two minutes of 
recovery.  Breath by breath data should be averaged in 20-second intervals.  Blood 
pressure should be recorded every 2-3 minutes with additional measurements as 
needed.  Oxygen saturation should be measured continuously.  Resting values will be 
selected from the baseline data.  Peak values will be selected from the last portion of 
the exercise.  The VE/VCO2 slope will be measured to the respiratory compensation 
point. 


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• The raw exercise data will be sent to a central site and reviewed by a centralized 
specialist to ensure consistency and accuracy of test performance.  The centralized 
specialist may communicate with the site and establish study specific analysis settings 
for assessments performed for purposes of this protocol. 
3.3.1.2 
Six-Minute Walk Test 
The intent of the 6MWT is to evaluate exercise capacity associated with carrying out 
activities of daily living.  All 6MWTs will be conducted by qualified, trained personnel in a 
designated 6MWT area which meets the requirements as outlined in Appendix 15.1.  The 
subject should rest (seated) for at least five minutes prior to the start of each 6MWT.  The 
start time of the pre-walk, and five minute rest period should be clearly documented in the 
subject’s medical records. 
A 6MWT will only be required at Screening if the subject has not previously undergone a 
6MWT at the study site and will serve as a practice test.  If conducted, it must be separated by 
at least one day from the 6MWT at Baseline.  Given that the 6MWT needs to be performed 
during inpatient hospitalization (Cohort 1 subjects only) and the subsequent study visits, it is 
permissible to conduct the 6MWT at different locations, if needed, during this study. 
Oxygen saturation and HR will be measured at rest prior to the 6MWT and monitored 
continuously during the walk.  Oxygen saturation may be measured by fingertip or forehead 
monitor.  Recovery monitoring (HR and oxygen saturation) will be performed and 
documented at minute 0 (immediately upon stopping the 6MWT), minute 1, minute 2 and 
minute 3 post-walk.  Recovery monitoring must continue until the HR is within 10 beats of 
resting values and the oxygen saturation is within 2% of resting values or until at least 
20 minutes of recovery monitoring has been performed and the Investigator considers the 
subject to be clinically stable. 
3.3.1.2.1 
Baseline Six-Minute Walk Test 
The 6MWT performed at Baseline must be conducted prior to the first dose of oral 
treprostinil.  If a practice 6MWT is conducted at Screening, the Baseline 6MWT must be 
conducted at least one day apart.  For the purposes of the 6MWT, if the subject was assessed 


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at Baseline using oxygen therapy, then all 6MWTs during the 24-week study should be 
conducted with the same oxygen flow rate and mode of administration.  The 6MWT should 
be conducted at least two hours prior to conducting the CPET. 
3.3.1.2.2 
Treatment Six-Minute Walk Tests 
The 6MWTs will be conducted during each day of the inpatient hospital stay (Cohort 1 
subjects only) and all subsequent study visits, and should occur within 2-6 hours of the 
subject’s last dose (i.e., most recent dose) of oral treprostinil.  Subjects receiving 
supplemental oxygen during the Baseline 6MWT must continue to receive the same flow rate 
and mode of oxygen therapy at all subsequent 6MWT assessments.  The 6MWT should be 
performed at least two hours prior the CPET at Week 24/Premature Termination. 
3.3.1.3 
Borg Dyspnea 
The Borg dyspnea score will be assessed prior to and following the completion of each 
6MWT.  The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea 
experienced during the 6MWT (Section 15.1).  Scores range from 0 (for the best condition) to 
10 (for the worst condition). 
3.3.1.4 
PAH Symptoms 
PAH symptoms (fatigue, dyspnea, edema, dizziness, syncope, chest pain, orthopnea) will be 
assessed at the Baseline visit prior to the initiation of oral treprostinil dosing and at all 
subsequent visits, including each day of the inpatient hospital stay (Cohort 1 subjects only).  
Scores range from 0 (for the best condition) to 3 (for the worst condition). 
3.3.1.5 
Functional Classification 
Subject clinical status will be assessed at Screening, Baseline, and all subsequent study visits.  
Functional classification will be recorded according to the Panama functional classifications 
for children with pulmonary hypertension and the WHO functional classification.  Functional 
classification scales are provided in Section 15.2. 
3.3.1.6 
N-terminal pro-BNP 
Plasma N-terminal pro-BNP concentration is a useful biomarker for PAH as it is associated 
with changes in right heart morphology and function [Fijalkowska, 2006].  NT pro-BNP 


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sample collection will occur at Baseline (or as part of the Screening visit assessment if the 
Screening and Baseline visits are combined) prior to starting oral treprostinil and repeated at 
Week 12 and Week 24/Premature Termination.  Blood for NT-pro-BNP assessment must be 
drawn prior to conducting the 6MWT or CPET. 
3.3.1.7 
Pediatric Quality of Life Inventory (PedsQLTM) 
Health-related quality of life will be assessed via the 23-item PedsQL questionnaire at 
Baseline (or as part of the Screening visit assessment if the Screening and Baseline visits are 
combined), Week 12, and Week 24/Premature Termination.  The appropriate questionnaire 
must be administered based upon the subject’s age group and in accordance with the 
questionnaire administration guidelines.  The PedsQL must be completed as the first 
assessment (after informed consent is obtained) before the respondents complete any other 
health data forms, and before they see their physician/healthcare provider or have other 
assessments performed.  An example of the PedsQL is provided in Section 15.3. 
3.3.2 
Safety 
During this study, treatment emergent changes in physical findings, vital signs, clinical 
laboratory parameters, and the development of AEs will be the primary assessments of safety. 
3.3.2.1 
Medical History and Physical Examinations 
A complete medical history, demographics, PAH history, and physical examination will be 
conducted at Screening.  If any changes to the medical history occur between the Screening 
and Baseline visit, those should be recorded.  Significant past or present illnesses, current 
prescription or nonprescription medications (including vitamins and herbal products), and 
history of medication allergies should be recorded.  Any significant changes to the subject’s 
medical condition, physical examination, and concomitant medications must be documented 
throughout the course of the study. 
A complete physical examination will be conducted by a physician at Screening and at 
Week 24/Premature Termination.  All treatment emergent clinically significant findings 
during the study will be reported as AEs. 


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3.3.2.2 
Vital Signs 
Vital signs will be assessed during all study visits, including every day of the inpatient 
hospital stay (Cohort 1 subjects only).  Vital signs measured will include blood pressure (BP, 
systolic and diastolic), HR, respiratory rate (RR), temperature (°C), and weight.  Vital signs 
must be assessed following at least five minutes of rest (sitting) to ensure accurate 
measurement.  No other measurements or procedures should be performed during this five-
minute period.  Vital signs will be collected prior to or after at least 30 minutes following the 
6MWT.  Vital signs should also be assessed in the case of abnormal clinical signs and 
symptoms.  Height will be recorded at Screening. 
3.3.2.3 
12-Lead ECG 
A 12-lead ECG will be recorded after at least five minutes rest in the semi-recumbent position 
at Baseline and repeated at Week 24/Premature Termination.  Recordings should include lead 
II as a rhythm strip and contain at least five QRS complexes.  The ECG parameters (after at 
least five minutes rest) include HR, PR interval, QT interval, QRS duration, and any clinically 
significant abnormalities. 
3.3.2.4 
Clinical Laboratory Assessments 
The results of all clinical laboratory tests conducted at Screening and Baseline must be 
assessed by the Investigator to determine each subject’s eligibility to participate in the study.  
Clinical laboratory results outside the normal reference range must be assessed and 
documented by the Investigator as to clinical significance.  Clinically significant refers to a 
laboratory value that is unusual with respect to the subject’s medical history or current health 
status.  
Clinically significant abnormal laboratory test values will be treated and/or followed-up until 
the symptoms or values return to normal or acceptable levels, as judged by the Investigator.  
When appropriate, medical tests and examinations will be performed to document resolution 
of event(s). 


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3.3.2.4.1 
Clinical Chemistry and Hematology 
Blood and urine specimens for the measurement and evaluation of clinical chemistry and 
hematology will be collected at the Screening and Baseline visits prior to administration of 
oral treprostinil and repeated at the Week 12 and Week 24/Premature Termination to assess 
for study treatment-emergent changes in clinical chemistry and hematological laboratory 
parameters. Values for the following parameters will be obtained: 
Electrolyte Panel 
Chemistry Panel 
Hematology Panel 
• 
Sodium 
• 
Total bilirubin 
• 
Hemoglobin  
• 
Potassium 
• 
Alkaline phosphatase 
• 
Hematocrit  
• 
Bicarbonate  
• 
Alanine aminotransferase  
• 
Red blood cell count  
• 
Chloride 
• 
Aspartate aminotransferase 
• 
Red blood cell morphology 
 
• 
Urea nitrogen 
• 
White blood cell count  
• 
Creatinine 
• 
Platelet count 
• 
Calcium 
 
• 
Albumin 
3.3.2.4.2 
Pregnancy Testing 
Females of childbearing potential include any female who has experienced menarche.  Urine 
pregnancy tests (for all females of child-bearing potential) will be conducted at Screening, 
Baseline, and all subsequent study visits.  A positive pregnancy test will exclude the subject 
from further participation in the study.  Pregnant subjects who are discontinued from the study 
will be transitioned to an alternate therapy at the discretion of the Investigator. 
3.3.2.5 
Adverse Events 
Adverse Events will be recorded throughout the course of the study from the time that each 
subject and/or caregiver signs the informed consent/assent form until the time screen failure is 
documented, or until the subject is either discontinued from the study or all Week 24 study 
assessments have been completed.  Each subject/caregiver will be directly questioned for AEs 
at each scheduled study visit and during required telephone contacts.  Subjects/caregivers will 
also be instructed to spontaneously report all AEs throughout the study.  Additionally, a 
detailed collection of prostacyclin-related AEs will be captured via a standardized diary 
completed by the subject and/or caregiver each day of the five day inpatient hospital stay 
during the transition from IV/SC Remodulin to oral treprostinil or all subjects in Cohort 1. 


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All AEs should be followed until either resolution (or return to normal or baseline values), 
until they are judged by the Investigator to no longer be clinically significant, or for at least 30 
days if the AE extends beyond the final study visit.  All AEs meeting the criteria for serious 
(i.e., serious adverse events [SAEs]) should be followed until resolution, death, or the subject 
is lost to follow-up even if they are ongoing more than 30 days after completion of the final 
study visit. 
All AEs/SAEs that occur while the subject is on oral treprostinil will be recorded as 
instructed in this protocol (Section 9.3). 
If, at any time, the subject withdraws from the study and/or changes from study drug to 
commercially available Orenitram, any AEs/SAEs that occur on Orenitram (including 
product use errors, product quality problems, and therapeutic failures) will be reported 
following local post-marketing reporting requirements.  These events will not be included in 
the eCRF. 
Pulmonary arterial hypertension symptoms (Section 3.3.1.4) and PAH disease related events 
(Section 9.1.4) should only be recorded as an AE if the event is serious, new, or unusual with 
respect to intensity, frequency, or duration as compared to symptoms in the subject’s medical 
history; or there is a reasonable possibility that the event was caused by the study drug. 
3.3.2.6 
Telephone Contact (All Cohorts) 
Daily telephone contact (excluding weekends for all subjects and inpatient hospital stay for 
Cohort 1 subjects) is required for the first two weeks of the study.  Weekly telephone contact 
is required from the Week 3 visit until the Week 12 visit and then at least every other week 
until the Week 24 visit. 
The purpose of the telephone contact is to instruct the subject/caregiver to titrate their dose of 
oral treprostinil and assess for AEs and concomitant medications.  Subject/caregiver may be 
contacted via email in lieu of a telephone call; however, email should not replace direct 
follow-up by telephone or in clinic for clinical significant AEs or other emergent issues.  All 
telephone or email contacts (i.e. any dosing instructions, AEs reported and/or medication 
changes) with the subject must be noted in the source documentation. 


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3.3.2.7 
Continued Access Plan 
Subjects who have completed the Week 24 Visit will be given the option for continued access 
to oral treprostinil.  During the Week 24 Visit, the Investigator should assess each subject’s 
eligibility for the Continued Access Plan. 
3.3.3 
Pharmacokinetics or Other Special Study 
3.3.3.1 
Pharmacokinetic Sampling 
Pharmacokinetic blood sampling will occur twice for each subject in Cohort 1; once during 
Baseline while the subject is still receiving IV/SC Remodulin prior to starting oral 
treprostinil, and again at Week 24 when the subject has reached a stable dose of oral 
treprostinil.  Subjects in Cohort 2 and 3 will undergo PK blood sampling at Week 24 only. 
All blood samples should be drawn within a ±10 minute window from their scheduled time 
point.  Record the time and reason for late blood draws and document hemolyzed samples in 
the eCRF.  Hemolyzed blood samples may be redrawn as able.  Pharmacokinetic parameters 
derived from treprostinil plasma concentration-time data will be determined for each subject. 
Appendix 15.5 contains a detailed description for the PK blood collection, processing, 
storage, and shipment of all samples. 
Baseline PK Assessment (Cohort 1 Only): 
At Baseline subjects in Cohort 1 will undergo an 8-hour PK assessment while receiving 
IV/SC Remodulin within seven days prior to the first dose of oral treprostinil.  Blood 
samples will be obtained from each subject at time 0 and the following subsequent time 
points:  4 and 8 hours after time 0 for a total of three blood samples.  During the Baseline 
phase, time 0 should be at the same time of day that it is estimated the Week 24 morning oral 
treprostinil dose will occur (i.e., if the subject/caregiver anticipates the first daily dose of oral 
treprostinil at Week 24 will be administered at 8 AM, time 0 should be 8 AM). 


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Baseline PK Assessment Sample Timelines: 
Baseline Time 
Points 
Sample Time of Day 
Comment (Cohort 1 subjects only while on  
IV/SC Remodulin) 
Time 0 
8:00 
Estimated time that the morning dose of oral treprostinil will 
occur at the Week 24 PK assessment. 
4 hours 
12:00 
All subsequent blood draws should occur within a ±10 minute 
window from their scheduled time point.  At Baseline all blood 
draws should be based off of time 0. 
8 hours 
16:00 
Week 24 PK Assessment (All Cohorts): 
At Week 24 all subjects (all cohorts) will undergo an 8-hour PK assessment while receiving 
oral treprostinil.  No oral treprostinil dose changes are allowed within five days of the 
Week 24 PK sampling, unless required to protect subject safety.  All subjects on a TID 
dosing regimen will undergo the Week 24 PK assessment based on the first daily dose 
(morning dose) of oral treprostinil.  If a subject is on a QID dosing regimen, the Investigator 
may conduct the PK assessment based on the first daily dose (morning dose) or the second 
daily dose (midday dose) at their discretion.  The PK assessment dose of oral treprostinil will 
be taken in the clinic and should occur approximately 8 hours after the prior evening’s last 
oral treprostinil dose for subjects using the morning dose for the PK assessment.  When using 
the midday dose for the PK assessment, the midday dose of oral treprostinil should occur 
approximately 4 to 6 hours after that day’s morning dose.   
Blood samples will be obtained from each subject at pre-dose (immediately prior [i.e., 
10 minutes ±5 minutes] to administration of the PK assessment dose of oral treprostinil) and 
the following time points:  2, 4, 6, and 8 hours after the PK assessment dose of oral 
treprostinil (all time points will be based off of the time the PK assessment dose is 
administered).  No other doses of oral treprostinil should be taken during the PK sampling 
period if the subject is on a TID regimen.  The second daily dose of oral treprostinil (midday 
dose) on a TID regimen will be taken in the clinic and after the final 8-hour PK sample is 
collected.  Subjects on a QID oral treprostinil regimen will take their next daily dose (midday 
dose or early evening dose [PM #1 dose] based on timing of PK assessment dose) between 
the 4 and 6 hour time points of the PK sampling (±10 minutes).  The PK assessment dose of 
oral treprostinil must be observed in the clinic by study personnel and taken with food.  A 


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brief description of the food ingested prior to the PK dose of oral treprostinil administration 
should be recorded in the source and eCRF.  Tablets must not be chewed or broken. 
Week 24 TID PK Assessment Sample Timelines: 
Week 24 Time Points Sample Time of Day Comment (all cohorts while on oral treprostinil) 
Previous evening dose 
24:00 
The previous evening last dose at the Week 24 PK assessment 
should be taken approximately 8 hours prior to the next 
morning oral treprostinil dose. 
Pre-dose 
7:50 
Blood draw should occur 10 minutes ±5 minutes prior to the 
morning dose of oral treprostinil. 
Morning dose 
8:00 
The morning dose at the Week 24 PK assessment will be taken 
in the clinic and should occur approximately 8 hours after the 
prior evening’s last oral treprostinil dose. 
2 hours 
10:00 
At Week 24 all blood draws should be based off of the morning 
dose of oral treprostinil. All subsequent blood draws should 
occur within a ±10 minute window from their scheduled time 
point.   
4 hours 
12:00 
6 hours 
14:00 
8 hours 
16:00 
Midday dose 
16:15 
The midday dose should be taken in the clinic with food and 
after the last PK assessment has been completed. 
Week 24 QID PK Assessment Based on Morning Dose Sample Timeline: 
Week 24 Time Points Sample Time of Day Comment (All cohorts while on oral treprostinil) 
Previous evening dose 
24:00 
The previous evening dose at the Week 24 PK assessment 
should be taken approximately 8 hours prior to the next 
morning oral treprostinil dose. 
Pre-dose 
7:50 
Blood draw should occur 10 minutes ±5 minutes prior to the 
morning dose of oral treprostinil. 
Morning dose 
8:00 
The morning dose at the Week 24 PK assessment will be taken 
in the clinic and should occur approximately 8 hours after the 
prior evening’s last oral treprostinil dose. 
2 hours 
10:00 
All blood draws should be based off of the morning dose of 
oral treprostinil.  All subsequent blood draws should occur 
within a ±10 minute window from their scheduled time point.   
Subjects on QID dosing should take their second daily dose of 
oral treprostinil (midday dose) between the 4 and 6 hour time 
points of the PK sampling (±10 minutes) 
4 hours 
12:00 
6 hours 
14:00 
8 hours 
16:00 


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Week 24 QID PK Assessment Based on Midday Dose Sample Timeline: 
Week 24 Time 
Points 
Sample Time of Day Comment (all cohorts while on oral treprostinil) 
Morning dose 
6:00 
The morning dose on the day of the Week 24 PK assessment 
should be taken approximately 4 to 6 hours prior to the midday 
dose of oral treprostinil.  
Pre-dose 
9:50 
Blood draw should occur 10 minutes ±5 minutes prior to the 
midday dose of oral treprostinil. 
Midday dose 
10:00 
The midday dose at the Week 24 PK assessment will be taken 
in the clinic and should occur approximately 4 to 6 hours after 
that day’s morning dose of oral treprostinil. 
2 hours 
12:00 
All blood draws should be based off of the midday dose of oral 
treprostinil.  All subsequent blood draws should occur within a 
±10 minute window from their scheduled time point.   
Subjects on QID dosing should take their third daily dose of 
oral treprostinil (early evening dose [PM #1]) between the 4 
and 6 hour time points of the PK sampling (±10 minutes) 
4 hours 
14:00 
6 hours 
16:00 
8 hours 
18:00 
 
3.3.3.2 
Cardiac Magnetic Resonance Imaging (cMRI) 
Cardiac MRI imaging will be performed in all subjects aged 10 years and older at Baseline 
and Week 24/Premature Termination; imaging may be optionally performed in subjects 
under the age of 10 years.  Cardiac MRI should be performed prior to the 6MWT and 
CPET, if done on the same day.  If subject requires anti-anxiety medication in order to 
undergo and still follow directions (no general anesthesia) during the cMRI (without 
contrast), then the cMRI should be performed on a separate day from the CPET and 
6MWT. 
The subject’s BP will be taken immediately prior to the cMRI assessment in the supine 
position to measure vascular parameters. 
The following parameters will be evaluated: 
• Right ventricular (RV) mass index 
• RV ejection fraction (RVEF) 
• Left ventricular (LV) ejection fraction (LVEF) 
• RV end-diastolic volume (RVEDV) index 
• RV end-systolic volume (RVESV) index 


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• RV stroke volume index 
• LV stroke volume index 
• RV cardiac output index 
The following additional parameters may be collected: 
• Flow pattern through the MPA by phase-sensitive gradient echo imaging 
• Flow pattern through the RPA by phase-sensitive gradient echo imaging 
• Flow pattern through the Ascending aorta by phase-sensitive gradient echo 
imaging 
• RV:LV end-systolic diameter ratio 
• Systolic septal flattening 
• Right atrial size 
• Presence of congenital heart disease 
• Atrial or ventricular shunt 
Cardiac MRI measurements from images will be analyzed by a centralized specialist reader 
to control for bias and to reduce inter-reader variability.  The centralized specialist reader 
may communicate with the site and establish study specific analysis settings for assessments 
performed for purposes of this protocol. 
3.4 
NUMBER OF CENTERS 
The study is a US-based multi-center study with approximately 10 centers participating. 
3.5 
NUMBER OF SUBJECTS 
A total of 40 subjects will be enrolled in this study.  Approximately 25 subjects will be 
enrolled between Cohort 1 and Cohort 2 of this study, and 15 subjects will be enrolled into 
Cohort 3. 
3.6 
ESTIMATED STUDY DURATION 
From Screening until study completion, expected duration of subject participation is 
approximately 28 weeks (four week screening period and 24 week treatment period). 


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4 
SUBJECT ELIGIBILITY 
Inclusion and exclusion criteria are to be assessed during the Screening period and 
reconfirmed at the Baseline visit prior to the first dose of oral treprostinil.  Study related 
procedures must be conducted during the Screening period after obtaining informed consent 
and assent (if applicable) to determine subject eligibility for the study. 
4.1 
INCLUSION CRITERIA 
A subject is eligible for inclusion in this study if all of the following criteria apply: 
1. Legal guardian informed consent and subject assent, if appropriate, to participate in 
the study is voluntarily given. 
2. The subject is between 7 and 17 years of age, inclusive, on the date informed consent 
is signed. 
3. Cohort 3: The subject must weigh a minimum of 22 kg at Screening. 
4. The subject has a current diagnosis of PAH (WHO Group I) associated with: 
a. Idiopathic or heritable PAH 
b. Persistent PAH for at least one year following surgical repair of a congenital 
systemic-to-pulmonary cardiac shunt, congenital heart disease, or other 
congenital heart lesions with no clinically significant residual defects and 
condition is stabilized hemodynamically 
c. PAH in subjects with unrepaired restricted atrial septal defect, ventricular 
septal defect, or patent ductus arteriosus; subject must have a resting post-
ductal oxygen saturation (off oxygen) of greater than 88% 
5. The subject has a current diagnosis of PAH confirmed by right heart catheterization 
(RHC) prior to the Screening visit with the following parameters: 
a. Mean pulmonary arterial pressure (mPAP) of ≥25 mmHg 
b. Pulmonary vascular resistance index (PVRi) of >3 Wood Units * m2 
c. Left ventricular end diastolic pressure (LVEDP) or pulmonary capillary wedge 
pressure (PCWP) of ≤15 mmHg 


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6. Cohort 1: The subject must have been receiving IV/SC Remodulin for at least 90 days 
without dose change for at least 30 days prior to Baseline.  The IV/SC Remodulin 
dose will be between 25-75 ng/kg/min, inclusive, for the first five subjects in the 
cohort.  Following a safety review, the dose range may be expanded to 
25-125 ng/kg/min, inclusive, for the remaining subjects.  Subjects must be receiving 
stable doses of all other PAH medications for at least 14 days prior to the Baseline 
assessments; exception for diuretics and anticoagulants as outlined in Section 4.3.1. 
7. Cohort 2: The subject must have been receiving inhaled prostacyclin for at least 90 
days and has been at the current stable dose without changes for at least 30 days prior 
to Baseline.  Subjects must be receiving stable doses of all other PAH medications for 
at least 14 days prior to the Baseline assessments; exception for diuretics and 
anticoagulants as outlined in Section 4.3.1. 
8. All Cohorts: All subjects must be optimally treated (as determined by the Investigator) 
with background PAH therapies (e.g., PDE-5i, ERA, soluble guanylate cyclase [sGC]) 
for at least 90 days and have been on a stable dose without changes (except 
documented weight based adjustments) for at least 30 days prior to the first dose of 
oral treprostinil. Subjects must be receiving stable doses of all other PAH medications 
for at least 14 days prior to the first dose of oral treprostinil; exception for diuretics 
and anticoagulants as outlined in Section 4.3.1. 
9. The subject is willing and able to swallow intact tablets whole without chewing, 
breaking, or splitting. 
10. The subject is willing and able to comply with the dietary requirements associated 
with the oral treprostinil dosing regimen. 
11. The subject must be on stable doses of other medical therapy for 14 days prior to 
Baseline visit with no dose adjustments, additions, or discontinuations.  Dose changes 
of diuretics are allowed if within the usual dose adjustments prescribed for the subject.  
Anticoagulants may be adjusted, but not discontinued or added, within 14 days of 


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Baseline.  Temporary discontinuation of anticoagulants when related to study related 
procedures is allowed. 
12. Females of childbearing potential include any female who has experienced menarche.  
Females of childbearing potential must practice true abstinence from intercourse, have 
an IUD, or must use two different forms of highly effective contraception for the 
duration of the study, and for at least 30 days after discontinuing oral treprostinil.  
Medically acceptable forms of effective contraception include approved hormonal 
contraceptives (such as birth control pills) or barrier methods (such as a condom or 
diaphragm) used with a spermicide.  For females of childbearing potential, a negative 
urine pregnancy test is required at Baseline prior to oral treprostinil administration.  
Males participating in the study must use a condom during intercourse for the duration 
of the study, and for at least 48 hours after discontinuing oral treprostinil. 
13. Subjects with a history of metallic implants, prior neurosurgical clip placement, or 
other potential contraindications to cMRI may be individually evaluated per site 
standard operating procedures for MRI performance. 
14. In the opinion of the Principal Investigator, the subject and/or legal guardian is able to 
communicate effectively with study personnel, and is considered reliable, willing and 
likely to be cooperative with protocol requirements, including attending all study 
visits. 
4.2 
EXCLUSION CRITERIA 
A subject is not eligible for inclusion in this study if any of the following criteria apply: 
1. The subject has a diagnosis of large unrestrictive ventricular septal defect or patent 
ductus arteriosus, Eisenmenger syndrome, congenital diaphragmatic hernia, or a 
chronic lung disease, such as bronchopulmonary dysplasia, or interstitial lung disease. 
2. The subject has a current disease severity of Panama functional class IIIb or IV. 
3. The subject has previously been exposed to oral treprostinil. 


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4. Cohort 1: the subject has had previous intolerance to treprostinil or epoprostenol due 
to systemic adverse effects that resulted in discontinuation of therapy.  This does not 
include site pain reactions or central venous catheter-related blood stream infections. 
5. Cohort 1 and 2: the subject is receiving IV/SC Remodulin or Tyvaso (as the inhaled 
prostacyclin) for any other disease or condition other than the treatment of PAH in 
accordance with the IV/SC Remodulin or Tyvaso package inserts (i.e., eligible 
subjects must have a WHO Group I PAH classification as defined in inclusion criteria 
#4). 
6. Cohort 3: the subject has been previously exposed to a prostacyclin within 30 days of 
Screening, with the exception of vasoreactivity testing. 
7. The subject is pregnant or lactating. 
8. The subject has a current diagnosis of uncontrolled sleep apnea as defined by their 
physician. 
9. The subject has severe renal insufficiency as defined by an estimated creatinine 
clearance (CrCl) <30 mL/min (Schwartz Formula) or the requirement for dialysis at 
Screening. 
10. The subject has moderate to severe hepatic dysfunction; defined as elevated liver 
function tests (AST or ALT) greater than or equal to three times the upper limit of 
normal at Screening, or Child Pugh class B or C hepatic disease. 
11. The subject has clinically significant anemia as defined by a hemoglobin and/or 
hematocrit level <75% of the lower limit of normal ranges according to age and 
gender. 
12. The subject has Down Syndrome. 


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13. The subject has uncontrolled systemic hypertension as evidenced by a systolic or 
diastolic blood pressure greater than the 95th percentile for age, height, and gender at 
Screening or Baseline. 
14. The subject and/or legal guardian has/have an unstable psychiatric condition or is/are 
mentally incapable of understanding the objectives, nature, or consequences of the 
trial, or has any condition in which the Investigator’s opinion would constitute an 
unacceptable risk to the subject’s safety. 
15. The subject has an active infection, or has any other cardiovascular, liver, renal, 
hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous 
system disease or condition that, in the opinion of the Investigator, may adversely 
affect the safety of the subject or interfere with the interpretation of study assessments. 
16. Subject is actively listed for transplantation. 
17. The subject is receiving an investigational drug, has an investigational device in place 
or has participated in an investigational drug or device study within 30 days prior to 
Baseline.  Participation in an observational study does not disqualify a potential 
subject from study participation.   
4.3 
PRESCRIBED THERAPY 
4.3.1 
Concomitant Medications 
Cohort 1: 
Subjects must have been receiving IV/SC Remodulin for at least 90 days prior to Baseline and 
have been at the current dose without changes for at least 30 days prior to Baseline. 
Cohort 2: 
Subjects must have been receiving inhaled prostacyclin for at least 90 days with no dose 
changes for at least 30 days prior to Baseline. 


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All Cohorts: 
Subjects must be optimally treated (as determined by the Investigator) with background PAH 
therapies (e.g., PDE-5i, ERA, sGC) for at least 90 days and have been on a stable dose 
without changes (except documented weight based adjustments) for at least 30 days prior to 
Baseline.  All attempts should be made to avoid dose adjustments of current PAH background 
therapy(ies) or the addition of another PAH therapy from Baseline to Week 24. 
Subjects must be receiving stable doses of all other medications for at least 14 days prior to 
the Baseline assessments.  Dose changes of diuretics are allowed if the dose adjustments are 
within the usual dose adjustments prescribed for the subject.  Dose adjustments of 
anticoagulants are permitted at any time during the study, as needed.  Anticoagulants may be 
temporarily discontinued during the study if necessary for the safety of study related or 
medically required procedures (e.g., RHC). 
For the purposes of the 6MWT, if the subject was assessed at Baseline using oxygen therapy, 
then all 6MWTs during the 24-week study should be conducted with the same oxygen flow 
rate and mode of administration.  All concomitant medications taken during the conduct of the 
study, including those taken for AEs or other medical events, must be recorded in the 
subject’s source documents and transcribed as required to the eCRF.  Dose changes of 
concomitant medications will not be captured in the eCRF. 
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
All subjects will receive treatment with oral treprostinil.  Subjects will be enrolled into a 
cohort based on their current PAH treatment regimen. 
5.2 
RANDOMIZATION 
No randomization will occur. 
5.3 
BLINDING 
This an open-label study; all subjects will receive oral treprostinil extended release tablets. 


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5.4 
STOPPING CRITERIA 
If any of the following events occur within the four weeks following the first dose of drug oral 
treprostinil given for all cohorts, the subject should be transitioned back to IV/SC Remodulin 
(Cohort 1 subjects only) or tapered off oral treprostinil, as appropriate, and discontinued from 
the study: 
• Unplanned hospitalization as a result of worsening PAH 
• Clinically significant worsening in PAH symptoms or signs, which the Investigator 
feels requires a change of current therapy.  
If two or more of the first five subjects in any cohort meet the stopping criteria, the data will 
be reviewed by a Data Safety Monitoring Board (DSMB) prior to enrolling additional subjects 
into that cohort. 
If any of these events happen after the first four weeks of the study, it is not required that a 
subject be removed from the study.  The Investigator will determine whether it is safe for a 
subject to remain in the study. 
6 
DRUGS AND DOSING (OR TREATMENT PROCEDURES) 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE 
Oral treprostinil will be provided as 0.125 mg (blue), 0.25 mg (green), 1 mg (yellow) or 2.5 
mg (pink) extended release tablets.  Subjects/caregivers must be instructed to take the 
appropriate amount of 0.125 mg, 0.25 mg, 1 mg and/or 2.5 mg tablets based upon their 
prescribed dose. 
Oral treprostinil will be dosed TID or QID at the discretion of the Investigator, with food.  
Dosing will take place approximately every 6 to 8 hours for TID dosing or approximately 
every 4 to 6 hours for QID dosing, with adjustments permitted based on the subject’s lifestyle 
and schedule.      Study subjects should take their study drug at approximately the same time 
each day. 
Tablets must be swallowed whole and not chewed as this will result in inappropriate delivery 
of the active ingredient.  If the tablet is inadvertently damaged during administration, the 


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subject/caregiver should contact site personnel in order to be monitored for the onset of 
symptoms due to possible inappropriate drug release. 
For subjects receiving oral treprostinil TID, dosing frequency may be adjusted from TID to 
QID if clinically indicated, at the discretion of the Investigator.  For applicable subjects, it is 
recommended, but not required, to take the total daily dose during TID dosing, and divide the 
total daily dose into a QID regimen using the closest, or lower, tablet strength as seen in the 
example table below.  Dose modifications should always occur in accordance with 
Investigator judgment. 
Example Transition from TID to QID Dosing of Oral Treprostinil 
TID Dosing Regimen 
Total Daily Dose 
with TID Dosing 
QID Dosing 
Regimen 
Total Daily Dose 
with QID Dosing 
1.75 mg TID 
5.25 mg 
1.25 mg QID 
5 mg 
2.5 mg TID 
7.5 mg 
1.875 mg QID 
7.5 mg 
3.75 mg TID 
11.25 mg 
2.75 mg QID 
11 mg 
5.5 mg TID 
16.5 mg 
4.125 mg QID 
16.5 mg 
8.25 mg TID 
24.75 mg 
6.125 mg QID 
24.5 mg 
10 mg TID 
30 mg 
7.5 mg QID 
30 mg 
6.1.1 
Cohort 1: IV/SC Remodulin to Oral Treprostinil Transition 
Once all entry criteria have been met and Baseline assessments completed, subjects should 
begin transition in the hospital from IV/SC Remodulin to oral treprostinil with a goal for 
complete transition off of IV/SC Remodulin within five days of the start of the transition.  If 
possible, Day 5 (or final day of hospital stay if transition occurred in less than 4 days) of 
hospital stay should be reserved as an observational period for subjects successfully 
transitioned to oral treprostinil and no longer receiving IV/SC Remodulin.  A cross titration 
will occur so that the dose of IV/SC Remodulin is decreased as the dose of oral treprostinil is 
increased.  Once subjects have been transitioned off IV/SC Remodulin, the dose of oral 
treprostinil may continue to be titrated to the appropriate optimal dose for that subject 
throughout the rest of the study. 


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Dosing guidelines: 
• 
The following equation can be used to estimate a comparable total daily dose of oral 
treprostinil (in mg) using the subject’s dose of IV/SC Remodulin (in ng/kg/min) and 
weight (in kg): 
Oral treprostinil total daily dose (mg) = 0.0072 x Remodulin dose (ng/kg/min) x 
weight 
• 
IV/SC Remodulin should not be decreased more than 30 ng/kg/min within a 24 hour 
period 
• 
Oral treprostinil should be increased in proportion to Remodulin decreases and the 
subject’s weight 
• 
IV/SC Remodulin doses should be adjusted (i.e., decreased) at the same time oral 
treprostinil dose is increased 
Example TID Dosing Schedule for a 35 kg Subject: 
Hospital Day 
IV/SC Remodulin 
(ng/kg/min) 
Oral Treprostinil 
(mg) 
Day 1 (0-24 hours) 
Morning (upon admission) 
65 
0 
Midday 
59 
0.5 
Evening 
53 
1 
Day 2 (24-48 hours) 
Morning 
47 
1.5 
Midday 
41 
2 
Evening 
35 
2.5 
Day 3 (48-72 hours) 
Morning 
29 
3 
Midday 
23 
3.5 
Evening 
17 
4. 
Day 4 (72-96 hours) 
Morning 
11 
4.5 
Midday 
5 
5 
Evening 
0 
5.5 (target dose) 
Day 5 (96-120 hours):  Observational period prior to hospital discharge 
Morning  
0 
continue to titrate if appropriate 
Midday 
0 
continue to titrate if appropriate 
Evening 
0 
continue to titrate if appropriate 
 


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Example QID Dosing Schedule for a 35 kg Subject: 
Hospital Day 
IV/SC Remodulin 
(ng/kg/min) 
Oral Treprostinil 
(mg) 
Day 1 (0-24 hours) 
Morning (upon admission) 
65 
0 
Midday 
61 
0.25 
Early Evening (PM #1) 
57 
0.5 
Late Evening (PM #2) 
53 
0.75 
Day 2 (24-48 hours) 
Morning 
48 
1.125 
Midday 
44 
1.375 
Early Evening (PM#1) 
40 
1.625 
Late Evening (PM #2) 
36 
1.875 
Day 3 (48-72 hours) 
Morning 
30 
2.25 
Midday 
26 
2.5 
Early Evening (PM #1) 
22 
2.75 
Late Evening (PM #2) 
18 
3 
Day 4 (72-96 hours) 
Morning 
12 
3.375 
Midday 
8 
3.625 
Early Evening (PM #1) 
4 
3.875 
Late Evening (PM #2) 
0 
4.125 (target dose) 
Day 5 (96-120 hours):  Observational period prior to hospital discharge 
Morning  
0 
continue to titrate if appropriate 
Midday 
0 
continue to titrate if appropriate 
Early Evening (PM #1) 
0 
continue to titrate if appropriate 
Late Evening (PM #2) 
0 
continue to titrate if appropriate 
 
If necessary for subject safety, the transition from IV/SC Remodulin may extend beyond five 
days.  Extended transitions must occur in hospital or subject must be willing and able to return 
to clinic as needed until the transition is complete.  The transition must be completed by Week 
4, or the subject will be withdrawn from the study.  Once a subject has completely 
transitioned off IV/SC Remodulin, dose escalations of oral treprostinil should occur in either 
0.125 mg or 0.25 mg increments every 24 hours, as tolerated.  Sudden dose escalation or 


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reductions should be avoided as they may lead to intolerable adverse effects or worsening of 
PAH.  Gradual dose titrations are recommended to reduce the risk to subjects. 
Routine contact between site personnel and the subject/caregiver should be conducted to 
monitor AEs and make decisions about dose titration between scheduled study visits.  Dose 
changes may be made at any time up until five days prior to the Week 24 visit.  Week 24 visit 
assessments can be performed over five days (120 hours) if needed; however, no oral 
treprostinil dose adjustments are allowed from five days prior to the Week 24 study visit, 
unless required to protect subject safety.  All dose changes will be documented and captured 
in the eCRF. 
6.1.2 
Cohort 2: Inhaled Prostacyclin to Oral Treprostinil Transition  
Once all entry criteria have been met and Baseline assessments completed, dosing of oral 
treprostinil will be initiated at 0.125 mg TID or QID at the discretion of the Investigator, with 
food.  Dosing will take place approximately every 6 to 8 hours for TID dosing or 
approximately every 4 to 6 hours for QID dosing, with adjustments permitted based on the 
subject’s lifestyle and schedule.  The first dose of 0.125 mg oral treprostinil should be taken at 
the study site.  A cross titration will occur so that doses of inhaled prostacyclin will be 
decreased as oral treprostinil is increased.  The transition must be completed by Week 4, or 
the subject will be withdrawn from the study. 
Oral treprostinil dose escalations may occur every 24 hours (following three or four 
consecutive doses depending on TID or QID dosing, respectively) and should occur in 
increments of 0.125 mg TID or QID, at the discretion of the Investigator, during the first four 
weeks of the study as clinically indicated.  Following four weeks of treatment, dose 
escalations may occur in either 0.125 mg or 0.25 mg increments every 24 hours, as tolerated.  
Sudden dose escalations or reductions should be avoided as they may lead to intolerable 
adverse effects or worsening of PAH.  Gradual dose titrations are recommended to reduce the 
risk to subjects. 
Routine contact between site personnel and the subject/caregiver should be conducted to 
monitor AEs and make decisions about dose titration between scheduled study visits.  Dose 


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changes may be made at any time up until five days prior to the Week 24 visit.  Week 24 visit 
assessments can be performed over five days (120 hours) if needed; however, no oral 
treprostinil dose adjustments are allowed from five days prior to the Week 24 study visit, 
unless required to protect subject safety.  All dose changes will be documented and captured 
in the eCRF. 
6.1.3 
Cohort 3:  Addition of Oral Treprostinil to Background PAH Therapy (De Novo 
Prostacyclin Subjects)  
Once all entry criteria have been met and Baseline assessments completed, dosing of oral 
treprostinil will be initiated at 0.125 mg TID or QID at the discretion of the Investigator, with 
food.  Dosing will take place approximately every 6 to 8 hours for TID dosing or 
approximately every 4 to 6 hours for QID dosing, with adjustments permitted based on the 
subject’s lifestyle and schedule.   The first dose of 0.125 mg oral treprostinil should be taken 
at the study site. 
Dose escalations may occur every 24 hours (following three or four consecutive doses 
depending on TID or QID dosing, respectively) and should occur in increments of 0.125 mg 
TID or QID at the discretion of the Investigator during the first four weeks of the study as 
clinically indicated.  Following four weeks of treatment, dose escalations may occur in either 
0.125 mg or 0.25 mg increments every 24 hours, as tolerated.  Sudden dose escalation or 
reductions should be avoided as they may lead to intolerable adverse effects or worsening of 
PAH.  Gradual dose titrations are recommended to reduce the risk to subjects. 
Routine contact between site personnel and the subject/caregiver will be conducted to monitor 
AEs and make decisions about dose titration between scheduled study visits.  Dose changes 
may be made at any time up until five days prior to the Week 24 visit.  Week 24 visit 
assessments can be performed over five days (120 hours) if needed; however, no oral 
treprostinil dose adjustments are allowed from five days prior to the Week 24 study visit, 
unless required to protect subject safety.  All dose changes will be documented and captured 
in the eCRF. 


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6.1.4 
Dosing Interruptions 
Subjects must not “make-up” or double-up on missed doses.  If dosing is interrupted for 
longer than 24 hours, consideration should be given to re-titrating the subject’s dose gradually 
to the last dose that was administered prior to the dose interruption, particularly in cases 
where the last dose prior to interruption was greater than 3 mg.  The upward “re-titration” in 
such instances may, at the Investigator’s discretion, be more rapid than the subject’s initial 
dose titration. 
In the event of a planned short-term treatment interruption for subjects unable to take oral 
medications, consider a temporary infusion of SC or IV treprostinil.  To calculate the total 
daily dose (mg) of treprostinil for the parenteral route use the following equation: 
Remodulin (ng/kg/min) = (139 x oral treprostinil total daily dose (mg) / weight (kg) 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
This is an open-label study; all subjects will receive treatment with oral treprostinil extended 
release tablets. 
6.3 
COMPLIANCE 
Each subject/caregiver will be provided with a dosing diary in order to record dosing 
information throughout the study.  Compliance with oral treprostinil will be assessed at 
Week 3, 6, 12, and 24/Premature Termination visits, as applicable.  At scheduled visits, 
subjects should be instructed to bring all oral treprostinil to the investigational site. 
Upon return of oral treprostinil (study drug) at Weeks 3, 6, 12, 24/Premature Termination, as 
applicable, the study coordinator or pharmacist must document the number of returned tablets 
of each strength and determine if the appropriate amount of oral treprostinil remains based 
upon the dose of oral treprostinil prescribed.  Compliance will be determined by comparing 
the doses that the subject reports taking in their dosing diary to the amount of oral treprostinil 
returned to the site.  Open bottles of oral treprostinil returned at Weeks 3, 6, 12, and 
24/Premature Termination will not be re-dispensed to the subject.  Any unopened bottles of 
oral treprostinil may be re-dispensed to the subject and site personnel will dispense additional 


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new supply of oral treprostinil at Weeks 3, 6, and 12 for the subsequent interval.  If necessary, 
additional oral treprostinil may be dispensed in between protocol-required visits. 
Each subject/caregiver will also be asked at each visit whether he or she has been compliant 
with dosing instructions.  Continued non-compliance may lead to withdrawal of the subject 
from the study, after consultation between the Investigator and the Sponsor. 
7 
EXPERIMENTAL PROCEDURES 
7.1 
SCREENING PHASE (ALL COHORTS) 
The Screening phase can begin up to 28 days prior to the Baseline visit.  Prior to the Baseline 
visit site personnel should complete a Pre-Baseline Review Form for review by the Medical 
Monitor prior to moving forward with any Baseline visit assessments. 
The recommended sequence of assessments for the Screening visit is as follows (if not 
combined with the Baseline visit): 
• 
Informed consent/assent 
• 
Inclusion/exclusion criteria review 
• 
Demographics 
• 
PAH history 
• 
Medical history 
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at least  
30 minutes following 6MWT); including height 
• 
Urine pregnancy test (females of child bearing potential) 
• 
Physical examination 
• 
Panama and WHO functional classification 
• 
Practice 6MWT/ Borg dyspnea score (only required if subject has not previously 
performed a 6MWT at the study site; 6MWT to be conducted following at least five 
minutes of rest and Borg dyspnea score to be conducted immediately following 
6MWT) 
• 
Clinical laboratory parameters  
• 
Adverse events 
• 
Concomitant medications 


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• 
Complete Pre-Baseline Review Form and submit to Sponsor for permission to move 
forward with the Baseline visit assessments 
7.2 
BASELINE VISIT (ALL COHORTS) 
The Baseline assessments can be conducted over five days (120 hours) prior to the first dose 
of oral treprostinil.  Pharmacokinetic assessments (Cohort 1 subjects only) may be scheduled 
up to seven days prior to the first dose of oral treprostinil.  Pharmacokinetic assessments at 
Baseline will not be conducted in Cohort 2 or Cohort 3 subjects.  The recommended sequence 
of assessments for Baseline visit is as follows (if not combined with Screening visit): 
• 
PedsQL questionnaire (must be performed as first assessment prior to seeing their 
physician or healthcare provider or completing any other forms or assessments) 
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at least 
30 minutes following 6MWT) 
• 
Urine pregnancy test (females of child bearing potential) 
• 
Clinical laboratory parameters  
• 
NT-pro-BNP (prior to 6MWT or CPET and first dose of oral treprostinil) 
• 
12-lead ECG (following at least five minutes of rest in the semi-recumbent position) 
• 
PAH symptoms 
• 
Panama and WHO functional classification 
• 
Inclusion/exclusion criteria review 
• 
Cardiac MRI (must be performed prior to the 6MWT and CPET if done on the same 
day;  if subject requires anti-anxiety medication (no general anesthesia) during the 
cMRI (without contrast), then the cMRI should be performed on a separate day from 
the CPET and 6MWT 
• 
6MWT/Borg dyspnea score (must be conducted prior to the first dose of oral 
treprostinil), includes oximetry and HR recovery monitoring (to be conducted 
following at least five minutes of rest); Borg dyspnea score to be conducted 
immediately following 6MWT) 
• 
CPET (if performed on same day as 6MWT, CPET should be conducted a minimum 
of two hours after 6MWT) 


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• 
Pharmacokinetics ([Cohort 1 subjects only] Section 3.3.3; may be conducted seven 
days prior to the first dose of oral treprostinil) 
• 
Dispense oral treprostinil, and provide subject diary/dosing instructions  
• 
First administration of oral treprostinil with food (Cohort 1 subjects will be admitted 
for an inpatient hospital stay for the transition) 
• 
Adverse events 
• 
Concomitant medications 
7.3 
COMBINED SCREENING AND BASELINE (ALL COHORTS) 
Screening and Baseline visits may be combined if all assessments are completed and entry 
criteria satisfied within five days (120 hours) prior to the first dose of oral treprostinil.  Prior 
to the first Baseline assessment, site personnel should complete a Pre-Baseline Review Form 
for review by the Medical Monitor prior to moving forward with any Baseline visit 
assessments.  The recommended sequence of assessments for a combined Screening and 
Baseline visit is as follows: 
Assessments to be completed as part of the Screening phase: 
• 
Informed consent/assent 
• 
PedsQL questionnaire (must be performed as first assessment prior to seeing their 
physician or healthcare provider or completing any other forms or assessments) 
• 
Inclusion/exclusion criteria review 
• 
Clinical laboratory parameters (enough blood should be drawn for local laboratory to 
confirm entry criteria of CrCl [Schwartz Formula], AST, ALT, and hemoglobin and/or 
hemocrit has been met, as well as for the complete panel for central laboratory 
processing) 
• 
NT-pro-BNP (prior to 6MWT or CPET and first dose of oral treprostinil; for central 
laboratory) 
• 
Urine pregnancy test (females of child bearing potential) 
• 
Physical examination 
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at least 
30 minutes following 6MWT); including height 


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• 
Demographics 
• 
PAH history 
• 
Medical history 
 
At this time, the Pre-Baseline Review Form and must be submitted to the Sponsor.  
Do not proceed with any of the following assessments until you receive the form back 
from the Sponsor with permission to move forward. 
 
Assessments to be completed as part of the Baseline phase: 
• 
PAH symptoms 
• 
Panama and WHO functional classification 
• 
Cardiac MRI (must be performed prior to the 6MWT and CPET if done on the same 
day;  if subject requires anti-anxiety medication (no general anesthesia) during the 
cMRI (without contrast), then the cMRI should be performed on a separate day from 
the CPET and 6MWT 
• 
12-lead ECG (following at least five minutes of rest in the semi-recumbent position) 
• 
6MWT/Borg dyspnea score (must be conducted prior to the first dose of oral 
treprostinil), includes oximetry and HR recovery monitoring (to be conducted 
following at least five minutes of rest); Borg dyspnea score to be conducted 
immediately following 6MWT); if subject requires a practice 6MWT, the test must be 
conducted and precede the Baseline 6MWT by at least one day. 
• 
CPET (if performed on same day as 6MWT, CPET should be conducted a minimum 
of two hours after 6MWT) 
• 
Pharmacokinetics ([Cohort 1 only] Section 3.3.3, may be conducted seven days prior 
to the first dose of oral treprostinil) 
• 
Dispense oral treprostinil, and provide subject diary/dosing instructions 
• 
First administration of oral treprostinil with food [Cohort 1 subjects will be admitted 
for an inpatient hospital stay for the transition] 
• 
Adverse events 
• 
Concomitant medications 


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7.4 
TREATMENT PHASE 
The following visits will be conducted in subjects during the 24-week study duration.  If the 
subject is in the hospital during one of the scheduled study visits, the assessments for that visit 
will be conducted as scheduled during the defined visit window. 
7.4.1 
Week 0/ Study Days 1-5 (Cohort 1 Only:  IV/SC Remodulin to Oral Treprostinil 
Transition) 
The subject will be admitted to the hospital prior to initiating the transition from IV/SC 
Remodulin to oral treprostinil.  Day 1 signifies the day of the first dose of oral treprostinil.  
For each day (Days 2-5) of the hospital stay, the following assessments will take place: 
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at 
least 30 minutes following 6MWT) 
• 
PAH symptoms 
• 
6MWT/Borg dyspnea score (should occur within 2-6 hours of the subject’s last dose 
of oral treprostinil),includes oximetry and HR recovery monitoring (to be conducted 
following at least five minutes of rest); Borg dyspnea score to be conducted 
immediately following 6MWT) 
• 
Dose adjustments of oral treprostinil and IV/SC Remodulin (TID or QID, as 
appropriate) 
• 
Adverse events (including daily administration of a detailed prostacyclin-related 
adverse events questionnaire) 
• 
Concomitant medications 
If the subject stays in the hospital longer than five days, these assessments do not need to be 
collected on the days beyond Day 5; with the exception of dose adjustments, collection of 
AEs and changes in concomitant medications which must be collected for the duration of the 
hospital stay.  Following discharge from the hospital, subjects/caregivers will be contacted 
daily (excluding weekends) via telephone or email by a member of the study team for the first 
two weeks of the study. 


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7.4.2 
Week 3 Visit (All Cohorts) 
During this visit, the recommended sequence of assessments is as follows:  
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at 
least 30 minutes following 6MWT) 
• 
Urine pregnancy test (females of childbearing potential) 
• 
PAH symptoms 
• 
Panama and WHO functional classification 
• 
6MWT/Borg dyspnea score (should occur within 2-6 hours of the subject’s last dose 
of oral treprostinil),includes oximetry and HR recovery monitoring (to be conducted 
following at least five minutes of rest); Borg dyspnea score to be conducted 
immediately following 6MWT) 
• 
Oral treprostinil (study drug) accountability, and provide subject diary/dosing 
instructions 
• 
Dose adjustments of oral treprostinil and IV/SC Remodulin/inhaled prostacyclin (if 
appropriate) 
• 
Adverse events 
• 
Concomitant medications 
After the visit, weekly contact between the site and subject/caregiver will continue until the 
Week 6 study visit.  
7.4.3 
Week 6 Visit (All Cohorts) 
During this visit, the recommended sequence of assessments is as follows:  
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at least 
30 minutes following 6MWT) 
• 
Urine pregnancy test (females of childbearing potential) 
• 
PAH symptoms 
• 
Panama and WHO functional classification 
• 
6MWT/Borg dyspnea score (should occur within 2-6 hours of the subject’s last dose 
of oral treprostinil),includes oximetry and HR recovery monitoring (to be conducted 


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following at least five minutes of rest); Borg dyspnea score to be conducted 
immediately following 6MWT) 
• 
Oral treprostinil accountability, and provide subject diary/dosing instructions 
• 
Dose adjustments of oral treprostinil 
• 
Adverse events 
• 
Concomitant medications 
After the visit, weekly contact between the site and subject/caregiver will continue until the 
Week 12 visit.  
7.4.4 
Week 12 Visit (All Cohorts) 
During this visit, the recommended sequence of assessments is as follows:  
• 
PedsQL questionnaire (must be performed as first assessment and as best as possible 
prior to seeing their physician or healthcare provider or completing any other forms or 
assessments) 
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at least 
30 minutes following 6MWT) 
• 
Urine pregnancy test (females of childbearing potential) 
• 
Clinical laboratory parameters 
• 
NT-pro-BNP (collected prior to 6MWT) 
• 
PAH symptoms 
• 
Panama and WHO functional class 
• 
6MWT/Borg dyspnea score (should occur within 2-6 hours of the subject’s last dose 
of oral treprostinil),includes oximetry and HR recovery monitoring (to be conducted 
following at least five minutes of rest); Borg dyspnea score to be conducted 
immediately following 6MWT) 
• 
Oral treprostinil accountability, and provide subject diary/dosing instructions 
• 
Dose adjustments of oral treprostinil, as needed 
• 
Adverse events  
• 
Concomitant medications 


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After the visit, contact between the site and subject/caregiver will occur at least every other 
week until the Week 24 visit.  
7.4.5 
Week 24 Visit (All Cohorts) 
The following assessments will occur during the Week 24 visit.  If needed, the visit 
assessments can be performed over five days (120 hours); however, no oral treprostinil dose 
adjustments are allowed from five days prior to the Week 24 study visit, unless required to 
protect subject safety, until all Week 24 visit assessments have been completed. 
• 
PedsQL questionnaire (must be performed as first assessment prior to seeing their 
physician or healthcare provider or completing any other forms or assessments) 
• 
Pharmacokinetics (Section 3.3.3; may be performed on separate day).  No oral 
treprostinil dose changes are allowed within five days of the Week 24 PK sampling, 
unless required to protect subject safety.  
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at least 
30 minutes following 6MWT) 
• 
Physical examination 
• 
Urine pregnancy test (females of childbearing potential) 
• 
Clinical laboratory parameters 
• 
NT-pro-BNP (prior to 6MWT or CPET) 
• 
12-lead ECG (following at least five minutes of rest in the semi-recumbent position) 
• 
PAH symptoms 
• 
Panama and WHO functional classification 
• 
Cardiac MRI (must be performed prior to the 6MWT and CPET if done on the same 
day;  if subject requires anti-anxiety medication (no general anesthesia) during the 
cMRI (without contrast), then the cMRI should be performed on a separate day from 
the CPET and 6MWT 
• 
6MWT/Borg dyspnea score (should occur within 2-6 hours of the subject’s last dose 
of oral treprostinil),includes oximetry and HR recovery monitoring (to be conducted 
following at least five minutes of rest); Borg dyspnea score to be conducted 
immediately following 6MWT) 


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• 
CPET (should be performed 2-6 hours after the morning dose of oral treprostinil 
[study drug] and prior to the next scheduled dose; if performed on same day as 
6MWT, CPET should conducted a minimum of two hours after 6MWT) 
• 
Oral treprostinil accountability 
• 
Adverse events  
• 
Concomitant medications 
• 
Investigator to assess subject’s eligibility for the Continued Access Plan 
7.4.6 
Premature Termination (All Cohorts) 
If a subject discontinues from the study prior to Week 24, the following assessments should 
occur prior to oral treprostinil discontinuation or as soon as possible after.  The recommended 
sequence of assessments is as follows:  
• 
PedsQL questionnaire (must be performed as first assessment and as best as possible 
prior to seeing their physician or healthcare provider or completing any other forms or 
assessments) 
• 
Pharmacokinetics (Section 3.3.3, if the subject is still receiving oral treprostinil at the 
time of discontinuation) 
• 
Vital signs (following at least five minutes of rest; collected prior to 6MWT or at least 
30 minutes following 6MWT) 
• 
Urine pregnancy test (females of childbearing potential) 
• 
Clinical laboratory parameters 
• 
NT-pro-BNP (prior to 6MWT or CPET) 
• 
Physical examination 
• 
12-lead ECG (following at least five minutes of rest in the semi-recumbent position) 
• 
PAH symptoms 
• 
Panama and WHO functional classification 
• 
Cardiac MRI (must be performed prior to the 6MWT and CPET if done on the same 
day;  if subject requires anti-anxiety medication (no general anesthesia) during the 
cMRI (without contrast), then the cMRI should be performed on a separate day from 
the CPET and 6MWT 


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• 
6MWT/Borg dyspnea score (should occur within 2-6 hours of the subject’s last dose 
of oral treprostinil),includes oximetry and HR recovery monitoring (to be conducted 
following at least five minutes of rest); Borg dyspnea score to be conducted 
immediately following 6MWT) 
• 
CPET (should be performed 2-6 hours after the morning dose of oral treprostinil and 
prior to the next scheduled dose; if performed on same day as 6MWT, CPET should 
conducted a minimum of two hours after 6MWT) 
• 
Oral treprostinil accountability 
• 
Adverse events 
• 
Concomitant medications 
7.4.7 
Continued Access Plan 
Subjects who have completed the Week 24 Visit will be given the option for continued access 
to oral treprostinil (Section 3.3.2.7).  During the Week 24 Visit, the Investigator should assess 
each subject’s eligibility for the Continued Access Plan. 
8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A subject may voluntarily withdraw or be withdrawn from the study and/or oral treprostinil 
(study drug) by the Investigator at any time for reasons including, but not limited to, the 
following: 
• 
Stopping criteria is met 
• 
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 oral treprostinil (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 
• 
Subject is female and became pregnant during the course of the study 


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If a subject is discontinued from the study prematurely, the Investigator must provide an 
explanation in the eCRF and complete the End of Study Record for that subject.  If oral 
treprostinil (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 
oral treprostinil prematurely due to an AE, the subject will be followed until either the 
Investigator determines that the AE has resolved, it is no longer considered clinically 
significant, the subject is lost to further follow-up, or for 30 days if the adverse event extends 
beyond the final visit. 
8.1.1 
Lost to Follow-up 
If a subject fails to return to clinic or respond after at least three documented attempts by the 
site to contact the subject by telephone or email, the Investigator should issue a written letter 
by certified mail requesting the legal guardian and/or caregiver contact the clinic.  If no 
response is received, the subject will be considered lost to follow-up.  The site will record the 
last date of contact in the eCRF as the termination date. 
8.2 
CRITERIA FOR TERMINATING THE STUDY 
The study may be stopped at any time if, in the opinion of the Investigator and/or Sponsor, 
continuation of the study represents a serious medical risk to the subjects.  This may include, 
but is not limited to, the presence of serious, life-threatening, or fatal AEs or AEs that are 
unacceptable in nature, severity, or frequency.  The Sponsor reserves the right to discontinue 
the study for any reason at any time. 
8.3 
CRITERIA FOR DISCONTINUING THE SITE 
The study may also be terminated at a given center if: 
• 
The Principal Investigator elects to discontinue the study 
• 
The Sponsor elects to discontinue the study at the site 
• 
U.S. FDA regulations are not observed 
• 
The protocol is repeatedly 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, including any abnormal 
sign (e.g., abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in the research, whether or not it is related to the 
use of the oral treprostinil (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. 
• 
A worsening of an existing symptom or condition or post-treatment events that occur 
as a result of protocol-mandated procedures (e.g., exacerbation of a pre-existing 
illness following the start of the study or an increase in frequency or intensity of a 
pre-existing episodic event or condition). 
Thus, no causal relationship with the study drug is implied by the use of the term "adverse 
event". 
An AE does not include the following: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion); however, the condition for which the surgery is required may be an 
adverse event.  Planned surgical measures permitted by the study protocol and the 
condition(s) leading to these measures are not adverse events. 
• 
Day to day fluctuations of pre-existing disease or conditions present or detected at the 
start of the study that do not worsen. 
• 
Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalizations for cosmetic elective surgery, social and/or convenience admissions). 
• 
The disease or disorder being studied or a sign or symptom associated with the 
disease or disorder unless more severe than expected for the subject’s condition. 


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9.1.2 
Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
oral treprostinil (study drug) caused the AE.  For the purposes of safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the oral 
treprostinil and the AE, as described in Section 15.4. 
9.1.3 
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 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
Results in a medically important event of reaction 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization, but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization or 
development of dependency or abuse.  Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction. 


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9.1.4 
Adverse Events Anticipated for PAH  
Events associated with disease under study: 
Expected events that are related to the disease under study are defined in Table 9-1.  These 
events are anticipated to occur in the study population at some frequency independent of drug 
exposure. 
All events that occur during the course of the study that are included on this list and/or felt to 
be related to the underlying disease under study by the Investigator should NOT be recorded 
as an AE unless the event is serious or unusual with respect to intensity, frequency, or 
duration, or there is a reasonable possibility that it may have been caused by oral treprostinil 
(study drug).  These events should be clearly documented in the subject medical record and 
identified as signs/symptoms of underlying disease under study.  All deaths and unplanned 
hospitalizations, regardless of underlying cause, will be reported as a SAE. 


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Table 9-1 
Expected Events Attributable to PAH (System Organ Class and 
PREFERRED Term, Ver. 17.1) 
Abdominal pain (Gastrointestinal disorders; 
ABDOMINAL PAIN) 
Hemoptysis (Respiratory, thoracic & 
mediastinal disorders; HAEMOPTYSIS) 
Anorexia (Metabolism and nutrition disorders; 
DECREASED APPETITE) 
Hypoxia (Respiratory, thoracic & mediastinal 
disorders; HYPOXIA) 
Ascites (Gastrointestinal disorders; ASCITES) 
Loss of consciousness (Nervous system 
disorders; LOSS OF CONSCIOUSNESS) 
Cardiac arrhythmia (Cardiac disorders; 
ARRHYTHMIA) 
Nausea (Gastrointestinal disorders; NAUSEA) 
Cardiac arrest (Cardiac disorders; CARDIAC 
ARREST) 
Edema (General disorders and administration 
site conditions; OEDEMA) 
Heart failure (including exacerbation of) 
(Cardiac disorders; CARDIAC FAILURE) 
Orthopnea (Cardiac disorders; 
ORTHOPNOEA) 
Chest pain (General disorders and 
administration site conditions; CHEST PAIN) 
Pallor (Vascular disorders; PALLOR) 
Cardiovascular collapse (Vascular disorders; 
CIRCULATORY COLLAPSE) 
Palpitations (Cardiac disorders; 
PALPITATIONS) 
Cor pulmonale (Cardiac disorders; COR 
PULMONALE) 
Cool extremities (General disorders and 
administration site conditions; PERIPHERAL 
COLDNESS) 
Cough (Respiratory, thoracic & mediastinal 
disorders; COUGH) 
Pulmonary arterial hypertension, exacerbation 
of (Vascular disorders; PULMONARY 
ARTERIAL HYPERTENSION) 
Cyanosis (Cardiac disorders; CYANOSIS) 
Sudden death (Cardiac disorders; SUDDEN 
DEATH) 
Dizziness (Cardiac disorders; DIZZINESS) 
Syncope (Nervous system disorders; 
SYNCOPE) 
Dyspnea at rest (Respiratory, thoracic & 
mediastinal disorders; DYSPNOEA) 
Vasovagal reaction (Nervous system disorders; 
PRESYNCOPE) 
Dyspnea on exertion (Respiratory, thoracic & 
mediastinal disorders; DYSPNOEA 
EXERTIONAL) 
Tachycardia (Cardiac disorders; 
TACHYCARDIA) 
Paroxysmal nocturnal dyspnea (Cardiac 
disorders; DYSPNOEA PAROXYSMAL 
NOCTURNAL) 
Vomiting (Gastrointestinal disorders; 
VOMITING) 
Exercise intolerance (General disorders and 
administration site conditions; EXERCISE 
TOLERANCE DECREASED) 
Weight loss  (Investigations; WEIGHT 
DECREASED) 
Fatigue (General disorders and administration 
site conditions; FATIGUE) 
Weight gain (Investigations; WEIGHT 
INCREASED) 
 


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9.2 
DOCUMENTATION OF ADVERSE EVENTS 
An AE or SAE occurring during the study must be documented in the subject’s source 
documents and on the appropriate eCRF page.  Information related to the AE such as onset 
and cessation date and times, intensity, seriousness, relationship to oral treprostinil (study 
drug), and outcome is also to be documented in the eCRF (see Appendix 15.4 for definitions).  
Where possible, AEs should be recorded using standard medical terminology.  The 
Investigator should attempt, if possible, to establish a diagnosis based on the presenting signs 
and symptoms.  If several signs or symptoms are clearly related to a medically-defined 
diagnosis or syndrome, the diagnosis or syndrome should be recorded on the eCRF page, not 
the individual signs and symptoms. 
9.3 
FOLLOW UP OF ADVERSE EVENTS 
All AEs should be followed until either resolution (or return to normal or baseline values), 
until they are judged by the Investigator to no longer be clinically significant, or for at least 
30 days if the AE extends beyond the final visit.  All SAEs that occur during the study will be 
followed until resolution, death, or the subject is lost to follow-up even if they are ongoing 
more than 30 days after completion of the final visit.  Supplemental measurements and/or 
evaluations may be necessary to investigate fully the nature and/or causality of an AE or SAE.  
This may include additional laboratory tests, diagnostic procedures, or consultation with other 
healthcare professionals.  The eCRF pages should be updated with any new or additional 
information as appropriate. 
If, at any time, the subject withdraws from the study and/or changes from study drug to 
commercially available Orenitram, any AEs/SAEs that occur on Orenitram (including 
product use errors, product quality problems, and therapeutic failures) will be reported 
following local post-marketing reporting requirements or Continued Access Plan local 
reporting requirements (Section 3.3.2.7).  These events will not be included in the protocol 
analysis. 
Pulmonary arterial hypertension symptoms (Section 3.3.1.4) and PAH disease related events 
(Section 9.1.4) should only be recorded as an AE if the event is serious, new, or unusual with 


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respect to intensity, frequency, or duration as compared to symptoms in the subject’s medical 
history; or there is a reasonable possibility that the event was caused by the study drug. 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
All SAEs, regardless of expectedness or causality, must be reported to the sponsor 
within 24 hours of awareness by fax or email (+ 1 919-313-1297; 
drugsafety@unither.com).  A completed SAE Notification Report form along with any 
relevant hospital records and autopsy reports should be provided to Global Drug Safety at 
United Therapeutics Corporation.  A follow-up SAE Notification Report form must be 
forwarded to the Global Drug Safety Department at United Therapeutics Corporation within 
48 hours of the receipt of any new or updated information.  The Investigator must also 
promptly notify their IRB of the SAE, including any follow-up information, in accordance 
with applicable national regulations and guidelines set forth by the IRB. 
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 
Notification Form and submitting via fax or e-mail to Global Drug Safety at United 
Therapeutics Corporation (+ 1 919-313-1297 or drugsafety@unither.com).  The United 
Therapeutics Global Drug Safety Department will follow-up with the Investigator to ensure 
appropriate data are provided regarding the outcome of the pregnancy, and to ask the 
Investigator to update the Pregnancy Notification Form.  Pregnancy only becomes an 
AE/SAE if there is an abnormal outcome, a spontaneous abortion, an elective termination for 
medical reasons, or a congenital anomaly in the offspring.  
9.6 
SAFETY REPORTS 
In accordance with national regulations, the Sponsor will notify the appropriate regulatory 
authority(ies), and all participating Investigators of any AE that is considered to be possibly 
attributable to oral treprostinil (study drug) and is both serious and unexpected.  The 
Investigator must report these AEs to IRBs in accordance with applicable national regulations 
and guidelines set forth by the IRB. 


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10 
STATISTICAL CONSIDERATIONS 
10.1 
DATA PROCESSING 
The results of all assessments will be transcribed into an eCRF for each subject who signs an 
ICF until study completion, or study discontinuation for any reason.  A representative from 
the Sponsor will verify eCRF data fields against source documentation.  All data transmitted 
from the site will be reviewed and entered into a quality assured computerized database.  Data 
clarifications will be generated and the database will be edited as appropriate.  The eCRF 
screens are to be reviewed by the Principal Investigator for completeness and accuracy.  The 
Principal Investigator must electronically sign each subject’s eCRF to signify their approval 
of the data.  The Principal Investigator will be required to re-sign an eCRF, if changes are 
made to a subject’s eCRF by the site after the Investigator has applied his/her signature.  The 
database will be final when all outstanding queries have been resolved and all data 
management quality assurance procedures are complete. 
10.2 
SAMPLE SIZE 
This study is intended to provide descriptive data only.  A sample size of 40 subjects 
(25 transition [IV/SC Remodulin and inhaled] subjects and 15 de novo subjects) was selected 
for feasibility and to provide a reasonably large experience base with which to draw 
conclusions about the safety of the proposed protocol for (1) transition from moderate to high 
doses of IV/SC Remodulin to oral treprostinil, (2) transition from inhaled prostacyclin to oral 
treprostinil, and (3) initiation of oral treprostinil as add-on therapy in de novo prostacyclin 
subjects.  No formal sample size computation was performed with respect to the primary 
objective of evaluating safety and tolerability as only descriptive reporting of safety data is 
planned.  The planned sample size of 10-15 subjects within a cohort is appropriate for further 
characterization of the safety, PK and clinical benefit of oral treprostinil in this symptomatic 
pediatric subject population with PAH. 
10.3 
ANALYSIS PLAN 
No formal hypotheses will be tested.  Descriptive statistics will be used to summarize the 
endpoints and baseline characteristics.  For all summaries, all available data will be presented 


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with no imputation for any missing data.  Subjects will contribute the data available up to the 
point of study completion, or study discontinuation for any reason.  Subjects who receive at 
least one dose of oral treprostinil will be included in the safety analysis population. 
10.3.1 
Primary Endpoint(s) 
The safety and tolerability of transitioning subjects from IV/SC Remodulin to oral treprostinil 
(Cohort 1) or from inhaled prostacyclin (Cohort 2) will be based on the percentage of subjects 
successfully transitioning to oral treprostinil.  A successful transition is defined as a subject 
from Cohort 1 or 2 who is receiving oral treprostinil and no longer receiving IV/SC 
Remodulin or inhaled prostacyclin, respectively at Week 4 and clinically maintained on oral 
treprostinil treatment through Week 24.  A successful initiation of oral treprostinil (Cohort 3) 
will be defined as a subject who has been clinically maintained on oral treprostinil through 
Week 24. 
10.3.2 
Secondary Endpoint(s) 
Analysis of secondary endpoints (6MWD, Borg dyspnea score, functional class, symptoms of 
PAH, CPET, PedsQL and cMRI parameters) will be descriptive in nature.  The PedsQL 
questionnaire scores will be computed in accordance with the established scoring instructions. 
Numeric endpoints for post-Baseline assessments will be compared to Baseline using the 
appropriate statistical test, and p-values will be calculated for descriptive purposes; no formal 
hypothesis testing is planned. 
Plasma samples will be analyzed for treprostinil using a validated bioanalytical plasma assay.  
Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic 
parameters, such as peak observed plasma concentration (Cmax), time to peak plasma 
concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), will be 
determined as able and summarized using descriptive statistics.  
10.3.3 
Safety Analyses 
All subjects who receive oral treprostinil (study drug) will be included in the safety 
population.  Statistical summaries of safety data will be descriptive and exploratory in nature, 


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focusing on the incidence of adverse experiences.  The safety data collected in this study will 
be presented in listings and summary tables. 
Treatment-emergent changes in vital signs, ECG recordings, incidence of treatment-emergent 
AEs, and treatment-emergent changes in clinical laboratory parameters (i.e., hematology, 
clinical chemistry, and urinalysis) and physical examination will be evaluated.   
All AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary.  The incidence of AEs within each cohort will be presented in 
summary tables overall and by system organ class and preferred term. 
Vital sign and clinical laboratory data collected prior to dosing will serve as Baseline values 
for evaluation of data collected during the treatment period.  Summary statistics will be 
calculated for measured values at each time point assessed, as well as change from baseline 
values within each cohort. 
No inferential statistical analyses are planned for safety data. 
10.4 
INTERIM ANALYSIS 
A DSMB will be established for the study, composed of approximately two to three 
independent members including physicians knowledgeable in the treatment of PAH and 
pediatric PAH.  Once five subjects have enrolled in Cohort 1 and transitioned from IV/SC 
Remodulin, the safety data will be reviewed by the DSMB.  The IV/SC Remodulin dose will 
be between 25-75 ng/kg/min, inclusive, for the first five subjects enrolled in Cohort 1.  
Following the DSMB safety review, the dose range may be expanded to 25-125 ng/kg/min, 
inclusive, for the remaining subjects. 
Additionally, if two or more of the first five subjects within any cohort meet the pre-specified 
stopping criteria, the data from that cohort will be reviewed prior to enrolling additional 
subjects into that cohort. 
Analysis of pharmacokinetic samples may be performed, as warranted, to guide dosing. 


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10.5 
OTHER ANALYSES 
Additional exploratory analyses may be conducted based on available study data. 
10.6 
DATA LISTINGS AND SUMMARIES 
The Safety population will be used for all data listings, summaries and figures.  All available 
data will be presented with no imputation for any missing data.  Subjects will contribute the 
data available up to the point of study completion, or study discontinuation for any reason. 
In general, listings will be sorted by subject, descriptive summaries will include number of 
observations (n), mean, standard deviation (SD), median, minimum, maximum for continuous 
variables and n and percent for categorical variables.  For all continuous variable summaries, 
n, arithmetic mean, median, minimum, maximum, SD, % coefficient of variation (CV), and 
95% confidence interval (CI) for the arithmetic mean will be provided.  
Plasma concentration data and derived pharmacokinetic parameters will be summarized and 
displayed in both tabular and graphical form.  Noncompartmental analysis of concentration 
time data will be performed using WinNonlin.  Comparative plots of individual concentration 
data will be produced separately for each cohort as well as summaries across subjects. 
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG  
United Therapeutics will supply oral treprostinil extended release tablets for administration in 
the study.  The tablets may be provided as 0.125, 0.25, 1, or 2.5 mg strengths.  Tablets contain 
0.125 mg treprostinil (equivalent to 0.15875 treprostinil diolamine), 0.25 mg treprostinil 
(equivalent to 0.3175 mg treprostinil diolamine), 1 mg of treprostinil (equivalent to 1.27 mg 
treprostinil diolamine) or 2.5 mg of treprostinil (equivalent to 3.175 mg treprostinil 
diolamine).  Oral treprostinil will be provided in child resistant bottles each containing 
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11.2 
LABELING  
Each bottle will be labeled in accordance with all applicable national regulations, to include at 
least the following information: oral treprostinil (study drug), strength, quantity, manufacture 
date, lot number, expiratory date, Sponsor name and address, protocol number, cautionary 
statements, and storage conditions. 
11.3 
STORAGE AND HANDLING OF CTM 
Bottles of oral treprostinil should not be stored above 25˚C (77˚F) with excursions permitted 
up to 30˚C (86˚F).  In addition, bottles should be stored in a secure, controlled location with 
appropriate temperature monitoring.  Oral treprostinil should not be frozen or exposed to heat. 
11.4 
SUPPLY AND RETURN OF CTM 
Study sites will be supplied with a sufficient quantity of oral treprostinil (study drug) to begin 
enrollment in the study.  Appropriate arrangements will be made for resupply with respect to 
each subject’s visit schedule.  Additional oral treprostinil supply may occur between protocol-
required visits as required. 
Subjects/caregivers should be instructed to return all oral treprostinil, including empty bottles, 
to the appropriate study personnel on an ongoing basis at each study visit. 
Unused oral treprostinil including both used and unused bottles should be retained by the 
study site and returned to a Sponsor designated location for destruction, or destroyed and 
documented according to institutional policy following consultation with the Sponsor after 
final drug accountability by Sponsor personnel. 
11.5 
DRUG ACCOUNTABILITY 
The Investigator is responsible for oral treprostinil (study drug) accountability and 
reconciliation.  The Investigator or his/her designee will be responsible for maintaining 
accurate records of the quantity and dates of all investigational product supplies received, and 
the amount administered to each subject.  The quantity of any investigational product lost, 
missing, destroyed, etc. must also be accounted for and documented.  At each subject visit, 


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site personnel should assess amount of drug dispensed, drug returned, and dosing information 
to confirm drug accountability and compliance. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
U.S. FDA OR APPLICABLE 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 
institutional research boards (IRBs) that require it.  Any additional national reporting 
requirements as specified by the applicable regulations, regulatory authorities, or IRB will 
also be fulfilled during the conduct of the study. 
12.2 
INFORMED CONSENT AND ASSENT REQUIREMENTS 
This study involves research in underage subjects.  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 and a legally authorized 
representative must sign and date an IRB-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 legally authorized representative and the original will be retained in the study site’s 
records.  Assent to participate in the study will be obtained and documented in underage 
subjects, in accordance with the IRB policy for obtaining assent.  
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
Prior to study initiation at each site, the Investigator will obtain approval for the study from an 
appropriate IRB and provide the Sponsor with a copy of the approval letter.  The IRB 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 prior to the start of 
the study. 


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If, during the study, it is necessary to amend either the protocol or the informed consent form, 
the Investigator is responsible for obtaining IRB approval of these amended documents prior 
to implementation.  Copies of the IRB 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 that require it. 
A written summary of the study will be provided by the Investigator to the IRB following 
study completion or termination according to the IRB standard procedures.  Additional 
updates will also be provided in accordance with the IRB’s standard procedures. 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical trial, the following documents will be provided to 
the site:  Investigators’ Brochure for oral treprostinil, protocol, model informed consent form, 
budget and clinical trial agreement template. 
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, 
financial disclosure form, IRB composition and roster, IRB protocol and informed consent 
approval letters, curriculum vitae of study staff listed on the Form FDA 1572 and an executed 
clinical trial agreement. 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  United Therapeutics 
Corporation and the agents of the Sponsor, the FDA or other regulatory bodies, and the IRB 
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 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. 


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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 prior to implementation. 
A report documenting study termination must also be submitted to and acknowledged by the 
appropriate IRB 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 two 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 two years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  The Investigator must 
notify United Therapeutics Corporation before any disposal or change in location of study 
records. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
In accordance with federal/national regulations, ICH, and GCP guidelines, monitors for 
United Therapeutics Corporation or its designee will periodically contact the 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 


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verification, verify drug accountability periodically, and identify any issues requiring 
resolution. 
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and his/her staff to the monitor to discuss any findings or any relevant 
issues. 


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14 
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Expert Review of Respiratory Med 2009; 3: 265-282. 
van Loon RL, et al. Outcome of pediatric patients with pulmonary arterial hypertension in the 
era of new medical therapies. Am J Cardiol 2010; 106:117–24. 
van Loon RL, et al. Pediatric Pulmonary Hypertension in the Netherlands Epidemiology and 
Characterization During the Period 1991 to 2005.  Circulation 2011; 124: 1755-1764. 
White RJ, et al. Safety And Tolerability Of Transitioning From Parenteral Treprostinil To 
Oral Treprostinil In Patients With Pulmonary Arterial Hypertension.  Am J Respir Crit Care 
Med 2014; 189: A2460. 
Yung D, et al. Outcomes in children with idiopathic pulmonary arterial hypertension. 
Circulation 2004; 110:660-665. 


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15 
APPENDICES 
15.1 
PROCEDURE FOR SIX-MINUTE WALK EXERCISE TEST AND DYSPNEA 
SCALE 
General Procedures 
The 6MWT should be administered by the same tester at each study site throughout the study.  
The administration of the test and specifications of the testing area should be generally 
consistent with the American Thoracic Society guidelines1 and the usual practice of the 
investigative site.   
The area used for the 6MWT should be pre-measured at approximately 30 meters in length 
and at least 2-3 meters in width.  There should be no turns or significant curves to the 6MWT 
area.  The length should be marked with gradations to ensure the accurate measurement of the 
distance walked.  The area should be well-ventilated.  The tester may be at the starting end of 
the corridor or at the midpoint of the corridor with a stop-watch.  Intermittent rest periods are 
allowed if the patient can no longer continue.  If the subject needs to rest briefly, he/she may 
stand or sit and then begin again when he/she is sufficiently rested but the clock will continue 
to run.  At the end of 6 minutes, the tester will call “stop” while simultaneously stopping the 
watch and then measure the distance walked. 
Oxygen saturation and HR will be measured at rest prior to the 6MWT and monitored 
continuously during the walk.  Oxygen saturation may be measured by fingertip or forehead 
monitor.  Recovery monitoring (HR and oxygen saturation) will be performed and 
documented at minute 0 (immediately upon stopping the 6MWT), minute 1, minute 2 and 
minute 3 post-walk.  Recovery monitoring must continue until the HR is within 10 beats of 
resting values and the oxygen saturation is within 2% of resting values or until at least 
20 minutes of recovery monitoring has been performed and the Investigator considers the 
                                                   
1 ATS Statement: Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care Med 2002; 166: 111–117. 


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subject to be clinically stable.  The Borg score will be assessed before and after the walk.  The 
recovery monitoring may be terminated early with approval from the Investigator only. 
Instructions to the Subject  
Subjects will be instructed that the preceding meal should be light.  Subjects should be told to 
wear comfortable clothing and sneakers or comfortable walking shoes.  The person 
administering the test will use the following exact dialogue with the subject: 
“The purpose of this test is to find out how far you can walk in 6 minutes.  You will 
start from this point and follow the hallway to the marker (e.g., chair) at the end, turn 
around and walk back.  When you arrive back at the starting point you will go back 
and forth again.  You will go back and forth as many times as you can in the 6-minute 
period.  You may stop and rest if you need to. Just remain where you are until you can 
go on again. However, the most important thing about the test is that you cover as 
much ground as you possibly can during the six minutes. I will tell you the time, and I 
will let you know when the 6 minutes are up.  When I say STOP, please stand right 
where you are.” 
After these instructions are given to the subject, the person administering the test will then 
ask: 
“Do you have any questions about the test?” 
The person administering the test will then start the test by saying the following to the subject: 
“Are you ready?” 
“Start when I say “GO.” 
The person administering the test will tell the subject the time at 2 and 4 minutes by saying: 
“You have completed 2 minutes.” 
And then by saying: 
“You have completed 4 minutes.” 


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No other instruction or encouragement will be given during the test.  Eye contact with the 
subject should be avoided during the test. 
Dyspnea Score 
Before and immediately after the walk, the person administering the test will obtain a rating 
of dyspnea using the dyspnea scale.  The person will use the following dialogue: 
“I would like to use the following scale to describe how out of breath you are (indicate 
the scale).  This scale uses 0 for no shortness of breath at all and 10 is the worst shortness 
of breath you have ever had.  Please point to a number that tells me how short of breath 
you feel right now.” 
15.2 
FUNCTIONAL CLASSIFICATION  
PANAMA FUNCTIONAL CLASSIFICATION FOR CHILDREN AGED 5- 16 YEARS 
 
WHO FUNCTIONAL CLASSIFICATION FOR PH 
Class I:  Patients with pulmonary hypertension but without resulting limitation of physical 
activity.  Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or 
near syncope. 
Class II:  Patients with pulmonary hypertension resulting in slight limitation of physical 
activity. These subjects are comfortable at rest, but ordinary physical activity causes undue 
dyspnea or fatigue, chest pain or near syncope. 


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Class III:  Patients with pulmonary hypertension resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Ordinary activity causes undue dyspnea or fatigue, 
chest pain, or near syncope. 
Class IV:  Patients with pulmonary hypertension with inability to carry out any physical 
activity without symptoms.  These subjects manifest signs of right heart failure.  Dyspnea 
and/or fatigue may be present even at rest.  Discomfort is increased by any physical activity. 


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15.3 
PEDIATRIC QUALITY OF LIFE INVENTORY (PEDSQL)   
Varni JW, et al. The PedsQLTM: Measurement Model for the Pediatric Quality of Life Inventory. Medical Care, 1999; 37:126-139.   
Varni JW, et al. The PedsQLTM 4.0: Reliability and validity of the Pediatric Quality of Life InventoryTM Version 4.0 Generic Core 
Scales in healthy and patient populations.  Medical Care, 2001; 39: 800-812.   
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15.4 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Principal Investigator or a designated member of his/her staff will probe each subject for 
any AEs that may have occurred.  The Investigator should always ask the same question when 
conducting the verbal probe in order to ensure uniformity between subjects.  The Investigator 
should ask: 
 
“How are you doing (feeling)?” 
Based on the subject’s response to this question, the Investigator should ask additional 
questions relevant to the specific complaint such as: 
 
“How severe is/was the symptom?” 
 
“How often did the symptom occur?” 
 
“How long did the symptom last?” 
It is the Investigator’s responsibility to review the results of all diagnostic and laboratory tests 
as they become available and ascertain if there is a clinically significant change from baseline.  
If the results are determined to be a clinically significant change from baseline, this should be 
reported as an AE.  The Investigator may repeat the diagnostic procedure or laboratory test or 
request additional tests to verify the results of the original tests.  When possible, a diagnosis 
associated with the abnormality should be used as the reported AE. 
Using provided definitions, the Investigator will then: 
(1) 
rate the intensity and seriousness of the AE,  
(2) 
estimate the causality of the AE to oral treprostinil (study drug), and  
(3) 
note actions taken to counteract the AE. 


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Definitions of Intensity, Seriousness, Causality, Action Taken, and Outcome 
INTENSITY 
An assessment of the relative intensity (severity) of an AE is based on the Investigator’s 
clinical judgment.  The maximum intensity encountered during the evaluation period should 
be checked. The assessment of intensity should be independent of the assessment of the 
seriousness of the AE.  
SERIOUSNESS 
A serious AE is one that represents an actual or potential significant hazard.  This includes, 
but is not limited to, an event that is fatal, life-threatening, permanently or severely disabling, 
requires or prolongs inpatient  hospitalization, is a congenital abnormality (offspring of 
subject) or is medically significant (important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious AE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition). 
Hospitalizations that would not be considered SAEs include those for: 
• Routine treatment or monitoring of the study indication not associated with any 
deterioration in condition (e.g., hospitalization for a routine RHC). 
• Treatment which was elective or pre-planned, for a pre-existing condition not 
associated with any deterioration in condition (e.g., pre-planned operation which does 
not lead to further complications etc.). 
• Treatment of an emergency, in an outpatient setting for an event not fulfilling any of 
the definitions of serious as given above and not resulting in hospital admission. 
CAUSALITY 
An estimate of causality between a specified AE and the study drug is made by the 
Investigator.  Several factors should be considered when determining causality.  These factors 
include temporal relationship and response to withdrawal or reintroduction of the study drug.   


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Definitions of the causality categories are as follows: 
• 
NOT RELATED - there is not a temporal relationship to study drug administration 
(too early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, or concurrent disease and the SAE,  or any of the following: 
• An event that precedes the first administration of the study drug 
• An event for which the cause is clearly related to an external event; 
• Temporal relationship to study drug is atypical 
• Is readily explained by an intercurrent illness AND has an expected level of 
severity, duration, and resolution 
• An alternative explanation (concomitant drug, intercurrent illness) is likely. 
• 
POSSIBLE - there is a reasonable causal relationship between the study drug and the 
SAE.  Dechallenge information is lacking or unclear- study drug administration was 
not modified in response to the SAE, or any of the following: 
• Has a reasonable temporal relationship to study drug 
• The event has a plausible biological link to the activity of the study drug 
• Is unlikely to be related to an intercurrent illness or has an unexpected degree of 
severity, duration or complication 
• Unlikely due to an alternative illness or external event (e.g. surgical procedure, 
accident) 
• 
PROBABLE - there is a reasonable causal relationship between the study drug and the 
SAE.  The event responds to dechallenge- the event resolves or improves with 
modification of study drug administration.  Rechallenge (the original study drug dose 
was not restarted) is not required or any of the following: 
• Has a reasonable temporal relationship to study drug 
• The event has a plausible biological link to the activity of the study drug 
• Not readily explained by an intercurrent illness 
• Not readily explained by external event 
• Improves on discontinuation of study drug  
• If study drug had been discontinued, may recur on reintroduction of study drug 


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ACTION TAKEN 
STUDY DRUG DOSE MODIFICATION* 
• Dose Not Changed - the dose or regimen of the study drug was not changed. 
• Drug Interrupted - administration of the study drug was stopped temporarily. 
• Drug Withdrawn - administration of the study drug was stopped permanently and 
not restarted. 
• Unknown - changes to the administration of the study drug cannot be determined. 
• Not Applicable  
*NOTE:  Only the last study drug action should be recorded in the eCRF.  For example, if the 
study drug is withdrawn and then the decision is made to restart, the dose modification of 
“Drug interrupted” should be reported on the SAE form. 
OUTCOME 
• Fatal - The study subject died. 
• Not Recovered / Not Resolved - The AE was ongoing at the time of death or at the 
time the subject was lost to follow up. 
• Recovered / Resolved - The AE resolved. 
• Recovered / Resolved with Sequelae - The AE is considered resolved however 
there is a residual sequelae.  Some events do not return to baseline, such as 
metastasis or progression of disease; however, once these events are determined by 
the Investigator to be stable or chronic, the Investigator may consider the event to 
be resolved or resolved with sequelae. 
• Recovering / Resolving - The AE is improving but is not yet completely 
recovered/resolved. 
• Unknown - The outcome of the AE cannot be determined. 


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15.5 
PHARMACOKINETIC SAMPLE PROCESSING  
Collection, Processing and Shipment of Plasma Specimens 
Cohort 1: A total of 8 approximately 3 mL blood specimens (approximately 24 mL) for PK 
analysis will be collected from each subject during the study.  Pharmacokinetic samples will 
be collected at Baseline and Week 24. 
Cohorts 2 and 3: A total of 5 approximately 3 mL blood specimens (approximately 15 mL) 
for PK analysis will be collected from each subject during the study.  Pharmacokinetic 
samples will be collected at Week 24 only. 
Pharmacokinetic Specimen Collection 
Collection may occur by venipuncture or cannula with a saline lock; the use of heparin is not 
permitted. 
Cohort 1:  The Baseline PK sampling will begin with a time 0 sample and the following 
subsequent time points:  4 and 8 hours after time 0.  At Baseline, time 0 should be at the same 
time of the day that it is estimated the Week 24 oral treprostinil (study drug) dose will occur. 
All Cohorts:  No oral treprostinil dose changes are allowed within five days of the Week 24 
PK sampling, unless required to protect subject safety.  All subjects on a TID dosing regimen 
will undergo the Week 24 PK assessment based on the first daily dose (morning dose) of oral 
treprostinil.  If a subject is on a QID dosing regimen, the Investigator may conduct the PK 
assessment based on the first daily dose (morning dose) or the second daily dose (midday 
dose) at their discretion.  The PK assessment dose of study drug at Week 24 should occur 
approximately 8 hours after the prior evening’s last dose of oral treprostinil for subjects using 
the morning dose for the PK assessment.  When using the midday dose for the PK assessment, 
the midday dose of study drug should occur 4 to 6 hours after that day’s morning dose.  The 
Week 24 PK sampling will begin with a pre-dose sample (immediately prior [i.e., 10 minutes 
±5 minutes] to the administration of the PK assessment oral treprostinil [study drug] dose), 
and the following subsequent time points:  2, 4, 6, and 8 hours after the PK assessment dose 


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of study drug (all time points will be based off of the time the PK assessment dose of study 
drug is administered).   
If the subject is on a TID regimen, no other doses of oral treprostinil should be taken during 
the PK sampling period; subjects should take their next dose of oral treprostinil (midday dose) 
after the final 8-hour PK sample is collected. 
If the subject is on a QID regimen, the subject will take their next daily dose (midday dose or 
early evening [PM #1] based on timing of PK assessment dose) between the 4 and 6 hour time 
points of the PK sampling (±10 minutes) with food, based on the subjects typical dosing 
schedule.   
Samples should be drawn within a ±10 minute window from their scheduled time point.  
Record the time and reason for late blood draws in the eCRF.  Hemolyzed blood samples may 
be redrawn.  Indicate hemolyzed sample in the eCRF. 
Specimen Processing 
• 
Collect approximately a 3 mL blood specimen in an evacuated glass tube containing  
K3-EDTA as an anticoagulant and immediately place the specimen on ice. 
• 
Within 1 hour of collection, centrifuge the specimen at 4 ºC for 10-15 minutes at 
3000 g. 
• 
Label the shipping tube with the subject number, treatment, and specimen collection 
time and date. 
• 
Pipette approximately 1 mL plasma into a shipping tube.  Pipette the remainder of the 
plasma into a second, identically labeled tube for use as a backup specimen. 
• 
Freeze samples immediately at -20 to -25ºC.  The 1 mL sample will be transported on 
dry ice to the Sponsor-designated laboratory for analysis.  The remainder sample will 
be retained at the site and transported later in the event of an emergency or if deemed 
necessary by the Sponsor. 


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Shipping Procedures 
• All shipments must be accompanied by a packing list.  Please note on the packing list 
any specimens that are hemolyzed. 
• Package the shipping tubes to prevent breakage and contamination in Styrofoam boxes 
containing a generous supply of dry ice that will allow for 3 days in transit. 
• Prior to the shipment of specimens, contact the Sponsor and the bioanalytical 
laboratory by phone and fax or email.  An advanced electronic copy of the packing list 
should also be provided to the laboratory. 
• Samples should be shipped overnight to the bioanalytical laboratory, on dry ice, on a 
Monday, Tuesday, or Wednesday. 

SAP_000.pdf: 
United Therapeutics Corp. 
TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
 
Page 1 
Document Type: 
Statistical Analysis Plan 
Protocol / Study No.: 
TDE-PH-206 
Final Date: 
 
15 Aug 2017 
Total Number of 
Pages including 
Appendices: 
 
 
31 
Classification: 
Confidential 
 
 
Title: 
A Multicenter, Open-Label, 24-Week, Uncontrolled Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Oral Treprostinil Extended 
Release Tablets Following Transition from Remodulin or Inhaled 
Prostacyclin Therapy or as Add-on to Current PAH Therapy in De Novo 
Prostacyclin Pediatric Subjects Aged 7 to 17 Years 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 


United Therapeutics Corp. 
TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
Final: 15 Aug 2017 
Confidential 
Page 2 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................ 2 
ABBREVIATIONS AND DEFINITIONS ............................................................................ 4 
1 PREFACE .......................................................................................................................... 5 
2 STUDY OBJECTIVES AND ENDPOINTS ................................................................... 5 
2.1 
Objectives ...................................................................................................................... 5 
2.1.1 
Primary Objective ................................................................................................... 5 
2.1.2 
Secondary Objective ................................................................................................ 5 
3 STUDY DESIGN ............................................................................................................... 6 
4 RANDOMIZATION ......................................................................................................... 7 
5 SEQUENCE OF PLANNED ANALYSES ..................................................................... 8 
6 SAMPLE SIZE CONSIDERATIONS ............................................................................ 8 
7 ANALYSIS POPULATIONS ........................................................................................... 9 
8 GENERAL CONSIDERATIONS FOR DATA ANALYSES ....................................... 9 
8.1 
Premature Discontinuation and Missing Data .......................................................... 9 
8.2 
Multiple Comparisons and Multiplicity ................................................................... 10 
9 STUDY POPULATION ................................................................................................. 10 
9.1 
Subject Accountability ............................................................................................... 10 
9.2 
Eligibility Criteria ...................................................................................................... 10 
9.3 
Protocol Deviations .................................................................................................... 11 
9.4 
Other Descriptions of Study Population .................................................................. 11 
9.4.1 
Demographics ........................................................................................................ 11 
9.4.2 
PAH History ........................................................................................................... 11 
9.4.3 
Medical History ..................................................................................................... 12 
9.4.4 
Prior Therapy ........................................................................................................ 12 
9.4.5 
Concomitant Medication ....................................................................................... 13 
10 EFFICACY ANALYSES ................................................................................................ 13 
10.1 Transition to Oral Treprostinil ................................................................................. 13 
10.2 Cardiopulmonary Exercise Testing .......................................................................... 13 
10.3 Six-Minute Walk Test ................................................................................................ 14 
10.4 Borg Dyspnea Score ................................................................................................... 15 
10.5 PAH Symptoms .......................................................................................................... 15 
10.6 Panama Functional Class .......................................................................................... 16 
10.7 WHO Functional Class .............................................................................................. 16 
10.8 N-terminal Pro-brain Natriuretic Peptide ............................................................... 16 
10.9 Pediatric Quality of Life Inventory .......................................................................... 16 
10.10 Cardiac Magnetic Resonance Imaging ..................................................................... 17 
11 SAFETY ANALYSES ..................................................................................................... 18 
11.1 Extent of Exposure ..................................................................................................... 18 


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11.2 Background Medication Changes ............................................................................. 19 
11.3 Adverse Events ........................................................................................................... 19 
11.4 Deaths .......................................................................................................................... 21 
11.5 Disease-related Events ............................................................................................... 21 
11.6 Vital Signs ................................................................................................................... 21 
11.7 Clinical Laboratory Evaluations ............................................................................... 22 
11.7.1 
Hematology ............................................................................................................ 22 
11.7.2 
Clinical Chemistry ................................................................................................. 22 
11.8 Other Safety Measures ............................................................................................... 23 
11.8.1 
Electrocardiogram ................................................................................................. 23 
12 PHARMACOKINETICS ............................................................................................... 23 
13 APPENDICES ................................................................................................................. 25 
13.1 List of Tables ............................................................................................................... 25 
13.2 List of Listings ............................................................................................................ 27 
13.3 List of Figures ............................................................................................................. 29 
 


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ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
cMRI 
Cardiac Magnetic Resonance Imaging 
CPET 
Cardiopulmonary Exercise Testing 
CSR 
Clinical Study Report 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ERA 
Endothelin Receptor Antagonist 
IQR 
Interquartile Range 
IV 
Intravenous(ly) 
LOCF 
Last Observation Carried Forward 
LV 
Left Ventricular 
LVEDP 
Left Ventricular End-Diastolic Pressure 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-proBNP 
N-Terminal Pro-Brain Natriuretic Peptide 
PAH 
Pulmonary Arterial Hypertension 
PDE5-I 
Phosphodiesterase Type 5 Inhibitor 
PedsQL 
Pediatric Quality of Life Inventory 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
QOL 
Quality of Life 
RV 
Right Ventricular 
RVEDV 
Right Ventricular End-Diastolic Volume 
RVEF 
Right Ventricular Ejection Fraction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
sGC 
Soluble Guanylate Cyclase 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 


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TDE-PH-206 Statistical Analysis Plan 
 
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Abbreviation 
Definition 
TID 
Three Times Daily 
UTC 
United Therapeutics Corporation 
VCO2 
Carbon Dioxide Output 
VE 
Minute Ventilation 
VO2 
Oxygen Uptake 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 
1 
PREFACE 
This statistical analysis plan (SAP) provides further details of the planned analyses for the 
TDE-PH-206 study, as presented in the original protocol, dated 29 July 2014, and subsequent 
amendments.  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 
2.1.1 
Primary Objective 
To assess the safety and tolerability of oral treprostinil extended release tablets in 3 cohorts of 
pediatric subjects with pulmonary arterial hypertension (PAH) aged 7 to 17 years: 
• Cohort 1:  Subjects transitioning from intravenous (IV) or subcutaneous (SC) 
Remodulin 
• Cohort 2:  Subjects transitioning from inhaled prostacyclin 
• Cohort 3:  As add-on to current PAH therapy in de novo prostacyclin subjects 
2.1.2 
Secondary Objective 
1. To assess the effect of oral treprostinil on the following (assessed in all cohorts): 
• Cardiopulmonary exercise testing (CPET) with progressive cycle ergometry 
• Symptoms of PAH 


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• Panama and World Health Organization (WHO) Functional Classification 
• 6-minute walk distance (6MWD) (with pulse oximetry and heart rate recovery 
monitoring) 
• Borg dyspnea score 
• Quality of life (QOL) assessed via the Pediatric Quality of Life Inventory 
(PedsQL) questionnaire 
• Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) 
• Cardiac magnetic resonance imaging (cMRI) 
2. To describe treprostinil pharmacokinetics (PK) in pediatric subjects with PAH aged 7 
to 17 years. 
3 
STUDY DESIGN 
This is a multicenter, open-label, safety and tolerability study of oral treprostinil administered 
3 times daily (TID) (approximately every 8 hours with adjustments permitted based on the 
subject’s lifestyle and schedule, but not sooner than every 6 hours) in pediatric PAH subjects 
7 to 17 years of age (1) transitioning from continuous IV/SC Remodulin, (2) transitioning 
from inhaled prostacyclin, or (3) as add-on to current PAH therapies in de novo prostacyclin 
subjects.  Eligible subjects will be assigned to a cohort based upon their PAH therapy at the 
time of enrollment.  
Up to 7 study visits will occur during the 24-week study at the following time points:  
Screening, Baseline, Weeks 0 (Cohort 1 only; in-patient hospital stay Days 1 to 5), 3, 6, 12, 
and 24.  
Cohort 1 Subjects 
Following completion of Baseline assessments, including an 8-hour PK assessment while 
receiving IV/SC Remodulin within 7 days prior to the first dose of oral treprostinil, subjects in 
Cohort 1 will undergo an inpatient hospital stay lasting approximately 5 days to transition 
from IV/SC Remodulin to oral treprostinil.  The target transition goal is 5 days and for the 
subject to be completely transitioned off IV/SC Remodulin prior to discharge from the 
hospital.  Subjects will be discharged from the hospital after they have transitioned off IV/SC 
Remodulin, reached their target oral treprostinil dose, or as the Investigator deems 
appropriate.  If necessary or if appropriate per Investigator discretion, subjects can prolong or 
complete the transition in an outpatient setting for a total transition time of up to 4 weeks.  


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The maximum time to titrate off IV/SC Remodulin is 4 weeks from the start of the transition; 
if the subject is not fully transitioned by Week 4, they will be removed from the study.  If the 
subject is in the hospital during one of the scheduled study visits, the assessments for that visit 
will be conducted as scheduled during the defined visit window. 
Cohort 2 and 3 Subjects 
Following completion of Baseline assessments, the first dose of 0.125 mg oral treprostinil 
should be taken at the study site.  Dosing of oral treprostinil will be initiated at 0.125 mg TID 
with food (approximately every 8 hours with adjustments permitted based on the subject’s 
lifestyle and schedule, but not sooner than every 6 hours).  Dose changes should be conducted 
under appropriate medical supervision in consultation with the study site.  
Dose Optimization/Evaluation Phase for ALL Cohorts 
Week 3, Week 6, and Week 12:  Subjects will return to the clinic for the following 
assessments:  vital signs, 6-minute walk test (6MWT)/Borg dyspnea score, Panama and WHO 
Functional Classification, symptoms of PAH, and safety assessments.  At each visit, females 
of childbearing potential will undergo a urine pregnancy test.  At Week 12, QOL (as 
measured by PedsQL questionnaire) and clinical laboratory assessments, including 
NT-proBNP testing, will occur.  
Week 24 (or premature discontinuation):  Subjects will return to the clinic for the following 
assessments:  vital signs, physical examination, 6MWT/Borg dyspnea score, CPET, Panama 
and WHO Functional Classification, symptoms of PAH, QOL assessment, NT-proBNP, 
cMRI, clinical laboratory assessments, electrocardiogram (ECG), and safety assessments.  
Females of childbearing potential will undergo a urine pregnancy test.  In addition, all 
subjects will undergo an 8-hour PK assessment. 
4 
RANDOMIZATION 
No randomization will occur.  All subjects will receive treatment with oral treprostinil.  
Subjects will be enrolled into a cohort based on their current PAH treatment regimen. 


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5 
SEQUENCE OF PLANNED ANALYSES 
A Data Safety Monitoring Board (DSMB) will meet after 5 subjects have enrolled in Cohort 1 
and transitioned from IV/SC Remodulin to evaluate any safety concerns.  The safety data will 
be prepared according to the separate DSMB analysis plan.  The IV/SC Remodulin dose will 
be 25 to 75 ng/kg/min, inclusive, for the first 5 subjects enrolled in Cohort 1.  Following the 
DSMB safety review, the dose range may be expanded to 25 to 125 ng/kg/min, inclusive, for 
the remaining subjects. 
Additionally, if 2 or more of the first 5 subjects within any cohort meet the pre-specified 
stopping criteria, the DSMB will review the data prior to enrolling additional subjects into 
that cohort. 
Analysis of PK samples may be performed, as warranted, to guide dosing. 
Upon completion of all study subjects, after all outstanding queries are resolved and all data 
management quality assurance procedures are completed, the database will be locked.  All 
data from the electronic case report form (eCRF), as well as data transmitted from external 
vendors for laboratory and PK presentation, will be included in the locked database.  All final 
analyses will be performed on the final locked database. 
6 
SAMPLE SIZE CONSIDERATIONS 
This study is intended to provide descriptive data only.  A sample size of 40 subjects 
(25 transition [IV/SC Remodulin and inhaled prostacyclin] subjects and 15 de novo subjects) 
was selected for feasibility and to provide a reasonably large experience base with which to 
draw conclusions about the safety of the proposed protocol for (1) transition from moderate to 
high doses of IV/SC Remodulin to oral treprostinil, (2) transition from inhaled prostacyclin to 
oral treprostinil, and (3) initiation of oral treprostinil as add-on therapy in de novo 
prostacyclin subjects.  No formal sample size computation was performed with respect to the 
primary objective of evaluating safety and tolerability, as only descriptive reporting of safety 
data is planned.  The planned sample size of 10 to 15 subjects within a cohort is appropriate 
for further characterization of the safety, PK, and clinical benefit of oral treprostinil in this 
pediatric subject population with PAH. 


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7 
ANALYSIS POPULATIONS 
The Safety population will include all subjects who receive at least 1 dose of oral treprostinil. 
The PK population will include all subjects who receive at least 1 dose of oral treprostinil and 
who provide adequate PK samples to estimate the treprostinil PK parameters.  A subject’s 
status in the PK population will be determined by the PK analysis and report writing vendor, 
, and provided to United Therapeutics Corporation (UTC) electronically. 
8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All of the data included in the final locked database will be listed.  In general, listings will be 
sorted by cohort, subject, 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 number of subjects, mean, standard 
deviation (SD), median, 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 percentage in each category.  
Percentages will be rounded to 1 decimal point.  Whenever practical, categories of discrete 
variables will be ordered and labeled as they appear in the eCRF, and all categories 
represented on the eCRF will be included in summaries, even when they do not apply to any 
subjects in the study. 
8.1 
PREMATURE DISCONTINUATION AND MISSING DATA 
Subjects may not complete the treatment period for a number of reasons, including but not 
limited to voluntary withdrawal, stopping criteria met, serious or life-threatening adverse 
event (AE), protocol deviation, behavior likely to undermine the validity of results, or 
pregnancy. 


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All available data from all safety subjects will be used as detailed in this SAP.  Subjects will 
contribute the data available up to the point of study completion, or study discontinuation for 
any reason. 
8.2 
MULTIPLE COMPARISONS AND MULTIPLICITY 
No adjustment for multiple comparisons will be made in these analyses, as no formal 
hypotheses are being tested. 
9 
STUDY POPULATION 
9.1 
SUBJECT ACCOUNTABILITY 
The listing of discontinued subjects will include all subjects who discontinued the study 
prematurely and will include cohort number, subject number, analysis population inclusion, 
date/time of last oral treprostinil dose, date subject discontinued from study, and reason for 
study discontinuation.  
The listing of subject accountability will include all subjects who were screened for study 
participation.  This listing will include cohort number, subject number, analysis population 
inclusion, informed consent date, enrollment status, reason for screen failure (if applicable), 
date subject completed or discontinued from study, completion status, reason for study 
discontinuation (if premature), whether subject was able to transition to oral treprostinil, and 
reason subject was unable to transition (is applicable).  Any stopping criteria met will also be 
listed for each subject. 
A listing of subjects excluded from the PK analysis will include cohort and subject number. 
The number of subjects who were screened, failed screening (along with reasons for screen 
failure), enrolled in the study, included in the Safety population, included in the PK 
population, discontinued from study prematurely (along with reasons for premature 
discontinuation), and died during the study will be summarized by cohort and overall. 
9.2 
ELIGIBILITY CRITERIA 
The eligibility criteria not met will be listed for all subjects, along with the date of the initial 
screening assessment.  The listing will include all eligibility criteria not met by criterion 


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number, as noted in the protocol.  If a subject meets all eligibility criteria, the listing will 
simply be blank for “Criteria not met.”  A footnote will be added to this listing referring the 
reviewer to the protocol for exact eligibility criteria language.  Entry criteria not met will be 
summarized by cohort and overall, displaying the number of subjects with at least 1 violation, 
as well as the specific criterion violated. 
9.3 
PROTOCOL DEVIATIONS 
Protocol deviations are collected via a Microsoft Excel spreadsheet outside of the eCRF.  The 
Clinical Trial Lead will provide the final protocol deviation spreadsheet at the conclusion of 
the study, which will include the subject number, timing of the deviation (visit number), 
deviation category (i.e., efficacy, safety, PK, informed consent, visit window, etc.), deviation 
description, and the classification of the deviation (major/minor).  A SAS dataset will be 
created from this spreadsheet and utilitized to create the listing of protocol deviations 
collected during the study for all subjects. 
9.4 
OTHER DESCRIPTIONS OF STUDY POPULATION 
9.4.1 
Demographics 
All demographic data will be listed for the Safety population, including date of birth, age at 
diagnosis (years), age at enrollment (years), gender, ethnicity, and race.  Age at diagnosis 
requires a calculation using the subject’s date of birth and date of initial PAH diagnosis.  Age 
at enrollment is calculated within the eCRF and will therefore be available in the raw datasets.  
Both ages will be rounded to 1 decimal place.  Age at diagnosis, age at enrollment, gender, 
ethnicity, and race will be summarized by cohort for the Safety population.  Age at diagnosis 
and age at enrollment will be summarized both descriptively and categorically using the age 
groups 7 to < 12 and 12 to ≤17 years. 
9.4.2 
PAH History 
Pulmonary arterial hypertension history data will be listed, including date of initial PAH 
diagnosis, years since PAH diagnosis, and current PAH diagnosis.  Current PAH diagnosis 
will be summarized by cohort. 


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9.4.3 
Medical History 
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terms.  These data and their coded values will be listed, including assessment date 
and all medical conditions collected.  Subjects with no significant medical history will have 
“None reported” denoted on the listing.  The number of subjects with at least 1 medical 
condition reported will be summarized by cohort, along with the medical conditions by the 
coded system organ class (SOC) and preferred term (PT).  The listing and summary table will 
include a footnote denoting the MedDRA version used for coding. 
9.4.4 
Prior Therapy 
Remodulin medication history data will be listed, including date Remodulin was first 
initiated, current Remodulin dose, Remodulin route, and date current Remodulin dose was 
initiated.  Inhaled medication history data will be listed, including date Tyvaso first initiated, 
current number of breaths per session of Tyvaso, current number of sessions per day of 
Tyvaso, date current Tyvaso dose was initiated, date Ventavis first initiated, current dose of 
Ventavis per session, current number of sessions per day of Ventavis, and date current 
Ventavis dose was initiated.  Background medication history data will be listed, including use 
of endothelin receptor antagonist (ERA) (yes/no), use of phosphodiesterase type 5 inhibitor 
(PDE5-I) (yes/no), use of soluble guanylate cyclase (sGC) stimulator (yes/no), and for each of 
the medication types, the generic name, date drug was first initiated, current total daily dose, 
and date current dose was initiated. 
The summary of Remodulin medication history will include descriptive statistics on the 
current Remodulin dose and route for Cohort 1 only.  The summary of inhaled medication 
history will include descriptive statistics of the current number of users, current number of 
breaths/current dose, and sessions per day for each medication (Tyvaso and Ventavis) by 
cohort.  The summary of background medication history will include descriptive statistics of 
the current number of users, generic medication names, and current total daily dose for each 
medication type (ERA, PDE5-I, and sGC stimulator) by cohort. 


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9.4.5 
Concomitant Medication 
Concomitant medications data will be coded using the World Health Organization Drug 
Dictionary (WHODD).  These data and their coded values will be listed, including medication 
name, start/end date (or ongoing), condition treated/indication, and AE, if applicable.  The 
number of subjects reporting at least 1 concomitant medication will be summarized by cohort, 
along with the concomitant medications utilizing the name from the WHODD. 
10 
EFFICACY ANALYSES 
All efficacy data will be listed for all enrolled subjects and summarized for all Safety 
population subjects. 
10.1 
TRANSITION TO ORAL TREPROSTINIL 
The safety and tolerability of transitioning subjects from IV/SC Remodulin to oral treprostinil 
(Cohort 1) or from inhaled prostacyclin (Cohort 2) will be based on the percentage of subjects 
successfully transitioning to oral treprostinil.  A successful transition is defined as a subject 
from Cohort 1 or 2 who is receiving oral treprostinil and no longer receiving IV/SC 
Remodulin or inhaled prostacyclin, respectively, at Week 4 and clinically maintained on oral 
treprostinil treatment through Week 24.  A successful initiation of oral treprostinil (Cohort 3) 
will be defined as a subject who has been clinically maintained on oral treprostinil through 
Week 24.  The number (percentage) of subjects who successfully transitioned to oral 
treprostinil, as well as those who did not successfully transition to oral treprostinil, will be 
summarized by cohort and overall.  The reasons for unsuccessful transition will also be 
summarized for those subjects who did not successfully transition to oral treprostinil. 
10.2 
CARDIOPULMONARY EXERCISE TESTING 
Cardiopulmonary exercise testing will be completed at Baseline and Week 24 or premature 
termination.  Exercise data will be sent to a central site and analyzed by a centralized 
specialist.  Cardiopulmonary exercise testing entails measurements of oxygen uptake (VO2), 
carbon dioxide output (VCO2), minute ventilation (VE), and other variables. 
The listing of CPET will include the scheduled visit; date/time of assessment; Remodulin, 
oral treprostinil, Tyvaso, and Ventavis dosing information prior to the CPET assessment, as 


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applicable; as well as baseline (pre-exercise) and exercise (post-exercise) peak VO2, 
post-exercise peak watts and VE/VCO2 slope, warm-up duration (minutes), exercise duration 
(minutes), and reason for test termination. 
A summary of CPET will be produced for data collected before the exercise (labelled 
“baseline” on the CRF) and after the exercise (labelled “exercise” on the CRF), separately.  
The summary of CPET before exercise will include descriptive statistics for VO2 at Baseline 
and Week 24 by cohort.  The summary of CPET after exercise will include descriptive 
statistics at Baseline and Week 24 for warm-up duration (minutes), exercise duration 
(minutes), peak VO2, VE/VCO2 slope, and peak watts.  Changes from Baseline to Week 24 in 
peak VO2, VE/VCO2 slope, and peak watts will also be descriptively summarized.  These 
changes will be compared within cohorts using a paired t-test and p-values will be calculated 
for descriptive purposes; no formal hypothesis testing is planned.  The number (percentage) of 
subjects reporting reasons for test termination will be summarized categorically (fatigue vs. 
other) by cohort. 
The dosing information prior to testing (number [percentage] of subjects taking each 
medication type and last dose) will also be summarized by cohort using descriptive statistics. 
10.3 
SIX-MINUTE WALK TEST 
The 6MWT is performed at Screening (optional), Baseline, Week 0 (Cohort 1 only), Week 3, 
Week 6, Week 12, and Week 24 or premature termination.  At each of these visits, 6MWT 
recovery monitoring (heart rate and oxygen saturation measurements) will occur immediately 
prior to walk, immediately upon stopping the walk, 1 minute post walk, 2 minutes post walk, 
and 3 minutes post walk.  The listing of 6MWT will include the assessment date/time; any 
Remodulin, oral treprostinil, Tyvaso, and Ventavis dosing information prior to the 6MWT 
assessment, as applicable; as well as whether subject attempted walk test (yes/no), reason not 
attempted (if applicable), total distance walked, Borg dyspnea score, oxygen receipt, and 
unusual circumstances.  Recovery monitoring data (time point, heart rate, oxygen saturation, 
and total recovery time [minutes]) will be listed separately. 


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The summary of 6MWT will include the number (percentage) of subjects who received 
oxygen during the test and experienced any unusual circumstances during the test for each 
cohort. 
The summary of 6MWD will include descriptive statistics for total distance walked by 
assessment visit and time point for each cohort.  Changes from Baseline to each post-Baseline 
time point in total distance walked will also be summarized by cohort and compared within 
cohort using a Wilcoxon signed-rank test.  P-values will be calculated for descriptive 
purposes; no formal hypothesis testing is planned. 
As a sensitivity analysis, total walk distance data will be imputed using the LOCF method, 
regardless of the reason for early termination.  The summary based on this imputation will 
follow the same layout as the no imputation analysis described above, while again using the 
Wilcoxon signed-rank test for descriptive purposes; no formal hypothesis testing is planned. 
The summary of 6MWT recovery monitoring will include descriptive statistics for each 
cohort of heart rate (bpm) and oxygen saturation (%) at each of the 5 time points of 
assessment at each visit, as well as descriptive statistics of total recovery time (minutes).   
10.4 
BORG DYSPNEA SCORE 
The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced 
during the 6MWT.  Scores range from 0 (for the best condition) to 10 (for the worst 
condition).  The Borg dyspnea score is captured in tandem with the 6MWT at Screening 
(optional), Baseline, Week 0 (Cohort 1 only), Week 3, Week 6, Week 12, and Week 24 or 
premature termination, and will therefore be included in the 6MWT listing.  The summary of 
Borg dyspnea score will present descriptive statistics of the Borg dyspnea score at each 
assessment time point by cohort.  Change from Baseline will also be summarized by cohort. 
10.5 
PAH SYMPTOMS  
PAH symptoms (fatigue, dyspnea, edema, dizziness, syncope, chest pain, and orthopnea) will 
be assessed at the Baseline visit prior to the initiation of oral treprostinil and at all subsequent 
visits, including each day during the Cohort 1 inpatient hospital stay.  Scores range from 0 (no 
symptom experienced) to 3 (symptom severe or frequent).  The scores for each symptom will 


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be listed for each cohort, subject, and time point in chronological order.  The scores for each 
symptom will be categorically summarized separately by cohort at each visit assessment.  
Shifts from Baseline will also be summarized utilizing category shifts as well as descriptive 
statistics at each post-Baseline visit separately by cohort. 
10.6 
PANAMA FUNCTIONAL CLASS  
The Panama Functional Class is collected at Screening, Baseline, Week 3, Week 6, Week 12, 
and Week 24 or premature termination.  The listing will include the date of assessment and 
the functional class (I, II, IIIa, IIIb, and IV).  The summary table will use descriptive statistics 
to present the number (percentage) of subjects within each functional class at each time point 
starting from Baseline.  Shifts from Baseline will also be summarized utilizing the categories 
improved, no change, and deteriorated at each post-Baseline visit separately by cohort. 
10.7 
WHO FUNCTIONAL CLASS 
The WHO Functional Class is collected at Screening, Baseline, Week 3, Week 6, Week 12, 
and Week 24 or premature termination.  The listing will include the date of assessment and 
the functional class (I, II, III, and IV).  The summary table will use descriptive statistics to 
present the number (percentage) of subjects within each functional class at each time point 
starting from Baseline and shifts from Baseline by cohort. 
10.8 
N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE  
The NT-proBNP is collected at Baseline prior to starting oral treprostinil and repeated at 
Week 12 and Week 24 or premature termination.  All results will be listed by cohort, subject, 
and assessment time point.  The results will then be summarized using descriptive statistics at 
each time point and paired changes from Baseline by cohort. 
10.9 
PEDIATRIC QUALITY OF LIFE INVENTORY  
Health-related QOL will be assessed via the 23-item child and parent PedsQL questionnaire at 
Baseline, Week 12, and Week 24 or premature termination.  The listings of both child and 
parent inventories will include the date of assessment, which report was used (young child, 
child, or teen), and the answers to the physical, emotional, social, and school functioning scale 
questions. 


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The PedsQL questionnaire is converted to 6 scores for summarization and interpretation:  
4 scale scores (1 each for Physical Functioning, Emotional Functioning, Social Functioning, 
and School Functioning), a Psychosocial Health Summary Score, and a Total Scale Score.  
For ease of interpretability, items are reverse scored and linearly transformed to a 0 to 
100 scale, so that higher scores indicate better quality of life.  To reverse score, the 0 to 
4 scale items are transformed to 0 to 100 as follows:  0=100, 1=75, 2=50, 3=25, 4=0. 
To create scale scores, the mean is computed as the sum of the items over the number of items 
answered (this accounts for missing data).  If more than 50% of the items in the scale are 
missing, the scale score will not be computed.  To create the Psychosocial Health Summary 
Score, the mean is computed as the sum of the items over the number of items answered in the 
Emotional, Social, and School Functioning Scales combined.  To create the Total Scale Score, 
the mean is computed as the sum of all the items over the number of items answered on all the 
scales. 
The summaries of both child and parent inventories will present descriptive statistics for each 
of the 6 scores by cohort, as well as changes from Baseline to both post-Baseline visits. 
10.10 CARDIAC MAGNETIC RESONANCE IMAGING 
Cardiac magnetic resonance imaging assessments were performed on all subjects aged 
10 years and older at Baseline and Week 24 or premature termination.  The following 
parameters were evaluated: 
• Right ventricular (RV) mass index 
• RV ejection fraction (RVEF) 
• Left ventricular (LV) ejection fraction (LVEF) 
• RV end-diastolic volume (RVEDV) index 
• RV end-systolic volume (RVESV) index 
• RV stroke volume index 
• LV stroke volume index 
• RV cardiac output indext 
The cMRI measurements from images will be analyzed by a centralized specialist to control 
for bias and to reduce inter-reader variability.  The results of these analyses will be transferred 


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to UTC for inclusion in the final study results.  The listing of cMRI assessments will include 
the date/time of assessment as well as the parameters noted above for each visit assessment.   
The summary of cMRI parameters will include descriptive statistics for each parameter at 
each visit as well as changes from Baseline by cohort.  The following additional exploratory 
parameters, if collected, may also be included: 
• 
Flow pattern through the main pulmonary artery by phase-sensitive gradient echo imaging 
• 
Flow pattern through the right pulmonary artery by phase-sensitive gradient echo imaging 
• 
Flow pattern through the ascending aorta by phase-sensitive gradient echo imaging 
• 
RV:LV end-systolic diameter ratio 
• 
Systolic septal flattening 
• 
Right atrial size 
• 
Presence of congenital heart disease 
• 
Atrial or ventricular shunt 
11 
SAFETY ANALYSES 
All safety summaries will be performed on the Safety population (see Section 7). 
11.1 
EXTENT OF EXPOSURE 
Oral treprostinil dosing will be listed by cohort and subject.  The listing will include the 
date/time of initial oral treprostinil dose, the initial dose (mg), and all subsequent dose 
changes with start date, morning dose, midday dose, and evening dose.   
Remodulin dosing will be listed by subject for Cohort 1 subjects only.  The listing will 
include the initial Remodulin dose (ng/kg/min) and all changes during the study, including the 
start date/time of the new dose as well as the new dose (ng/kg/min). 
Tyvaso dosing will be listed by subject for Cohort 2 subjects only.  The listing will include 
the number of initial Tyvaso breaths per session, the number of initial Tyvaso sessions per 
day, and all changes during the study; including the start date of new dose, number of breaths 
per session, and number of sessions per day. 
Ventavis dosing will be listed by subject for Cohort 2 subjects only.  The listing will include 
the initial Ventavis dose (X mcg with X mcg/mL), the number of initial Ventavis sessions per 


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day, and all changes during the study, including the start date of new dose, new dose, and 
number of sessions per day. 
The oral treprostinil dosing and exposure summary will include descriptive statistics for initial 
oral treprostinil dose, oral treprostinil dose when Remodulin dose is 0.0, oral treprostinil dose 
at time of hospital discharge, oral treprostinil dose when subject is first off Tyvaso/Ventavis, 
and final oral treprostinil dose (mg) by cohort.  Oral treprostinil dose will be calculated as the 
sum of the doses administered on a given day divided by the number of doses administered 
that day.  The Remodulin dosing and exposure summary will include descriptive statistics for 
initial Remodulin dose (ng/kg/min). The Tyvaso dosing and exposure summary will include 
descriptive statistics for initial Tyvaso breaths per session and a categorical summary of 
number of initial Tyvaso sessions per day.  The Ventavis dosing and exposure summary will 
include descriptive statistics for initial Ventavis dose per session and a categorical summary 
of number of initial Ventavis sessions per day. 
Oral treprostinil doses will be plotted over time for each individual subject using a different 
plot for each cohort.  The mean oral treprostinil doses will then be plotted over time on a 
single plot by cohort.  Remodulin doses will be plotted over time for each individual subject 
(Cohort 1 only).  Tyvaso doses will be plotted over time for each individual subject (Cohort 2 
only). 
11.2 
BACKGROUND MEDICATION CHANGES 
Endothelian receptor agonist, PDE5-I, and sGC stimulator dosing changes will be listed by 
cohort and subject.  The listings will include if there were changes in the specific background 
medication (yes/no), the name of generic drug, the total daily dose, and the start date.  The 
summary of background medication changes will include the number of subjects reporting 
any changes to each background medication type by cohort. 
11.3 
ADVERSE EVENTS 
The AEs are collected from the time the informed consent form is signed until study 
termination.  There are a number of AEs that are considered expected events given the 
underlying disease of study, PAH.  These expected events attributable to PAH were not 


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recorded as an AE unless the event was serious or unusual with respect to intensity, 
frequency, or duration, or there was a reasonable possibility that it may have been caused by 
the study drug. 
Adverse events will be coded using MedDRA PTs and SOC.  All AEs reported in the eCRF 
will be listed, including non-treatment-emergent and treatment-emergent events.  
Non-treatment-emergent AEs are defined as those AEs starting prior to the date of first oral 
treprostinil dosing.  Treatment-emergent adverse events (TEAEs) are defined as those AEs 
starting on or after the date of first oral treprostinil dosing.  The listing will include cohort, 
subject number, verbatim term, PT, SOC, treatment-emergent status, start/stop date, 
seriousness, severity, frequency, relationship to oral treprostinil, action taken with oral 
treprostinil, relationship to background medication, action taken with background medication, 
and outcome. 
The TEAEs will be summarized first in an overall summary, which includes the number of 
subjects with at least 1 TEAE, at least 1 oral treprostinil attributable TEAE, at least 1 serious 
TEAE, at least 1 TEAE leading to oral treprostinil discontinuation, at least one background 
therapy attributable TEAE, at least one TEAE leading to background therapy discontinuation, 
and any fatal TEAEs.  The overall summaries will also include the number of events for each 
of these categories.  
Non-treatment-emergent AEs will be summarized by cohort using PTs.  The PTs will be 
sorted by decreasing overall frequency.  
The TEAEs and serious TEAEs will be summarized by cohort using SOC/PT and PT, 
separately.  The summaries will include the number and percentage of subjects reporting and 
the number of events reported for each SOC/PT and each PT, respectively, for each cohort, in 
order of decreasing overall frequency, both within SOC and PT.  
The TEAEs will be summarized by severity within PT.  The TEAEs and serious TEAEs 
considered attributable to oral treprostinil will be summarized by SOC/PT and PT, as 


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described above.  The TEAEs leading to oral treprostinil discontinuation will be summarized 
by PT. 
11.4 
DEATHS 
Information for all subjects who died within 30 days of the last dose of treatment, including 
the cohort, date of death, last oral treprostinil dose date, last oral treprostinil dose (mg), cause 
of death, PT, and relationship to oral treprostinil will be listed.  The number and percentage of 
subjects who died will be summarized by cohort along with the causes of death reported.  
11.5 
DISEASE-RELATED EVENTS 
Disease-related events that appeared or worsened (with clinical significance) during the study 
will be captured, including abdominal pain, anorexia, ascites, cool extremities, cor pulmonale, 
cough, cyanosis, hemoptysis, heart failure (or exacerbation of), hypoxia, loss of 
consciousness, nausea, pallor, palpitations/cardiac arrhythmia, paroxysmal nocturnal dyspnea, 
exacerbation of pulmonary hypertension, tachycardia, weight loss/gain, vasovagal reaction, 
and vomiting.  The assessment of each of these disease-related events will be listed by cohort 
and subject.  The number and percentage of subjects noting the onset or worsening of each of 
these events will be summarized by cohort. 
11.6 
VITAL SIGNS 
Vitals signs (blood pressure [systolic and diastolic], heart rate, respiratory rate, and 
temperature [◦C]) along with weight measurements will be captured during all study visits, 
including days of the inpatient hospital stay for Cohort 1.  Height and body mass index were 
recorded at Screening only.  
All vital sign assessments, including weight and height, will be listed by cohort, subject, and 
scheduled time point in chronological order using the units captured on the eCRF.  Weight 
and height will be converted to a single unit for summarization; specifically, weight will be 
converted to kg and height will be converted to cm.  The summary of vital signs will include 
descriptive statistics of the applicable parameters at each time point by cohort, including 
changes from Baseline.   


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11.7 
CLINICAL LABORATORY EVALUATIONS 
11.7.1 
Hematology 
Hematology laboratory evaluations were performed at Screening, Baseline, Week 12, and 
Week 24 or premature termination.  Hematology data, including hemoglobin (g/L), 
hematocrit (fraction), red blood cell count (x 1012/L), red blood cell morphology (as required), 
white blood cell count (x 109/L), and platelet count (absolute) (x 109/L) will be listed by 
cohort and time point, including collection date/time, reference range, and high/low flags. 
The summary of hematology laboratory parameters will include descriptive statistics of all 
parameters at each time point (except Screening), including changes from Baseline by cohort. 
Additionally a shift table will be generated displaying the number (percent) of subjects with 
low, normal, and high values at baseline and each post-baseline visit. 
Mean values of red blood cell count, hemoglobin, hematocrit, platelet count (absolute), and 
white blood cell count will be plotted across time starting at Baseline, using a different 
plotting symbol for each cohort.  The time points plotted will be denoted as Baseline, Week 
12, and Week 24.  For plotting purposes, to prevent outlying values from skewing the 
majority of the data, the maximum y-axis value will follow the rule of 1.5 x IQR above the 
third quartile, calculated separately for each lab parameter.  All values falling outside of the 
1.5 x IQR limit will not be plotted.  A footnote denoting this methodology will be added to 
each plot.  
11.7.2 
Clinical Chemistry 
Clinical chemistry laboratory evaluations were performed at Screening, Baseline, Week 12, 
and Week 24 or premature termination.  Clinical chemistry data, including sodium (mmol/L), 
potassium (mmol/L), bicarbonate (x 109/L), chloride (mmol/L), total bilirubin (umol/L), 
alkaline phosphatase (IU/L), alanine aminotransferase (ALT) (IU/L), aspartate 
aminotransferase (AST) (IU/L), blood urea nitrogen (BUN) (mmol/L), creatinine (umol/L), 
calcium (mmol/L), and albumin (g/L) will be listed by cohort and time point, including the 
collection date/time, reference range, and high/low flags. 


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TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
Final: 15 Aug 2017 
Confidential 
Page 23 
The summary of clinical chemistry laboratory parameters will include descriptive statistics of 
all parameters at each time point (except Screening), including changes from Baseline by 
cohort. Additionally a shift table will be generated displaying the number (percent) of subjects 
with low, normal, and high values at baseline and each post-baseline visit. 
Mean values of sodium, potassium, chloride, bicarbonate, calcium, albumin, total bilirubin, 
alkaline phosphatase, ALT, AST, BUN, and creatinine will be plotted across time starting at 
Baseline, using a different plotting symbol for each cohort.  The time points plotted will be 
denoted as Baseline, Week 12, and Week 24.  For plotting purposes, to prevent outlying 
values from skewing the majority of the data, the maximum y-axis value will follow the rule 
of 1.5 x IQR above the 3rd quartile, calculated separately for each lab parameter.  All outlying 
values falling outside of the 1.5 x IQR limit will not be plotted.  A footnote denoting this 
methodology will be added to each plot. 
11.8 
OTHER SAFETY MEASURES 
11.8.1 
Electrocardiogram 
The ECG assessments will be completed at Baseline and Week 24 or premature termination.  
The ECG parameters collected will include heart rate, PR interval, QT interval, QRS duration, 
ECG results (normal/abnormal), and any abnormalities, including assessment of clinical 
significance and change from Baseline.  The listing will include date/time of assessment as 
well as all parameters measured for each assessment time point by cohort and subject.  All 
12-lead ECG parameters will be summarized descriptively at each assessment time point by 
cohort.  
12 
PHARMACOKINETICS 
Blood samples will be drawn from each subject at Baseline (Cohort 1 only) and Week 24 or 
premature termination to allow for the determination of the PK of oral treprostinil.  At 
Baseline, 3 samples will be obtained for Cohort 1 subjects only at Time 0 (pre-dose) and at 
4 and 8 hours after Time 0.  At Week 24, all subjects will have 5 samples obtained at Time 0 
(pre-dose) and at 2, 4, 6, and 8 hours after Time 0. 


United Therapeutics Corp. 
TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
Final: 15 Aug 2017 
Confidential 
Page 24 
The listing of PK blood samples will include sample date/time, blood sample time point, 
whether sample was taken (yes/no), whether oral treprostinil was being taken (yes/no), 
date/time of previous day’s oral treprostinil dose, previous day’s oral treprostinil dose (mg), 
date/time of morning oral treprostinil dose, morning oral treprostinil dose (mg), time of 
midday oral treprostinil dose, midday oral treprostinil dose (mg), whether Remodulin was 
being taken (yes/no), date/time of last Remodulin dose change, last Remodulin dose 
(ng/kg/min), whether Tyvaso/Ventavis was being taken (yes/no), date/time of last 
Tyvaso/Ventavis dose, last number of Tyvaso breaths (per session), and last Ventavis dose 
(per session). 
The PK bioanalytical work will be conducted by 
 will be 
conducting the PK analysis and writing the PK report.  The PK report will be transferred to 
UTC for inclusion in the CSR. 


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TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
Final: 15 Aug 2017 
Confidential 
Page 25 
13 
APPENDICES 
13.1 
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 
Output Name 
14.1.1 
Summary of Subject Accountability 
_acct 
14.1.2 
Summary of Demographics 
_demog 
14.1.3 
Summary of PAH History 
_pahhx 
14.1.4 
Summary of Entry Criteria Not Met 
_ic 
14.1.5 
Summary of Medical History 
_mh 
14.1.6 
Summary of Remodulin Medication History 
_remodhx 
14.1.7 
Summary of Inhaled Medication History 
_inhalehx 
14.1.8 
Summary of Background Medication History 
_backgr 
14.1.9 
Summary of Concomitant Medications 
_cm 
14.1.10 
Summary of Oral Treprostinil Dosing and Exposure 
_oral 
14.1.11 
Summary of Remodulin Dosing and Exposure 
_remodulin 
14.1.12 
Summary of Tyvaso Dosing and Exposure 
_tyvaso 
14.1.13 
Summary of Ventavis Dosing and Exposure 
_ventavis 
14.1.14 
Summary of Background Medication Changes 
_backchg 
14.2.1 
Summary of Transition to Oral Treprostinil 
_transition 
14.2.2.1 
Summary of Cardiopulmonary Exercise Testing Before 
Exercise 
_cpet_before 
14.2.2.2 
Summary of Cardiopulmonary Exercise Testing After 
Exercise 
_cpet_after 
14.2.2.3 
Summary of Dosing Prior to Cardiopulmonary Exercise 
Testing 
_cpet_dose 
14.2.3.1 
Summary of 6-Minute Walk Test 
_walk 
14.2.3.2 
Summary of 6-Minute Walk Distance During Week 0 for 
Cohort 1 
_6mwd 
14.2.3.3 
Summary of 6-Minute Walk Distance 
_6mwd 
14.2.3.4 
Summary of 6-Minute Walk Distance – LOCF Imputation 
_6mwd_locf 
14.2.3.5 
Summary of 6-Minute Walk Test Recovery Monitoring 
During Week 0 for Cohort 1 
_6mwt_recover 
14.2.3.6 
Summary of 6-Minute Walk Test Recovery Monitoring 
_6mwt_recover 
14.2.4.1 
Summary of Borg Dyspnea Score During Week 0 for 
Cohort 1 
_borg 
14.2.4.2 
Summary of Borg Dyspnea Score 
_borg 
14.2.5.1 
Summary of Pulmonary Arterial Hypertension Symptoms 
During Week 0 for Cohort 1 
_pahsymp 
14.2.5.2 
Summary of Pulmonary Arterial Hypertension Symptoms  
_pahsymp 


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TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
Final: 15 Aug 2017 
Confidential 
Page 26 
Table Number 
Table Title 
Output Name 
14.2.6 
Summary of Panama Functional Class 
_panama 
14.2.7 
Summary of WHO Functional Class 
_who 
14.2.8 
Summary of NT-proBNP Results 
_ntpro 
14.2.9.1 
Summary of Child Pediatric Quality of Life Inventory 
_cpqol 
14.2.9.2 
Summary of Parent Pediatric Quality of Life Inventory 
_ppqol 
14.2.9.3 
Summary of Cardiac Magnetic Resonance Imaging 
Parameters 
_cmri 
14.3.1.1 
Overall Summary of Adverse Events 
_ae 
14.3.1.2 
Summary of Non-Treatment-emergent Adverse Events by 
Preferred Term 
_nonteae 
14.3.1.3 
Summary of Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
_ae_soc 
14.3.1.4 
Summary of Treatment-emergent Adverse Events by 
Preferred Term 
_ae_pt 
14.3.1.5 
Summary of Attributable Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term  
_relae_soc 
14.3.1.6 
Summary of Attributable Treatment-emergent Adverse 
Events by Preferred Term 
_relae_pt 
14.3.1.7 
Summary of Treatment-emergent Adverse Events by 
Preferred Term and Severity 
_ae_sev 
14.3.1.8 
Summary of Treatment-emergent Adverse Events Leading 
to Oral Treprostinil Discontinuation by Preferred Term 
_ae_discon 
14.3.1.9 
Summary of Serious Treatment-emergent Adverse Events 
by System Organ Class and Preferred Term  
_sae_soc 
14.3.1.10 
Summary of Serious Treatment-emergent Adverse Events 
by Preferred Term 
_sae_pt 
14.3.1.11 
Summary of Serious Attributable Treatment-emergent 
Adverse Events by System Organ Class and Preferred Term 
_relsae_soc 
14.3.1.12 
Summary of Serious Attributable Treatment-emergent 
Adverse Events by Preferred Term 
_relsae_pt 
14.3.1.13 
Summary of Disease-related Events 
_dre 
14.3.2.1 
Listing of Deaths 
_death 
14.3.2.2 
Summary of Deaths 
_ldeath 
14.3.2.3 
Listing of Serious Adverse Events 
_lsae 
14.3.4.1 
Summary of Vital Signs During Week 0 for Cohort 1 
_vs 
14.3.4.2 
Summary of Vital Signs 
_vs 
14.3.4.3.1 
Summary of Hematology Laboratory Data 
_lb 
14.3.4.3.2 
Summary of Hematology Shifts 
_lbshft 
14.3.4.4.1 
Summary of Clinical Chemistry Laboratory Data 
_lb 
14.3.4.4.2 
Summary of Clinical Chemistry Shifts 
_lbshft 
14.3.4.5 
Summary of 12-Lead Electrocardiogram Parameters 
_ecg 


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TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
Final: 15 Aug 2017 
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Page 27 
13.2 
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 
Output Name 
16.2.1.1 
Listing of Discontinued Subjects 
_disc 
16.2.1.2 
Listing of Subject Accountability 
_acct 
16.2.2.1 
Listing of Protocol Deviations 
_deviate 
16.2.2.2 
Listing of Eligibility Criteria 
_elig 
16.2.3 
Listing of Subjects Excluded from the Pharmacokinetic 
Analysis 
_pksubjs 
16.2.4.1 
Listing of Demographics 
_demog 
16.2.4.2 
Listing of PAH History  
_pahhx 
16.2.4.3 
Listing of Medical History 
_mh 
16.2.4.4.1 
Listing of Remodulin Medication History 
_remodhx 
16.2.4.4.2 
Listing of Inhaled Medication History 
_inhalehx 
16.2.4.4.3 
Listing of Background Medication History 
_backgr 
16.2.4.4.4 
Listing of Background Medication Changes 
_back_chg 
16.2.4.5 
Listing of Concomitant Medications 
_cm 
16.2.5.1.1 
Listing of Oral Treprostinil Dosing 
_oral 
16.2.5.1.2 
Listing of Remodulin Dosing 
_remod 
16.2.5.1.3 
Listing of Tyvaso Dosing 
_tyvaso 
16.2.5.1.4 
Listing of Ventavis Dosing 
_vent 
16.2.5.1.5 
Listing of ERA Dosing Changes 
_era 
16.2.5.1.6 
Listing of PDE-5 Inhibitor Dosing Changes 
_pde 
16.2.5.1.7 
Listing of sGC Stimulator Dosing Changes 
_sgc 
16.2.5.2 
Listing of Pharmacokinetic Results 
_pk 
16.2.6.1 
Listing of Cardiopulmonary Exercise Testing 
_cpet 
16.2.6.2 
Listing of 6-Minute Walk Test 
_6mwt 
16.2.6.3 
Listing of 6-Minute Walk Test Recovery Monitoring 
_recov 
16.2.6.4 
Listing of PAH Symptoms 
_pahsymp 
16.2.6.5 
Listing of Panama Functional Class 
_pfc 
16.2.6.6 
Listing of WHO Functional Class 
_who 
16.2.6.7 
Listing of NT-proBNP Results 
_ntpro 
16.2.6.8.1 
Listing of Child Pediatric Quality of Life Inventory 
_cqol 
16.2.6.8.2 
Listing of Parent Pediatric Quality of Life Inventory 
_pqol 
16.2.6.9 
Listing of Cardiac Magnetic Resonance Imaging 
Assessments 
_cmri 
16.2.7.1 
Listing of Adverse Events 
_ae 
16.2.7.2 
Listing of Disease-related Events 
_dre 


United Therapeutics Corp. 
TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
Final: 15 Aug 2017 
Confidential 
Page 28 
Appendix Number 
Listing Title 
Output Name 
16.2.8.1 
Listing of Hematology Laboratory Parameters 
_lb 
16.2.8.2 
Listing of Clinical Chemistry Laboratory Parameters 
_lb 
16.2.8.3 
Listing of Vital Signs 
_vs 
16.2.8.4 
Listing of Electrocardiogram Results 
_ecg 
 


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TDE-PH-206 Statistical Analysis Plan 
 
Oral Treprostinil 
Final: 15 Aug 2017 
Confidential 
Page 29 
13.3 
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 
Output Name 
14.2.5.1 
Plot of Oral Treprostinil Dosing Over Time for Cohort 1 
_oral_c1 
14.2.5.2 
Plot of Oral Treprostinil Dosing Over Time for Cohort 2 
_oral_c2 
14.2.5.3 
Plot of Oral Treprostinil Dosing Over Time for Cohort 3 
_oral_c3 
14.2.5.4 
Plot of Mean Oral Treprostinil Doses Over Time by Cohort 
_oral_mean 
14.2.5.5 
Plot of Remodulin Dosing Over Time for Cohort 1 
_rem_c1 
14.2.5.6 
Plot of Tyvaso Dosing Over Time for Cohort 2 
_tyv_c2 
14.3.4.1.1 
Plot of Red Blood Cell Count Over Time 
_rbc 
14.3.4.1.2 
Plot of Hemoglobin Over Time 
_hgb 
14.3.4.1.3 
Plot of Hematocrit Over Time 
_hmt 
14.3.4.1.4 
Plot of Platelet Count (Absolute) Over Time 
_platelet 
14.3.4.1.5 
Plot of White Blood Cell Count Over Time 
_wbc 
14.3.4.2.1 
Plot of Sodium Over Time 
_sodium 
14.3.4.2.2 
Plot of Potassium Over Time 
_potas 
14.3.4.2.3 
Plot of Chloride Over Time 
_chloride 
14.3.4.2.4 
Plot of Bicarbonate Over Time 
_bicarbon 
14.3.4.2.5 
Plot of Calcium (Total) Over Time 
_calcium 
14.3.4.2.6 
Plot of Albumin Over Time 
_album 
14.3.4.2.7 
Plot of Total Bilirubin Over Time 
_bili 
14.3.4.2.8 
Plot of Alkaline Phosphatase Over Time 
_alkphos 
14.3.4.2.9 
Plot of Alanine Aminotransferase Over Time 
_alt 
14.3.4.2.10 
Plot of Aspartate Aminotransferase Over Time 
_ast 
14.3.4.2.11 
Plot of Blood Urea Nitrogen Over Time 
_bun 
14.3.4.2.12 
Plot of Serum Creatinine Over Time 
_creat