Conditions: Pulmonary Hypertension Interstitial Lung Disease Combined Pulmonary Fibrosis and Emphysema
Keywords: Treprostinil PH ILD CPFE 6 Minute Walk Test
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 243
Healthy volunteers: no

Brief summary:
This is a multicenter, open-label trial to evaluate the safety and efficacy of inhaled treprostinil in subjects with pre-capillary pulmonary hypertension (PH) associated with interstitial lung disease (ILD) including combined pulmonary fibrosis and emphysema (CPFE). The study will include about 266 patients who completed all required assessments in the RIN-PH-201 study at approximately 100 clinical trial centers. The study will continue Your participation in this study is voluntary and will last until you discontinue from the study or the study ends. The study will continue until each subject reaches the Week 108 visit or until inhaled treprostinil become commercially available for patients with PH associated with ILD including CPFE (whichever is sooner).

Detailed description:

Arms:
arm 1: Open-label access

Interventions: intervention 1: Inhaled Treprostinil
Intervention descriptions: intervention 1: Inhaled treprostinil up to 15 breaths (90 mcg) four times daily

Protocol document:
Prot_000.pdf: 
United Therapeutics Corp. 
RIN-PH-202 
 
Protocol Amendment 1 
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 
Page 1 
An Open-Label Extension study of Inhaled Treprostinil in 
Subjects with Pulmonary Hypertension due to Parenchymal Lung 
Disease 
IND 70,362 
Protocol RIN-PH-202 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
 
Original Protocol Date: 
14 October 2015 
Amendment 1 
18 August 2016  
 
 
 
 
 
 
 


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LIST OF CONTACTS FOR STUDY 
Study Sponsor: 
United Therapeutics Corp. 
55 TW Alexander Drive  
Research Triangle Park, NC 27709 
 
 
Telephone: 
 
Fax: 
 
 
@unither.com 
 
Product Leader 
Telephone:  
 
Fax:    
2 
@unither.com 
 
  
Medical Monitor 
Telephone: 
  
Fax: 
 
 
@unither.com 
UT Global Drug Safety 
SAE Phone:  
 
SAE Fax:  
 
@unither.com 
 
Clinical Laboratory: 
 
 
 
  
 
     
 


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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “An Open-Label Extension study of Inhaled 
Treprostinil in Subjects with Pulmonary Hypertension due to Parenchymal Lung Disease,” 
protocol amendment 1 dated 18 August 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 inhaled treprostinil and 
acknowledge that review of the information contained in the Clinical Investigators’ Brochure 
is a requirement for Investigators before using inhaled treprostinil in a clinical trial. 
This protocol has been received for information only and must not be implemented before all 
necessary regulatory agency and Ethics Committee / Institutional Review Board approval 
documents have been obtained. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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PROTOCOL SYNOPSIS 
Title  
An Open-Label Extension study of Inhaled Treprostinil in 
Subjects with Pulmonary Hypertension due to Parenchymal 
Lung Disease 
Study Phase 
Phase II/III 
Indication 
Pre-capillary pulmonary hypertension (PH) associated with 
interstitial lung disease (ILD) including combined 
pulmonary fibrosis and emphysema (CPFE) 
Primary Objective 
To provide or continue to provide inhaled treprostinil for 
eligible subjects who participated in the RIN-PH-201 study 
Secondary Objectives 
To evaluate the long-term safety and efficacy of inhaled 
treprostinil in subjects with PH associated with ILD 
including CPFE 
Efficacy Endpoints 
1. Peak six-minute walk distance (6MWD)  
2. N-terminal pro-Brain Natriuretic Peptide 
(NT-proBNP)  
3. Quality of life as measured by the St. George's 
Respiratory Questionnaire (SGRQ)  
4. Optional evaluation of change in biomarkers 
(specific targets to be determined) from Baseline to 
Week 48 (or study discontinuation if prior to 
Week 48) 
5. Change in distance saturation product (DSP) 
Safety Endpoints 
1. Adverse events (AEs) 
2. Oxygenation  
a. Pulse oximetry (saturation of peripheral 
capillary oxygenation [SpO2]) 
b. Supplemental oxygen requirement (L/min) 
3. Pulmonary function: 
a. Forced expiratory volume in one second 
(FEV1) 


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b. Forced vital capacity (FVC) 
c. Total lung capacity (TLC) 
d. Lung diffusion capacity (DLCO) 
4. Clinical laboratory parameters 
5. Vital signs 
6. Hospitalizations due to a cardiopulmonary 
indication 
7. Exacerbations of underlying lung disease; defined as 
an acute, clinically significant, respiratory 
deterioration characterized by evidence of new 
widespread alveolar abnormality  
Study Design 
Multi-center, open-label study for eligible subjects who 
participated in RIN-PH-201. 
Sample Size 
Approximately 266 subjects who completed protocol RIN-
PH-201 
Summary of Subject 
Eligibility Criteria 
Inclusion criteria: 
1. Subject voluntarily gives informed consent to 
participate in the study. 
2. The subject participated in study RIN-PH-201 and: 
a. remained on study drug and completed all 
scheduled study visits or 
b. permanently discontinued study drug during 
the RIN-PH-201 study due to clinical 
worsening and completed all remaining 
required scheduled study visits or  
c. was enrolled in study RIN-PH-201 at the 
time that the study/study subject was 
discontinued by the sponsor. 
3. Females of reproductive potential must be non-
pregnant (as confirmed by a urine pregnancy test at 
Baseline) and non-lactating, and will: 
a. Either abstain from intercourse (when it is in 
line with their preferred and usual lifestyle), 
or  


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b. Use two medically acceptable, highly-
effective forms of contraception for the 
duration of study, and at least 30 days after 
discontinuing study drug.   
4. Males must use a condom for the duration of 
treatment and for at least 48 hours after 
discontinuing study drug. 
Exclusion criteria: 
1. The subject is pregnant or lactating. 
2. The subject was prematurely discontinued from 
study RIN-PH-201 due to treatment related AEs. 
3. The subject was prematurely discontinued from 
study RIN-PH-201 due to clinical worsening and 
did not undergo premature termination assessments 
prior to discontinuing study drug and/or did not 
complete all remaining study visits through the 
final scheduled visit. 
4. The subject developed a concurrent illness or 
condition during the conduct of RIN-PH-201 
which, in the opinion of the Investigator, would 
represent a risk to overall health if they enrolled in 
this study. 
Drug Dosage  
and Formulation 
Inhaled treprostinil (6 mcg/breath)  
Treatment phase:  
All subjects will initiate inhaled treprostinil at a dose of 
3 breaths (18 mcg) four times daily (during waking hours).  
Study drug doses should be maximized throughout the 
study, dose escalations (additional one breath four times 
daily) can occur up to every three days with a maximum 
dosing regimen of up to 15 breaths (90 mcg) four times 
daily, as clinically tolerated. 
Control Group 
None 
Route of  
Administration 
Inhaled 


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Procedures 
Subjects will be assessed at Baseline, Week 4, Week 12, 
and every 12 weeks thereafter through Week 108.  Study 
visits will continue until each subject reaches Week 108 or 
until inhaled treprostinil become commercially available for 
patients with pre-capillary PH associated with ILD 
(whichever is sooner). 
Key Assessments:  
 Blood for NT-ProBNP will be obtained at Baseline, 
Week 48, and Week 108/study termination.  
 Blood for clinical labs will be obtained at all 
scheduled study visits. 
 A peak six minute walk test (6MWT) will be 
conducted at all scheduled study visits.     
 Pulse oximetry will be performed immediately prior 
to, during, and immediately after each scheduled 
6MWT.     
 Pulmonary function tests (PFTs) will be conducted 
at Baseline, Week 12, Week 48, and Week 
108/study termination.     
 SGRQ will be conducted at Baseline, Week 48, and 
Week 108/study termination.   
 Hospitalizations due to cardiopulmonary indications 
and exacerbations of underlying lung disease will be 
evaluated from the time of informed consent until 
study discontinuation.  
 
An optional blood sample will be collected for the 
analysis of biomarkers (specific targets to be 
determined) at Baseline and Week 48 (or study 
termination if prior to Week 48). 
Statistical Considerations All data will be summarized in tables and listings.   
Sponsor 
United Therapeutics Corp. 
55 T.W. Alexander Dr. 
P.O. Box 14186 
Research Triangle Park, NC 27709 
United States of America 


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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY .................................................................................... 2 
INVESTIGATOR’S AGREEMENT ..................................................................................... 3 
PROTOCOL SYNOPSIS ....................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................ 8 
TABLE OF IN-TEXT TABLES .......................................................................................... 11 
1 BACKGROUND AND RATIONALE .......................................................................... 12 
1.1 
DEFINITION OF CLINICAL PROBLEM ............................................................. 12 
1.2 
INHALED TREPROSTINIL BACKGROUND ...................................................... 12 
1.2.1 
General Pharmacology .......................................................................................... 12 
1.2.2 
General Toxicology ................................................................................................ 13 
1.2.3 
Clinical Experience ................................................................................................ 14 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION ............................................................................................ 15 
1.4 
CLINICAL HYPOTHESIS ....................................................................................... 16 
2 OBJECTIVES ................................................................................................................. 16 
2.1 
EFFICACY ENDPOINTS ......................................................................................... 16 
2.2 
SAFETY ENDPOINTS .............................................................................................. 17 
3 EXPERIMENTAL PLAN .............................................................................................. 17 
3.1 
STUDY DESIGN ........................................................................................................ 17 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ............................................ 18 
3.3 
CLINICAL ASSESSMENTS .................................................................................... 20 
3.3.1 
Efficacy ................................................................................................................... 20 
3.3.1.1 
Six-Minute Walk Test (6MWT) ........................................................................ 20 
3.3.1.2 
St. George’s Respiratory Questionnaire .......................................................... 20 
3.3.1.3 
N-terminal pro-brain natriuretic peptide (NT-proBNP) ............................... 20 
3.3.1.4 
Optional Biomarker ........................................................................................... 20 
3.3.1.5 
Change in DSP.................................................................................................... 21 
3.3.2 
Safety ...................................................................................................................... 21 
3.3.2.1 
Physical Examinations ....................................................................................... 21 
3.3.2.2 
Vital Signs ........................................................................................................... 21 
3.3.2.3 
Clinical Laboratory Assessments ..................................................................... 22 
3.3.2.4 
Pulmonary Function Tests (PFTs) ................................................................... 22 
3.3.2.5 
Oxygenation ........................................................................................................ 23 
3.3.2.6 
Adverse Events ................................................................................................... 23 
3.3.2.7 
Concomitant Medications ................................................................................. 24 
3.3.2.8 
Hospitalization due to Cardiopulmonary Indications .................................... 24 
3.3.2.9 
Exacerbations of Underlying Lung Disease ..................................................... 24 
3.3.2.10 
Telephone/Email Contact .................................................................................. 25 


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3.3.2.11 
Continued Access Plan ...................................................................................... 25 
3.4 
NUMBER OF SUBJECTS ........................................................................................ 25 
3.5 
NUMBER OF CENTERS .......................................................................................... 26 
3.6 
ESTIMATED STUDY DURATION ......................................................................... 26 
4 SUBJECT ELIGIBILITY .............................................................................................. 26 
4.1 
INCLUSION CRITERIA .......................................................................................... 26 
4.2 
EXCLUSION CRITERIA ......................................................................................... 27 
4.3 
PRESCRIBED THERAPY ........................................................................................ 27 
5 SUBJECT ENROLLMENT ........................................................................................... 27 
5.1 
TREATMENT ASSIGNMENT ................................................................................ 27 
5.2 
RANDOMIZATION .................................................................................................. 27 
5.3 
BLINDING .................................................................................................................. 27 
6 DRUGS AND DOSING (OR TREATMENT PROCEDURES) ................................. 28 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE ................................. 28 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT ..................................... 29 
6.3 
COMPLIANCE .......................................................................................................... 29 
7 EXPERIMENTAL PROCEDURES ............................................................................. 30 
7.1 
BASELINE .................................................................................................................. 30 
7.2 
TREATMENT PHASE .............................................................................................. 31 
7.2.1 
Week 4 Visit ........................................................................................................... 31 
7.2.2 
Week 12 Visit ......................................................................................................... 32 
7.2.3 
Follow-up Visits (every 12 weeks after Week 12 until Week 108 / Study 
Termination) .......................................................................................................... 32 
7.3 
Week 108 / STUDY TERMINATION VISIT .......................................................... 33 
7.3.1 
Study Contacts ....................................................................................................... 34 
7.3.2 
Continued Access Plan .......................................................................................... 34 
8 STUDY TERMINATION ............................................................................................... 34 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ....................................................... 34 
8.2 
LOST TO FOLLOW-UP ........................................................................................... 35 
8.3 
CRITERIA FOR TERMINATING THE STUDY .................................................. 35 
8.4 
CRITERIA FOR DISCONTINUING THE SITE ................................................... 35 
9 ADVERSE EVENT REPORTING ................................................................................ 36 
9.1 
DEFINITIONS ........................................................................................................... 36 
9.1.1 
Adverse Event ........................................................................................................ 36 
9.1.2 
Serious Adverse Event .......................................................................................... 37 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ..................................................... 37 
9.3 
FOLLOW UP OF ADVERSE EVENTS .................................................................. 38 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ....................... 38 
9.5 
PREGNANCY ............................................................................................................ 39 
9.6 
SAFETY REPORTS .................................................................................................. 39 


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10 STATISTICAL CONSIDERATIONS .......................................................................... 39 
10.1 DATA PROCESSING ................................................................................................ 39 
10.2 SAMPLE SIZE ........................................................................................................... 40 
10.3 ANALYSIS PLAN ...................................................................................................... 40 
10.4 INTERIM ANALYSES .............................................................................................. 40 
10.5 OTHER ANALYSES ................................................................................................. 40 
10.6 DATA LISTINGS AND SUMMARIES ................................................................... 40 
10.7 DATA MONITORING COMMITTEE ................................................................... 40 
11 PACKAGING AND FORMULATION ........................................................................ 40 
11.1 CONTENTS OF STUDY DRUG .............................................................................. 40 
11.2 LABELING ................................................................................................................. 41 
11.3 STORAGE AND HANDLING OF CLINICAL TRIAL MATERIAL (CTM) .... 41 
11.4 SUPPLY AND RETURN OF CTM .......................................................................... 42 
11.5 DRUG ACCOUNTABILITY .................................................................................... 42 
12 REGULATORY AND ETHICAL OBLIGATION ...................................................... 43 
12.1 APPLICABLE REGULATORY REQUIREMENTS ............................................. 43 
12.2 INFORMED CONSENT REQUIREMENTS ......................................................... 43 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ....................................................................................................................... 43 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ......................................... 44 
12.5 SUBJECT CONFIDENTIALITY ............................................................................. 44 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 45 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .......................... 45 
13.2 STUDY DOCUMENTATION AND STORAGE .................................................... 45 
13.3 STUDY MONITORING AND DATA COLLECTION .......................................... 45 
14 REFERENCES ................................................................................................................ 47 
15 APPENDICES ................................................................................................................. 49 
15.1 PROCEDURE FOR SIX-MINUTE WALK TEST ................................................. 49 
15.2 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE 
EVENTS ...................................................................................................................... 51 
15.3 ST. GEORGE’S RESPIRATORY QUESTIONNAIRE ......................................... 55 
 


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TABLE OF IN-TEXT TABLES 
Table 6-1 Recommended Inhaled Treprostinil Dose Escalation Table ................................. 28 
 


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1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
Pulmonary hypertension (PH) is defined as an elevation in pulmonary arterial pressure and 
pulmonary vascular resistance.  The World Health Organization (WHO) classifies PH due to 
lung diseases and/or hypoxemia as WHO Group 3 PH (Simonneau 2009).  This classification 
includes PH due to interstitial lung disease (ILD) including combined pulmonary fibrosis and 
emphysema (CPFE).   
Interstitial lung disease encompasses a heterogeneous group of parenchymal lung diseases 
that are characterized by significant scarring or fibrosis of the bronchioles and alveolar sacs 
within the lungs.  Increased fibrotic tissue in ILD prevents oxygenation and free gas exchange 
between the pulmonary capillaries and alveolar sacs.  The symptomatology of ILD is non-
specific, and covers a wide range of symptoms, whose severity can vary substantially among 
patients.  The incidence of PH in ILD has been reported in up to 86% of patients and is 
associated with a poorer prognosis and decreased quality of life (Nathan 2008, Nathan 2013).   
Combined pulmonary fibrosis and emphysema characterized by emphysema, fibrosis, and 
abnormalities of gas exchange (Jankowich 2012).  Up to 50% of CPFE patients have been 
reported to develop PH with increased pulmonary vascular resistance (PVR) associated with a 
decreased survival (Cottin 2010; Seeger 2013). 
There are no approved treatments for PH in patients with ILD or CPFE; however, the results 
of some approved therapies for pulmonary arterial hypertension (PAH) have stimulated 
further investigation in these indications (Seeger 2013, Saggar 2014, Agarwal 2015, Roccia 
2013).   
1.2 
INHALED TREPROSTINIL BACKGROUND 
1.2.1 
General Pharmacology 
Treprostinil, 2-[[(1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-
hydroxyoctyl]-1Hbenz[f]inden-5-yl]oxy]acetic acid, is a chemically stable tricyclic analogue 
of prostacyclin.  The pharmacology of treprostinil is well-characterized and approved for the 


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treatment of PAH following either the subcutaneous (SC), intravenous (IV), inhaled (as 
treprostinil sodium), or oral (as treprostinil diolamine) routes of administration. 
Prostacyclin is known to lower pulmonary artery pressure, increase cardiac output without 
affecting the heart rate, improve systemic oxygen transport and possibly reverse pulmonary 
arterial remodeling.  There is increasing evidence that the ability to block the proliferation of 
pulmonary artery smooth muscle cells, along with vasodilation, may contribute to the 
therapeutic effects of prostacyclin in the treatment of PAH.  Treprostinil acts by triggering 
direct vasodilation of the 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 inhibited adenosine diphosphate induced 
platelet aggregation in human and rat platelet rich plasma.  In animals, the vasodilatory effects 
of treprostinil reduce right and left ventricular afterload, thereby increasing cardiac output and 
stroke volume.  The mechanism of action of treprostinil is therefore likely to be multifactorial. 
Treprostinil for inhalation (Tyvaso®) is approved in the United States and Israel for the 
treatment of PAH (WHO Group I) in patients with New York Heart Association (NYHA) 
functional classification III symptoms, to increase exercise ability.  
1.2.2 
General Toxicology 
A well-defined clinical safety profile exists for treprostinil sodium; acute toxicity studies, 
repeat-dose toxicity studies, reproductive toxicity studies, and genotoxicity studies have been 
performed in both rats and dogs and support the chronic administration to patients 
(Remodulin® Package Insert 2014). 
The toxicokinetic profile of treprostinil was also evaluated in acute and repeat dose toxicity 
studies of up to 13 weeks in duration in rodents and dogs which supported the chronic 
administration of inhaled treprostinil to patients.  In addition, a two-year rat carcinogenicity 
study was performed with treprostinil inhalation at target doses up to 5.26, 10.6, and 
34.1 mcg/kg/day which found no evidence for carcinogenic potential associated with inhaled 
treprostinil in rats at systemic exposure levels up to 35 times the clinical exposure at the target 


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maintenance dose of 54 mcg.  Refer to the inhaled treprostinil Clinical Investigators Brochure 
for a full description of nonclinical data. 
1.2.3 
Clinical Experience 
A series of acute and chronic investigator-initiated clinical studies were conducted with 
inhaled treprostinil to optimize the formulation for inhalation, determine dose response, 
tolerability, and safety and also to evaluate safety and tolerability when combined with other 
PAH therapies (Channick 2006, Voswinckel 2006).  In the acute dosing studies, 
administration of inhaled treprostinil resulted in pulmonary vasodilation at relatively low 
doses.  In the chronic studies, administration of inhaled treprostinil resulted in sustained 
improvement of exercise capacity. 
A randomized, double blind, placebo controlled, Phase III study (TRIUMPH-I) was 
conducted to assess the safety and efficacy of inhaled treprostinil in combination with 
approved PAH therapies.  Two hundred and thirty-five subjects who were clinically stable on 
an approved background oral PAH therapy (bosentan or sildenafil) were randomly allocated 
to receive either placebo or inhaled treprostinil for 12 weeks.  The primary efficacy endpoint 
was change in exercise capacity at Week 12 as measured by six-minute walk distance 
(6MWD).  At Week 12, subjects receiving inhaled treprostinil had a median improvement of 
+21.6 meters in 6MWD and subjects in the placebo group had a median improvement of 
+3.0 meters.  The Hodges-Lehmann placebo-corrected median change from baseline in peak 
6MWD was +20.0 meters (p=0.00044).  The durability of this result was supported by 
secondary measures related to the trough 6MWD, which was measured at least four hours 
after the last dose of inhaled treprostinil.  At Week 12, trough 6MWD showed a placebo-
corrected median treatment effect of 13.7 meters (p=0.0066).  The most commonly reported 
adverse events (AEs) in the inhaled treprostinil group were cough (54%), headache (41%), 
and nausea (19%).  There were no remarkable treatment related changes in vital signs, 
physical examination findings, chest x-rays, pulmonary function tests, or clinical laboratory 
parameters (McLaughlin 2010). 
An open-label, extension study of the TRIUMPH-I study to evaluate the use of long-term 
inhaled treprostinil therapy was also conducted (TRIUMPH-OL).  Subjects received one to 


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12 breaths (6 to 72 mcg) four times daily to achieve daily doses of 24 to 288 mcg.  The 
longest duration of inhaled treprostinil exposure in the open-label study was 5.4 years and the 
mean duration 2.3 years.  There were observed improvements in median 6MWD at 6, 12, 18 
and 24 months of 28, 31, 32 and 18 meters, respectively.  These data support the durability of 
improvement in 6MWD obtained with inhaled treprostinil as demonstrated during the double-
blind phase of the study.  Therapeutic benefit was also noted with improvements in the Borg 
dyspnea score, NYHA functional classification and quality of life (QOL).  Survival was 
robust with one and two year Kaplan-Meier survival estimates of 97% and 91%, respectively, 
for subjects that remained in the trial.  The most frequently reported AEs during the open-
label study were cough (39%), headache (31%), upper respiratory tract infection (22%), and 
nausea (22%).  There were no clinically significant changes in clinical chemistry or 
hematology parameters.  Unique findings that related to the inhaled route of administration, in 
addition to cough, were throat pain and throat irritation, occurring in 12% and 10% of 
subjects, respectively.  These events were usually of mild or moderate severity and transient 
in duration.  In a few subjects, these specific AEs were more pronounced as six subjects (3%) 
discontinued inhaled treprostinil due to cough, including one subject (<1%) with dry throat 
(Benza 2011). 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION  
Inhaled treprostinil has shown clinical improvements in exercise capacity after 12 weeks of 
therapy in patients with WHO Group I PH (McLaughlin 2010).  Inhaled treprostinil is 
expected to directly target the more ventilated portion of the lungs in patients with WHO 
Group 3 PH minimizing the risk of ventilation perfusion mismatch and allowing for 
improvements in exercise capacity (Seeger 2013).   
The use of inhaled prostacyclin therapy in patients with WHO Group 3 PH has been recently 
evaluated.  In particular, Wang and colleagues (Wang 2015) reported data on 67 COPD 
patients with PH and found no change in arterial blood gases when a single dose of iloprost 
was administered during right heart catheterization (RHC).  In addition, Bajwa and colleagues 
recently completed a prospective 16-Week study in nine COPD subjects with PH which 


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reported no notable changes in arterial blood gases over the 16-Week treatment period 
(Bajwa submitted).  Finally, Agarwal and colleagues (Agarwal 2015) recently presented data 
on 35 patients with WHO Group 3 PH who received treatment with inhaled treprostinil for six 
months.  This retrospective review reported a mean increase from baseline in 6MWD of 
61 meters with obstructive and restrictive patients reporting mean increases of 71 meters and 
50 meters, respectively.  Notably, this study also found that inhaled treprostinil was well 
tolerated with cough being the most commonly reported AE.  Data from these recently 
completed pilot studies suggest that inhaled treprostinil can be safely administered in patients 
with WHO Group 3 PH.  
1.4 
CLINICAL HYPOTHESIS 
This open-label study will evaluate the safety of continued therapy with inhaled treprostinil in 
subjects who have completed RIN-PH-201.  This study hypothesizes that long-term safety 
findings will be similar to those observed in the randomized, placebo controlled study (RIN-
PH-201).   
2 
OBJECTIVES 
The primary objective of this study is to provide or continue to provide inhaled treprostinil for 
eligible subjects who participated in the RIN-PH-201 study. 
Secondary objectives are to assess the long-term safety and efficacy of inhaled treprostinil in 
subjects with PH associated with ILD including CPFE. 
2.1 
EFFICACY ENDPOINTS 
To evaluate the effect of continued long-term therapy with inhaled treprostinil on the 
following: 
1. Peak 6MWD 
2. N-terminal pro-Brain Natriuretic Peptide (NT-proBNP)  
3. Quality of life as measured by the St. George's Respiratory Questionnaire (SGRQ) 
4. Optional evaluation of change in biomarkers (specific targets to be determined) from 
Baseline to Week 48 (or study discontinuation if prior to Week 48) 
5. Change in distance saturation product (DSP)  


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2.2 
SAFETY ENDPOINTS  
To evaluate the effect of continued long-term therapy with inhaled treprostinil on the 
following: 
1. Adverse events (AEs) 
2. Oxygenation  
a. Pulse oximetry (saturation of peripheral capillary oxygenation [SpO2]) 
b. Supplemental oxygen (L/min) requirement  
3. Pulmonary function: 
a. Forced expiratory volume in one second (FEV1) 
b. Forced vital capacity (FVC) 
c. Total lung capacity (TLC) 
d. Lung diffusion capacity (DLCO) 
4. Clinical laboratory parameters 
5. Vital signs 
6. Hospitalizations due to a cardiopulmonary indication 
7. Exacerbations of underlying lung disease; defined as an acute, clinically significant, 
respiratory deterioration characterized by evidence of new widespread alveolar 
abnormality. 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a multi-center, open-label study.  Study visits will occur at Baseline, Weeks 4, 12, and 
every 12 weeks thereafter until Week 108.  The study will continue until each subject has 
completed Week 108 or until inhaled treprostinil become commercially available for patients 
with pre-capillary PH associated with ILD including CPFE (whichever is sooner). 
A schedule of study visits and assessments is presented in Section 3.2. 


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3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
Study Procedures 
Baseline1 
Treatment Phase 
Study Week 
 
Week 42 
Week 122 
Follow-up Visits  
(every 12 weeks 
through study 
termination)2 
Week 108 / Study 
Termination Visit 
Informed Consent1 
X 
 
 
 
 
Subject Eligibility1 
X 
 
 
 
 
SGRQ1 
X 
 
 
X13 
X 
Physical Examination1 
X 
 
 
 
X 
Vital Signs1,3 
X 
X 
X 
X 
X 
Clinical Laboratory Assessments1 
X 
X 
X 
X 
X 
N-terminal proBNP1,4 
X 
 
 
X13 
X 
Blood sample for biomarker 
evaluation (optional)5 
X 
 
 
X13 
X13 
Urine Pregnancy Test1,6 
X 
X 
X 
X 
X 
Peak 6MWT1,7 
X 
X 
X 
X 
X 
Pulse Oximetry1,8 
X 
X 
X 
X 
X 
Documentation of Supplemental 
Oxygen Requirement  
X 
X 
X 
X 
X 
PFTs1,9 
X 
 
X 
X13 
X 
Dosing instructions / Dosing / 
Accountability 
X 
X 
X 
X 
X 
Telephone/Email Contact10 
 
X 
X 
X 
 
Adverse Events11,12 
X 
X 
X 
X 
X 
Concomitant Medications  
X 
X 
X 
X 
X 
Hospitalizations14 
X 
X 
X 
X 
X 
Exacerbations of Underlying Lung 
Disease15 
X 
X 
X 
X 
X 


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NT-ProBNP: N-terminal brain natriuretic peptide; PFTs: pulmonary function tests; PH: pulmonary hypertension; SGRQ: St. George Respiratory Questionnaire; 
6MWT: six-minute walk test  
1  Baseline assessments (6MWT, pulse oximetry, PFTs, SGRQ, clinical laboratory assessments, NT-ProBNP, urine pregnancy test, optional biomarker sample [as 
applicable], vitals, and physical examination) for this study are those collected at the Study Termination Visit (Week 16) from study RIN-PH-201 and prior to 
initiation of open-label study drug.  Informed consent and subject eligibility criteria are exclusive to this protocol.   
2  The visit window for the Week 4 visit is ± 5 days; the visit window for all other visits  is ± 14 days.  Visits are scheduled based off of the day of first dose of 
study drug for the RIN-PH-202 study (i.e., four weeks after the first dose of study drug in this open-label study).  
3  Vital signs must be collected after five minutes of rest (seated); no other measurements or procedures should be performed during this five minute period.  When 
applicable, vital signs should be collected prior to the 6MWT.  If vital signs cannot be obtained prior to the 6MWT then they should be obtained after recovery 
from the 6MWT.  Vital signs measured will include blood pressure (systolic and diastolic), heart rate (HR), respiratory rate (RR), temperature, and weight.   
4  Blood for NT-proBNP assessment must be drawn prior to conducting the 6MWT at Week 48 and Study Termination.   
5  For subjects consenting to the optional biomarker sample.  The optional biomarker sample must be drawn prior to conducting the 6MWT at Week 48 only or 
upon early termination if subjects discontinue the study prior to Week 48. 
6  For females of childbearing potential.   
7  The peak 6MWT must occur within 10 to 60 minutes after the most recent study drug dose.  Prior to the start of each 6MWT the subject should rest (seated) for 
at least 10 minutes.  
8  Pulse oximetry will be performed immediately prior to, during, and immediately after each 6MWT.  Pulse oximetry will include the measurement of SpO2 and 
HR.  The SpO2 and HR obtained immediately prior to and immediately following completion of the 6MWT will be recorded in the eCRF.  In addition, the 
lowest recorded SpO2 (and corresponding HR) obtained during each 6MWT will be recorded in the eCRF.  
9  PFTs will include the evaluation of FEV1, FVC, TLC, and DLCO.  PFTs should be performed after recovering from the 6MWT. 
10  Telephone contact should occur at least weekly for the first 12 weeks of the study and at least monthly thereafter.  Telephone contact may be replaced by a 
face-to-face interaction on the weeks where study visits occur and the information can be obtained during the visit.  Subjects may be contacted via email in 
lieu of a telephone call.  A copy of the emails and/or telephone contact sheets must be documented in the subject’s source documentation.  Email should not 
replace direct follow-up by phone or in clinic for clinically significant AEs or other emergent issues.  
11  Any AEs that are ongoing at the Study Termination Visit from study RIN-PH-201 should be recorded as continuing AEs in this open-label study. 
12  Any AEs that are ongoing at the Study Termination Visit for this protocol (RIN-PH-202) should be followed for up to 30 days after completion of the Study 
Termination Visit.  
13  During the follow-up assessments (scheduled every 12 weeks after Week 12), the SRGQ, PFTs, and NT-pre-BNP are only required at Week 48 and Week 
108/Study Termination.  For those subjects consenting to the optional biomarker sample, this sample is only required at Week 48 (or upon early termination if 
prior to Week 48).  
14  Hospitalizations due to cardiopulmonary indications must be recorded in the eCRF from the time of informed consent until study termination.  Adverse events 
resulting in hospitalizations, regardless of cause or duration, should also be recorded as SAEs per Appendix 15.2.  
15  Exacerbations of underlying lung disease; defined as an acute, clinically significant, respiratory deterioration characterized by evidence of new widespread 
alveolar abnormality.  Exacerbations will also be recorded as AEs.   


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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
3.3.1.1 
Six-Minute Walk Test (6MWT) 
The 6MWT is a validated and reliable measure of exercise capacity in patients with chronic 
respiratory diseases (Holland 2014).  This study will utilize an unencouraged peak 6MWT to 
minimize potential bias associated with encouragement.  All 6MWTs will be conducted by 
qualified, trained personnel in a designated 6MWT area which meets the requirements as 
described in Appendix 15.1.  Prior to the start of each 6MWT the subject must rest (seated) 
for at least 10 minutes.  The peak 6MWT must be conducted between 10 to 60 minutes after 
the most recent dose of study drug.   
A peak 6MWT will be conducted at Baseline as part of the Study Termination (Week 16) 
assessments from protocol RIN-PH-201.  A peak 6MWT will also be performed at Week 4, 
Week 12, every 12 weeks thereafter, and at Week 108/Study Termination.   
3.3.1.2 
St. George’s Respiratory Questionnaire 
The SGRQ will be conducted at Baseline as part of the Study Termination (Week 16) 
assessments from protocol RIN-PH-201.  The SGRQ will also be conducted at Week 48 and 
at Week 108/Study Termination.  The SGRQ should be completed as the first assessment 
during these visits before the subject completes any of the other scheduled visit assessments.  
A copy of the SGRQ can be found in Appendix 15.3. 
3.3.1.3 
N-terminal pro-brain natriuretic peptide (NT-proBNP) 
Plasma NT-proBNP concentration is a useful biomarker associated with changes in right heart 
morphology and function (Fijalkowska 2006).  NT-proBNP sample collection will occur at 
Baseline as part of the Study Termination (Week 16) assessments from protocol RIN-PH-201.  
NT-proBNP will also be collected at Week 48 and at Week 108/Study Termination.  Blood 
for NT-proBNP assessment must be drawn prior to conducting the 6MWT. 
3.3.1.4 
Optional Biomarker 
For subjects consenting to the optional biomarker sample, blood will be collected for the 
evaluation of biomarkers (specific targets to be determined) at Baseline as part of the Study 


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Termination (Week 16) assessments from protocol RIN-PH-201 and at Week 48 (or upon 
early termination if prior to Week 48). 
3.3.1.5 
Change in DSP  
Change in DSP is the product of distance walked and lowest oxygen saturation recorded 
during the 6MWT.  This assessment has been shown to be predictive of mortality in patients 
with idiopathic pulmonary fibrosis and as such will be evaluated as an exploratory endpoint in 
this study (Lettieri 2006).  Change in DSP will be calculated from Baseline to Week 4, 
Week 12, every 12 weeks thereafter, and at Week 108/Study Termination.  
3.3.2 
Safety 
During this study, treatment emergent changes in physical examination (PE) findings, vital 
signs, clinical laboratory parameters, PFTs, oxygenation, hospitalizations due to a 
cardiopulmonary indication, exacerbations of underlying lung disease, and the development 
of AEs after treatment will be the primary assessments of safety.   
3.3.2.1 
Physical Examinations 
A complete physical examination (PE) will be conducted during Baseline as part of the Study 
Termination (Week 16) assessments from protocol RIN-PH-201.  A follow-up PE will also be 
performed at the Study Termination Visit.  Any clinically significant changes from Baseline 
noted during the course of the study or during the Study Termination PE should be reported as 
AEs.     
3.3.2.2 
Vital Signs 
Vital signs will be assessed at Baseline as part of the Study Termination (Week 16) 
assessments from protocol RIN-PH-201 and at each subsequent study visit and at the Study 
Termination Visit.  Vital signs measured will include blood pressure (systolic and diastolic), 
heart rate (HR), respiratory rate (RR), temperature, 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.  When 
applicable, vital signs should be collected prior to the 6MWT.  If vital signs cannot be 
obtained prior to the 6MWT, they should be obtained after recovery from the 6MWT.  Vital 
signs should also be assessed in the case of abnormal clinical signs and symptoms. 


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3.3.2.3 
Clinical Laboratory Assessments 
Clinical laboratory parameters will be assessed at Baseline as part of Study Termination 
assessments from protocol RIN-PH-201.  Clinical laboratory assessments will also be 
assessed at Week 4, Week 12, at every scheduled Follow-up Visit thereafter, and at the Week 
108/Study Termination Visit.  Clinical laboratory parameters to be assessed at the study visits 
are listed below: 
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 
 
Clinical laboratory results outside the normal reference range must be assessed for clinical 
significance by the Investigator.  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 reported as AEs and treated and/or 
followed-up until the symptoms or values return to normal or acceptable levels, as judged by 
the Investigator.  Where appropriate, medical tests and examinations will be performed to 
assess and document resolution. 
A urine pregnancy test will be collected at every visit for females of childbearing potential.  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. 
3.3.2.4 
Pulmonary Function Tests (PFTs) 
Pulmonary Function Tests (PFTs) will be assessed at Baseline as part of the Study 
Termination (Week 16) assessments from protocol RIN-PH-201 and at Week 12, Week 48, 
and at Week 108/Study Termination.  If the PFT is done both prior to and after a 


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bronchodilator, only the pre-bronchodilator values will be recorded.  Pulmonary function tests 
should be conducted after recovery from the 6MWT.   
The following parameters will be recorded (absolute values and % predicted): FEV1, FVC, 
TLC, and DLCO (uncorrected for hemoglobin and lung volume). 
3.3.2.5 
Oxygenation 
3.3.2.5.1 
Pulse Oximetry 
Pulse oximetry will be assessed immediately prior to, throughout the conduct of, and 
immediately after each scheduled 6MWT assessment at Baseline (as part of the RIN-PH-201 
Study Termination Visit), Week 4, Week 12, every 12 weeks thereafter, and at Study 
Termination.  Pulse oximetry will include the collection of SpO2 and HR.  The SpO2 and HR 
obtained immediately prior to and immediately following completion of the 6MWT will be 
recorded in the electronic case report form (eCRF).  In addition, the lowest recorded SpO2 
with the associated HR obtained during each 6MWT will be recorded in the eCRF. 
When possible, pulse oximetry should be recorded using the provided pulse oximeter 
(Nonin 3150).  In the event the provided pulse oximeter cannot be used (i.e., subject has 
known issues with obtaining accurate readings from a finger probe, etc.) an alternative device 
may be used with prior sponsor approval so long as the same device is used for all planned 
6MWT.   
3.3.2.5.2 
Supplemental Oxygen Requirement 
The amount of supplemental oxygen (L/min) required at rest will be assessed at Baseline and 
at regularly scheduled visits.  The amount of supplemental oxygen required at the 6MWT 
assessment will also be recorded for each 6MWT assessment. 
3.3.2.6 
Adverse Events 
Any AEs that are ongoing at the Study Termination Visit for the RIN-PH-201 study should be 
recorded as continuing AEs in this open-label study. 
Adverse events will be recorded throughout the course of the study from the time that each 
subject signs the ICF until the subject is either discontinued from the study or all Study 
Termination assessments have been completed.  Each subject will be questioned for AEs at 


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each scheduled study visit and during required telephone/email contacts.  Subjects will also be 
instructed to spontaneously report all AEs throughout the study.  
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 (Study Termination).  All AEs/SAEs that occur while the subject is on study 
drug will be recorded as instructed in this protocol. 
Sections 9 and 15.2 provide the guidelines and definitions for recording AEs. 
3.3.2.7 
Concomitant Medications 
All concomitant medications taken during the conduct of the study, including those taken for 
AEs or other medical events, should be recorded in the subject’s source documents and 
captured in the eCRF as required.  Concomitant medications that were ongoing at the end of 
the RIN-PH-201 study will be recorded in the eCRF for the open-label study. 
3.3.2.8 
Hospitalization due to Cardiopulmonary Indications 
Hospitalizations due to cardiopulmonary indications must be recorded in the eCRF from the 
time of informed consent until study termination.  Adverse events resulting in 
hospitalizations, regardless of cause or duration should also be recorded as SAEs per 
Appendix 15.2.  Please note that, when possible, study medication should be continued during 
hospitalizations.   
3.3.2.9 
Exacerbations of Underlying Lung Disease 
An exacerbation of underlying lung disease is defined as an acute, clinically significant, 
respiratory deterioration characterized by evidence of new widespread alveolar abnormality 
(Collard 2016).   
As adapted from the publication by Collard and colleagues (Collard 2016), the following 
diagnostic criteria may be used to help support a diagnosis of acute exacerbation: 


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1. Previous or concurrent diagnosis of ILD including CPFE 
2. Acute worsening or development of dyspnea  typically of less than one month duration 
3. CT with new bilateral ground-glass opacity and/or consolidation superimposed on a 
background pattern consistent with usual interstitial pneumonia pattern 
4. Deterioration not fully explained by cardiac failure or fluid overload 
For the purposes of this protocol, events that are clinically considered to meet the definition of 
acute exacerbation but fail to meet all four diagnostic criteria due to missing CT data should 
still be considered an exacerbation for reporting purposes. 
Exacerbations of underlying lung disease should be recorded throughout the duration of the 
study from the time of informed consent until study termination.  Exacerbations of underlying 
lung disease will also be reported as AEs or SAEs per Appendix 15.2. 
3.3.2.10 
Telephone/Email Contact 
Weekly telephone/email contact is required for the first 12 weeks of the study to instruct the 
subject to titrate their dose of study drug and to assess for AEs and concomitant medications.  
After the first 12 weeks, telephone/email contact must occur at least monthly.  
Telephone/email contact may be replaced by a face-to-face interaction on the weeks where 
study visits occur and the information can be obtained during the visit.  The subject 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 clinically 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. 
3.3.2.11 
Continued Access Plan 
Subjects who have completed the Week 108/Study Termination Visit will be given the option 
for continued access to inhaled treprostinil.  During Week 108/Study Termination Visit, the 
Investigator should assess each subject’s eligibility for the Continued Access Plan. 
3.4 
NUMBER OF SUBJECTS 
Approximately 266 subjects who completed protocol RIN-PH-201. 


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3.5 
NUMBER OF CENTERS 
This study is a multi-center with approximately 100 participating study centers.  Only those 
centers who participated in the RIN-PH-201 study will take part in this study. 
3.6 
ESTIMATED STUDY DURATION 
The study will continue until each subject reaches Week 108 or until inhaled treprostinil 
become commercially available for patients with pre-capillary PH associated with ILD 
(whichever is sooner).   
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 open-label study drug.  Study related 
procedures must be conducted during the Screening period after obtaining informed consent 
to determine subject eligibility for the study. 
4.1 
INCLUSION CRITERIA 
1. Subject voluntarily gives informed consent to participate in the study. 
2. The subject participated in study RIN-PH-201 and: 
a. remained on study drug and completed all scheduled study visits or 
b. permanently discontinued study drug during the RIN-PH-201 study due to 
clinical worsening and completed all remaining required scheduled study visits 
or  
c. was enrolled in study RIN-PH-201 at the time that the study/study subject was 
discontinued by the sponsor. 
3. Females of reproductive potential1 must be non-pregnant (as confirmed by a urine 
pregnancy test at Baseline) and non-lactating, and will: 
a. Either abstain from intercourse (when it is in line with their preferred and usual 
lifestyle), or  
b. Use two medically acceptable, highly-effective forms of contraception2 for the 
duration of study, and at least 30 days after discontinuing study drug.   
4. Males must use a condom for the duration of treatment and for at least 48 hours after 
discontinuing study drug. 
1  Females who are successfully sterilized (surgical sterilization methods include hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or are postmenopausal (defined as amenorrhea for at least 12 consecutive months) are 
not considered to be of reproductive potential. 
2  Medically acceptable, highly-effective forms of contraception can include approved hormonal contraceptives (oral, 
injectable, and implantable), and barrier methods (such as a condom or diaphragm) when used with a spermicide.  
For women of reproductive potential, a negative pregnancy test is required at Screening and Baseline prior to 
initiating study drug. 


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4.2 
EXCLUSION CRITERIA 
1. The subject is pregnant or lactating. 
2. The subject was prematurely discontinued from study RIN-PH-201 due to treatment 
related AEs. 
3. The subject was prematurely discontinued from study RIN-PH-201 due to clinical 
worsening and did not undergo premature termination assessments prior to 
discontinuing study drug and/or did not complete all remaining study visits through 
the final scheduled visit. 
4. The subject developed a concurrent illness or condition during the conduct of RIN-
PH-201 which, in the opinion of the Investigator, would represent a risk to overall 
health if they enrolled in this study. 
4.3 
PRESCRIBED THERAPY 
In this open-label study, there are no restrictions on concomitant medications with the 
exception of the permanent addition (29 days or more) of infused prostacyclin therapy.  
Subjects who receive permanent infused prostacyclin therapy must discontinue this open-label 
study.   
All concomitant medications taken during the conduct of the study, including those taken for 
AEs or other medical events, should be recorded in the subject’s source documents and 
transcribed into the eCRF as required.  The flow rate of supplemental oxygen should be 
recorded as outlined in Section 3.3.2.5.2.   
Subjects who initiate pulmonary rehabilitation during the course of the study should also 
record this information in the eCRF. 
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
All subjects will receive inhaled treprostinil during this open-label study.  Subjects will retain 
the same subject number as assigned for the RIN-PH-201 study.   
5.2 
RANDOMIZATION 
This study is not randomized.   
5.3 
BLINDING 
This study is not blinded.   


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6 
DRUGS AND DOSING (OR TREATMENT PROCEDURES) 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE 
Treprostinil for inhalation solution (0.6 mg/mL) is delivered via an ultrasonic nebulizer which 
emits a dose of approximately 6 mcg per breath.  All subjects will receive study drug (inhaled 
treprostinil) using the commercially available TD-100 ultrasonic nebulizer (Tyvaso Inhalation 
System®).  Subjects will be trained on inhalation of study drug using the nebulizer device.  
Detailed instructions for the use of these devices will be provided to all study subjects.  In 
addition, all subjects will receive a copy of the commercially available Tyvaso Inhalation 
System Instructions for Use (IFU) for the TD-100 ultrasonic nebulizer.    
All subjects will initiate study therapy at 3 breaths (18 mcg) regardless of treatment 
assignment or dose in the randomized study.  Open-label study drug will be initiated after 
study drug is discontinued from the RIN-PH-201 (blinded study) and after the subject has 
signed informed consent and enrolled into the open-label study.  Study drug doses should be 
maximized throughout the study, dose escalations (additional one breath four times daily) can 
occur up to every three days with a maximum dosing regimen of up to 15 breaths (90 mcg) 
four times daily, as clinically tolerated.  Table 6-1 provides a guideline for recommended dose 
escalations. 
Table 6-1 
Recommended Inhaled Treprostinil Dose Escalation Table 
Study Day1 
Single Dose 
Total Daily Dose 
Titrating to maximum dose of up to 15 breaths as clinically tolerated 
1-3 
3 breaths QID (18 mcg) 
72 mcg 
4-6 
4 breaths QID (24 mcg) 
96 mcg 
7-9 
5 breaths QID (30 mcg) 
120 mcg 
10-12 
6 breaths QID (36 mcg) 
144 mcg 
13-15 
7 breaths QID (42 mcg) 
168 mcg 
16-18 
8 breaths QID (48 mcg) 
192 mcg 
19-21 
9 breaths QID (54 mcg) 
216 mcg 
22-24 
10 breaths QID (60 mcg) 
240 mcg 
25-27 
11 breaths QID (66 mcg) 
264 mcg 
28-30 
12 breaths QID (72 mcg) 
288 mcg 
31 (and beyond) 
Up to 15 breaths QID (90 mcg) 
360 mcg 
* 
QID: four times daily; mcg: micrograms 
1  Study day refers to the days on study drug with Day 1 referring to the first dose of study drug. 


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The dosing schedule is recommended as a guide only.  The Investigator may determine the 
appropriate dosing schedule on an individual subject basis, considering tolerability and 
functional improvement.  More frequent dose titrations may be considered at the discretion of 
the treating physician.   
If subjects are unable to tolerate the initial three breaths, they may decrease their next dose to 
one or two breaths of study drug (as determined by the Investigator) four times a day during 
waking hours.  The subject will then gradually increase their dose to reach a minimum of 
three breaths and titrate to up to a maximum of 15 breaths four times a day during waking 
hours. 
Dose changes should be conducted under appropriate medical supervision in consultation with 
the study site.  Telephone calls/emails between the site and subject should occur prior to each 
dose adjustment or at least weekly for the first 12 weeks (and monthly thereafter) to monitor 
for AEs and make decisions about dose titration.   
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
This study is not blinded. 
6.3 
COMPLIANCE 
Subjects will be required to bring all empty study drug ampoules to each scheduled study 
visit.  Starting at Week 12, all study drug returned by the subject (used and unused) will be 
collected and new study drug will be dispensed.  Study drug will not be supplied at the Week 
4 visit unless required for emergency purposes (i.e., to replace lost study drug, etc.); however, 
the subject should still return empty drug ampules for drug accountability purposes.  The 
appropriate study personnel must document the number of used and unused ampoules and 
determine if the appropriate amount of study drug remains based on the dose of study drug 
prescribed.   
Subject compliance with the prescribed dosage regimen will be monitored throughout the 
study.  At each study visit, the subject will be asked whether he or she has been compliant 
with dosing instructions.  If it is determined that a subject is not compliant with study drug 
then site personnel must re-educate the subject on proper dosing compliance and its 


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importance.  Continued non-compliance may lead to withdrawal of the subject from the study, 
after consultation between the Investigator and the Sponsor. 
Subjects may use a dosing diary to track dosing during the open-label study at discretion of 
the investigator/subject.   
7 
EXPERIMENTAL PROCEDURES 
7.1 
BASELINE 
All data collected at the subject’s Study Termination Visit (Week 16) during RIN-PH-201 and 
prior to initiating open-label study drug will serve as Baseline assessments for this study.  
Subjects must sign an informed consent form and meet inclusion/exclusion criteria specific to 
this protocol.  The recommended sequence of events for Baseline is displayed below: 
 Informed consent (prior to any study assessments) 
 Inclusion/exclusion criteria 
 SGRQ (questionnaire must be administered prior to any results, procedures, or blood 
draws)* 
 Physical examination* 
 Vital signs (following at least five minutes of rest; collected prior to 6MWT or after 
recovery from the 6MWT)* 
 Urine pregnancy test, for women of childbearing potential* 
 Blood draws for clinical laboratory parameters* 
 NT-proBNP (must be drawn prior to 6MWT)* 
 Collection of blood sample for evaluation of biomarkers (optional)* 
 Peak 6MWT (must be conducted between 10 to 60 minutes after the most recent dose 
of study drug and following at least 10 minutes of rest [sitting])* 
 Pulse oximetry (to be performed immediately prior to and throughout the conduct of 
the 6MWT)* 
 Documentation of supplemental oxygenation requirement (L/min) 
 PFTs (to be performed after recovery from the 6MWT)* 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 Adverse events  
 Concomitant medications* 
 Study drug administration (all subjects will be initiated on inhaled treprostinil at a 
dose of 3 breaths four times daily during waking hours).   


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*Assessments conducted during the Study Termination Visit (Week 16) for the RIN-PH-201 study will not need to be 
repeated. 
Adverse events that were ongoing at the end of the RIN-PH-201 study will be recorded as 
ongoing events for this open-label study.  Concomitant medications that were ongoing at the 
RIN-PH-201 Study Termination Visit will be recorded in the eCRF for the open-label study.  
Once the subject signs the informed consent form for this study, all AEs must be recorded and 
documented in the eCRF for this study until the time of study discontinuation.  Telephone 
calls/email to the subject must begin within one week of the subject receiving the first dose of 
study drug and continue to be made weekly for the first 12 weeks of the study.  After the first 
12 weeks, phone calls must be made at least monthly.  Dose titration should occur as outlined 
in Section 6.1. 
7.2 
TREATMENT PHASE 
7.2.1 
Week 4 Visit 
Subjects are to return to the study site at Week 4.  This visit should be conducted within ± 
5 days of the scheduled visit (as determined by the first dose of open-label study drug).  The 
recommended sequence of events for the Week 4 visit is below: 
 Blood draws for clinical laboratory parameters  
 Urine pregnancy test, for women of childbearing potential 
 Vital signs (following at least five minutes of rest) 
 Peak 6MWT (must be conducted between 10 to 60 minutes after the most recent dose 
of study drug and following at least 10 minutes of rest [sitting]) 
 Pulse oximetry (to be performed immediately prior to, throughout the conduct of, and 
immediately following the 6MWT) 
 Documentation of supplemental oxygenation requirement (L/min) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 Adverse events  
 Concomitant medications 
 Study drug accountability (Study drug will be returned but not be supplied at the 
Week 4 visit unless required for emergency purposes [i.e., to replace lost study drug, 
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Telephone calls/email to the subject should continue to be made weekly for the first 12 weeks 
of the study.  After the first 12 weeks, phone calls must be made at least monthly.  Dose 
titration should occur as needed in occurrence with Section 6.1. 
7.2.2 
Week 12 Visit 
Subjects are to return to the study site at Week 12.  This visit should be conducted within 
± 14 days of the scheduled visit (as determined by the first dose of open-label study drug).  
The recommended sequence of events for the Week 12 visit is below: 
 Blood draws for clinical laboratory parameters  
 Urine pregnancy test, for women of childbearing potential 
 Vital signs (following at least five minutes of rest) 
 Peak 6MWT (must be conducted between 10 to 60 minutes after the most recent dose 
of study drug and following at least 10 minutes of rest [sitting]) 
 Pulse oximetry (to be performed immediately prior to, throughout the conduct of, and 
immediately following the 6MWT) 
 Documentation of supplemental oxygenation requirement (L/min) 
 PFTs (to be performed after recovery from the 6MWT) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 Adverse events  
 Concomitant medications 
 Study drug accountability  
Telephone calls/email to the subject should continue to be made at least monthly for the 
remainder of the study.   
7.2.3 
Follow-up Visits (every 12 weeks after Week 12 until Week 108 / Study 
Termination) 
Subjects are to return to the study site every 12 weeks after Week 12 (as determined by the 
first dose of open-label study drug).  These visits should be conducted within ± 14 days of the 
scheduled visit (as determined by the first dose of open-label study drug).  The recommended 
sequence of events for the follow-up visits is below: 
 SGRQ (questionnaire must be administered prior to any results, procedures, or blood 
draws; Week 48 ONLY)* 


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 Urine pregnancy test, for women of childbearing potential  
 Blood draws for clinical laboratory parameters  
 NT-proBNP (must be drawn prior to 6MWT; Week 48 ONLY)* 
 Collection of blood sample for evaluation of biomarkers (optional; Week 48 ONLY) 
 Vital signs (following at least five minutes of rest) 
 Peak 6MWT (must be conducted between 10 to 60 minutes after the most recent dose 
of study drug and following at least 10 minutes of rest [sitting]) 
 Pulse oximetry (to be performed immediately prior to, throughout the conduct of, and 
immediately following the 6MWT) 
 Documentation of supplemental oxygenation requirement (L/min) 
 PFTs (to be performed after recovery from the 6MWT; Week 48 ONLY)* 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 Adverse events  
 Concomitant medications 
 Study drug accountability  
*Assessments conducted during the Week 48 visits ONLY. 
Telephone calls/email to the subject should continue to be made at least monthly for the 
remainder of the study.   
7.3 
WEEK 108 / STUDY TERMINATION VISIT 
The Week 108 visit will be the Study Termination Visit.  In addition, if a subject discontinues 
the study prior to Week 108, they will complete a Study Termination Visit.  If possible, each 
subject should remain on study drug until they have completed the Study Termination Visit.  
The following assessments will occur at the Study Termination Visit: 
 SGRQ (questionnaire must be administered prior to any results, procedures, or blood 
draws) 
 Physical examination 
 Vital signs (following at least five minutes of rest; collected prior to 6MWT or after 
recovery from the 6MWT) 
 Urine pregnancy test, for women of childbearing potential 
 Blood draws for clinical laboratory parameters 
 NT-proBNP (must be drawn prior to 6MWT) 
 Collection of blood sample for evaluation of biomarkers (optional; only in those 
subjects who discontinue prior to Week 48) 


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 Peak 6MWT (must be conducted between 10 to 60 minutes after the most recent dose 
of study drug and following at least 10 minutes of rest [sitting]) 
 Pulse oximetry (to be performed immediately prior to, throughout the conduct of, and 
immediately following the 6MWT) 
 Documentation of supplemental oxygenation requirement (L/min) 
 PFTs (to be performed after recovery from the 6MWT) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 Adverse events  
 Concomitant medications 
 Study drug accountability 
7.3.1 
Study Contacts 
All subjects will be contacted at least once a week for the first 12 weeks and then monthly 
thereafter via telephone or email (or more often as needed) to follow-up on adherence of the 
correct dose titration of study drug, and to assess for AEs and concomitant medications.  A 
copy of emails and/or telephone contact sheets must be documented in the subject’s source 
documentation.  Email should not replace direct follow-up by telephone or in clinic for 
clinically significant AEs or other emergent issues.  All study contacts (i.e., any dosing 
instructions, AEs reported, and/or medication changes) with the subject will be recorded.  
The weekly study contacts may be replaced by a face-to-face interaction on the weeks where 
study visits occur and the information can be obtained during the visit.  
7.3.2 
Continued Access Plan 
Subjects who have completed the Week 108/Study Termination Visit will be given the option 
for continued access to inhaled treprostinil (Section 3.3.2.11).  During Week 108/Study 
Termination 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 study drug by the 
Investigator at any time for reasons including, but not limited to, the following: 


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 The subject wishes to withdraw from further participation. 
 A serious or life-threatening AE occurs or the Investigator considers that it is 
necessary to discontinue study drug to protect the safety of the subject. 
 The subject consistently deviated from the protocol. 
 The subject’s behavior is likely to undermine the validity of his/her results. 
 The subject permanently initiates an infused prostacyclin therapy for >29 days. 
 The subject becomes pregnant. 
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 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 study drug 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 AE extends beyond the final visit. 
8.2 
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 subject to 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. 
8.3 
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. 
8.4 
CRITERIA FOR DISCONTINUING THE SITE 
The study may also be terminated at a given site if: 
 The Investigator elects to discontinue the study. 


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 The Sponsor elects to discontinue the study at the site. 
 U.S. Food and Drug Administration (FDA), European, or national regulations are not 
observed. 
 The protocol is consistently violated. 
 Changes in personnel or facilities adversely affect performance of the study. 
9 
ADVERSE EVENT REPORTING  
9.1 
DEFINITIONS 
9.1.1 
Adverse Event  
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product which does not necessarily have to have a causal relationship with this treatment.  An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not related to the use of the medicinal product. 
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 AE. 
 Planned surgical measures permitted by the study protocol and the condition(s) 
leading to these measures are not AEs. 
 Day to day fluctuations of pre-existing disease or conditions present or detected at the 
 start of the study that do not worsen. 
 Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalizations for cosmetic elective surgery, social and/or convenience admissions). 


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 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. 
9.1.2 
Serious Adverse Event  
A serious adverse event (SAE) is an AE occurring at any time after informed consent 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 subject was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization, but might jeopardize the 
subject or might require intervention to prevent 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. 
9.2 
DOCUMENTATION OF ADVERSE EVENTS 
An AE or SAE occurring during the study must be documented in the subject’s source 
documents and on the appropriate eCRF page.  Information relating to the AE such as onset 
and cessation date and times, intensity, seriousness, relationship to study drug, and outcome is 
also to be documented in the eCRF (see Appendix 15.2 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 


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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 four weeks after completion of the final study visit.  Supplemental measurements 
and/or evaluations may be necessary to investigate fully the nature and/or causality of an AE 
or SAE.  This may include additional laboratory tests, diagnostic procedures, or consultation 
with other healthcare professionals.  The eCRF pages should be updated with any new or 
additional information as appropriate. 
If, at any time, the subject withdraws from the study and/or changes from study drug to 
commercially available Tyvaso, any AEs/SAEs that occur on Tyvaso (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 (see Section 3.3.2.11).  These events will not be included in the protocol 
analysis. 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
All SAEs, regardless of expectedness or causality, must be reported to the Sponsor by 
fax/email 
) within 24 hours of awareness.  
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 Global Drug 
Safety at United Therapeutics Corporation within 24 hours of the receipt of any new or 
updated information.  The Investigator must also promptly notify their Investigational Review 
Board (IRB) or Ethics Committee (EC) of the SAE, including any follow-up information, in 
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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 
).  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 study drug and is both serious and unexpected.  The Investigator must report 
these AEs to their IRB or EC in accordance with applicable national regulations and 
guidelines set forth by the IRB or EC. 
10 
STATISTICAL CONSIDERATIONS 
10.1 
DATA PROCESSING 
The results of 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 Investigator for completeness and accuracy.  The 
Investigator must electronically sign each subject’s eCRF to signify his/her approval of the 
data.  The Investigator will be required to re-sign an eCRF if changes are made to a subject’s 
eCRF by the site after the Investigator initially signs the eCRF.  The database will be final 
when all outstanding queries have been resolved and all data management quality assurance 
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10.2 
SAMPLE SIZE 
No formal sample size calculation has been conducted.  All eligible subjects from RIN-PH-
201 may enter this study. 
10.3 
ANALYSIS PLAN 
All safety and efficacy data will be summarized in tables and listings and analyzed for trends 
over time.  No formal hypothesis testing is planned.  
The safety population will be defined as all subjects in the study that received inhaled 
treprostinil at any time during the course of the study.  Safety analyses will be performed on 
the safety population.  All AEs as recorded by the Investigators will be assigned MedDRA 
preferred terms by the sponsor for reporting purposes.  
10.4 
INTERIM ANALYSES 
Interim analyses for safety data will be performed at the request of the Data Monitoring 
Committee (DMC).  Interim analyses for efficacy data are not planned for this study. 
10.5 
OTHER ANALYSES 
Exploratory analyses may be conducted based on available study data. 
10.6 
DATA LISTINGS AND SUMMARIES 
All data gathered in this study will be presented in summary tables and listings in the clinical 
study report. 
10.7 
DATA MONITORING COMMITTEE 
A DMC will be established for the study including physicians knowledgeable in the treatment 
of PH.  Throughout the course of the study the DMC will meet on a regular basis to monitor 
the safety of the study.  Meetings will occur as outlined in the DMC charter.   
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG  
The Sponsor will supply study drug (treprostinil inhalation solution, 0.6 mg/mL), as clear 
liquid in 2.9 mL ampoules.  The ampoules will be packaged in groups of four, sealed in 
aluminum pouches.  There will be nine pouches per carton and each subject will receive three 


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cartons at Baseline, Week 12, and each scheduled follow-up visit thereafter (i.e., every 
12 weeks).  Study drug will not be supplied at the Week 4 visit unless required for emergency 
purposes (i.e., to replace lost study drug, etc.). 
The Sponsor will supply commercially available TD-100 nebulizers (Tyvaso Inhalation 
System®) and accessories to the site in standard packaging labeled with the study number.  
The Tyvaso Inhalation will also be provided with the commercially available Instructions for 
Use (IFU). 
Each subject will continue to use the assigned nebulizers provided in the RIN-PH-201 study 
for this study.  In addition, the subjects will be provided with three months’ worth of plastic 
accessories at Baseline, Week 12, and each scheduled follow-up visit thereafter.  Nebulizers 
will be replaced at least every two years (date determined based off of first use in RIN-PH-
201). 
11.2 
LABELING  
The foil pouch and the outer carton will each be labeled with the same information and sent to 
the site.  At a minimum, the study medication outer packaging (pouch and carton) will be 
labeled to disclose clearly the product name, study number, kit identification number, expiry 
date, Sponsor’s name and address, instructions for use, and storage information (subject to 
regulatory requirements in each study region or country).   
Study subjects will receive commercially available TD-100 nebulizers and accessories 
separately from study drug.  Study subjects will utilize the TD-100 nebulizers from the RIN-
PH-201 study at study entry.  Subjects will receive replacement parts every three months as 
part of device resupply kit.  The nebulizers and accessories will be supplied using standard 
packaging labeled with the study number.   
11.3 
STORAGE AND HANDLING OF CLINICAL TRIAL MATERIAL (CTM) 
All study drug will be stored at room temperature 25°C (77°F) with excursions permitted to 
15°C-30°C (59°F – 86°F).  Study drug should not be frozen, refrigerated, or exposed to heat.  
Keep the ampoules in the foil pouch to protect from light.  Once the foil pouch is opened, use 


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within seven days.  See investigational medicinal product label for information on use and 
storage of the product.   
Study drug will be stored in a securely locked cabinet or enclosure with appropriate 
temperature monitoring.  Access should be strictly limited to the Investigators and their 
designees.  Neither the Investigators nor any designees may provide study drug to any subject 
not participating in this protocol. 
11.4 
SUPPLY AND RETURN OF CTM 
Study sites will be supplied with a sufficient quantity of study drug to begin enrollment in the 
study.  At Baseline, an IXRS will be utilized to assign study drug for the first 12-week 
treatment interval.  At subsequent study visits, the IXRS will be utilized by study staff to 
assign subsequent study drug kits to the subjects.  Starting at Week 12 and at every scheduled 
study visit thereafter, all study drug dispensed to a subject should be returned to the study site, 
including all used and unused ampoules.  Subjects may also return used ampoules at the Week 
4 visit; however, unused ampules should not be returned until the Week 12 visit to ensure the 
subject has enough drug to get through Week 12. 
At the end of the study, nebulizers used during the study should be collected from each 
subject. 
11.5 
DRUG ACCOUNTABILITY 
The Investigator is responsible for study drug accountability and reconciliation overall and on 
a per subject basis.  Drug accountability records are to be maintained during the study and 
these records include, but are not limited to: the amount of study drug received from the 
sponsor, the amount dispensed to each subject, and the amount of used/unused study drug 
returned to the site from the subject.  
At each visit, site personnel will: 
 Collect and document all study drug returned by the subject (both used and unused 
[unused drug will not be collected at the Week 4 visit to ensure the subject has enough 
drug to get through the Week 12 visit]).   
 Compute study drug compliance using the dosing instructions given to the subject 
since the previous study visit and the amount of study drug returned. 


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 Re-educate the subject about the importance of following the prescribed dosing 
regimen (if compliance is low). 
 Review the subject dosing diary, if applicable (the use of a dosing diary is optional for 
this open-label study) 
Once a representative from the Sponsor is able to confirm drug accountability for a completed 
subject, unused study drug and nebulizers will be returned to a Sponsor designated location 
for destruction. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
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 
IRBs/ECs that require it.  Any additional national reporting requirements as specified by the 
applicable regulations, regulatory authorities, or IRB/EC will also be fulfilled during the 
conduct of the study. 
12.2 
INFORMED CONSENT REQUIREMENTS 
Before a subject is enrolled in the study, the Investigator or his/her designees must explain the 
purpose and nature of the study, including potential benefits and risks and all study 
procedures to the subject.  The subject must sign and date an IRB/EC-approved informed 
consent form prior to the conduct of any study-related activities.  A copy of the signed 
consent form will be given to the subject and the original will be retained in the study site’s 
records. 
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
Prior to study initiation at each site, the Investigator will obtain approval for the study from an 
appropriate IRB/EC and provide the sponsor with a copy of the approval letter.  The IRB/EC 
must also review and approve the study site’s 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 


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must be forwarded to the Sponsor for review before submission to the IRB/EC prior to the 
start of the study. 
If, during the study, it is necessary to amend either the protocol or the informed consent form, 
the Investigator is responsible for obtaining IRB/EC approval of these amended documents 
prior to implementation.  Copies of the IRB/EC correspondence and approval letters must be 
sent to the Sponsor. 
During the conduct of the study, an annual progress report will be compiled by the Sponsor 
for submission to those IRBs/ECs that require it. 
A written summary of the study will be provided by the Investigator to the IRB/EC following 
study completion or termination according to the IRB or EC standard procedures.  Additional 
updates will also be provided in accordance with the IRB/EC’s standard procedures. 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical trial, at a minimum, the following documents will 
be provided to the site:  Investigators’ Brochure, Protocol, Informed Consent Form, Dosing 
Diary, the Tyvaso Inhalation System IFU, Budget Agreement, and Case Report Form. 
At a minimum, 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/EC Composition and Roster, IRB/EC 
protocol and informed consent approval letters, and Curriculum Vitae of study staff listed on 
the 1572. 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  United Therapeutics 
Corporation, the FDA or other regulatory bodies, and the IRB/EC governing this study may 
inspect the medical records of any subject involved in this study.  The Investigator may 
release the subject’s medical records to employees or agents of the Sponsor, the IRB/EC or 
the FDA or appropriate local regulatory agencies for purposes of checking the accuracy of the 


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data.  A number will be assigned to all subjects and any report published will not identify the 
subject’s name. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially adversely affect the safety of participating 
subjects or that alter the scope of the investigation, the scientific quality of the study, the 
experimental design, dosages, duration of therapy, assessment variables, the number of 
subjects treated, or subject selection criteria may be made only after consultation between 
United Therapeutics Corporation or its designee and the Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory 
authorities and IRB/EC prior to implementation. 
A report documenting study termination must also be submitted to and acknowledged by the 
appropriate IRB/EC for each study site. 
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 
REFERENCES 
Agarwal, M. and A. Waxman (2015).  Inhaled Treprostinil in Group-3 Pulmonary 
Hypertension.  International Heart and Lung Transplant.  Nice France. 
ATS Statement: Guidelines for the Six-Minute Walk Test.  Am J Respir Crit Care Med 2002; 
166: 111–117. 
Bajwa, A., A. Shujaat, C. Thomas, et al (2015).  The impact of inhaled treprostinil sodium 
inhalation on ventilation perfusion matching when used in patients with group 1 PAH with 
concomitant COPD.  Chest.  Montreal Canada. 
Benza, R. L., W. Seeger, V. V. McLaughlin, et al (2011). "Long-term effects of inhaled 
treprostinil in patients with pulmonary arterial hypertension: the Treprostinil Sodium 
Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study 
open-label extension." Journal of Heart Lung Transplantion 30(12): 1327-1333. 
Channick, R. N., H. Olschewski, W. Seeger, et al (2006). "Safety and efficacy of inhaled 
treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension." Journal of the 
American College of Cardiology 48(7): 1433-1437. 
Collard, H.R., C.J. Ryerson, T.J. Corte, et al (2016).  “Acute exacerbation of idiopathic 
pulmonary fibrosis: an international working group report.”  American Journal of Respiratory 
and Critical Care Medicine.  
Cottin, V., J. Le Pavec, G. Prėvot, et al (2010).  “Pulmonary hypertension in patients with 
combined pulmonary fibrosis and emphysema syndrome.”  European Respiratory Journal 
351: 105-111.   
Fijalkowska, A., M. Kurzyna, A. Torbicki, et al (2006). "Serum N-terminal brain natriuretic 
peptide as a prognostic parameter in patients with pulmonary hypertension." Chest 129(5): 
1313-1321. 
Holland, A. E., M. A. Spruit, T. Troosters, et al (2014). "An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease." European Respiratory Journal 44(6): 1428-1446. 
Jankowich, M. D. and S. I. Rounds (2012).  “Combined pulmonary fibrosis and emphysema 
syndrome: a review.”  Chest 141(1): 222-231. 
Lettieri, C. J., S. D. Nathan, R. F. Browning, et al (2006).  “The distance-saturation product 
predicts mortality in idiopathic pulmonary fibrosis”.  Respiratory Medicine 100:  1734-1741. 
McLaughlin, V. V., R. L. Benza, L. J. Rubin, et al (2010). "Addition of inhaled treprostinil to 
oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial." 
Journal of the American College of Cardiology 55(18): 1915-1922. 


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Nathan, S. D. (2008). "Pulmonary hypertension in interstitial lung disease." International 
Journal of Clinical Practice 62(SUPPL.160): 21-28. 
Nathan, S. D. and P. M. Hassoun (2013). "Pulmonary hypertension due to lung disease and/or 
hypoxia." Clinical Chest Medicine 34(4): 695-705. 
Remodulin (treprostinil) Injection package insert.  United Therapeutics Corp.  Research 
Triangle Park, NC.  December 2014. 
Roccia, F., B. Campolo, and L. Gallelli, et al.  “Effects of ambrisentan in a patient affected by 
combined pulmonary fibrosis and emphysema and by severe pulmonary hypertension: 
clinical, functional, and biomolecular findings.”  Clinical Drug Investigation 33(6): 451-457. 
Saggar R, D. Khanna, A. Vaidya, et al (2014).  “Changes in right heart hemodynamics and 
echocardiographic function in an advanced phenotype of pulmonary hypertension and right 
heart dysfunction associated with pulmonary fibrosis.” Thorax 69, no. 2: 123-9. 
Seeger, W., Y. Adir, J. A. Barbera, et al (2013). "Pulmonary hypertension in chronic lung 
diseases." Journal of the American College of Cardiology 62(25 Suppl): D109-116. 
Simonneau, G., I. M. Robbins, M. Beghetti, et al (2009). "Updated clinical classification of 
pulmonary hypertension." Journal of the American College of Cardiology 54(1 Suppl): S43-
54. 
Travis, W., U. Costabel, D. Hansell, et al (2013).  “An Official American Thoracic 
Society/European Respiratory Society Statement: Update of the International 
Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias.”  American Journal 
of Respiratory and Critical Care medicine 188(6): 733-748. 
Voswinckel, R., H. A. Ghofrani, F. Grimminger, et al (2006). "Inhaled treprostinil [corrected] 
for treatment of chronic pulmonary arterial hypertension."  Annals of Internal Medicine 
144(2): 149-150. 
Wang, L., L. Bai, R. Sapkota, et al (2015).  Hemodynamic and gas exchange effects of 
iloprost in patients with chronic obstructive pulmonary disease and pulmonary hypertension.  
Pulmonary Vascular Research Institute.  Guangzhou, China.   


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15 
APPENDICES 
15.1 
PROCEDURE FOR SIX-MINUTE WALK TEST 
General Procedures 
The 6MWT should be administered by the same tester at each study site throughout the study, 
whenever possible.  The administration of the test and specifications of the testing area should 
be generally consistent with the American Thoracic Society guidelines1,2 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 to 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 subject can no longer continue.  If the subject needs 
to rest briefly, he/she may stand or sit and then begin again when he/she is sufficiently rested 
but the clock will continue to run.  At the end of 6 minutes, the tester will call “stop where 
you are” while simultaneously stopping the watch and then measure the distance walked.   
Instructions to the Subject  
Subjects will be instructed that the preceding meal should be light.  Subjects should be told to 
wear comfortable clothing and sneakers or comfortable walking shoes.  The person 
administering the test will use the following exact dialogue with the subject: 
“The purpose of this test is to find out how far you can walk in 6 minutes.  You will start from 
this point and follow the hallway to the marker (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.” 


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After these instructions are given to the subject, the person administering the test will then 
ask: 
“Do you have any questions about the test?” 
The person administering the test will then start the test by saying the following to the subject: 
“Are you ready?” 
“Start when I say “GO.” 
The person administering the test will tell the subject the time at each minute by saying: 
“You have 5 minutes to go.” 
“You have 4 minutes to go.” 
“You have 3 minutes to go.” 
“You have 2 minutes to go.” 
“You have 1 minute to go.” 
At 6 minutes, the person administering the test will tell the subject: “stop where you are.” 
No other instruction or encouragement will be given during the test.  Eye contact with the 
subject should be avoided during the test. 
1  ATS Statement: Guidelines for the Six-Minute Walk Test.  Am J Respir Crit Care Med 2002; 166: 111–117. 
2  Holland, A. E., M. A. Spruit, T. Troosters, M. A. Puhan, V. Pepin, D. Saey, M. C. McCormack, B. W. Carlin, F. C. 
Sciurba, F. Pitta, J. Wanger, N. MacIntyre, D. A. Kaminsky, B. H. Culver, S. M. Revill, N. A. Hernandes, V. 
Andrianopoulos, C. A. Camillo, K. E. Mitchell, A. L. Lee, C. J. Hill and S. J. Singh (2014). "An official European 
Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory 
disease." Eur Respir J 44(6): 1428-1446. 
 


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15.2 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Investigator or a designated member of his/her staff will probe each subject for any AEs 
that may have occurred.  The Investigator should always ask the same question when 
conducting the verbal probe in order to ensure uniformity between subjects.  The Investigator 
should ask: 
“How are you doing (feeling)?” 
Based on the subject’s response to this question, the Investigator should ask additional 
questions relevant to the specific complaint such as: 
“How severe is/was the symptom?” 
“How often did the symptom occur?” 
“How long did the symptom last?” 
It is the Investigator’s responsibility to review the results of all diagnostic and laboratory tests 
as they become available and ascertain if there is a clinically significant change from 
Baseline.  If the results are determined to be a clinically significant change from Baseline, this 
should be reported as an AE.  The Investigator may repeat the diagnostic procedure or 
laboratory test or request additional tests to verify the results of the original tests.  When 
possible, a diagnosis associated with the abnormality should be used as the reported AE. 
Using provided definitions, the Investigator will then: 
(1) rate the intensity and seriousness of the AE, (2) estimate the causality of the AE to study 
drug, and (3) note actions taken to counteract the AE. 
Definitions of Intensity, Seriousness, Causality, Action Taken, and Outcome 
INTENSITY 
An assessment of the relative intensity (severity) of an AE is based on the Investigator’s 
clinical judgment.  The maximum intensity encountered during the evaluation period should 
be checked.  The assessment of intensity should be independent of the assessment of the 
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SERIOUSNESS 
A serious AE is one that represents an actual or potential significant hazard.  This includes, 
but is not limited to, an event that is fatal, life-threatening, permanently or severely disabling, 
requires or prolongs inpatient hospitalization*, is a congenital abnormality (offspring of 
subject) or is medically significant (important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition). 
*Hospitalizations that would not be considered SAEs include those for: 
 Routine treatment or monitoring of the study indication not associated with any 
deterioration in condition (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.  
Definitions of the causality categories are as follows: 
 NOT RELATED – There is not a temporal relationship to study drug administration 
(too early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, or concurrent disease and the SAE, or any of the following: 
 An event that precedes the first administration of study drug 
 An event for which the cause is clearly related to an external event 
 Temporal relationship to study drug is atypical 
 Is readily explained by an intercurrent illness AND has an expected level of 
severity, duration and resolution 
 An alternative explanation (concomitant drug, intercurrent illness) is likely 
 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: 


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 Has a reasonable temporal relationship to study drug 
 The event has a plausible biological link to the activity of the study drug 
 Is unlikely to be related to an intercurrent illness or has an unexpected degree 
of severity, duration or complication 
 PROBABLE – There is a reasonable causal relationship between the study drug and 
the SAE.  The event responds to dechallenge - the event resolves or improves with 
modification of study drug administration.  Rechallenge (the original study drug was 
restarted) is not required, or any of the following: 
 Has a reasonable temporal relationship to study drug 
 The event has a plausible biologic link to the activity of the study drug 
 Not readily explained by an intercurrent illness 
 Not readily explained by external event 
 Improves on discontinuation of study drug 
 If study drug has been discontinued, may recur or reintroduction of study drug 
ACTION TAKEN 
STUDY DRUG DOSE MODIFICATION* 
 Dose Not Changed – The dose or regimen of the study drug was not changed. 
 Dose Increased – The dose or regimen of study drug was increased  
 Dose Decreased – The dose or regimen of study drug was decreased 
 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 
residual sequelae.  Some events do not return to baseline, such as metastasis or 


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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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15.3 
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE  


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1
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE
ENGLISH FOR THE UNITED STATES
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ)
This questionnaire is designed to help us learn much more about how your
breathing is troubling you and how it affects your life. We are using it to find out
which aspects of your illness cause you the most problems, rather than what the
doctors and nurses think your problems are.
Please read the instructions carefully and ask if you do not understand anything.
Do not spend too long deciding about your answers.
Before completing the rest of the questionnaire:
Please check one box to show how you describe
your current health:
Very good

Good

Fair

Poor

Very poor

Copyright reserved
P.W. Jones, PhD FRCP
Professor of Respiratory Medicine,
St. George’s University of London,
Jenner Wing,
Cranmer Terrace,
Tel. +44 (0) 20 8725 5371
London SW17 ORE, UK.
Fax +44 (0) 20 8725 5955


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2
St. George’s Respiratory Questionnaire
PART 1
Please describe how often your respiratory problems have affected you over the past 4 weeks.
Please check () one box for each question:
almost
every
day
several
days
a week
a few
days
a month
only with
respiratory
infections
not
at
all
1.
Over the past 4 weeks, I have coughed:





2.
Over the past 4 weeks, I have brought up
phlegm (sputum):





3.
Over the past 4 weeks, I have had shortness
of breath:





4.
Over the past 4 weeks, I have had wheezing
attacks:





5.
How many times during the past 4 weeks have you suffered from
severe or very unpleasant respiratory attacks?
Please check () one:
more than 3 times 
3 times 
2 times 
1 time 
none of the time 
6.
How long did the worst respiratory attack last?
(Go to Question 7 if you did not have a severe attack)
Please check () one:
a week or more 
3 or more days 
1 or 2 days 
less than a day 
7.
Over the past 4 weeks, in a typical week, how many good days
(with few respiratory problems) have you had?
Please check () one:
No good days 
1 or 2 good days 
3 or 4 good days 
nearly every day was good 
every day was good 
8.
If you wheeze, is it worse when you get up in the morning?
Please check () one:
No 
Yes 


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3
St. George’s Respiratory Questionnaire
PART 2
Section 1
How would you describe your respiratory condition?
Please check () one:
The most important problem I have 
Causes me quite a lot of problems 
Causes me a few problems 
Causes no problems 
If you have ever held a job:
Please check () one:
My respiratory problems made me stop working altogether 
My respiratory problems interfere with my job or made me change my job 
My respiratory problems do not affect my job 
Section 2
These are questions about what activities usually make you feel short of breath these days.
For each statement please check
() the box that applies
to you these days:
True
False
Sitting or lying still 

Washing or dressing yourself 

Walking around the house 

Walking outside on level ground 

Walking up a flight of stairs 

Walking up hills 

Playing sports or other physical activities 



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4
St. George’s Respiratory Questionnaire
PART 2
Section 3
These are more questions about your cough and shortness of breath these days.
For each statement please check
() the box that applies
to you these days:
True
False
Coughing hurts 

Coughing makes me tired 

I am short of breath when I talk 

I am short of breath when I bend over 

My coughing or breathing disturbs my sleep 

I get exhausted easily 

Section 4
These are questions about other effects that your respiratory problems may have on you these
days.
For each statement, please
check () the box that
applies to you these days:
True
False
My cough or breathing is embarrassing in public


My respiratory problems are a nuisance to my family, friends or neighbors


I get afraid or panic when I cannot catch my breath


I feel that I am not in control of my respiratory problems


I do not expect my respiratory problems to get any better


I have become frail or an invalid because of my respiratory problems


Exercise is not safe for me


Everything seems too much of an effort


Section 5
These are questions about your respiratory treatment. If you are not receiving treatment go to
section 6.
For each statement, please
check () the box that applies
to you these days:
True
False
My treatment does not help me very much 

I get embarrassed using my medication in public 

I have unpleasant side effects from my medication 

My treatment interferes with my life a lot 



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5
St. George’s Respiratory Questionnaire
PART 2
Section 6
These are questions about how your activities might be affected by your respiratory problems.
For each statement, please check ()
the box that applies to you
because of your respiratory problems:
True
False
I take a long time to get washed or dressed


I cannot take a bath or shower, or I take a long time to do it


I walk slower than other people my age, or I stop to rest


Jobs such as household chores take a long time, or I have to stop to rest


If I walk up one flight of stairs, I have to go slowly or stop


If I hurry or walk fast, I have to stop or slow down


My breathing makes it difficult to do things such as walk up hills, carry things
up stairs, light gardening such as weeding, dance,
bowl or play golf


My breathing makes it difficult to do things such as carry heavy loads,
dig in the garden or shovel snow, jog or walk briskly (5 miles per hour),
play tennis or swim


My breathing makes it difficult to do things such as very heavy
manual work, ride a bike, run, swim fast,
or play competitive sports


Section 7
We would like to know how your respiratory problems usually affect your daily life.
For each statement, please check ()
the box that applies to you because of
your respiratory problems:
True
False
I cannot play sports or do other physical activities 

I cannot go out for entertainment or recreation 

I cannot go out of the house to do the shopping 

I cannot do household chores 

I cannot move far from my bed or chair 



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6
St. George’s Respiratory Questionnaire
Here is a list of other activities that your respiratory problems may prevent you from doing. (You
do not have to check these, they are just to remind you of ways your shortness of breath may
affect you):
Going for walks or walking the dog
Doing activities or chores at home or in the garden
Sexual intercourse
Going to a place of worship, or a place of entertainment
Going out in bad weather or into smoky rooms
Visiting family or friends or playing with children
Please write in any other important activities that your respiratory problems may stop you from
doing:
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Now please check the box (one only) that you think best describes how your respiratory problems
affect you:
It does not stop me from doing anything I would like to do 
It stops me from doing one or two things I would like to do 
It stops me from doing most of the things I would like to do 
It stops me from doing everything I would like to do 
Thank you for completing this questionnaire. Before you finish would you please make sure that you have
answered all the questions.

SAP_001.pdf: 
United Therapeutics Corp. 
RIN-PH-202 Statistical Analysis Plan Amendment 1 
 
Inhaled Treprostinil 
Version 21 OCT 2019 
Confidential 
Page 1 
Document Type: Statistical Analysis Plan 
Amendment 1 
Protocol/Study No.: 
RIN-PH-202 
Finalization 
Date: 
21 OCT 2019 
 
Total Number of Pages 
including Appendices: 
22 
Classification: 
Confidential 
 
 
Title: 
An Open-Label Extension Study of Inhaled Treprostinil in Subjects with Pulmonary 
Hypertension due to Parenchymal Lung Disease 
Author: 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
All content contained herein is confidential and proprietary information of 
United Therapeutics Corporation and shall not be disclosed in whole or in part except as 
permitted by a signed contract with United Therapeutics Corporation. © 2019 
United Therapeutics Corporation 


United Therapeutics Corp. 
RIN-PH-202 Statistical Analysis Plan Amendment 1 
 
Inhaled Treprostinil 
Version 21 OCT 2019 
Confidential 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................ 2 
Table of In-Text Tables .......................................................................................................... 3 
ABBREVIATIONS AND DEFINITIONS ............................................................................ 4 
1 PREFACE .......................................................................................................................... 5 
2 STUDY OBJECTIVES AND ENDPOINTS ................................................................... 5 
2.1 
OBJECTIVES ............................................................................................................... 5 
2.2 
ENDPOINTS ................................................................................................................. 5 
2.2.1 
Efficacy ..................................................................................................................... 5 
2.2.2 
Safety ........................................................................................................................ 6 
3 STUDY DESIGN ............................................................................................................... 6 
4 RANDOMIZATION ......................................................................................................... 6 
5 SEQUENCE OF PLANNED ANALYSES ..................................................................... 7 
6 SAMPLE SIZE CONSIDERATIONS ............................................................................ 7 
7 ANALYSIS POPULATIONS ........................................................................................... 7 
8 GENERAL CONSIDERATIONS FOR DATA ANALYSES ....................................... 7 
8.1 
EXAMINATION OF SUBGROUPS .......................................................................... 8 
8.2 
PREMATURE DISCONTINUATION AND MISSING DATA .............................. 8 
8.3 
MULTIPLE COMPARISONS AND MULTIPLICITY ........................................... 8 
8.4 
ASSESSMENT WINDOWS ........................................................................................ 8 
8.4.1 
Multiple Evaluations Within the Same Analysis Window ................................... 9 
8.5 
DERIVED AND TRANSFORMED DATA ............................................................... 9 
9 STUDY POPULATION ................................................................................................. 10 
9.1 
SUBJECT ACCOUNTABILITY .............................................................................. 10 
9.2 
ELIGIBILITY CRITERIA ....................................................................................... 11 
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATION ........................................ 11 
9.3.1 
Demographics ........................................................................................................ 11 
9.3.2 
Baseline Characteristics ........................................................................................ 11 
9.3.3 
PH-ILD History ..................................................................................................... 12 
9.3.4 
Concomitant Medications ..................................................................................... 12 
9.3.5 
Inhaled Treprostinil Dosing .................................................................................. 12 
10 EFFICACY ANALYSES ................................................................................................ 13 
10.1 6-MINUTE WALK TEST ......................................................................................... 13 
10.2 N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE .................................... 13 
10.3 ST. GEORGE’S RESPIRATORY QUESTIONNAIRE ......................................... 14 
10.4 DISTANCE SATURATION PRODUCT ................................................................. 14 
11 SAFETY ANALYSES ..................................................................................................... 14 
11.1 ADVERSE EVENTS .................................................................................................. 14 
11.2 DEATHS ..................................................................................................................... 15 


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11.3 HOSPITALIZATIONS DUE TO CARDIOPULMONARY INDICATIONS ...... 16 
11.4 EXACERBATIONS OF UNDERLYING LUNG DISEASE ................................. 16 
11.5 OXYGENATION ....................................................................................................... 17 
11.5.1 
Pulse Oximetry ....................................................................................................... 17 
11.5.2 
Supplemental Oxygen ........................................................................................... 17 
11.6 PULMONARY FUNCTION TESTS ........................................................................ 18 
11.7 CLINICAL LABORATORY TESTS ....................................................................... 18 
11.8 VITAL SIGNS ............................................................................................................ 19 
12 APPENDICES ................................................................................................................. 20 
12.1 LIST OF TABLES ..................................................................................................... 20 
12.2 LIST OF LISTINGS .................................................................................................. 22 
12.3 LIST OF FIGURES ................................................................................................... 22 
Table of In-Text Tables 
Table 8-1 
Assessment Windows for Scheduled Visits ...................................................... 9 
Table 8-2 
Derivation of Time to Event ........................................................................... 10 
  
 
 


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Version 21 OCT 2019 
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ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
CPFE 
Combined pulmonary fibrosis and emphysema 
CSR 
Clinical study report 
DLCO 
Lung diffusion capacity 
DMC 
Data Monitoring Committee 
DSP 
Distance saturation product 
eCRF 
Electronic Case Report Form 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
ILD 
Interstitial lung disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-proBNP 
N-Terminal pro-brain natriuretic peptide 
PFT 
Pulmonary function test 
PH 
Pulmonary hypertension 
PH-ILD 
Pulmonary hypertension associated with interstitial lung disease 
PT 
Preferred Term 
SAP 
Statistical analysis plan 
SGRQ 
St. George’s Respiratory Questionnaire 
SOC 
System Organ Class 
SpO2 
Saturation of peripheral capillary oxygenation 
TLC 
Total lung capacity 
WHO 
World Health Organization 


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Version 21 OCT 2019 
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1 
PREFACE 
This plan provides further details of the planned analyses for the RIN-PH-202 study as 
presented in the study protocol.  This plan, based on the original RIN-PH-202 study protocol 
dated 14 October 2015 and the subsequent study protocol amendment (latest version study 
protocol amendment 1 dated 18 August 2016), provides further details of the planned analyses 
stated in the study protocol and may include additional planned analyses.  Additional post hoc 
or unplanned analyses that are not defined in this statistical analysis plan (SAP) may be 
performed.  Such analyses will be documented in the clinical study report (CSR). 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
OBJECTIVES 
The primary objective of this study is to provide or continue to provide inhaled treprostinil for 
eligible subjects who participated in the RIN-PH-201 study. 
Secondary objectives are to assess the long-term safety and efficacy of inhaled treprostinil in 
subjects with pulmonary hypertension (PH) associated with interstitial lung disease (ILD) 
including combined pulmonary fibrosis and emphysema (CPFE). 
2.2 
ENDPOINTS 
2.2.1 
Efficacy 
To evaluate the effect of continued long-term therapy with inhaled treprostinil, the efficacy 
endpoints are: 
 Peak 6-Minute Walk Distance (6MWD) 
 N-terminal pro-brain natriuretic peptide (NT-proBNP) 
 Quality of life as measured by the St. George’s Respiratory Questionnaire (SGRQ) 
 Optional evaluation of change in biomarkers from Baseline to Week 48 (or study 
discontinuation if prior to Week 48) 
 Change in distance saturation product (DSP) 
The changes in biomarkers from Baseline to Week 48 are an optional evaluation and their 
analysis will be detailed in a separate document and not covered in this SAP. 


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2.2.2 
Safety 
To evaluate the effect of continued long-term therapy with inhaled treprostinil, the safety 
endpoints are: 
 Adverse events (AEs) 
 Oxygenation 
o Pulse oximetry (saturation of peripheral capillary oxygenation [SpO2]) 
o Supplemental oxygen (L/min) 
 Pulmonary function tests (PFTs) 
o Forced expiratory volume in 1 second (FEV1) 
o Forced vital capacity (FVC) 
o Total lung capacity (TLC) 
o Lung diffusion capacity (DLCO) 
 Clinical laboratory parameters 
 Vital signs 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease defined as an acute, clinically significant, 
respiratory deterioration characterized by evidence of new widespread alveolar 
abnormality 
3 
STUDY DESIGN 
This is a multicenter, open-label study.  Subject visits will occur at Baseline, Weeks 4, 12, and 
every 12 weeks thereafter until Week 108.  The study will continue until each subject has 
completed Week 108 or until inhaled treprostinil becomes commercially available for patients 
with pre-capillary pulmonary hypertension associated with interstitial lung disease (PH-ILD) 
including CPFE (whichever is sooner). 
4 
RANDOMIZATION 
This study is not randomized.  All subjects will receive inhaled treprostinil during this 
open-label study if they completed Week 16 of the parent study (RIN-PH-201).  However, 
some analyses will be based on the treatment assignment in the parent study. 


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5 
SEQUENCE OF PLANNED ANALYSES 
Along with the safety information from the parent study, safety information from the 
RIN-PH-202 study will be provided to the Data Monitoring Committee (DMC) periodically 
for safety review. 
After study completion and unblinding for the parent study, a data cut for the RIN-PH-202 
study will be performed to facilitate the analyses for the RIN-PH-201 study.  Analyses based 
on additional data cuts and the final analyses at the time of study closing will be performed 
separately. 
6 
SAMPLE SIZE CONSIDERATIONS 
No formal sample size calculation has been conducted.  It is expected that approximately 
266 subjects who completed protocol RIN-PH-201 will be enrolled into this open-label 
extension study. 
7 
ANALYSIS POPULATIONS 
All available data from all subjects will be used as detailed in this analysis plan. 
The Safety Population will include any subject who received inhaled treprostinil at any time 
during the study.  All analyses are based on the Safety Population. 
8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All data included in each data cut will be listed.  In general, listings will be sorted by subject 
number and scheduled assessment (if applicable) or the visit date and will be organized by 
treatment group in the parent study.  Listings will include assessment date, assessment time (if 
available), and study day.  Study day is calculated as the assessment date minus the date of the 
first inhaled treprostinil dose in the RIN-PH-202 study + 1.  For data collected on a fixed 
schedule, the assessment identifier will also be included in the listing. 
In general, data will be summarized by visit window.  The visit window is calculated based on 
the time from the first dosing date of inhaled treprostinil in the RIN-PH-202 study.  For all 
presentations of the summary tables, the data will be presented by subjects in the inhaled 
treprostinil and placebo groups from the parent study (RIN-PH-201) and overall. 


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For continuous variables, summary statistics will include the mean, standard deviation, 
median, minimum, and maximum.  Minimums and maximums will be expressed using the 
level of precision to which the variable was collected.  All other statistics will be rounded 
using an additional decimal point.  For discrete variables, summaries will include the 
frequency and percent in each category.  Percentages will be rounded to 1 decimal point.  
Whenever practical, categories of discrete variables will be ordered and labeled as they appear 
in the Electronic Case Report Form (eCRF), and all categories represented on the eCRF will 
be included in summaries, even when they do not apply to any subjects in the study. 
8.1 
EXAMINATION OF SUBGROUPS 
Exploratory subgroup analyses may be performed as data permit. 
8.2 
PREMATURE DISCONTINUATION AND MISSING DATA 
A subject may voluntarily withdraw or be withdrawn from the study and/or study drug by the 
Investigator at any time for reasons including, but not limited to, the following: 
 The subject wishes to withdraw from further participation. 
 A serious or life-threatening AE occurs or the Investigator considers that it is 
necessary to discontinue study drug to protect the safety of the subject. 
 The subject consistently deviated from the protocol. 
 The subject’s behavior is likely to undermine the validity of his/her results. 
 The subject permanently initiates an infused prostacyclin therapy for >29 days. 
 The subject becomes pregnant. 
All available data from all subjects in the Safety Population, as defined in Section 7, will be 
used as detailed in this analysis plan. 
Missing data will not be imputed. 
8.3 
MULTIPLE COMPARISONS AND MULTIPLICITY 
No multiple comparison adjustments are planned for the analyses of this study. 
8.4 
ASSESSMENT WINDOWS 
For efficacy and safety assessments, Baseline is defined as the last measurement prior to the 
first dose of inhaled treprostinil in the RIN-PH-202 study. 


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The assessments will be mapped into the analysis visit windows based on Table 8-1. 
Table 8-1 
Assessment Windows for Scheduled Visits 
Visit 
Target  
Study Day 
Study Day Interval 
 
Baseline 
1 
Study Day 1 
 
Week 4 
29 
1< Study Day 57 
 
Week 12 
85 
57< Study Day 127 
 
All other visits 
169, 253, etc 
Target Study Day ±42 
Note: Study Day = (Assessment Date) - (First inhaled treprostinil Dosing Date) +1 
8.4.1 
Multiple Evaluations Within the Same Analysis Window 
After all the observations have been assigned according to Table 8-1, if there are multiple 
valid observations for an assessment within an assigned analysis visit window, only one of 
these observations will be used for summary statistics.  The observation to be used will be 
determined using the following hierarchy (in decreasing order): 
 The observation closest to the target study day 
 The later observation if 2 observations are equally close to the target study day. 
8.5 
DERIVED AND TRANSFORMED DATA 
The time to event will be calculated for each of the following variables as detailed in  
Table 8-2: 
 Hospitalization due to a cardiopulmonary indication 
 Exacerbation of underlying disease 
 Death 


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Table 8-2 
Derivation of Time to Event 
Parameter 
Scenario 
Formula 
Status 
Time to 
hospitalization 
(weeks) 
Subjects with hospitalization 
during the study 
= (Hospitalization date – first visit date +1)/7 
0 (event) 
Subjects without 
hospitalization during the 
study 
= (Last assessment date – first visit date +1)/7 1 (censored) 
Time to 
exacerbation 
(weeks) 
Subjects with exacerbation 
during the study 
= (Exacerbation date – first visit date +1)/7 
0 (event) 
Subjects without 
exacerbation during the study = (Last assessment date – first visit date +1)/7 1 (censored) 
Time to death 
(weeks) 
Subjects who died during the 
study 
= (Death date – first visit date +1)/7 
0 (event) 
Subjects who completed or 
discontinued prematurely 
= (Last assessment date – first visit date +1)/7 1 (censored) 
9 
STUDY POPULATION 
9.1 
SUBJECT ACCOUNTABILITY 
A listing of subject disposition and inhaled treprostinil exposure will include subject number, 
treatment group in the parent study, first and last inhaled treprostinil dose date/time in the 
RIN-PH-202 study, date completed/discontinued the study, cut-off date, study drug exposure 
(weeks), reason for discontinuation, and any other details regarding reason for 
discontinuation.  The summary of subject accountability will include the number (percent) of 
subjects by treatment group who completed the study without early termination, the number 
of subjects who completed inhaled treprostinil treatment by each visit achieved, the number of 
subjects who discontinued inhaled treprostinil treatment, and the reason for discontinuation.  
This summary will be provided by treatment group in the parent study and overall. 
Inhaled treprostinil exposure and the total subject-years of inhaled treprostinil exposure will 
be summarized by treatment group in the parent study and overall. 


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In addition, for subjects who were in the inhaled treprostinil treatment group in the parent 
study (RIN-PH-201), their exposure to inhaled treprostinil in the parent study will be 
combined with the RIN-PH-202 study.  The overall exposure to inhaled treprostinil across 
both the parent study and the RIN-PH-202 study will be summarized. 
9.2 
ELIGIBILITY CRITERIA 
The listing of entry criteria for all subjects will include each subject’s treatment group in the 
parent study, status regarding meeting all eligibility criteria (yes/no), and an explanation if not 
all eligibility criteria are met.  The summary of entry criteria will include the number and 
percent of subjects who did meet and the number and percent of subjects who did not meet all 
eligibility criteria by treatment group in the parent study and overall. 
In addition, a listing will be provided for protocol deviations.  The listing will include the 
subject number, deviation date, deviation type, deviation severity, and deviation description 
by treatment group in the parent study.  Deviations will be reviewed by the clinical team prior 
to database lock and those that might affect subject safety or efficacy outcomes will be 
considered “Major.”  All other deviations will be classified as “Minor.” 
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATION 
9.3.1 
Demographics  
The listing of subject demographics will include subject number, assessment date, date of 
birth, subject age (years), sex, ethnicity, race, height, weight, and body mass index (BMI).  
Age will be calculated based on the first inhaled treprostinil dose date in the RIN-PH-202 
study.  The summary of demographics will include descriptive statistics for age (years) at first 
dose of inhaled treprostinil and categorical summaries for age (<65 years of age, 65 to 
<80 years of age, and ≥80 years of age), sex, ethnicity, race, height, weight, and BMI, where 
weight is the measure before the first dose of inhaled treprostinil for the RIN-PH-202 study 
and height is obtained from the parent study. 
9.3.2 
Baseline Characteristics 
Baseline characteristics will include 6MWD, 6MWD category (≤350 m versus >350 m and 
≤median Baseline 6MWD versus >median Baseline 6MWD), DLCO percent predicted 


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(<40% versus ≥40%), NT-proBNP, and PFTs and will be summarized by treatment group in 
the parent study and overall.  Baseline measurements are defined as the last measurement 
prior to the first inhaled treprostinil dose in the RIN-PH-202 study.  Baseline characteristics 
will be included in the appropriate listings. 
9.3.3 
PH-ILD History 
Information related to subjects’ PH-ILD history will be listed.  The listing will include the 
date of initial PH diagnosis, years since PH diagnosis, etiology of ILD (including idiopathic 
interstitial pneumonia subcategory), date of confirmatory computed tomography scan, and the 
date of confirmatory lung biopsy, if performed. 
The current ILD diagnosis (ILD category) and time since PH diagnosis will be summarized 
by parent study treatment group and overall. 
9.3.4 
Concomitant Medications 
All concomitant medications recorded on the eCRF will be mapped to a standard name and 
Anatomical Therapeutic Chemical (ATC) Levels 1 to 4 using the WHODrug Global.  The 
ATC Levels 2 and 4 and verbatim term of all concomitant medications will be listed for all 
subjects.  This listing will include the date started (or indication that drug was ongoing from 
parent study), date discontinued (or indication that drug was ongoing at end of study), and the 
condition(s) treated/indication(s).  Summaries will be provided for medications ongoing from 
the parent study and for those added in the RIN-PH-202 study.  Each summary will be 
provided by treatment group in the parent study and overall and will include the number 
(percent) of subjects reporting each medication by ATC Level 2 and Level 4.  If ATC Level 4 
is not available for a medication, ATC Level 3 will be substituted.  If ATC Level 3 is not 
available, ATC Level 2 will be substituted.  If ATC Level 2 is not available, ATC Level 1 will 
be substituted. 
9.3.5 
Inhaled Treprostinil Dosing  
In the RIN-PH-202 study, inhaled treprostinil dosing information will be recorded whenever a 
change occurs in the dose.  A listing and a summary will be provided for inhaled treprostinil 
dosing.  The listing will include initial dose (number of breaths for each session and number 


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of breaths for the day), date of this initial dose, and dose and date of each dose change.  
Dosing at each analysis visit will be summarized.  The summary will include both the 
numeric summaries and the categorical summaries for number of breaths per session as well 
as the number of breaths per day.  If study drug is dosed differently across different sessions 
on the same day, the maximum number of breaths will be used for summarization.  A 
summary of overall duration of exposure will be included, as well as the final dose 
(breath/session) and the maximum study drug dose (breath/session) reached for each subject 
(numerically and categorically). 
For study treatment compliance, the number and percentage of days with dose >0 breaths will 
be calculated and summarized. 
10 
EFFICACY ANALYSES 
10.1 
6-MINUTE WALK TEST 
The listing of the 6-Minute Walk Test (6MWT) will include subject number, analysis visit, 
assessment date/time (day), last inhaled treprostinil dose date/time (day), the last inhaled 
treprostinil dose (number of breaths), hours from last inhaled treprostinil dose to 6MWT, 
6MWD results and associated changes from Baseline, use of supplemental oxygen, and any 
circumstances affecting the 6MWT.  The summaries of 6MWD will be provided by treatment 
assignment in the parent study (inhaled treprostinil or placebo) and overall by visit.  The 
summaries will include descriptive statistics for 6MWD at each analysis visit and the change 
from Baseline.  Baseline is defined as the last 6MWD measured prior to the first dose of 
inhaled treprostinil in the RIN-PH-202 study.  Additionally, a plot of mean change from 
Baseline in 6MWD at each study visit by parent study treatment group will be provided. 
10.2 
N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE 
NT-proBNP values and associated changes from Baseline will be listed and the listing will 
include subject number, analysis visit, and assessment date (day).  NT-proBNP values and 
change from Baseline values will be summarized by parent study treatment group and overall 
at each analysis visit.  The summary will also include the geometric mean and geometric 
standard deviation.  Baseline is defined as the last NT-proBNP value obtained prior to the first 
dose of inhaled treprostinil in the RIN-PH-202 study. 


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10.3 
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE 
SGRQ total and domain scores will be listed and the listing will include subject number, 
analysis visit, assessment date (day), and parent study treatment group.  SGRQ total and 
domain scores and the associated changes from Baseline values will be summarized by parent 
study treatment group at each analysis visit.  Baseline scores will be calculated from the last 
SGRQ administered prior to the first dose of inhaled treprostinil in the RIN-PH-202 study. 
10.4 
DISTANCE SATURATION PRODUCT 
DSP will be calculated as follows: 
Parameter 
Formula 
DSP (m%) 
=  (Distance walked in meters) x (Lowest oxygen saturation 
recorded during the 6MWT) 
Abbreviations: 6MWT, 6-Minute Walk Test; DSP, Distance Saturation Product 
DSP values and associated changes from Baseline will be listed and the listing will include 
subject number, analysis visit, and assessment date (day).  DSP values and change from 
Baseline values will be summarized by parent study treatment group at each analysis visit.  
Baseline is defined as the last DSP value obtained prior to the first dose of inhaled treprostinil 
in the RIN-PH-202 study. 
11 
SAFETY ANALYSES 
11.1 
ADVERSE EVENTS 
AEs are captured from the time the Informed Consent Form is signed.  Any AEs that are 
ongoing at the Study Termination Visit from study RIN-PH-201 are recorded as continuing 
AEs in the RIN-PH-202 study.  All AEs with an onset date on or after the first dose of inhaled 
treprostinil in the RIN-PH-202 study or AEs ongoing from the parent study will be included 
in data listings and summaries. 
The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and all summaries will utilize the Preferred Term (PT) and/or System Organ Class (SOC) to 
categorize AEs.  All AEs will be organized by treatment group in the parent study and listed 
by subject, including onset date (day), cessation date (day), verbatim term, corresponding 


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SOC and PT, seriousness, date AE became serious, severity, frequency, relationship to study 
drug, action taken with study drug, and outcome. 
The overall summary of AEs includes the number of subjects with any AE, the number of 
subjects with any study drug-related AEs, the number of subjects with AEs leading to study 
drug withdrawal, the number of subjects with AEs leading to death, the number of subjects 
with any serious AEs, and the number of subjects with any study drug-related serious AEs. 
The summaries of AEs by SOC and PT will be provided by parent study treatment group and 
overall.  The summaries of AEs, serious AEs, non-serious AEs, AEs probably or possibly 
related to inhaled treprostinil, and AEs leading to permanent discontinuation of inhaled 
treprostinil will include the number of subjects (percent of subjects) and number of events for 
each reported PT. 
The total number of AEs and the AE rates will be calculated and summarized for each 
display, as appropriate.  The AE rate will be calculated as the total number of AEs divided by 
the total patient years of exposure to study drug per treatment group in the parent study. 
11.2 
DEATHS 
All deaths will be listed (including those occurring within 30 days of the last inhaled 
treprostinil dose for subjects who discontinued prematurely) by subject, and will include the 
subject number, treatment group in the parent study, date of assessment (day), date of 
death (day), first and last inhaled treprostinil doses in the RIN-PH-202 study, and cause of 
death (including other, specify text [if applicable]).  A summary of deaths will be presented 
by the parent study treatment group and overall and will include the number (percent) of 
subjects who died (including those occurring within 30 days of the last inhaled treprostinil 
dose for subjects who discontinued prematurely) and their causes of death. 
Time to death will be summarized by parent study treatment group and overall using 
product-limit estimates calculated by the Kaplan-Meier method and displayed graphically as 
Kaplan-Meier curves.  A tabular summary of this analysis will include the number of subjects 


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at risk (sample size), estimated median duration, and a 95% confidence interval for the 
median duration for each parent study treatment group and overall. 
In addition, a Cox proportional hazards model may be fit for time to death to obtain the 
hazard ratio and its associated 95% confidence interval.  The model will include parent study 
treatment group as an explanatory variable. 
11.3 
HOSPITALIZATIONS DUE TO CARDIOPULMONARY INDICATIONS 
All hospitalizations will be listed including admission date, discharge date, and hospitalization 
status at the end of the study.  Those hospitalizations due to cardiopulmonary indications will 
be flagged.  This listing will be organized by parent study treatment group. 
The number and percentage of subjects who experience any hospitalizations and any 
hospitalizations due to cardiopulmonary indications will be summarized by parent study 
treatment group and overall.  Additionally, the total number of hospitalizations due to 
cardiopulmonary indications per subject will be categorized by parent study treatment group 
and overall. 
Kaplan-Meier analyses and Cox regression as described in Section 11.2 will also be done. 
11.4 
EXACERBATIONS OF UNDERLYING LUNG DISEASE 
All exacerbations of underlying lung disease will be listed including start date, end date, 
status at the beginning and end of the study, whether the exacerbation was considered serious, 
and if so, the date the event became serious. 
The number and percentage of subjects who experience exacerbations of underlying lung 
disease will be summarized by parent study treatment group and overall.  Additionally, the 
total number of exacerbations of underlying lung disease per subject will be categorized by 
parent study treatment group and overall. 
Kaplan-Meier analyses and Cox regression as described in Section 11.2 will also be 
performed. 


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11.5 
OXYGENATION 
Oxygenation is measured by pulse oximetry (SpO2 and supplemental oxygen requirement 
[L/min]) during each 6MWT.  At each 6MWT, pulse oximetry (for SpO2) will be measured at 
pre-walk, during walk, and post-walk.  During walk, the lowest SpO2 will be recorded.  All 
pulse oximetry results along with the collection date/time (study day) will be listed.  Heart 
rate will be listed for pre-walk and post-walk only. 
Heart rate will be summarized by parent study treatment group and overall, by time point 
(pre-walk and post-walk) and visit.  The summary will be provided for the original values, 
change from pre-walk for each visit, and change from Baseline values.  For change from 
Baseline calculations, the measurements pre-walk and post-walk at post-Baseline visits will 
be compared with the measurements at corresponding pre-walk and post-walk at Baseline. 
11.5.1 
Pulse Oximetry 
SpO2 will be summarized by parent study treatment group and overall at each time point 
(pre-walk, during walk, and post-walk) and analysis visit.  The summary will be provided for 
the original values, change from pre-walk for each visit, and change from Baseline values.  
For change from Baseline calculations, the measurements pre-walk, during walk, and 
post-walk at post-Baseline visits will be compared with the measurements at corresponding 
pre-walk, during walk, and post-walk at Baseline.  Baseline is defined as the last values 
obtained prior to the first dose of inhaled treprostinil in the RIN-PH-202 study. 
In addition, for each time point at each visit, the number and percentage of subjects with 
SpO2 or lowest SpO2 <80%, ≥80% to <88%, and ≥88%, and with SpO2 dropping ≥10% 
during walk and/or post-walk from pre-walk, will be summarized by parent study treatment 
group and overall. 
11.5.2 
Supplemental Oxygen 
At each visit, supplemental oxygen requirements will be collected at rest and during 6MWT.  
These data will be listed, including visit, 6MWT date/time, and oxygen use at rest and during 
walk.  The number and percentage of subjects requiring supplemental oxygen use at rest and 
during the 6MWT will also be summarized by parent study treatment group and overall.  


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Supplemental oxygen level at rest at each visit and the corresponding changes from Baseline 
will be summarized by parent study treatment group and overall. 
11.6 
PULMONARY FUNCTION TESTS 
The PFT parameters include: 
 FEV1 and percent predicted value, 
 FVC and percent predicted value, 
 TLC and percent predicted value, and 
 DLCO for carbon monoxide and percent predicted value. 
If the PFT is done both prior to and after a bronchodilator, only pre-bronchodilator values will 
be recorded and listed.  The listing will include subject number, analysis visit, and assessment 
date (day) as well as each PFT result and the percent predicted values for each PFT.  All PFT 
parameters (absolute values and percent predicted values) and their respective change from 
Baseline values will be summarized by parent study treatment group and overall at each visit. 
11.7 
CLINICAL LABORATORY TESTS 
The following clinical chemistry parameters will be evaluated by the central laboratory: 
Parameter 
Units 
Sodium 
mmol/L 
Potassium 
mmol/L 
Bicarbonate 
mmol/L 
Chloride 
mmol/L 
Total bilirubin 
umol/dL 
Alkaline phosphatase 
U/L 
Alanine aminotrasferase 
U/L 
Aspartate aminotransferase 
U/L 
Urea nitrogen 
mmol/dL 
Creatinine 
umol/L 
Calcium 
mmol/L 
Albumin 
g/L 


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The following hematology parameters will be evaluated by the central laboratory: 
Parameter 
Units 
Hemoglobin 
g/dL 
Hematocrit 
% 
Red blood cell count 
106/uL 
Red blood cell morphology 
 
White blood cell count 
103/uL 
Platelet count 
103/uL 
Values that are “high” or “low” with respect to the reference range provided by the central 
laboratory will be flagged with an “H” or an “L,” respectively.  All parameters will be listed 
for all subjects and assessments, along with their respective “high/low” flags. 
Values of these parameters at each visit, and their corresponding changes from Baseline, will 
be descriptively summarized by parent study treatment group and overall. 
For each parameter, the frequency and percentage of subjects within each parent study 
treatment group and overall who had “low,” “normal,” or “high” Baseline values, then 
subsequently had “low,” “normal,” or “high” follow-up values at each visit, will be presented 
in a shift summary. 
Pregnancy test results for female subjects will be summarized by parent study treatment group 
and overall and listed by subject number, analysis visit, and pregnancy status. 
11.8 
VITAL SIGNS 
Vital sign results will be mapped to analysis visit based on assessment date.  The vital sign 
data will be listed by subject and parent study treatment group for each analysis visit by 
assessment date/time (day), weight, heart rate, blood pressure, respiration rate, and 
temperature.  The original measures and their changes from Baseline (defined as the last 
measurement prior to the first inhaled treprostinil dosing in the RIN-PH-202 study) will be 
summarized for all analysis visits by the parent study treatment group and overall. 


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12 
APPENDICES 
12.1 
LIST OF TABLES 
Table Number 
Table Title 
14.1.1 
Summary of Subject Accountability 
14.1.2 
Summary of Inhaled Treprostinil Exposure 
14.1.3 
Summary of Inhaled Treprostinil Exposure in RIN-PH-201 and RIN-
PH-202 Studies  
14.1.4.1 
Summary of Entry Criteria Violation 
14.1.4.2 
Summary of Protocol Deviations 
14.1.5 
Summary of Demographics 
14.1.6 
Summary of Baseline Characteristics 
14.1.7 
Summary of PH-ILD History 
14.1.8.1 
Summary of Concomitant Medications Ongoing from RIN-PH-201 
14.1.8.2 
Summary of Concomitant Medications Added during the RIN-PH-202 
Study 
14.1.9 
Summary of Inhaled Treprostinil Dosing and Exposure 
14.1.10 
Summary of Inhaled Treprostinil Treatment Compliance 
14.2.1.1 
Summary of 6MWD (meter) by Visit  
14.2.1.2 
Summary of NT-proBNP (pg/mL) by Visit 
14.2.1.3.1 
Summary of SGRQ Total Score by Visit 
14.2.1.3.2 
Summary of SGRQ Symptoms Score by Visit 
14.2.1.3.3 
Summary of SGRQ Activity Score by Visit 
14.2.1.3.4 
Summary of SGRQ Impacts Score by Visit 
14.2.1.4 
Summary of Distance Saturation Product (m%) by Visit 
14.3.1.1 
Overall Summary of Adverse Events 
14.3.1.2 
Summary of Adverse Events by System Organ Class and Preferred 
Term 
14.3.1.3 
Summary of Adverse Events by Preferred Term 
14.3.1.4 
Summary of Deaths 
14.3.1.5 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term 
14.3.1.6 
Summary of Non-Serious Adverse Events by System Organ Class and 
Preferred Term 
14.3.1.7 
Summary of Adverse Events Probably or Possibly Related to Study 
Drug by System Organ Class and Preferred Term 


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Table Number 
Table Title 
14.3.1.8 
Summary of Adverse Events Leading to Permanent Discontinuation of 
Study Drug by Preferred Term 
14.3.1.9 
Summary of Adverse Events by System Organ Class, Preferred Term, 
and Severity 
14.3.1.10 
Summary of Adverse Events by Study Drug Dose at AE Onset 
14.3.2.1 
Listing of Deaths 
14.3.2.2 
Listing of Serious Adverse Events 
14.3.3.1 
Summary of SpO2 (%) Measured by Pulse Oximetry by Visit 
14.3.3.2 
Summary of SpO2 Category by Visit 
14.3.3.3 
Summary of Heart Rate (beats/min) Measured by Pulse Oximetry by 
Visit 
14.3.3.4 
Summary of Supplemental Oxygen Use by Visit 
14.3.3.5 
Summary of Supplemental Oxygen Use (L/min) by Visit 
14.3.3.6 
Summary of Pulmonary Function Tests by Visit 
14.3.3.7 
Summary of Subjects with ≥20% Decrease in FEV1 from Baseline 
14.3.4.1 
Summary of Laboratory Data – Clinical Chemistry 
14.3.4.2 
Summary of Clinical Chemistry Shifts from Baseline by Visit 
14.3.4.3 
Summary of Laboratory Data – Hematology 
14.3.4.4 
Summary of Hematology Shifts from Baseline by Visit 
14.3.4.5  
Summary of Vital Signs by Visit 
14.3.4.6 
Summary of Hospitalizations 
14.3.4.7 
Summary of Exacerbations of Underlying Lung Disease 


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12.2 
LIST OF LISTINGS 
Appendix Number 
Listing Title 
16.2.1 
Subject Disposition and Study Drug Exposure 
16.2.2.1 
Entry Criteria 
16.2.2.2 
Protocol Deviations 
16.2.4.1 
Demographics 
16.2.4.2 
PH-ILD History 
16.2.4.3 
Concomitant Medications  
16.2.5 
Inhaled Treprostinil Dosing 
16.2.6.1 
6-Minute Walk Test 
16.2.6.2 
NT-proBNP 
16.2.6.3 
St. George’s Respiratory Questionnaire 
16.2.6.4 
Pulse Oximetry and Distance Saturation Product 
16.2.7 
Adverse Events 
16.2.8.1 
Laboratory Results – Clinical Chemistry 
16.2.8.2 
Laboratory Results – Hematology 
16.2.8.3 
Pregnancy Test Results (Female Subjects Only) 
16.2.8.4 
Vital Signs 
16.2.8.5 
Pulmonary Function Tests 
16.2.8.6 
Hospitalizations 
16.2.8.7 
Exacerbations of Underlying Lung Disease 
12.3 
LIST OF FIGURES 
Figure Number 
Figure Title 
14.2.1 
Mean Change from Baseline in 6MWD (meter) by Visit 
14.3.1 
Kaplan-Meier Plot of Time to Death 
14.3.2 
Kaplan-Meier Plot of Time to Hospitalization 
14.3.3 
Kaplan-Meier Plot of Time to Hospitalization due to 
Cardiopulmonary Indications 
14.3.4 
Kaplan-Meier Plot of Time to Exacerbation of Underlying Lung 
Disease