Clinical trial NCT02630316
Conditions: Pulmonary Hypertension Interstitial Lung Disease Combined Pulmonary Fibrosis and Emphysema
Keywords: Treprostinil PH ILD CPFE 6 Minute Walk Test
Sponsor: United Therapeutics
Start date: 2017-02-03; Completion date: 2019-12-26
Enrollment: 326 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multicenter, randomized (1:1 inhaled treprostinil: placebo), double-blinded, placebo-controlled 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 included 326 patients at approximately 120 clinical trial centers. The treatment phase of the study lasted approximately 16 weeks. Patients who completed all required assessments were eligible to enter an open-label, extension study (RIN-PH-202).

Detailed description:
Study RIN-PH-201 was a multicenter, randomized, double-blind, placebo controlled, 16 week, parallel group study designed to investigate the safety and efficacy of inhaled treprostinil in subjects with PH-ILD. Subjects initiated inhaled treprostinil or placebo at a dose of 3 breaths (18 mcg) 4 times daily (QID) (during waking hours). Study drug doses were maximized throughout the study. Dose escalations (additional 1 breath QID) could occur up to every 3 days with a target dosing regimen of 9 breaths (54 mcg) QID and a maximum dose of 12 breaths (72 mcg) QID, as clinically tolerated. Subjects were assessed during Screening and Baseline to determine eligibility for the study. Once eligible, 5 Treatment Phase visits to the clinic were required at Week 4, Week 8, Week 12, Week 15, and Week 16 (final study visit). An Early Termination (ET) Visit was conducted for subjects who discontinued prior to Week 16; all assessments planned for the final Week 16 Visit were conducted during the ET Visit, if applicable. Subjects were contacted at least weekly by telephone or email to assess tolerance to study drug, AEs, and changes to concomitant medications. Efficacy assessments consisted of 6-minute walk distance (6MWD), plasma N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration, and incidence of clinical worsening. Exploratory endpoints included change in St. George's Respiratory Questionnaire (SGRQ), change in distance saturation product (DSP), time to exacerbation of underlying lung disease, and pulmonary function tests (PFT). Safety assessments consisted of the development of AEs, vital signs, clinical laboratory parameters, ECG parameters, hospitalizations due to cardiopulmonary indications, exacerbations of underlying lung disease, and oxygenation. Subjects who remained on study drug, completed all assessments during the 16-week Treatment Phase, and met all eligibility criteria were eligible for the open-label extension study (RIN-PH-202). Additionally, subjects who withdrew from study drug prior to Week 16 due to clinical worsening and returned to the clinic for scheduled visits (excluding the Week 15 Visit) were eligible for RIN PH-202.

Arms: arm 1: Matching placebo inhaled using an ultrasonic nebulizer four times daily arm 2: Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily
Interventions: intervention 1: Inhaled Treprostinil intervention 2: Placebo
Intervention descriptions: intervention 1: Inhaled treprostinil (6 mcg/breath) administered four times daily intervention 2: Placebo administered four times daily

Protocol documents:
Prot_002.pdf: 
United Therapeutics Corp. 
  
RIN-PH-201 Protocol Amendment 3 
Inhaled Treprostinil 
CONFIDENTIAL AND PROPRIETARY, UNITED THERAPEUTICS CORPORATION 
All content contained herein is confidential and proprietary information of United Therapeutics 
Corporation and shall not be disclosed in whole or in part except as permitted by a signed contract with 
United Therapeutics Corporation. © 2017 United Therapeutics Corporation 
Page 1 
 
A Multicenter, Randomized, Double-Blinded, Placebo-Controlled 
Trial to Evaluate the Safety and Efficacy of Inhaled Treprostinil 
in Subjects with Pulmonary Hypertension due to Parenchymal 
Lung Disease 
IND 70,362 
Protocol RIN-PH-201 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 21 October 2015 
Amendment 1 
20 November 2015 
Amendment 2 
13 September 2016 
Amendment 3 
15 February 2017 
 
 
 


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Inhaled Treprostinil 
Version Date 15 Feb 2017  
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LISTOFCONTACTSFORSTUDY
Study Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive  
Research Triangle Park, NC 27709 
 
 
 
 
 
 
Clinical Trial Leader 
Telephone: 
 
Fax: 
 
 
 
 
 
Product Leader 
Telephone:   
 
Fax:    
 
 
 
 
 
  
Medical Monitor 
Telephone: 
  
Fax: 
 
 
 
 
SAE Phone:    
 
SAE Fax:  
  
 
 
 
Clinical Laboratory 
 
 
 
 
   
 
 
 
 
 


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INVESTIGATOR’SAGREEMENT
I have read the attached protocol entitled “A Multicenter, Randomized, Double-Blinded, 
Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Inhaled Treprostinil in 
Subjects with Pulmonary Hypertension due to Parenchymal Lung Disease,” protocol 
amendment 3 dated 15 February 2017 and agree to abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Guideline for Good 
Clinical Practice 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 Investigator’s Brochure for inhaled treprostinil and acknowledge 
that review of the information contained in the Investigator’s Brochure is a requirement for 
Investigators before using inhaled treprostinil in a clinical study. 
This protocol has been received for information only and must not be implemented before all 
necessary regulatory agency and Ethics Committee/Institutional Review Board approval 
documents have been obtained. 
 
  
Signature of Principal Investigator 
 Date 
 
  
 
  
Printed Name of Principal Investigator 
  
 


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Version Date 15 Feb 2017  
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PROTOCOLSYNOPSIS
Title  
A Multicenter, Randomized, Double-Blinded, Placebo-
Controlled Trial to Evaluate the Safety and Efficacy 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 evaluate the safety and efficacy of inhaled treprostinil in 
subjects with PH associated with ILD including CPFE 
Primary Endpoint 
To evaluate the change in 6-minute walk distance (6MWD) 
measured at peak exposure from Baseline to Week 16 
Secondary Endpoints 
To evaluate the effect of inhaled treprostinil on the 
following parameters:  
 
1. Change in peak 6MWD from Baseline to Week 12 
2. Change in plasma concentration of N-terminal pro-
brain natriuretic peptide (NT-proBNP) from 
Baseline to Week 16 
3. Change in trough 6MWD from Baseline to Week 15 
Exploratory Endpoints 
To evaluate the effect of inhaled treprostinil on the 
following parameters: 
 
1. Change in peak 6MWD from Baseline to Week 4 
2. Change in peak 6MWD from Baseline to Week 8 
3. Change in quality of life (QOL) as measured by the 
St. George
's Respiratory Questionnaire (SGRQ) 
from Baseline to Week 16 
4. Time to clinical worsening will be evaluated as an 
exploratory endpoint from the time of 
randomization until 1 of the following criteria are 
met: 
a. Hospitalization due to a cardiopulmonary 
indication 


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b. Decrease in 6MWD > 15% from Baseline 
directly related to disease under study, at 2 
consecutive visits and at least 24 hours apart 
c. Death (all causes) 
d. Lung transplantation 
5. Change in distance saturation product (DSP) from 
Baseline to Week 16 
6. Optional evaluation of change in biomarkers 
(specific targets to be determined) from Baseline to 
Week 16 
7. Optional evaluation of whole genome sequence at 
Baseline 
Safety Endpoints 
1. Adverse events (AEs) 
2. Oxygenation  
a. Pulse oximetry (saturation of peripheral 
capillary oxygenation [SpO
2]) 
b. Supplemental oxygen requirement (L/min) 
3. Pulmonary function: 
a. Forced expiratory volume in 1 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. Electrocardiograms (ECG) 
7. Hospitalization due to a cardiopulmonary indication 
8. Exacerbations of underlying lung disease; defined as 
an acute, clinically significant, respiratory 
deterioration characterized by evidence of new 
widespread alveolar abnormality 
Study Design 
Multicenter, randomized, double-blinded, placebo-
controlled, 16-week, parallel group study 
Sample Size 
Approximately 314 subjects at approximately 120 centers  


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Summary of Subject 
Eligibility Criteria 
Inclusion criteria: 
1. Subject voluntarily gives informed consent to 
participate in the study. 
2. Males and females aged 18 years or older at the 
time of informed consent. 
a. Females of reproductive potential must be 
non-pregnant (as confirmed by a urine 
pregnancy test at screening) and non-
lactating, and will: 
i. Either abstain from intercourse 
(when it is in line with their preferred 
and usual lifestyle), or  
ii. Use 2 medically acceptable, highly-
effective forms of contraception
 for 
the duration of study, and at least 
30 days after discontinuing study 
drug.   
b. Males with a partner of childbearing 
potential must use a condom for the duration 
of treatment and for at least 48 hours after 
discontinuing study drug. 
3. The subject has a confirmed diagnosis of World 
Health Organization (WHO) Group 3 PH based on 
computed tomography (CT) imaging, which 
demonstrates evidence of diffuse parenchymal 
lung disease performed within 6 months prior to 
randomization.  Subjects may have any form of 
ILD or CPFE.  
4. Subjects are required to have a right heart 
catheterization (RHC) within 1 year prior to 
randomization with the following documented 
parameters: 
a. Pulmonary vascular resistance 
(PVR) > 3 Wood Units (WU) and  
b. A pulmonary capillary wedge pressure 
(PCWP) of ≤ 15 mmHg and 
c. A mean pulmonary arterial pressure (mPAP) 
of ≥ 25 mmHg 
5. Baseline 6MWD ≥ 100 meters 


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6. Subjects on a chronic medication for underlying 
lung disease (ie, pirfenidone, nintedanib, etc) must 
be on a stable and optimized dose for ≥ 30 days 
prior to randomization.   
7. In the opinion of the Investigator, the subject is 
able to communicate effectively with study 
personnel, and is considered reliable, willing and 
likely to be cooperative with protocol 
requirements, including attending all study visits. 
8. Subjects with connective tissue disease (CTD) 
must have a Baseline FVC of < 70%.   
Exclusion criteria: 
1. The subject has a diagnosis of pulmonary arterial 
hypertension (PAH) or PH for reasons other than 
WHO Group 3 PH-ILD as outlined in inclusion 
criterion 3.   
2. The subject has shown intolerance or significant 
lack of efficacy to a prostacyclin or prostacyclin 
analogue that resulted in discontinuation or 
inability to effectively titrate that therapy. 
3. The subject has received any PAH approved 
therapy including: prostacyclin therapy (ie, 
epoprostenol, treprostinil, iloprost, or beraprost; 
except for acute vasoreactivity testing), IP receptor 
agonist (selexipag), endothelin receptor antagonist 
(ERA), phosphodiesterase type 5 inhibitor 
(PDE5-I), or soluble guanylate cyclase (sGC) 
stimulator within 60 days of randomization.   
4. The subject has evidence of clinically significant 
left-sided heart disease as defined by:  
a. PCWP > 15 mmHg  
b. Left ventricular ejection fraction < 40%.   
Note: Subjects with abnormal left ventricular 
function attributable entirely to impaired left 
ventricular filling due to the effects of right 
ventricular overload (ie, right ventricular 
hypertrophy and/or dilatation) will not be 
excluded. 
5. The subject is receiving > 10 L/min of oxygen 
supplementation by any mode of delivery at rest at 
Baseline. 


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6. Current use of any inhaled tobacco/marijuana 
products or a significant history of drug abuse at 
the time of informed consent.   
7. Exacerbation of underlying lung disease or active 
pulmonary or upper respiratory infection within 
30 days of randomization. 
8. Initiation of pulmonary rehabilitation within 
12 weeks prior to randomization. 
9. In the opinion of the Investigator, the subject has 
any condition that would interfere with the 
interpretation of study assessments or has any 
disease or condition (ie, peripheral vascular 
disease, musculoskeletal disorder, morbid obesity) 
that would likely be the primary limit to 
ambulation (as opposed to PH).  
10. Use of any investigational drug/device, or 
participation in any investigational study with 
therapeutic intent within 30 days prior to 
randomization. 
11. Severe concomitant illness limiting life expectancy 
(< 6 months). 
12. Acute pulmonary embolism within 90 days of 
randomization.   
Drug Dosage  
and Formulation 
Inhaled treprostinil (6 mcg/breath) or placebo 
Treatment Phase:  
All subjects will initiate inhaled treprostinil or placebo at a 
dose of 3 breaths (18 mcg) 4 times daily (during waking 
hours).  Study drug doses should be maximized throughout 
the study, dose escalations (additional 1 breath 4 times 
daily) can occur up to every 3 days with a target dosing 
regimen of 9 breaths (54 mcg) 4 times daily and a 
maximum dose of 12 breaths (72 mcg) 4 times daily, as 
clinically tolerated. 
Control Group 
Placebo 
Route of  
Administration 
Inhaled 


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Procedures 
Subjects will be assessed during Screening and Baseline to 
determine eligibility for the study.  Once eligible, 
5 Treatment Phase visits to the clinic will be required at 
Week 4, Week 8, Week 12, Week 15, and Week 16 (final 
study visit).  An Early Termination (ET) Visit will be 
conducted for subjects who end treatment prior to Week 16; 
all assessments planned for the final Week 16 Visit will be 
conducted during the ET Visit, as applicable.  Subjects will 
also be contacted at least weekly by telephone or email to 
assess tolerance to study drug, AEs, and changes to 
concomitant medications. 
Key Assessments:  
 Pregnancy test: Females of childbearing potential 
will undergo a urine pregnancy test at Screening 
followed by urine pregnancy tests at Baseline and 
every subsequent scheduled study visit or ET. 
 Blood for NT-proBNP and clinical labs will be 
obtained at Baseline, Week 8, and Week 16 or ET.  
 A peak 6-minute walk test (6MWT) will be 
conducted at Baseline, Week 4, Week 8, Week 12, 
and Week 16 or ET.   
 A trough 6MWT will be performed at Week 15 (at 
least 24 hours prior to the Week 16 6MWT).   
 Pulse oximetry will be performed immediately prior 
to, during, and immediately after each 6MWT. 
 Pulmonary function tests (PFTs) will be conducted 
at Baseline, Week 8, and Week 16 or ET. 
 SGRQ will be completed at Baseline and Week 16 
or ET. 
 An optional blood sample will be collected for 
whole genome sequencing at Baseline. 
 An optional blood sample will be collected for the 
analysis of biomarkers (specific targets to be 
determined) at Baseline and Week 16 or ET. 
 An ECG will be conducted at Baseline and Week 16 
or ET. 
 Hospitalizations due to cardiopulmonary indications 
and exacerbations of underlying lung disease will be 
evaluated from the time of informed consent until 
study discontinuation.    
 


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 Time to clinical worsening will be evaluated from 
the time of randomization until study 
discontinuation.   
Statistical Considerations Using an allocation ratio of 1:1 between inhaled treprostinil 
and placebo, a sample size of approximately 266 subjects 
(133 per treatment) would provide at least 90% power at a 
significance level of 0.05 (2-sided hypothesis) to detect a 
30 meter between-treatment difference in the change from 
Baseline to Week 16 in 6MWD measured at peak exposure 
assuming a standard deviation of 75 meters.  The total 
sample size will be approximately 314 subjects to account 
for a discontinuation rate of approximately 15%.   
The primary efficacy endpoint is the change in 6MWD 
measured at peak exposure from Baseline to Week 16.  The 
clinical hypothesis is that inhaled treprostinil will improve 
exercise capacity after 16 weeks of therapy as compared 
with placebo when administered to subjects with PH 
associated with ILD including CPFE.  Non-parametric 
analysis of covariance will be used to estimate the treatment 
effect.  The magnitude of treatment effect will be estimated 
with the Hodges-Lehmann median difference between 
2 treatment groups.  For subjects who discontinue from the 
study early, the last observation carried forward method 
will be used to impute the 6MWD at Week 16. 
Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive 
P.O. Box 14186 
Research Triangle Park, NC 27709 
United States of America 


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TABLEOFCONTENTS
LISTOFCONTACTSFORSTUDY....................................................................................2 
INVESTIGATOR’S AGREEMENT.....................................................................................3 
PROTOCOLSYNOPSIS.......................................................................................................4 
TABLEOFCONTENTS......................................................................................................11 
TableofIn-TextTables........................................................................................................14 
1 BACKGROUNDANDRATIONALE..........................................................................15 
1.1 DEFINITIONOFCLINICALPROBLEM.............................................................15 
1.2 INHALEDTREPROSTINILBACKGROUND......................................................15 
1.2.1 
GeneralPharmacology..........................................................................................15 
1.2.2 
GeneralToxicology................................................................................................16 
1.2.3 
ClinicalExperience................................................................................................17 
1.3 RATIONALEFORDEVELOPMENTOFSTUDYDRUGIN
DISEASE/CONDITION............................................................................................18 
1.4 CLINICALHYPOTHESIS.......................................................................................19 
2 OBJECTIVES.................................................................................................................19 
2.1 PrimaryEndpoint......................................................................................................19 
2.2 SecondaryEndpoints.................................................................................................19 
2.3 ExploratoryEndpoints..............................................................................................19 
2.4 SafetyEndpoints.........................................................................................................20 
3 EXPERIMENTALPLAN..............................................................................................20 
3.1 STUDYDESIGN........................................................................................................20 
3.2 OVERALLSCHEDULEOFTIMESANDEVENTS............................................22 
3.3 CLINICALASSESSMENTS....................................................................................26 
3.3.1 
Efficacy...................................................................................................................26 
3.3.1.1 
6-Minute WalkTest...........................................................................................26 
3.3.1.2 
St. George’s Respiratory Questionnaire..........................................................27
 
3.3.1.3 
N-terminalPro-brainNatriureticPeptide.......................................................28 
3.3.1.4 
TimetoClinical Worsening..............................................................................28 
3.3.1.5 
ChangeinDistanceSaturationProduct..........................................................28 
3.3.1.6 
OptionalBiomarker...........................................................................................29
 
3.3.1.7 
Optional WholeGenomeSequencing...............................................................29
 
3.3.2 
Safety......................................................................................................................29 
3.3.2.1 
MedicalHistoryandPhysicalExaminations...................................................29 
3.3.2.2 
VitalSigns...........................................................................................................29 
3.3.2.3 
12-LeadElectrocardiogram..............................................................................30 
3.3.2.4 
ClinicalLaboratoryAssessments.....................................................................30 
3.3.2.5 
PulmonaryFunctionTests................................................................................31 
3.3.2.6 
Oxygenation........................................................................................................32 
3.3.2.7 
AdverseEvents...................................................................................................32 


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3.3.2.8 
Concomitant Medications.................................................................................33 
3.3.2.9 
HospitalizationduetoCardiopulmonaryIndications....................................33 
3.3.2.10 ExacerbationsofUnderlyingLungDisease.....................................................33 
3.3.2.11 WeeklyTelephone/EmailContact....................................................................34 
3.4 NUMBEROFSUBJECTS........................................................................................34 
3.5 NUMBEROFCENTERS..........................................................................................34 
3.6 ESTIMATEDSTUDYDURATION.........................................................................34 
4 SUBJECTELIGIBILITY..............................................................................................34 
4.1 INCLUSIONCRITERIA..........................................................................................35 
4.2 EXCLUSIONCRITERIA.........................................................................................35 
4.3 PRESCRIBEDTHERAPY........................................................................................36 
5 SUBJECTENROLLMENT...........................................................................................37 
5.1 TREATMENTASSIGNMENT................................................................................37 
5.2 RANDOMIZATION..................................................................................................37 
5.3 BLINDING..................................................................................................................37 
6 DRUGSANDDOSING(ORTREATMENTPROCEDURES).................................38 
6.1 DRUGDOSAGE,ADMINISTRATION,ANDSCHEDULE................................38 
6.2 ACCESSTOBLINDEDTREATMENTASSIGNMENT.....................................39 
6.3 COMPLIANCE..........................................................................................................39 
7 EXPERIMENTALPROCEDURES.............................................................................40 
7.1 SCREENINGVISIT..................................................................................................40
 
7.2 BASELINE/RANDOMIZATIONVISIT.................................................................41 
7.3 COMBINEDSCREENINGANDBASELINE........................................................42 
7.4 TREATMENTPHASE: WEEKS4,8,AND12......................................................44 
7.5 TREATMENTPHASE: WEEK15(TROUGH).....................................................45 
7.6 ENDOFSTUDY(WEEK16)AND/OREARLYTERMINATIONVISIT.........46 
7.7 STUDYCONTACTS.................................................................................................47 
7.8 ACCESSTOOPEN-LABELSTUDY......................................................................47 
8 STUDYTERMINATION...............................................................................................48 
8.1 CRITERIAFORSUBJECT WITHDRAWAL.......................................................48 
8.2 LOSTTOFOLLOW-UP...........................................................................................48
 
8.3 CRITERIAFORTERMINATINGTHESTUDY..................................................49 
8.4 CRITERIAFORDISCONTINUINGTHESITE...................................................49 
9 ADVERSEEVENTREPORTING................................................................................49 
9.1 DEFINITIONS...........................................................................................................49 
9.1.1 
AdverseEvent........................................................................................................49 
9.1.2 
SeriousAdverseEvent..........................................................................................50 
9.2 DOCUMENTATIONOFADVERSEEVENTS.....................................................51 
9.3 FOLLOW-UPOFADVERSEEVENTS..................................................................51 
9.4 REPORTINGRESPONSIBILITIESOFTHEINVESTIGATOR.......................51 


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9.5 PREGNANCY............................................................................................................52 
9.6 SAFETYREPORTS..................................................................................................52 
10 STATISTICALCONSIDERATIONS..........................................................................52 
10.1 DATAPROCESSING................................................................................................52 
10.2 SAMPLESIZE...........................................................................................................53 
10.3 ANALYSISPLAN......................................................................................................53 
10.3.1 PrimaryEfficacyEndpoint...................................................................................53 
10.3.2 SecondaryEfficacyEndpoints..............................................................................54 
10.3.3 ExploratoryEndpoints..........................................................................................54 
10.3.4 SafetyAnalyses......................................................................................................55 
10.4 INTERIMANALYSES..............................................................................................56 
10.5 OTHERANALYSES.................................................................................................56 
10.6 DATALISTINGSANDSUMMARIES...................................................................56 
10.7 DATA MONITORINGCOMMITTEE...................................................................56 
11 PACKAGINGANDFORMULATION........................................................................56 
11.1 CONTENTSOFSTUDYDRUG..............................................................................56 
11.1.1 StudyDrug.............................................................................................................56 
11.1.2 StudyDevice...........................................................................................................56 
11.2 LABELING.................................................................................................................57 
11.2.1 StudyDrug.............................................................................................................57 
11.2.2 StudyDevice...........................................................................................................57 
11.3 STORAGEANDHANDLINGOFCLINICALSTUDY MATERIAL.................57 
11.4 SUPPLYANDRETURNOFCLINICALSTUDY MATERIAL..........................57 
11.5 DRUGACCOUNTABILITY....................................................................................58 
12 REGULATORYANDETHICALOBLIGATION......................................................58 
12.1 APPLICABLEREGULATORYREQUIREMENTS.............................................58 
12.2 INFORMEDCONSENTREQUIREMENTS.........................................................59 
12.3 INDEPENDENTETHICSCOMMITTEE/INSTITUTIONALREVIEW
BOARD.......................................................................................................................59 
12.4 PRESTUDYDOCUMENTATIONREQUIREMENTS.........................................60 
12.5 SUBJECTCONFIDENTIALITY.............................................................................60 
13 ADMINISTRATIVEANDLEGALOBLIGATIONS.................................................60 
13.1 PROTOCOLAMENDMENTSANDSTUDYTERMINATION..........................60 
13.2 STUDYDOCUMENTATIONANDSTORAGE....................................................61 
13.3 STUDY MONITORINGANDDATACOLLECTION..........................................61 
14 REFERENCES................................................................................................................62 
15 APPENDICES.................................................................................................................64 
15.1 PROCEDUREFOR6-MINUTE WALKTEST.....................................................64 
15.2 GUIDELINESANDDEFINITIONSFORRECORDINGADVERSE
EVENTS......................................................................................................................66 


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15.3 ST. GEORGE’S RESPIRATORY QUESTIONNAIRE.........................................70
 
TableofIn-TextTables
Table 6-1 
Recommended Inhaled Treprostinil Dose Escalation Table 
........................... 38 
 


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1 
BACKGROUNDANDRATIONALE
1.1 DEFINITIONOFCLINICALPROBLEM
Pulmonary hypertension (PH) is defined as an elevation in pulmonary arterial pressure and 
pulmonary vascular resistance (PVR).  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 (Travis 2013, Seeger 2013).  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 (QOL) (Nathan 2008, Nathan 2013).   
Combined pulmonary fibrosis and emphysema is 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 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 INHALEDTREPROSTINILBACKGROUND
1.2.1 
GeneralPharmacology
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 (HR), 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, Argentina, and Israel 
for the treatment of PAH (WHO Group 1) in patients with New York Heart Association 
(NYHA) Functional Classification III symptoms, to increase exercise ability.  
1.2.2 
GeneralToxicology
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 2-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 Investigator’s Brochure for a 
full description of nonclinical data. 
1.2.3 
ClinicalExperience
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 6-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 4 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 (PE) findings, chest x-rays, pulmonary function tests (PFTs), 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 1 to 


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12 breaths (6 to 72 mcg) 4 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 QOL.  Survival was robust with 1 and 
2 year Kaplan-Meier survival estimates of 97% and 91%, respectively, for subjects that 
remained in the study.  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 6 subjects (3%) discontinued inhaled treprostinil 
due to cough, including 1 subject (<1%) with dry throat (Benza 2011). 
1.3 RATIONALEFORDEVELOPMENTOFSTUDYDRUGIN
DISEASE/CONDITION
Inhaled treprostinil has shown clinical improvements in exercise capacity after 12 weeks of 
therapy in patients with WHO Group 1 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 chronic 
obstructive pulmonary disease (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 9 COPD subjects with PH which reported no notable changes in arterial blood gases over 
the 16-Week treatment period (Bajwa 2016).  Finally, Agarwal and colleagues (Agarwal 


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2015) recently presented data on 35 patients with WHO Group 3 PH who received treatment 
with inhaled treprostinil for 6 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 CLINICALHYPOTHESIS
This study hypothesizes that inhaled treprostinil will improve exercise capacity after 16 weeks 
of therapy as compared with placebo when administered to subjects with PH associated with 
ILD including CPFE.   
2 
OBJECTIVES
To evaluate the safety and efficacy of inhaled treprostinil in subjects with PH associated with 
ILD including CPFE. 
2.1 PRIMARYENDPOINT
To evaluate the change in 6MWD measured at peak exposure from Baseline to Week 16.   
2.2 SECONDARYENDPOINTS
To evaluate the effect of inhaled treprostinil on the following parameters:  
1. Change in peak 6MWD from Baseline to Week 12 
2. Change in plasma concentration of N-terminal pro-brain natriuretic peptide  
(NT-proBNP) from Baseline to Week 16 
3. Change in trough 6MWD from Baseline to Week 15 
2.3 EXPLORATORYENDPOINTS
To evaluate the effect of inhaled treprostinil on the following parameters: 
1. Change in peak 6MWD from Baseline to Week 4 
2. Change in peak 6MWD from Baseline to Week 8 
3. Change in QOL as measured by the St. George
's Respiratory Questionnaire (SGRQ) 
from Baseline to Week 16 
4. Time to clinical worsening from the time of randomization until 1 of the following 
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a. Hospitalization due to a cardiopulmonary indication 
b. Decrease in 6MWD > 15% from Baseline directly related to disease under study, 
at 2 consecutive visits and at least 24 hours apart 
c. Death (all causes) 
d. Lung transplantation 
5. Change in distance saturation product (DSP) from Baseline to Week 16 
6. Optional evaluation of change in biomarkers (specific targets to be determined) from 
Baseline to Week 16 
7. Optional evaluation of whole genome sequence at Baseline 
2.4 SAFETYENDPOINTS
To evaluate the effect of inhaled treprostinil on the following parameters: 
1. 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 1 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. Electrocardiograms (ECG) 
7. Hospitalization due to a cardiopulmonary indication 
8. Exacerbations of underlying lung disease; defined as an acute, clinically significant, 
respiratory deterioration characterized by evidence of new widespread alveolar 
abnormality 
3 
EXPERIMENTALPLAN
3.1 STUDYDESIGN
This is a multicenter, randomized, double-blinded, placebo-controlled, 16-week, parallel 
group study.  Subject eligibility will be based on inclusion and exclusion criteria described in 
Section 4.  Approximately 314 eligible subjects will be randomized to study treatment in a 
1:1 ratio.  Subjects will be stratified based on Baseline 6MWD (≤ 350 meters and 
> 350 meters).  Subjects will be treated with either inhaled treprostinil (6 mcg/breath) or 
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The study will consist of the following phases: 
Screening Phase: Prospective subjects will undergo a screening evaluation within 30 days 
prior to the Baseline Visit (first dose of study drug).  During this phase, eligible 
subjects will sign the informed consent form (ICF) and undergo screening assessments 
as described in Sections 7.1 and 7.3.  The Screening and Baseline assessments may be 
combined if all entry criteria are satisfied within 48 hours prior to the first dose of 
study drug.  Baseline PFTs and 6-minute walk test (6MWT) used to confirm eligibility 
criteria must be performed prior to randomization. 
Baseline Visit: The Baseline assessments may be conducted over a 48-hour period prior 
to the first dose of study drug to allow for scheduling of all activities.  Eligible 
subjects will undergo Baseline assessments (Sections 7.2 and 7.3), be assigned to a 
treatment group based on the randomization schedule, and receive the first dose of 
study drug (Day 1 is defined as the day the first dose of study drug is given).  The 
Screening and Baseline assessments may be combined if all entry criteria are satisfied 
within 48 hours prior to the first dose of study drug.  Baseline PFTs and 6MWT used 
to confirm eligibility criteria must be performed prior to randomization. 
Treatment Phase: The Treatment Phase consists of 5 study visits to the clinic at Week 4, 
Week 8, Week 12, Week 15, and Week 16 (final study visit; at least 24 hours after the 
Week 15 Visit).  Subjects will also be contacted at least weekly by telephone or email 
to assess subject tolerance to study drug, AEs, and changes to concomitant 
medications.   
A schedule of visits and assessments is presented in Section 3.2.  








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k   Pulse oximetry will be performed immediately prior to, during, and immediately following each 6MWT.  Pulse oximetry will include the measurement of SpO
2 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 SpO
2 obtained during each 6MWT will be recorded in the eCRF. 
l   PFTs will include the evaluation of FEV1, FVC, TLC, and DLCO.  Baseline PFTs must be performed prior to randomization.  PFTs should be performed after 
recovering from the Baseline, Week 8, and Week 16 or ET 6MWTs. 
m   At least weekly telephone contact is required throughout the study (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.
 
n   All AEs will be documented from the time of informed consent until the time screen failure is documented, or until the subject is either discontinued from the study or 
all Week 16 study assessments have been completed and should be followed until either resolution (or return to normal or baseline values), until they are judged by the 
Investigator to no longer be clinically significant, or for at least 30 days if the AE extends beyond the final study visit (Week 16). 
o   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.
 
p   Exacerbations of underlying lung disease; defined as an acute, clinically significant, respiratory deterioration characterized by evidence of new widespread alveolar 
abnormality (see Section 3.3.2.10).  Exacerbations will also be recorded as AEs or SAEs per Appendix 15.2.   
q   Time to clinical worsening will be measured from the time of randomization until 1 of the following criteria are met: hospitalization due to a cardiopulmonary 
indication; decrease in 6MWD > 15% from Baseline directly related to the disease under study, at 2 consecutive visits and at least 24 hours apart; death (all causes); or 
lung transplantation. 
r   Once all entry criteria have been met and the randomized treatment assignment confirmed, the first dose of study drug (3 breaths; 18 mcg) will be inhaled in the clinic, 
followed by at least a 1 hour observation period (Defined as Day 1). 
s   Subjects who permanently discontinue study drug during the 16-week Treatment Phase are encouraged to undergo premature termination assessments prior to 
discontinuing study drug and are required complete all remaining scheduled study visits through Week 16 (excluding the Week 15 Visit) to be eligible for entry into the 
open-label study.   
t   The premature termination of study drug visit should be conducted prior to study drug discontinuation or as close as possible to the last dose of study drug. 


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3.3 CLINICALASSESSMENTS
3.3.1 
Efficacy
3.3.1.1 6-Minute WalkTest
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 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.  This 6MWT protocol applies to the practice (if applicable), Baseline, 
and treatment 6MWTs.  Subjects receiving supplemental oxygen during the Baseline 6MWT 
must continue to receive the same flow rate at all subsequent 6MWT assessments.  Pulmonary 
rehabilitation may not be introduced to a subject’s treatment regimen between randomization 
and Week 16 or until the permanent discontinuation of study drug.  Pulse oximetry is to be 
performed immediately prior to, during, and immediately following each scheduled 6MWT as 
outlined in Section 3.3.2.6.1. 
3.3.1.1.1 
Practice 6-Minute Walk Test 
All subjects must have a documented 6MWT conducted at the study site on the course 
intended for use during the study.  Subjects who have not previously performed the 6MWT at 
the study site on the course intended for use during the study, must perform a practice 6MWT 
at the study site at least 1 day prior to the Baseline Visit. 
3.3.1.1.2 
Baseline 6-Minute Walk Test 
The Baseline 6MWT must be performed prior to randomization.  Pulse oximetry is to be 
performed immediately prior to, during, and immediately following each scheduled 6MWT as 
outlined in Section 3.3.2.6.1.  
Note:  The Baseline 6MWT (not the practice 6MWT) will determine the subject’s eligibility 
to participate in the study (6MWD ≥ 100 meters per inclusion criteria). 


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3.3.1.1.3 
Treatment 6-Minute Walk Tests 
3.3.1.1.3.1 Peak 6-Minute Walk Tests 
Peak 6MWTs will be conducted at Weeks 4, 8, 12, and 16 or Early Termination (ET).  The 
6MWT must be conducted between 10 to 60 minutes after the most recent dose of study drug.  
If subjects are receiving supplemental oxygen during the Baseline 6MWT, they must continue 
to receive the same flow rate at all subsequent 6MWT assessments.  The Week 16 peak 
6MWT should occur at least 24 hours after the Week 15 Visit.  Refer to Appendix 15.1 for 
guidelines regarding the 6MWT assessment.  Pulse oximetry is to be performed immediately 
prior to, during, and immediately following each scheduled 6MWT as outlined in Section 
3.3.2.6.1. 
3.3.1.1.3.2 Trough 6-Minute Walk Test 
A trough 6MWT will be performed during the Week 15 Visit.  The trough 6MWT must be 
performed at least 4 hours after the most recent dose of study drug and at least 24 hours prior 
to the Week 16 6MWT.  If subjects are receiving supplemental oxygen during the Baseline 
6MWT, they must continue to receive the same flow rate at all subsequent 6MWT 
assessments.  Refer to Appendix 15.1 for guidelines regarding the 6MWT assessment.  Pulse 
oximetry is to be performed immediately prior to, during, and immediately following each 
scheduled 6MWT as outlined in Section 3.3.2.6.1. 
Subjects who discontinue study drug prematurely prior to the Week 15 Visit do not need to 
return to the clinic for the Week 15 Visit to be eligible for participation in the open-label 
extension study (Section 7.8). 
3.3.1.2 St. George’s RespiratoryQuestionnaire
The SGRQ will be conducted at Baseline (prior to study drug) or as part of the Screening 
Visit assessment if the Screening and Baseline Visits are combined and at Week 16 (or ET for 
those subjects discontinuing study drug/study prematurely).  The SGRQ should be completed 
as the first assessment during these visits (after informed consent is obtained) before the 
subject completes any of the other scheduled visit assessments.  A copy of the SGRQ can be 
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3.3.1.3 N-terminalPro-brainNatriureticPeptide
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 (or as part of the Screening Visit assessment if the Screening and Baseline Visits are 
combined) prior to starting study drug, Week 8, and Week 16 or ET.  Blood for NT-proBNP 
assessment must be drawn prior to conducting the 6MWT. 
3.3.1.4 TimetoClinical Worsening
Time to clinical worsening will be evaluated as an exploratory endpoint from the time of 
randomization until 1 of the following criteria are met: 
a. Hospitalization due to a cardiopulmonary indication 
b. Decrease in 6MWD > 15% from Baseline directly related to disease under study, at 
2 consecutive visits and at least 24 hours apart 
c. Death (all causes) 
d. Lung transplantation 
Because there are no Food and Drug Administration (FDA) approved therapies for the 
treatment of WHO Group 3 PH, subjects experiencing clinical worsening may remain on 
study therapy for the duration of the study (or until criteria for study termination are met per 
Section 8.1 of the protocol).  However, if a subject is removed from study therapy due to 
clinical worsening, the subject must return to the clinic for regularly scheduled study visits 
(excluding the Week 15 Visit) to be eligible for the open-label extension study (Section 7.8).  
Subjects experiencing death or lung transplantation will be discontinued from the study per 
Section 8.1 of the protocol. 
3.3.1.5 ChangeinDistanceSaturationProduct
Change in DSP is the product of distance walked and lowest SpO
2 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 from Baseline to Week 16 or ET in DSP will be calculated.  


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3.3.1.6 OptionalBiomarker
For subjects consenting to the optional biomarker sample, blood will be collected for the 
evaluation of biomarkers (specific targets to be determined) at Baseline and at Week 16 or 
ET.  
3.3.1.7 Optional WholeGenomeSequencing
For subjects consenting to whole genome sequence analysis, a blood sample will be collected 
at Baseline.  These samples will be shipped to the central laboratory for processing and 
storage prior to analysis.  Whole genome sequences will be analyzed for genetic makers that 
may be associated with clinical response and tolerability.      
3.3.2 
Safety
During this study, treatment emergent changes in PE findings, vital signs, clinical laboratory 
parameters, ECG parameters, PFTs, oxygenation, and the development of AEs after treatment 
will be the primary assessments of safety.  Hospitalizations due to cardiopulmonary 
indications will also be recorded from the time of informed consent until study termination (or 
ET for those subjects discontinuing the study prematurely).  Exacerbations of underlying lung 
disease will also be recorded from the time of informed consent until study termination.   
3.3.2.1 MedicalHistoryandPhysicalExaminations
A complete medical history, demographics, PH history, and PE will be conducted during 
Screening.  If any changes to the medical history occur between the Screening and Baseline 
Visit, those should be recorded.  Significant past or present illnesses, current prescription or 
nonprescription medications (including vitamins and herbal products), and history of allergies 
or idiosyncratic responses to drugs should be recorded.  Any significant changes to the 
subject’s medical condition and PE must be documented throughout the course of the study.  
A complete PE will also be conducted by appropriate study personnel (as documented on the 
Delegation of Authority Log) at the Week 16 or ET Visit.  Any clinically significant changes 
from Baseline noted during the Week 16 or ET PE should be reported as AEs. 
3.3.2.2 VitalSigns
Vital signs will be assessed at Screening, Baseline, and each subsequent study visit or ET.  
Vital signs measured will include blood pressure (systolic and diastolic), HR, respiratory rate 


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(RR), temperature, and weight.  Height will be assessed at Screening only.  Vital signs must 
be assessed following at least 5 minutes of rest (sitting) to ensure accurate measurement.  No 
other measurements or procedures should be performed during this 5-minute period.  When 
possible, vital signs should be collected prior to the 6MWT.  If vital signs cannot be obtained 
prior to the 6MWT, they should be obtained after recovery of the 6MWT.  Vital signs should 
also be assessed in the case of abnormal clinical signs and symptoms. 
3.3.2.3 12-LeadElectrocardiogram
A 12-lead ECG will be recorded after at least 5 minutes of rest in the semi-recumbent position 
at Baseline (prior to study drug) and repeated at the Week 16 or ET Visit.  Recordings should 
include lead II as a rhythm strip and contain at least 5 QRS complexes.  ECG parameters to be 
collected include rhythm, HR, PR interval, QT interval, QRS duration, and any clinically 
significant abnormalities. 
3.3.2.4 ClinicalLaboratoryAssessments
The results of all clinical laboratory tests conducted at Screening and Baseline must be 
assessed by the Investigator to determine each subject’s eligibility to participate in the study 
prior to starting study drug.  Screening and Baseline clinical laboratory assessments can be 
combined into a single blood draw if all eligibility criteria are met within 48 hours prior to the 
first dose of study drug at Baseline.  Central laboratory data are ultimately used to qualify 
subjects for the study.  However, for subjects who are well known to the Investigator and who 
are clinically stable, the Investigator may confirm eligibility using local laboratory values so 
as not to delay randomization while waiting for central laboratory results if the Screening and 
Baseline Visits are combined.  
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. 


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3.3.2.4.1 
Clinical Chemistry and Hematology 
Blood for the measurement and evaluation of clinical chemistry and hematology, will be 
collected at the Screening and Baseline Visits prior to administration of study drug and 
repeated at Week 8 and Week 16 or ET to assess for treatment-emergent changes in clinical 
chemistry and hematological laboratory parameters.  Values for the following parameters will 
be obtained: 
Electrolyte Panel 
Chemistry Panel 
Hematology Panel 
 Sodium 
 Total bilirubin 
 Hemoglobin  
 Potassium 
 Alkaline phosphatase 
 Hematocrit  
 Bicarbonate  
 Alanine aminotransferase  
 Red blood cell count  
 Chloride 
 Aspartate aminotransferase  Red blood cell morphology 
 
 Urea nitrogen 
 White blood cell count  
 Creatinine 
 Platelet count 
 Calcium 
 
 Albumin 
3.3.2.4.2 
Pregnancy Testing   
Females of childbearing potential will undergo a urine pregnancy test at Screening followed 
by urine pregnancy tests at Baseline and each subsequent study visit (or Baseline Visit if the 
Screening and Baseline Visits are combined) or ET.  A positive pregnancy test will exclude 
the subject from further participation in the study.  Pregnant subjects who are discontinued 
from the study will be transitioned to an alternate therapy at the discretion of the Investigator. 
3.3.2.5 PulmonaryFunctionTests
Pulmonary Function Tests will be assessed at Baseline and repeated at Week 8 and Week 16 
or ET.  Baseline PFTs are to be conducted prior to randomization and after recovery from the 
6MWT.  The Week 8 and Week 16 or ET PFTs should be conducted after recovery from the 
6MWT.  If the PFTs are done both prior to and after a bronchodilator, only the pre-
bronchodilator values will be recorded.   
The following parameters will be recorded (absolute values and % predicted): FEV1, FVC, 
TLC, and DLCO (uncorrected for hemoglobin and lung volume). 


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3.3.2.6 Oxygenation
3.3.2.6.1 
Pulse Oximetry 
Pulse oximetry will be assessed immediately prior to, throughout the conduct of, and 
immediately after each scheduled 6MWT assessment at Baseline, Week 4, Week 8, Week 12, 
Week 15, and Week 16 or ET.  Pulse oximetry will also be performed at Screening during the 
practice 6MWT assessment as applicable.  Pulse oximetry will include the collection of SpO2 
and HR.  The SpO
2 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 SpO
2 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 (ie, 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.   
3.3.2.6.2 
Supplemental Oxygen Requirement 
The amount of supplemental oxygen (L/min) required at rest will be assessed at Baseline and 
at regularly scheduled visits or ET.  The amount of supplemental oxygen required at the 
6MWT assessment will also be recorded for each 6MWT assessment. 
3.3.2.7 AdverseEvents
Adverse events will be recorded throughout the course of the study from the time that each 
subject signs the ICF until the time screen failure is documented, or until the subject is either 
discontinued from the study or all Week 16 study assessments have been completed.  Each 
subject will be questioned for AEs at 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 (ie, serious adverse events [SAEs]) should be followed until resolution, death, or the 


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subject is lost to follow-up even if they are ongoing more than 30 days after completion of the 
final study visit (Week 16 or ET).  All AEs/SAEs that occur while the subject is in study will 
be recorded as instructed in this protocol. 
Sections 9 and 15.2 provide the guidelines and definitions for recording AEs. 
3.3.2.8 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. 
3.3.2.9 HospitalizationduetoCardiopulmonaryIndications
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.   
3.3.2.10 ExacerbationsofUnderlyingLungDisease
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: 
1. Previous or concurrent diagnosis of ILD including CPFE 
2. Acute worsening or development of dyspnea typically of less than 1 month duration 
3. Computed topography (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 4 diagnostic criteria due to missing CT data should still 
be considered an exacerbation for reporting purposes. 


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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.   
3.3.2.11 WeeklyTelephone/EmailContact
Weekly telephone/email contact is required throughout the 16-week study to instruct the 
subject to titrate their dose of study drug and to assess for AEs and concomitant medications.  
Weekly 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 (ie, any dosing instructions, AEs reported and/or 
medication changes) with the subject must be noted in the source documentation. 
3.4 NUMBEROFSUBJECTS
Using an allocation ratio of 1:1 between inhaled treprostinil and placebo, a sample size of 
approximately 266 subjects (133 per treatment) would provide at least 90% power at a 
significance level of 0.05 (2-sided hypothesis) to detect a 30 meter between-treatment 
difference in the change from Baseline to Week 16 in 6MWD assuming a standard deviation 
of 75 meters.  The total sample size will be approximately 314 subjects to account for a 
discontinuation rate of approximately 15%.   
3.5 NUMBEROFCENTERS
This study is multicenter with approximately 120 participating study centers. 
3.6 ESTIMATEDSTUDYDURATION
From Screening until study completion, expected duration of study participation is 
approximately 20 weeks (includes a 4-week Screening period and 16-week Treatment Phase). 
4 
SUBJECTELIGIBILITY
Inclusion and exclusion criteria are to be assessed during the Screening period and 
reconfirmed at the Baseline Visit prior to the first dose of study drug.  Study related 
procedures must be conducted during the Screening period after obtaining informed consent 
to determine subject eligibility for the study. 


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4.1 INCLUSIONCRITERIA
1. Subject voluntarily gives informed consent to participate in the study. 
2. Males and females aged 18 years or older at the time of informed consent. 
a. Females of reproductive potential1 must be non-pregnant (as confirmed by a urine 
pregnancy test at screening) and non-lactating, and will: 
i. Either abstain from intercourse (when it is in line with their preferred and 
usual lifestyle), or  
ii. Use 2 medically acceptable, highly-effective forms of contraception2 for 
the duration of study, and at least 30 days after discontinuing study drug.   
b. Males with a partner of childbearing potential must use a condom for the duration 
of treatment and for at least 48 hours after discontinuing study drug. 
3. The subject has a confirmed diagnosis of WHO Group 3 PH based on CT imaging, 
which demonstrates evidence of diffuse parenchymal lung disease performed within 
6 months prior to randomization.  Subjects may have any form of ILD or CPFE.  
4. Subjects are required to have a RHC within 1 year prior to randomization with the 
following documented parameters: 
a. Pulmonary vascular resistance (PVR) > 3 Wood Units (WU) and  
b. A pulmonary capillary wedge pressure (PCWP) of < 15 mmHg and 
c. A mean pulmonary arterial pressure (mPAP) of > 25 mmHg 
5. Baseline 6MWD ≥ 100 meters. 
6. Subjects on a chronic medication for underlying lung disease (ie, pirfenidone, 
nintedanib, etc) must be on a stable and optimized dose for ≥ 30 days prior to 
randomization.   
7. In the opinion of the Investigator, the subject is able to communicate effectively with 
study personnel, and is considered reliable, willing and likely to be cooperative with 
protocol requirements, including attending all study visits. 
8. Subjects with connective tissue disease (CTD) must have a Baseline FVC of < 70%.  
4.2 EXCLUSIONCRITERIA
1. The subject has a diagnosis of PAH or PH for reasons other than WHO Group 3 PH-
ILD as outlined in inclusion criterion 3.   
2. The subject has shown intolerance or significant lack of efficacy to a prostacyclin or 
prostacyclin analogue that resulted in discontinuation or inability to effectively titrate 
that therapy. 
                                                 
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 
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3. The subject has received any PAH approved therapy including: prostacyclin therapy 
(ie, epoprostenol, treprostinil, iloprost, or beraprost; except for acute vasoreactivity 
testing), IP receptor agonist (selexipag), endothelin receptor antagonist (ERA), 
phosphodiesterase type 5 inhibitor (PDE5-I), or soluble guanylate cyclase (sGC) 
stimulator within 60 days of randomization. 
4. The subject has evidence of clinically significant left-sided heart disease as defined 
by:  
a. PCWP > 15 mmHg  
b. Left ventricular ejection fraction < 40%.   
Note: Subjects with abnormal left ventricular function attributable entirely to impaired left 
ventricular filling due to the effects of right ventricular overload (ie, right ventricular 
hypertrophy and/or dilatation) will not be excluded. 
5. The subject is receiving > 10 L/min of oxygen supplementation by any mode of 
delivery at rest at Baseline. 
6. Current use of any inhaled tobacco/marijuana products or significant history of drug 
abuse at the time of informed consent.   
7. Exacerbation of underlying lung disease or active pulmonary or upper respiratory 
infection within 30 days of randomization. 
8. Initiation of pulmonary rehabilitation within 12 weeks prior to randomization. 
9. In the opinion of the Investigator, the subject has any condition that would interfere 
with the interpretation of study assessments or has any disease or condition (ie, 
peripheral vascular disease, musculoskeletal disorder, morbid obesity) that would 
likely be the primary limit to ambulation (as opposed to PH). 
10. Use of any investigational drug/device, or participation in any investigational study 
with therapeutic intent within 30 days prior to randomization. 
11. Severe concomitant illness limiting life expectancy (< 6 months). 
12. Acute pulmonary embolism within 90 days of randomization. 
4.3 PRESCRIBEDTHERAPY
Subjects must not be receiving any prostacyclin (ie, epoprostenol, treprostinil, iloprost, 
beraprost, or any other prostacyclin therapy) within 60 days prior to randomization (unless 
used for acute vasoreactivity testing) until study termination.  Subjects must also not be 
receiving any other FDA approved PAH background therapies including:  an IP receptor 
agonist, ERA, PDE5-I, and/or sGC stimulator within 60 days of randomization through the 
permanent discontinuation of study drug or study termination.   
Subjects on a chronic medication for underlying lung disease (ie, pirfenidone, nintedanib, etc) 
must be on a stable and optimized dose for ≥ 30 days prior to randomization.  Subjects may 


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not newly initiate pirfenidone or nintedanib from randomization through the permanent 
discontinuation of study drug or study termination.   
Subjects may not initiate pulmonary rehabilitation (rehab) within 12 weeks prior to 
randomization until the permanent discontinuation of study drug or study termination. 
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 3.3.2.6.2.   
5 
SUBJECTENROLLMENT
5.1 TREATMENTASSIGNMENT
Subjects will be randomized (1:1) to receive treatment with inhaled treprostinil (6 mcg/breath) 
or placebo.   
5.2 RANDOMIZATION
Subjects will be randomized (1:1) to receive treatment with inhaled treprostinil (6 mcg/breath) 
or placebo.  An IXRS will be utilized for the central randomization procedure.  Sites will 
enter values of the qualifying 6MWT and the date the test was conducted into the IXRS and 
will be notified if the subject qualifies for the study.   
All subjects will be randomized using a centrally administered stratified permuted block 
randomization, stratified by Baseline 6MWD (≤ 350 meters and > 350 meters).   
Prior to randomization, site personnel should complete a Pre-Baseline Review Form for 
review and approval by the Medical Monitor. 
5.3 BLINDING
The Investigator, study site, subject and Sponsor will not be aware of the treatment allocation.  
All clinical study material will be provided as blinded 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.   
If subjects are unable to tolerate the initial 3 breaths, they may decrease their next dose to 1 or 
2 breaths of study drug (as determined by the Investigator) 4 times a day during waking hours.  
The subject will then gradually increase their dose to reach a minimum of 3 breaths, and 
titrate to a target dose of 9 breaths and a maximum dose of 12 breaths 4 times a day during 
waking hours, as clinically tolerated. 
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 to monitor for AEs, clinical worsening events, and make 
decisions about dose titration.   
6.2 ACCESSTOBLINDEDTREATMENTASSIGNMENT
During the study, the site personnel, subject, and Sponsor will remain blinded to the treatment 
assignment of all subjects.  A medical emergency (eg, a life threatening event) constitutes the 
only reason for unblinding during the Treatment Phase.  Appropriate communications must 
take place between the site and the Sponsor before accessing the IXRS to allow unblinding of 
a subject’s treatment assignment. 
6.3 COMPLIANCE
Each subject will be provided with a dosing diary in order to record dosing information from 
randomization until Week 16.  Subjects will be required to bring the completed dosing diary 
and all empty and unused study drug ampoules to each scheduled study visit.  At each visit, 
all study drug returned by the subject (used and unused) will be collected and new study drug 
will be dispensed.  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 


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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 
importance.  Continued non-compliance may lead to withdrawal of the subject from the study, 
after consultation between the Investigator and the Sponsor. 
7 
EXPERIMENTALPROCEDURES
Screening may begin up to 30 days prior to first dose of study drug.  Baseline assessments 
may be conducted over a 48-hour period prior to the first dose of study drug to allow for 
scheduling of all activities.  Alternately, the Screening and Baseline assessments may be 
conducted in 1 visit if all assessments are performed and all entry criteria are satisfied within 
the 48 hours prior to randomization and first dose of study drug.   
7.1 SCREENINGVISIT
The recommended sequence of assessments for the Screening Visit is as follows (if not 
combined with the Baseline Visit [see Section 7.3 for the recommended sequence of events 
for the combined Screening/Baseline Visit]): 
 Informed consent 
 Inclusion/exclusion criteria review 
o If necessary, the following procedures may be performed during the 30 day 
Screening window if required to satisfy inclusion/exclusion criteria (previous 
medical records documenting eligibility criteria may also be used provided the 
previous records document subject eligibility within the protocol mandated 
timelines, as applicable): 
 RHC (Must be performed within 1 year prior to randomization.  If a historical 
RHC is not available in this timeframe, a RHC may be performed during 
Screening so long as it is performed at least 5 days prior to randomization 
[Baseline (Day 1)]; a RHC cannot be combined with the Baseline Visit).  
Select RHC parameters will be recorded in the eCRF including: mPAP, PVR, 
PCWP, and vasodilator response (as applicable). 
 CT scan (must be performed within 6 months prior to randomization).  A 
redacted copy of the CT scan used to confirm subject eligibility should be sent 
to the Sponsor. 
 Although not required for eligibility, the date of lung biopsy for subjects with a 
biopsy confirmed diagnosis of ILD will be recorded in the eCRF. 
 Demographics 
 PH history 
 Medical history 


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 PE 
 Vital signs (following at least 5 minutes of rest; collected prior to 6MWT or after 
recovery from the 6MWT, if practice 6MWT is applicable); including height, weight, 
RR, HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and 
temperature. 
 Blood draws for clinical laboratory parameters  
 Urine pregnancy test, for women of childbearing potential 
 Practice 6MWT (only required if the subject has not previously performed a 6MWT at 
the study site; to be conducted 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, if applicable) 
 Documentation of supplemental oxygen requirement (L/min) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 AEs 
 Concomitant medications 
 Complete and submit Pre-Baseline Review Form to the Sponsor for Medical Monitor 
review prior to randomization 
7.2 BASELINE/RANDOMIZATIONVISIT
All Baseline assessments must be performed prior to the first dose of study drug.  Baseline 
assessments may be conducted over a 48-hour period prior to the first dose of study drug to 
allow for scheduling of assessments; however, the Baseline 6MWT must occur prior to 
randomization.  The recommended sequence of assessments for the Baseline Visit is as 
follows (if not combined with the Screening Visit [see Section 7.3 for the recommended 
sequence of events for the combined Screening/Baseline Visit]): 
 SGRQ (questionnaire must be administered prior to any results, procedures, or blood 
draws) 
 Vital signs (following at least 5 minutes of rest; collected prior to 6MWT or after 
recovery from the 6MWT); including weight, RR, HR, SBP, DBP, and temperature. 
 Urine pregnancy test, for women of childbearing potential 
 Blood draws for clinical laboratory parameters  
 NT-proBNP (must be drawn prior to 6MWT and first dose of study drug; for central 
laboratory processing only) 
 Collection of blood sample for evaluation of biomarkers (optional) 
 Collection of blood sample for evaluation of whole genome sequence (optional) 
 12-lead ECG (following at least 5 minutes of rest in the semi-recumbent position) 


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 Documentation of supplemental oxygen requirement (L/min) 
 6MWT (must be conducted prior to randomization; to be conducted 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) 
 PFTs (must be done prior to randomization and after recovery from the Baseline 
6MWT) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 AEs  
 Concomitant medications 
 Re-confirm inclusion/exclusion criteria (Baseline 6MWD [not the practice Screening 
6MWD] will be used for inclusion/exclusion verification) 
 Randomization using IXRS 
 Administer study drug and provide dosing instructions and device training (subject 
must remain in the clinic for at least 1 hour after the first dose of study drug for 
observation) 
 Time to clinical worsening will be evaluated as an exploratory endpoint from the time 
of randomization until 1 of the following criteria are met: 
o Hospitalization due to a cardiopulmonary indication 
o Decrease in 6MWD > 15% from Baseline directly related to disease under study, 
at 2 consecutive visits and at least 24 hours apart 
o Death (all causes) 
o Lung transplantation 
7.3 COMBINEDSCREENINGANDBASELINE
The Screening and Baseline assessments may be conducted in 1 visit if all assessments are 
performed and all entry criteria are satisfied within 48 hours prior to randomization and 
dosing of study drug.  Baseline PFTs, 6MWT, and CT (if a historical assessment is not 
available within 6 months prior to randomization) assessments used to determine eligibility 
criteria may be performed on the same day but prior to randomization.  The recommended 
order of assessments for a combined Screening and Baseline Visit is outlined below. 
Assessments to be completed as part of the Screening Visit: 
 Informed consent 
 SGRQ (questionnaire must be administered prior to any results, procedures, or blood 
draws) 
 Inclusion/exclusion criteria review 


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o RHC (Must be performed within 1 year prior to randomization.  If a historical 
RHC is not available in this timeframe, a RHC may be performed during 
Screening so long as it is performed at least 5 days prior to randomization 
[Baseline (Day 1)]; a RHC cannot be combined with the Baseline Visit).  Select 
RHC parameters will be recorded in the eCRF including: mPAP, PVR, and 
PCWP, and vasodilator response (as applicable). 
o CT scan (must be performed within 6 months prior to randomization).  A redacted 
copy of the CT scan used to confirm subject eligibility should be sent to the 
Sponsor. 
o Although not required for eligibility, the date of lung biopsy for subjects with a 
biopsy confirmed diagnosis of ILD will be recorded in the eCRF. 
 Blood draws for clinical laboratory parameters (enough blood should be drawn for 
local laboratory to confirm the entry criteria for hemoglobin, as well as for the 
complete panel for central laboratory processing) 
 NT-proBNP (must be drawn prior to 6MWT and first dose of study drug; for central 
laboratory processing only) 
 Collection of blood sample for evaluation of biomarkers (optional) 
 Collection of blood sample for evaluation of whole genome sequence (optional) 
 Demographics 
 PH history 
 Medical history 
 PE 
 Vital signs (following at least 5 minutes of rest; collected prior to the 6MWT or after 
recovery from the 6MWT); including height, weight, RR, HR, SBP, DBP, and 
temperature. 
 Documentation of supplemental oxygen requirement (L/min) 
 Practice 6MWT to be conducted 1 day prior to Baseline assessments (only required if 
the subject has not previously performed a 6MWT at the study site; to be conducted 
following at least 10 minutes of rest [sitting]) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 AEs  
 Concomitant medications 
 Complete and submit the Pre-Baseline Review Form to the Sponsor for Medical 
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Assessments to be completed as part of the Baseline Visit: 
 Urine pregnancy test, for women of childbearing potential 
 12-Lead ECG (following at least 5 minutes of rest in the semi-recumbent position) 
 6MWT (must be conducted prior to randomization; to be conducted 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) 
 PFTs (must be done prior to randomization and after recovery from the Baseline 
6MWT).   
 Re-confirm inclusion/exclusion criteria (Baseline 6MWD [not the practice Screening 
6MWD] will be used for inclusion/exclusion verification) 
 Randomization using IXRS 
 Administer study drug and provide dosing instructions and device training (subject 
must remain in the clinic for at least 1 hour after the first dose of study drug for 
observation) 
 Time to clinical worsening will be evaluated as an exploratory endpoint from the time 
of randomization until 1 of the following criteria are met: 
o Hospitalization due to a cardiopulmonary indication 
o Decrease in 6MWD > 15% from Baseline directly related to disease under study, 
at 2 consecutive visits and at least 24 hours apart 
o Death (all causes) 
o Lung transplantation 
7.4 TREATMENTPHASE: WEEKS4,8,AND12
The following assessments to be completed during the Treatment Phase:  
 Vital signs (following at least 5 minutes of rest; collected prior to 6MWT or after 
recovery from 6MWT); including weight, RR, HR, SBP, DBP, and temperature. 
 Documentation of supplemental oxygen requirement (L/min) 
 Urine pregnancy test, for women of childbearing potential 
 Blood draws for clinical laboratory parameters (Week 8 only) 
 NT-proBNP (must be drawn prior to 6MWT; for central laboratory processing only 
[Week 8 only]) 
 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) 
 PFTs (Week 8 only; to be performed after recovery from the 6MWT) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 


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 Time to clinical worsening will be evaluated as an exploratory endpoint from the time 
of randomization until 1 of the following criteria are met: 
o Hospitalization due to a cardiopulmonary indication 
o Decrease in 6MWD > 15% from Baseline directly related to disease under study, 
at 2 consecutive visits and at least 24 hours apart. 
o Death (all causes) 
o Lung transplantation 
 AEs  
 Concomitant medications 
 Dosing instructions/study drug accountability  
Please note the visit window for the Week 4, Week 8, and Week 12 Visits is ± 5 days. 
7.5 TREATMENTPHASE: WEEK15(TROUGH)
 Vital signs (following at least 5 minutes of rest; collected prior to 6MWT or after 
recovery from the 6MWT); including weight, RR, HR, SBP, DBP, and temperature. 
 Documentation of supplemental oxygen requirement (L/min) 
 Urine pregnancy test, for women of childbearing potential 
 Trough 6MWT (at least 4 hours after the last dose of study drug)  
 Pulse oximetry (to be performed immediately prior to, throughout the conduct of, and 
immediately following the 6MWT) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 Time to clinical worsening will be evaluated as an exploratory endpoint from the time 
of randomization until 1 of the following criteria are met: 
o Hospitalization due to a cardiopulmonary indication 
o Decrease in 6MWD > 15% from Baseline directly related to disease under study, 
at 2 consecutive visits and at least 24 hours apart 
o Death (all causes) 
o Lung transplantation 
 AEs  
 Concomitant medications 
 Dosing instructions/study drug accountability  
Please note the visit window for the Week 15 Visit is ± 5 days and at least 24 hours prior to 
the Week 16 6MWT.  If a subject discontinues study drug prematurely, the subject does not 
need to return to the clinic for the Week 15 Visit.  


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7.6 ENDOFSTUDY(WEEK16)AND/OREARLYTERMINATIONVISIT
The assessments to be completed during the Week 16 Visit are listed below in the 
recommended sequence of events.  If a decision is made to early terminate a subject from 
study drug or from the study in its entirety, the following assessments should be conducted as 
soon as possible and prior to study drug discontinuation, if possible.  If the subject 
permanently discontinues study drug prior to Week 16 for any reason, the subject should be 
encouraged to remain in the study and complete all visits (excluding the Week 15 Visit) up to 
and including Week 16: 
 SGRQ (questionnaire must be administered prior to any results, procedures, or blood 
draws) 
 PE 
 Vital signs (following at least 5 minutes of rest; collected prior to 6MWT or after 
recovery from the 6MWT); including weight, RR, HR, SBP, DBP, and temperature. 
 Documentation of supplemental oxygen requirement (L/min) 
 12-Lead ECG (following at least 5 minutes of rest in the semi-recumbent position) 
 Urine pregnancy test, for women of childbearing potential 
 Blood draws for clinical laboratory parameters 
 NT-proBNP (must be drawn prior to 6MWT; for central laboratory processing only) 
 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, throughout the conduct of, and 
immediately following the 6MWT) 
 PFTs (to be performed after recovery from the 6MWT) 
 Hospitalizations due to a cardiopulmonary indication 
 Exacerbations of underlying lung disease 
 Time to clinical worsening will be evaluated as an exploratory endpoint from the time 
of randomization until 1 of the following criteria are met: 
o Hospitalization due to a cardiopulmonary indication 
o Decrease in 6MWD > 15% from Baseline directly related to disease under study, 
at 2 consecutive visits and at least 24 hours apart 
o Death (all causes) 
o Lung transplantation 
 AEs  
 Concomitant medications 
 Study drug accountability 


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Subjects who remain on study drug, complete all assessments during the 16-week Treatment 
Phase, and meet all eligibility criteria for the open-label extension study (RIN-PH-202) are 
eligible for an open-label extension study (RIN-PH-202).  Additionally, subjects who are 
withdrawn from study drug prior to Week 16 due to clinical worsening should continue to 
return to the clinic for scheduled visits (excluding the Week 15 Visit) to be eligible for the 
open-label study.  Refer to Section 7.8 for more information regarding access to the open-
label study.   
7.7 STUDYCONTACTS
During the Treatment Phase, all subjects will be contacted at least once a week 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 (ie, 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.  
7.8 ACCESSTOOPEN-LABELSTUDY
Subjects who remain on study drug, complete all assessments during the 16-week Treatment 
Phase, and who meet all eligibility criteria for the open-label extension study (RIN-PH-202) 
are eligible for an open-label extension study (RIN-PH-202).  Additionally, subjects who 
experience clinical worsening and are withdrawn from study drug prior to Week 16 should 
undergo premature termination assessments prior to discontinuing study drug (when possible) 
and complete all remaining scheduled study visits (excluding the Week 15 Visit) through 
Week 16 to be eligible for entry into the open-label study.   
Subjects who permanently discontinue study drug during the 16-week Treatment Phase due to 
treatment-related AEs are not eligible for entry into the open-label study even if they 
complete all remaining scheduled study visits.  The site personnel must never be unblinded to 
the treatment assignment of these subjects unless required for safety reasons.  


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Subjects who permanently discontinue study drug during the 16-week Treatment Phase and 
do not undergo premature termination assessments prior to discontinuing study drug and/or 
who do not complete all remaining study visits (excluding the Week 15 Visit) through the 
Week 16 Visit are also not eligible for entry into the open-label study.  The site personnel 
must never be unblinded to the treatment assignment of these subjects, unless medically 
necessary. 
8 
STUDYTERMINATION
8.1 CRITERIAFORSUBJECT WITHDRAWAL
A subject may voluntarily withdraw or be withdrawn from the study and/or study drug by the 
Investigator at any time for reasons including, but not limited to, the following: 
 The subject wishes to withdraw from further participation. 
 A serious or life-threatening AE occurs or the Investigator considers that it is 
necessary to discontinue study drug to protect the safety of the subject. 
 The subject consistently deviated from the protocol. 
 Lung transplantation. 
 The subject becomes pregnant. 
 The subject’s behavior is likely to undermine the validity of his/her results.  
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. 
If a subject discontinues study drug prematurely for any reason, the subject should be 
encouraged to remain in the study and attend the remaining scheduled study visits (excluding 
the Week 15 Visit) up to and including Week 16. 
8.2 LOSTTOFOLLOW-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 


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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 CRITERIAFORTERMINATINGTHESTUDY
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 CRITERIAFORDISCONTINUINGTHESITE
The study may also be terminated at a given site if: 
 The Investigator elects to discontinue the study. 
 The Sponsor elects to discontinue the study at the site. 
 United States 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 
ADVERSEEVENTREPORTING
All AEs/SAEs that occur while the subject is participating in the study will be recorded as 
instructed in this protocol (Section 9.2).  
9.1 DEFINITIONS
9.1.1 
AdverseEvent
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. 


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 A worsening of an existing symptom or condition or post-treatment events that occur 
as a result of protocol-mandated procedures (eg, exacerbation of a pre-existing illness 
following the start of the study or an increase in frequency or intensity of a pre-
existing episodic event or condition). 
Thus, no causal relationship with the study drug is implied by use of the term "adverse event." 
An AE does not include the following: 
 Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
however, the condition for which the surgery is required may be an AE. 
 Planned surgical measures permitted by the study protocol and the condition(s) 
leading to these measures are not AEs. 
 Day to day fluctuations of pre-existing disease or conditions present or detected at the 
start of the study that do not worsen. 
 Situations where an untoward medical occurrence has not occurred (eg, 
hospitalizations for cosmetic elective surgery, social and/or convenience admissions). 
 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 
SeriousAdverseEvent
A 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 1 of the other outcomes listed above.  


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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 DOCUMENTATIONOFADVERSEEVENTS
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 
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-UPOFADVERSEEVENTS
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 4 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. 
9.4 REPORTINGRESPONSIBILITIESOFTHEINVESTIGATOR
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 
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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 
procedures are complete. 
10.2 SAMPLESIZE
Using an allocation ratio of 1:1 between inhaled treprostinil and placebo, a sample size of 
approximately 266 subjects (133 per treatment) would provide at least 90% power at a 
significance level of 0.05 (2-sided hypothesis) to detect a 30 meter between-treatment 
difference in the change from Baseline in 6MWD assuming a standard deviation of 75 meters.  
The total sample size will be approximately 314 subjects to account for a discontinuation rate 
of approximately 15%.   
10.3 ANALYSISPLAN
Details of the efficacy and safety analyses are provided below.  A separate statistical analysis 
plan will document further details of the statistical methods to be employed, including any 
changes to planned analyses specified within this protocol.  The analysis plan will be finalized 
prior to any unblinding of study data by the Sponsor.  Unless otherwise specified, all 
statistical tests will be 2-sided at alpha level of 0.05.  All statistical calculations will be 
completed using the latest version of SAS
®. 
The Intent-to-Treat (ITT) population will be defined as all subjects randomized into the study 
and receive at least 1 dose of study drug; all ITT subjects will be counted in the group to 
which they were randomized, regardless of the study drug they were actually given.  All 
efficacy analyses will be performed on this ITT population, unless otherwise specified.  The 
Safety population will be defined as all subjects enrolled into the study who received at least 
1 dose of study drug; all Safety population subjects will be counted in the group 
corresponding to the study drug actually received, regardless of randomized assignment.  All 
safety analyses will be performed on this Safety population, unless otherwise specified.   
10.3.1 
PrimaryEfficacyEndpoint
The primary efficacy endpoint is the change in 6MWD measured at peak exposure from 
Baseline to Week 16.  This study hypothesizes that inhaled treprostinil will improve exercise 
capacity after 16 weeks of therapy as compared with placebo when administered to subjects 


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with PH associated with ILD including CPFE.  Non-parametric analysis of covariance will be 
used to estimate the treatment effect.  The magnitude of treatment effect will be estimated 
with the Hodges-Lehmann median difference between 2 treatment groups.  For subjects who 
discontinue from the study early, the last observation carried forward method will be used to 
impute the 6MWD at Week 16. 
10.3.2 
SecondaryEfficacyEndpoints
The effect of inhaled treprostinil will be formally tested on the following 3 secondary efficacy 
endpoints:  
1. Change in peak 6MWD from Baseline to Week 12 
2. Change in plasma concentration of NT-proBNP from Baseline to Week 16 
3. Change in trough 6MWD from Baseline to Week 15 
The similar approach for the analysis of primary efficacy endpoint will be used.  No 
adjustment for multiplicity is planned. 
10.3.3 
ExploratoryEndpoints
The effect of inhaled treprostinil will be evaluated on the following parameters: 
1. Change in peak 6MWD from Baseline to Week 4 
2. Change in peak 6MWD at from Baseline to Week 8 
3. Change in SGRQ from Baseline to Week 16 
4. Time to clinical worsening will be evaluated as an exploratory endpoint from the time 
of randomization until 1 of the following criteria are met: 
a. Hospitalization due to a cardiopulmonary indication 
b. Decrease in 6MWD > 15% from Baseline directly related to disease under study, 
at 2 consecutive visits and at least 24 hours apart 
c. Death (all causes) 
d. Lung transplantation 
5. Change in DSP from Baseline to Week 16 
6. Optional evaluation of change in biomarkers (specific targets to be determined) from 
Baseline to Week 16 
7. Optional evaluation of whole genome sequence at Baseline 
For changes in peak 6MWD and SGRQ, a similar approach for the analysis of primary 
efficacy endpoint will be used.  For time to clinical worsening, Kaplan-Meier estimator will 
be provided and log-rank test will be used to compare the treatment difference. 


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10.3.4 
SafetyAnalyses
The safety of inhaled treprostinil will be evaluated by comparison of the following parameters 
between the 2 treatment groups: 
1. AEs 
2. Oxygenation  
a. Pulse oximetry (SpO2) 
b. Supplemental oxygen (L/min) requirement  
3. Pulmonary function: 
a. FEV1 
b. FVC 
c. TLC 
d. DLCO 
4. Clinical laboratory parameters 
5. Vital signs 
6. 12-Lead ECG 
7. Hospitalization due to cardiopulmonary indications 
8. Exacerbations of underlying lung disease; defined as an acute, clinically significant, 
respiratory deterioration characterized by evidence of new widespread alveolar 
abnormality 
All AEs as recorded by the Investigators will be assigned a Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class by the Sponsor for reporting 
purposes.  The summary of AEs will include the number and percentage of subjects, as well 
as the number of events reported for each preferred term.  No inferential analyses are planned 
for the AEs. 
Data collected prior to dosing will serve as Baseline values for the evaluation of data collected 
during the Treatment Phase.  Summary statistics will be calculated for measured values and 
changes from Baseline values.  Treatment-emergent changes in vital signs, ECGs, PFTs, 
oxygenation parameters, and clinical laboratory parameters will be summarized by treatment 
group.  Incidence of hospitalization due to cardiopulmonary indications and exacerbations of 
underlying lung disease will be summarized by treatment group.  No inferential analyses are 
planned on these safety endpoints. 


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10.4 INTERIMANALYSES
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 OTHERANALYSES
Exploratory analyses may be conducted based on available study data. 
10.6 DATALISTINGSANDSUMMARIES
All data gathered in this study will be presented in summary tables and listings in the clinical 
study report. 
10.7 DATA MONITORINGCOMMITTEE
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.  The DMC will 
be blinded to individual subject treatment allocation during the review process.  All analyses 
will be prepared by an independent external consultant and reviewed only by the DMC as 
defined in the DMC charter.  The Sponsor will only have access to blinded study data during 
this process. 
11 
PACKAGINGANDFORMULATION
11.1 CONTENTSOFSTUDYDRUG
11.1.1 
StudyDrug
The Sponsor will supply study medication (treprostinil inhalation solution, 0.6 mg/mL or 
placebo), as clear liquid in 2.9 mL ampoules.  The ampoules will be packaged in groups of 4, 
sealed in aluminum pouches.  There will be 9 pouches per carton.  
11.1.2 
StudyDevice
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 System will also be provided with the commercially available IFU. 
Each subject will receive 2 nebulizers at the start of the study.  In addition, the subjects will 
be provided with a month worth of plastic accessories at each study visit.   


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11.2 LABELING
11.2.1 
StudyDrug
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, IFU, and storage information (subject to regulatory 
requirements in each study region or country).   
11.2.2 
StudyDevice
Study subjects will receive commercially available TD-100 nebulizers and accessories 
separately from study drug.  Study subjects will receive 2 devices at Baseline supplied as a 
device starter kit.  Subjects will receive replacement parts as part of a monthly device 
resupply kit.  The nebulizers and accessories will be supplied using standard packaging 
labeled with the study number.   
11.3 STORAGEANDHANDLINGOFCLINICALSTUDY MATERIAL
All study drug will be stored at room temperature 25°C (77°F) with excursions permitted to 
15°C to 30°C (59°F to 86°F).  Study drug should not be frozen, refrigerated, or exposed to 
heat.  Keep the ampoules in the foil pouch to protect from light.  Once the foil pouch is 
opened, use within 7 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 SUPPLYANDRETURNOFCLINICALSTUDY MATERIAL
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 randomize the subjects and assign the 
appropriate study drug for the first 4-week treatment interval.  At subsequent study visits, the 
IXRS will be utilized by study staff to assign subsequent study drug kits to the subjects based 


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upon their current treatment allocation.  At each study visit, all study drug dispensed to a 
subject should be returned to the study site, including all used and unused ampoules.   
At the end of the study, nebulizers used during the study should be collected from each 
subject not continuing into the open-label extension study.  Subjects continuing into the 
open-label extension study will retain their devices for use in the open-label extension study. 
11.5 DRUGACCOUNTABILITY
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).   
 Compute study drug compliance using the dosing instructions given to the subject 
since the previous study visit and the amount of study drug returned. 
 Re-educate the subject about the importance of following the prescribed dosing 
regimen (if compliance is low). 
Once a representative from the Sponsor is able to confirm drug accountability for a completed 
subject, study drug will be returned to a Sponsor designated location for destruction and/or 
destroyed onsite per institutional policy.  At the end of the study, nebulizers used during the 
study should be collected from each subject not continuing into the open-label extension 
study.  These nebulizers will be returned to a Sponsor designated location for destruction.  In 
the event of device malfunction, at any point during the study, the nebulizer should be 
returned to the Sponsor.  Subjects continuing into the open-label extension study will retain 
their devices for use in the open-label extension study. 
12 
REGULATORYANDETHICALOBLIGATION
12.1 APPLICABLEREGULATORYREQUIREMENTS
The study will be conducted in accordance with International Council for Harmonisation 
(ICH) and Good Clinical Practice (GCP) guidelines and all applicable national regulations.  


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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 INFORMEDCONSENTREQUIREMENTS
Before a subject is enrolled in the study, the Investigator or his/her designees must explain the 
purpose and nature of the study, including potential benefits and risks and all study 
procedures to the subject.  The subject must sign and date an IRB/EC-approved ICF prior to 
the conduct of any study-related activities.  A copy of the signed consent form will be given 
to the subject and the original will be retained in the study site’s records. 
12.3 INDEPENDENTETHICSCOMMITTEE/INSTITUTIONALREVIEWBOARD
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 ICF and any other written information provided 
to the subject prior to enrollment, as well as any advertising materials used for subject 
recruitment.  Copies of the ICF and advertising materials must be forwarded to the Sponsor 
for review before submission to the IRB/EC prior to the start of the study. 
If, during the study, it is necessary to amend either the protocol or the ICF, the Investigator is 
responsible for obtaining IRB/EC approval of these amended documents prior to 
implementation.  Copies of the IRB/EC correspondence and approval letters must be sent to 
the Sponsor. 
During the conduct of the study, an annual progress report will be compiled by the Sponsor 
for submission to those IRBs/ECs that require it. 
A written summary of the study will be provided by the Investigator to the IRB/EC following 
study completion or termination according to the IRB/EC’s standard procedures.  Additional 
updates will also be provided in accordance with the IRB/EC’s standard procedures. 


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12.4 PRESTUDYDOCUMENTATIONREQUIREMENTS
Before the commencement of the clinical study, at a minimum, the following documents will 
be provided to the site:  Investigator’s Brochure, Protocol, ICF, Subject Dosing Diary, the 
Tyvaso Inhalation System IFU, Clinical Trial Agreement, Budget Agreement, and eCRF. 
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 Form FDA 1572. 
12.5 SUBJECTCONFIDENTIALITY
Every effort will be made to keep medical information confidential.  United Therapeutics 
Corporation, the FDA or other regulatory bodies, and the IRB/EC governing this study may 
inspect the medical records of any subject involved in this study.  The Investigator may 
release the subject’s medical records to employees or agents of the Sponsor, the IRB/EC or 
the FDA or appropriate local regulatory agencies for purposes of checking the accuracy of the 
data.  A number will be assigned to all subjects and any report published will not identify the 
subject’s name. 
13 
ADMINISTRATIVEANDLEGALOBLIGATIONS
13.1 PROTOCOLAMENDMENTSANDSTUDYTERMINATION
Protocol amendments that could potentially adversely affect the safety of participating 
subjects or that alter the scope of the investigation, the scientific quality of the study, the 
experimental design, dosages, duration of therapy, assessment variables, the number of 
subjects treated, or subject selection criteria may be made only after consultation between 
United Therapeutics Corporation or its designee and the Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory 
authorities and IRB/EC prior to implementation. 
A report documenting study termination must also be submitted to and acknowledged by the 
appropriate IRB/EC for each study site. 


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At the end of the study, where applicable, a final report will be provided to the local 
regulatory agencies. 
13.2 STUDYDOCUMENTATIONANDSTORAGE
In accordance with federal/national regulations, ICH, and GCP guidelines, the Investigator 
must retain study records for at least 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  The Investigator must notify United Therapeutics 
Corporation before any disposal or change in location of study records. 
13.3 STUDY MONITORINGANDDATACOLLECTION
In accordance with federal/national regulations, ICH, and GCP guidelines, monitors for 
United Therapeutics Corporation or its designee will periodically contact the site and conduct 
on-site visits.  During these visits, the monitor will at a minimum:  confirm ethical treatment 
of subjects, assess study progress, review data collected, conduct source document 
verification, verify drug accountability periodically, and identify any issues requiring 
resolution.   
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and his/her staff to the monitor to discuss any findings or any relevant 
issues. 


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14 
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echocardiographic function in an advanced phenotype of pulmonary hypertension and right 
heart dysfunction associated with pulmonary fibrosis.  Thorax.  2014;69(2):123-129. 
Seeger W, Adir Y, Barbera JA, et al.  Pulmonary hypertension in chronic lung diseases.  J Am 
Coll Cardiol.  2013;62(25 Suppl): D109-116. 
Simonneau G, Robbins IM, Beghetti M, et al.  Updated clinical classification of pulmonary 
hypertension.  J Am Coll Cardiol.  2009;54(1 Suppl):S43-54. 
Travis WD, Costabel U, Hansell DM, et al.  An official American Thoracic Society/European 
Respiratory Society statement: Update of the international multidisciplinary classification of 
the idiopathic interstitial pneumonias.  Am J Respir Crit Care Med.  2013;188(6):733-748. 
Voswinckel R, Ghofrani HA, Grimminger F, et al.  Inhaled treprostinil [corrected] for 
treatment of chronic pulmonary arterial hypertension.  Ann Intern Med.  2006;144(2):149-
150. 
Wang L, Bai L, Sapkota R, et al.  Hemodynamic and gas exchange effects of iloprost in 
patients with chronic obstructive pulmonary disease and pulmonary hypertension.  The PVRI 
8th Annual World Congress on Pulmonary Vascular Disease.  The 7
th Annual National 
Congress on Pulmonary Embolism and Pulmonary Vascular Diseases.  January 14-18, 2015.  
Guangzhou, China.   


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15 
APPENDICES
15.1 PROCEDUREFOR6-MINUTE WALKTEST
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.  Subjects receiving supplemental oxygen during the Baseline 
6MWT must continue to receive the same flow rate at all subsequent 6MWT assessments. 
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 must be no turns or significant curves to the 6MWT 
area.  The length should be marked with gradations to ensure the accurate measurement of the 
distance walked.  The area should be well ventilated.  The tester may be at the starting end of 
the corridor or at the midpoint of the corridor with a stop-watch.  Intermittent rest periods are 
allowed if the subject can no longer continue.  If the subject needs to rest briefly, he/she may 
stand or sit and then begin again when he/she is sufficiently rested but the clock will continue 
to run.  At the end of 6 minutes, the tester will call “stop where you are” while simultaneously 
stopping the watch and then measure the distance walked.   
Instructions to the Subject  
Subjects will be instructed that the preceding meal should be light.  Subjects should be told to 
wear comfortable clothing and sneakers or comfortable walking shoes.  The person 
administering the test will use the following exact dialogue with the subject: 
“The purpose of this test is to find out how far you can walk in 6 minutes.  You will 
start from this point and follow the hallway to the marker (eg, chair) at the end, turn 
around and walk back.  When you arrive back at the starting point you will go back 
                                                 
1 ATS Statement: Guidelines for the Six-Minute Walk Test.  Am J Respir Crit Care Med 2002; 166: 111117. 
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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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 6-minutes.  I will tell you the time, and I 
will let you know when the 6 minutes are up.  When I say ‘STOP,’ please stand right 
where you are.” 
After these instructions are given to the subject, the person administering the test will then 
ask: 
“Do you have any questions about the test?” 
The person administering the test will then start the test by saying the following to the subject: 
“Are you ready?” 
“Start when I say ‘GO.’” 
The person administering the test will tell the subject the time at each minute by saying: 
“You have 5 minutes to go.” 
“You have 4 minutes to go.” 
“You have 3 minutes to go.” 
“You have 2 minutes to go.” 
“You have 1 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. 


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15.2 GUIDELINESANDDEFINITIONSFORRECORDINGADVERSEEVENTS
The Investigator or a designated member of his/her staff will probe each subject for any AEs 
that may have occurred.  The Investigator should always ask the same question when 
conducting the verbal probe in order to ensure uniformity between subjects.  The Investigator 
should ask: 
“How are you doing (feeling)?” 
Based on the subject’s response to this question, the Investigator should ask additional 
questions relevant to the specific complaint such as: 
“How severe is/was the symptom?” 
“How often did the symptom occur?” 
“How long did the symptom last?” 
It is the Investigator’s responsibility to review the results of all diagnostic and laboratory tests 
as they become available and ascertain if there is a clinically significant change from 
Baseline.  If the results are determined to be a clinically significant change from Baseline, this 
should be reported as an AE.  The Investigator may repeat the diagnostic procedure or 
laboratory test or request additional tests to verify the results of the original tests.  When 
possible, a diagnosis associated with the abnormality should be used as the reported AE. 
Using provided definitions, the Investigator will then: 
(1) rate the intensity and seriousness of the AE, (2) estimate the causality of the AE to study 
drug, and (3) note actions taken to counteract the AE. 
Definitions of Intensity, Seriousness, Causality, Action Taken, and Outcome 
INTENSITY 
An assessment of the relative intensity (severity) of an AE is based on the Investigator’s 
clinical judgment.  The maximum intensity encountered during the evaluation period should 
be checked.  The assessment of intensity should be independent of the assessment of the 
seriousness of the AE.   


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SERIOUSNESS 
A serious AE is one that represents an actual or potential significant hazard.  This includes, 
but is not limited to, an event that is fatal, life-threatening, permanently or severely disabling, 
requires or prolongs inpatient hospitalization*, is a congenital abnormality (offspring of 
subject) or is medically significant (important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition). 
*Hospitalizations that would not be considered SAEs include those for: 
 Routine treatment or monitoring of the study indication not associated with any 
deterioration in condition (eg, hospitalization for a routine RHC). 
 Treatment which was elective or pre-planned, for a pre-existing condition not 
associated with any deterioration in condition (eg, pre-planned operation which does 
not lead to further complications etc). 
 Treatment of an emergency, in an outpatient setting for an event not fulfilling any of 
the definitions of serious as given above and not resulting in hospital admission. 
CAUSALITY 
An estimate of causality between a specified AE and the study drug is made by the 
Investigator.  Several factors should be considered when determining causality.  These factors 
include temporal relationship and response to withdrawal or reintroduction of the study drug.  
Definitions of the causality categories are as follows: 
 NOT RELATED  There is not a temporal relationship to study drug administration 
(too early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, or concurrent disease and the SAE, or any of the following: 
o An event that precedes the first administration of study drug 
o An event for which the cause is clearly related to an external event 
o Temporal relationship to study drug is atypical 
o Is readily explained by an intercurrent illness AND has an expected level of 
severity, duration, and resolution 
o 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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o Has a reasonable temporal relationship to study drug 
o The event has a plausible biological link to the activity of the study drug 
o 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: 
o Has a reasonable temporal relationship to study drug 
o The event has a plausible biologic link to the activity of the study drug 
o Not readily explained by an intercurrent illness 
o Not readily explained by external event 
o Improves on discontinuation of study drug 
o 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 
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. 


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 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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ST.GEORGE’SRESPIRATORYQUESTIONNAIRE
ENGLISHFORTHEUNITEDSTATES
ST.GEORGE’SRESPIRATORYQUESTIONNAIRE(SGRQ)
Thisquestionnaireisdesignedtohelpuslearnmuchmoreabouthowyour
breathingistroublingyouandhowitaffectsyourlife. Weareusingittofindout
whichaspectsofyourillnesscauseyouthemostproblems,ratherthanwhatthe
doctorsandnursesthinkyourproblemsare.
Pleasereadtheinstructionscarefullyandaskifyoudonotunderstandanything.
Donotspendtoolongdecidingaboutyouranswers.
Beforecompletingtherestofthequestionnaire:
Pleasecheckoneboxtoshowhowyoudescribe
yourcurrenthealth:
Verygood

Good

Fair

Poor

Verypoor

Copyrightreserved
P.W.Jones,PhDFRCP
ProfessorofRespiratoryMedicine,
St.George’sUniversityofLondon,
Jenner Wing,
CranmerTerrace,
Tel.+44(0)2087255371
LondonSW17ORE,UK.
Fax+44(0)2087255955


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St.George’sRespiratoryQuestionnaire
PART1
Pleasedescribehowoftenyourrespiratoryproblemshaveaffectedyouoverthepast4weeks.
Pleasecheck()oneboxforeachquestion:
almost
every
day
several
days
aweek
afew
days
amonth
onlywith
respiratory
infections
not
at
all
1. Overthepast4weeks,Ihavecoughed:





2. Overthepast4weeks,Ihavebroughtup
phlegm(sputum):





3. Overthepast4weeks,Ihavehadshortness
ofbreath:





4. Overthepast4weeks,Ihavehadwheezing
attacks:





5. Howmanytimesduringthepast4weekshaveyousufferedfrom
severeorveryunpleasantrespiratoryattacks?
Pleasecheck()one:
morethan3times 
3times 
2times 
1time 
noneofthetime 
6. Howlongdidtheworstrespiratoryattacklast?
(GotoQuestion7ifyoudidnothaveasevereattack)
Pleasecheck()one:
aweekormore 
3ormoredays 
1or2days 
lessthanaday 
7. Overthepast4weeks,inatypicalweek,howmanygooddays
(withfewrespiratoryproblems)haveyouhad?
Pleasecheck()one:
Nogooddays 
1or2gooddays 
3or4gooddays 
nearlyeverydaywasgood 
everydaywasgood 
8. Ifyouwheeze,isitworsewhenyougetupinthemorning?
Pleasecheck()one:
No 
Yes 


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St.George’sRespiratoryQuestionnaire
PART2
Section1
Howwouldyoudescribeyourrespiratorycondition?
Pleasecheck()one:
ThemostimportantproblemIhave 
Causesmequitealotofproblems 
Causesmeafewproblems 
Causesnoproblems 
Ifyouhaveeverheldajob:
Pleasecheck()one:
Myrespiratoryproblemsmademestopworkingaltogether 
Myrespiratoryproblemsinterferewithmyjobormademechangemyjob 
Myrespiratoryproblemsdonotaffectmyjob 
Section2
Thesearequestionsaboutwhatactivitiesusually makeyoufeelshortofbreaththesedays.
Foreachstatementpleasecheck
()theboxthatapplies
toyouthesedays:
True 
False
Sittingorlyingstill  

Washingordressingyourself  

Walkingaroundthehouse  

Walkingoutsideonlevelground  

Walkingupaflightofstairs  

Walkinguphills  

Playingsportsorotherphysicalactivities  



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St.George’sRespiratoryQuestionnaire
PART2
Section3
Theseare morequestionsaboutyourcoughandshortnessofbreaththesedays.
Foreachstatementpleasecheck
()theboxthatapplies
toyouthesedays:
True 
False
Coughinghurts  

Coughingmakesmetired  

IamshortofbreathwhenItalk  

IamshortofbreathwhenIbendover  

Mycoughingorbreathingdisturbsmysleep  

Igetexhaustedeasily  

Section4
Thesearequestionsaboutothereffectsthatyourrespiratoryproblemsmayhaveonyouthese
days.
Foreachstatement,please
check()theboxthat
appliestoyouthesedays:
True 
False
Mycoughorbreathingisembarrassinginpublic


Myrespiratoryproblemsareanuisancetomyfamily,friendsorneighbors


IgetafraidorpanicwhenIcannotcatchmybreath 

IfeelthatIamnotincontrolofmyrespiratoryproblems 

Idonotexpectmyrespiratoryproblemstogetanybetter 

Ihavebecomefrailoraninvalidbecauseofmyrespiratoryproblems 

Exerciseisnotsafeforme


Everythingseemstoomuchofaneffort


Section5
Thesearequestionsaboutyourrespiratorytreatment.Ifyouarenotreceivingtreatmentgoto
section6.
Foreachstatement,please
check()theboxthatapplies
toyouthesedays:
True 
False
Mytreatmentdoesnothelpmeverymuch  

Igetembarrassedusingmymedicationinpublic  

Ihaveunpleasantsideeffectsfrommymedication  

Mytreatmentinterfereswithmylifealot  



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St.George’sRespiratoryQuestionnaire
PART2
Section6
Thesearequestionsabouthowyouractivities mightbeaffectedbyyourrespiratoryproblems.
Foreachstatement,pleasecheck()
theboxthatappliestoyou
becauseofyourrespiratoryproblems:
True 
False
Itakealongtimetogetwashedordressed 

Icannottakeabathorshower,orItakealongtimetodoit 

Iwalkslowerthanotherpeoplemyage,orIstoptorest 

Jobssuchashouseholdchorestakealongtime,orIhavetostoptorest


IfIwalkuponeflightofstairs,Ihavetogoslowlyorstop 

IfIhurryorwalkfast,Ihavetostoporslowdown 

Mybreathingmakesitdifficulttodothingssuchaswalkuphills,carrythings
upstairs,lightgardeningsuchasweeding,dance,
bowlorplaygolf


Mybreathingmakesitdifficulttodothingssuchascarryheavyloads,
diginthegardenorshovelsnow,jogorwalkbriskly(5milesperhour),
playtennisorswim


Mybreathingmakesitdifficulttodothingssuchasveryheavy
manualwork,rideabike,run,swimfast,
orplaycompetitivesports


Section7
Wewouldliketoknowhowyourrespiratoryproblemsusually affectyourdailylife.
Foreachstatement,pleasecheck()
theboxthatappliestoyoubecauseof
yourrespiratoryproblems:
True 
False
Icannotplaysportsordootherphysicalactivities  

Icannotgooutforentertainmentorrecreation  

Icannotgooutofthehousetodotheshopping  

Icannotdohouseholdchores  

Icannotmovefarfrommybedorchair  



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St.George’sRespiratoryQuestionnaire
Hereisalistofotheractivitiesthatyourrespiratoryproblems maypreventyoufromdoing.(You
donothavetocheckthese,theyarejusttoremindyouofwaysyourshortnessofbreath may
affectyou):
Goingforwalksorwalkingthedog
Doingactivitiesorchoresathomeorinthegarden
Sexualintercourse
Goingtoaplaceofworship,oraplaceofentertainment
Goingoutinbadweatherorintosmokyrooms
Visitingfamilyorfriendsorplayingwithchildren
Pleasewriteinanyotherimportantactivitiesthatyourrespiratoryproblemsmaystopyoufrom
doing:
..............................................................................................
..............................................................................................
..............................................................................................
..............................................................................................
Nowpleasecheckthebox(oneonly)thatyouthinkbestdescribeshowyourrespiratoryproblems
affectyou:
ItdoesnotstopmefromdoinganythingIwouldliketodo 
ItstopsmefromdoingoneortwothingsIwouldliketodo 
ItstopsmefromdoingmostofthethingsIwouldliketodo 
ItstopsmefromdoingeverythingIwouldliketodo 
Thankyouforcompletingthisquestionnaire.Beforeyoufinishwouldyoupleasemakesurethatyouhave
answeredallthequestions.

SAP_003.pdf: 
United Therapeutics Corp. 
RIN-PH-201 Statistical Analysis Plan 
 
Inhaled Treprostinil 
Version 27 FEB 2019 
Confidential 
Page 1 
 
Document Type: 
Statistical Analysis Plan 
Protocol / Study No.: 
RIN-PH-201 
First Draft Date: 
Finalization Date: 
10 APR 2018 
27 FEB 2019 
Total Number of 
Pages including 
Appendices: 
39 
Classification: 
Confidential 
Version:  
2.0 
Title: 
A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Safety and 
Efficacy of Inhaled Treprostinil in Subjects with Pulmonary Hypertension due to Parenchymal 
Lung Disease  
 
Author:  
 
 
 
 
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY, UNITED THERAPEUTICS 
CORPORATION 
All content contained herein is confidential and proprietary information of United 
Therapeutics Corporation and shall not be disclosed in whole or in part except as permitted by 
a signed contract with United Therapeutics Corporation. © 2019 United Therapeutics 
Corporation 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................ 2 
Table of In-Text Tables .......................................................................................................... 3 
ABBREVIATIONS AND DEFINITIONS ............................................................................ 4 
1 PREFACE .......................................................................................................................... 6 
2 STUDY OBJECTIVES AND ENDPOINTS ................................................................... 6 
2.1 
PRIMARY ENDPOINT .............................................................................................. 6 
2.2 
SECONDARY ENDPOINTS ...................................................................................... 6 
2.3 
EXPLORATORY ENDPOINTS ................................................................................ 6 
2.4 
SAFETY ENDPOINTS ................................................................................................ 7 
3 STUDY DESIGN ............................................................................................................... 7 
4 SEQUENCE OF PLANNED ANALYSES ..................................................................... 8 
5 SAMPLE SIZE CONSIDERATIONS ............................................................................ 9 
6 ANALYSIS POPULATIONS ........................................................................................... 9 
7 INTERIM ANALYSES .................................................................................................. 10 
8 GENERAL CONSIDERATIONS FOR DATA ANALYSES ..................................... 10 
8.1 
COVARIATES ........................................................................................................... 11 
8.2 
EXAMINATION OF SUBGROUPS ........................................................................ 11 
8.3 
PREMATURE DISCONTINUATION AND MISSING DATA ............................ 12 
8.3.1 
Missing Data Handling for 6MWD ...................................................................... 12 
8.3.2 
Missing Data Handling for Other Efficacy Assessments ................................... 13 
8.4 
MULTIPLE COMPARISONS AND MULTIPLICITY ......................................... 13 
8.5 
DERIVED AND TRANSFORMED DATA ............................................................. 14 
8.6 
ASSESSMENT WINDOWS ...................................................................................... 15 
9 STUDY POPULATION ................................................................................................. 17 
9.1 
SUBJECT ACCOUNTABILITY .............................................................................. 17 
9.2 
PROTOCOL DEVIATIONS ..................................................................................... 18 
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATION ........................................ 18 
9.3.1 
Demographics ........................................................................................................ 18 
9.3.2 
Baseline Characteristics ........................................................................................ 19 
9.3.3 
Medical History and PH-ILD History ................................................................. 19 
9.3.4 
Concomitant Medications ..................................................................................... 19 
10 EFFICACY ANALYSES ................................................................................................ 20 
10.1 PRIMARY EFFICACY MEASURES ...................................................................... 20 
10.1.1 
Primary Efficacy Analyses .................................................................................... 20 
10.1.1.1 
Hypothesis ........................................................................................................... 20 
10.1.1.2 
Primary Efficacy Analysis ................................................................................. 20 
10.1.1.3 
Sensitivity and Subgroup Analyses .................................................................. 23 
10.2 SECONDARY EFFICACY MEASURES ................................................................ 24 


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10.2.1 
Change in Peak 6MWD at Week 12 .................................................................... 24 
10.2.2 
Change in NT-proBNP at Week 16 ...................................................................... 24 
10.2.3 
Change in Trough 6MWD at Week 15 ................................................................ 25 
10.3 EXPLORATORY EFFICACY MEASURES .......................................................... 26 
10.3.1 
Change in Peak 6MWD at Weeks 4 and 8 .......................................................... 26 
10.3.2 
Change in SGRQ at Week 16 ............................................................................... 26 
10.3.3 
Time to Clinical Worsening .................................................................................. 27 
10.3.4 
Change in DSP ....................................................................................................... 28 
11 HEALTH OUTCOMES ................................................................................................. 29 
11.1 QUALITY OF LIFE MEASURES ........................................................................... 29 
11.2 RESOURCE UTILIZATION MEASURES ............................................................ 29 
12 SAFETY ANALYSES ..................................................................................................... 29 
12.1 EXTENT OF EXPOSURE ........................................................................................ 29 
12.2 ADVERSE EVENTS .................................................................................................. 30 
12.3 OXYGENATION ....................................................................................................... 31 
12.4 PULMONARY FUNCTION TESTS ........................................................................ 32 
12.5 CLINICAL LABORATORY EVALUATIONS ...................................................... 32 
12.5.1 
Clinical Chemistry ................................................................................................. 32 
12.5.2 
Hematology ............................................................................................................ 33 
12.5.3 
Pregnancy Test ....................................................................................................... 34 
12.6 OTHER SAFETY MEASURES ............................................................................... 34 
12.6.1 
Electrocardiograms ............................................................................................... 34 
12.6.2 
Hospitalizations ...................................................................................................... 34 
12.6.3 
Vital Signs ............................................................................................................... 34 
12.6.4 
Exacerbations of Underlying Lung Disease ........................................................ 35 
13 PHARMACOKINETICS ............................................................................................... 35 
14 REFERENCES ................................................................................................................ 35 
15 LIST OF TABLES, LISTINGS AND FIGURES ......................................................... 36 
15.1 LIST OF TABLES ..................................................................................................... 36 
15.2 LIST OF LISTINGS .................................................................................................. 38 
15.3 LIST OF FIGURES ................................................................................................... 39 
 
Table of In-Text Tables 
Table 8-1 
Imputation Rules for Peak 6MWD ................................................................. 12 
Table 8-2 
Imputation Rules for Trough 6MWD ............................................................. 13 
Table 8-3 
Derivation of Time to Clinical Worsening...................................................... 14 
Table 8-4 
Assessment Windows for Scheduled Visits .................................................... 16 
 


United Therapeutics Corp. 
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ABBREVIATIONS AND DEFINITIONS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BMI 
Body mass index 
BOCF 
Baseline Observation Carried Forward 
CHP 
Chronic Hypersensitivity Pneumonitis 
CPFE 
Combined Pulmonary Fibrosis and Emphysema 
CSR 
Clinical study report 
CT 
Computed Tomography 
CTD 
Connective tissue disease 
DLCO 
Lung diffusion capacity 
DMC 
Data Monitoring Committee 
DSP 
Distance saturation product 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early termination 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
HR 
Heart rate 
ICF 
Informed consent form 
IIP 
Idiopathic interstitial pneumonia 
ILD 
Interstitial lung disease 
ITT 
Intent-to-treat 
LOCF 
Last observation carried forward 
LRCF 
Last rank carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measurement 
NT-proBNP 
N-Terminal pro-brain natriuretic peptide 
PAPm 
Pulmonary artery pressure mean 
PCWP 
Pulmonary capillary wedge pressure 
PFT 
Pulmonary function test 
PH 
Pulmonary hypertension 
PH-ILD 
Pulmonary hypertension associated with interstitial lung 
disease 


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P-R 
Time between P wave and beginning of QRS complex in 
electrocardiography 
PT 
Preferred Term 
PVR 
Pulmonary vascular resistance 
Q-T 
Electrocardiographic interval from beginning of QRS 
complex to end of the T wave 
QTc 
QT interval corrected for heart rate 
QRS 
Electrocardiographic wave interval 
RHC 
Right heart catheterization 
RMST 
Restricted mean survival time 
SAE 
Serious adverse event 
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-DD 
World Health Organization Drug Dictionary 
WU 
Wood Units 
 


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1 
PREFACE 
This plan provides further details of the planned analyses for the RIN-PH-201 study as 
presented in the study protocol.  This plan, based on the original RIN-PH-201 study protocol 
dated 21 Oct 2015 and the subsequent study protocol amendments (latest version study 
protocol amendment 3 dated 15 February 2017), provides further details of the planned 
analyses stated in the study protocol as well as any 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 
The primary objective of this study is to evaluate the 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). 
2.1 
PRIMARY ENDPOINT 
The primary endpoint is the change in 6-Minute Walk Distance (6MWD) measured at peak 
exposure from Baseline to Week 16. 
2.2 
SECONDARY ENDPOINTS 
The secondary endpoints are:  
1. Change in peak 6MWD from Baseline to Week 12 
2. Change in plasma concentration of N-terminal pro-brain natriuretic peptide 
(NT-proBNP) from Baseline to Week 16 
3. Change in trough 6MWD from Baseline to Week 15 
2.3 
EXPLORATORY ENDPOINTS 
Exploratory endpoints are:  
1. Change in peak 6MWD from Baseline to Week 4 
2. Change in peak 6MWD from Baseline to Week 8 
3. Change in quality of life as measured by the St. George’s Respiratory Questionnaire 
(SGRQ) from Baseline to Week 16 
4. Time to clinical worsening will be evaluated as an exploratory endpoint from the time 
to randomization until 1 of the following criteria are met: 


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a. Hospitalization due to a cardiopulmonary indication 
b. Decrease in 6MWD >15% from Baseline directly related to disease under study, at 
2 consecutive visits, and at least 24 hours apart 
c. Death (all causes) 
d. Lung transplantation 
5. Change in distance saturation product (DSP) from Baseline to Week 16  
Exploratory endpoints of optional evaluation are change in biomarkers from Baseline to 
Week 16, and optional evaluation of whole genome sequence. They will be specified in 
separate documents and not covered in this statistical analysis plan. 
2.4 
SAFETY ENDPOINTS 
Safety endpoints will be used to evaluate safety based on the following assessments: 
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 1 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. Electrocardiograms (ECG) 
7. Hospitalization due to a cardiopulmonary indication. 
8. 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, randomized, double-blinded, placebo-controlled, 16-week, parallel 
group study.  Subject eligibility will be based on the inclusion and exclusion criteria described 
in Section 4 of the protocol.  Approximately 314 eligible subjects will be randomized to study 


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treatments (inhaled treprostinil or placebo) in a 1:1 ratio.  Subjects will be stratified based on 
Baseline 6MWD (≤350 meters versus >350 meters). 
Subjects will be treated with either inhaled treprostinil (6 mcg/breath) or placebo. 
The study will consist of the following phases: 
Screening Phase: Prospective subjects will undergo a screening evaluation within 
30 days prior to the Baseline Visit (randomization and first dose of study drug).  
During this phase, eligible subjects will sign the informed consent form (ICF) and 
undergo Screening assessments.  The Screening and Baseline assessments may be 
combined if all entry criteria are satisfied within 48 hours prior to the first dose of 
study drug.  Baseline pulmonary function tests (PFTs) and 6-Minute Walk Test 
(6MWT) used to confirm eligibility criteria may be performed on the same day but 
prior to the first dose of study drug. 
Baseline Visit: The Baseline assessments may be conducted over a 48-hour period prior 
to the first dose of study drug to allow for scheduling of all activities.  Eligible 
subjects will undergo Baseline assessments, be assigned to a treatment group based on 
the randomization schedule, and receive the first dose of study drug (Day 1 is defined 
as the day the first dose of study drug is given).  The Screening and Baseline 
assessments may be combined if all entry criteria are satisfied within 48 hours prior to 
the first dose of study drug.  Baseline PFTs and 6MWT used to confirm eligibility 
criteria may be performed on the same day but prior to the first dose of study drug. 
Treatment Phase: The Treatment phase consists of 5 study visits to the clinic at Week 4, 
Week 8, Week 12, Week 15, and Week 16 (final study visit; at least 24 hours after the 
Week 15 Visit [final study visit/early termination {ET}]).  Subjects will also be 
contacted at least weekly by telephone or email to assess subject tolerance to study 
drug, AEs, and changes to concomitant medications. 
4 
SEQUENCE OF PLANNED ANALYSES 
Interim Safety Analyses 
Interim safety analyses are intended to be performed according to the Data Monitoring 
Committee (DMC) Charter.  In particular, interim safety analyses are planned following the 
enrollment of approximately 25%, 50%, and 75% of subjects in the study, or at least annually 
(whichever is sooner).  All analyses will be prepared by an independent external consultant and 
reviewed only by the independent DMC as defined in the DMC Charter.  The Sponsor will 
only have access to the blinded study data during this process.  Interim efficacy analyses are 
not planned in this study. 


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Dry-run Analysis Prior to Database Lock (Soft Lock) 
At the completion of the study enrollment and prior to the database lock, a dry-run analysis is 
planned.  This dry-run analysis utilizes a dummy randomization schedule in a blinded fashion.  
The purpose of the dry-run analysis is to verify programming of the analysis data sets and the 
planned tables, listings, and figures, and to identify any data issues.  Programming and data 
issues identified through the dry-run process will be resolved prior to the database lock and 
study unblinding. 
Final Analysis after Database Lock and Study Unblinding 
After the database has been quality assured and locked, the treatment assignments will be 
provided to the sponsor’s project statistician by the central randomization service and all 
planned analyses described in this document will be performed.  By intent, no changes will be 
made to the clinical database after unblinding.  However, any changes that are deemed 
necessary, after unblinding, will be clearly documented in the CSR. 
5 
SAMPLE SIZE CONSIDERATIONS 
Using an allocation ratio of 1:1 between inhaled treprostinil and placebo, a sample size of 
approximately 266 subjects (133 per treatment) would provide at least 90% power at a 
significance level of 0.05 (2-sided hypothesis) to detect a 30 meter between-treatment 
difference in the change from Baseline to Week 16 in 6MWD, assuming a standard deviation 
of 75 meters. 
The total sample size will be approximately 314 subjects to account for a discontinuation rate 
of approximately 15%. 
6 
ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) population is defined as all subjects randomized into the study who 
received at least 1 dose of study drug.  All ITT subjects will be counted in the group to which 
they were randomized, regardless of the study drug they were given.  All efficacy analyses 
will be performed on this ITT population, unless otherwise specified. 


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The Safety population is defined as all subjects enrolled into the study who received at least 1 
dose of study drug.  All Safety population subjects will be counted in the group corresponding 
to the study drug received, regardless of randomized assignment.  All safety analyses will be 
performed on this Safety population, unless otherwise specified. 
The Per-protocol population will include all subjects in ITT population, excluding subjects 
with major protocol deviations that may have an impact on the primary efficacy analyses.  
The major protocol deviations and the subject’s exclusion from the Per-protocol population 
will be reviewed at a blinded data review meeting and documented prior to the database lock 
and the study unblinding. 
7 
INTERIM ANALYSES 
There is no interim efficacy analysis for this study.  
A DMC will be established for the study including physicians knowledgeable in the treatment 
of PH and a statistician.  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.  
All analyses will be prepared by an independent external consultant and reviewed only by the 
DMC as defined in the DMC Charter.  The Sponsor will only have access to blinded study 
data during this process. The details regarding the interim safety analysis will be included in a 
separate statistical analysis plan. 
8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All the data collected in the electronic Case Report Form (eCRF) will be listed.  In general, 
listings will be sorted by treatment group, subject number, and scheduled assessment (if 
applicable).  Listings will include assessment date, assessment time (if available), study day, 
and all relevant data collected in the eCRFs.  For data collected on a fixed schedule, the 
assessment identifier or the nominal time point will also be included on the listing.  Repeat or 
redundant observations within an assessment window and observations that do not fall within 
any predefined assessment window (and will, therefore, be excluded from summaries) will be 
flagged in these listings.  Subjects who are not to be included in the analysis population (eg, 
Safety population, Per-protocol population) will be flagged. 


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In general, the data will be summarized by scheduled assessment (if applicable) within each 
treatment group.  For continuous variables, summary statistics will include the mean, standard 
deviation, median, minimum, and maximum.  For summaries of non-normal data such as 
6MWD, interquartile range (lower quartile, upper quartile) may also be included.  Minimums 
and maximums will be expressed using the level of precision in which the variable was 
collected.  All other statistics will be rounded, using an additional decimal place than was 
collected.  For discrete variables, summaries will include the frequency and percentage in 
each category.  Percentages will be rounded to 1 decimal place.  For all inferential analyses 
and descriptive comparisons, p-values will be rounded to 4 decimal places.  Values less than 
0.0001 will be denoted as <0.0001, and values greater than 0.9999 will be denoted as >0.9999 
whenever practical, categories of discrete variables will be ordered and labelled as they 
appear in the eCRF, and all categories represented on the case report form will be included in 
summaries, even when they do not apply to any subjects in the study. 
Unless otherwise specified, all statistical tests will be 2-sided at alpha level 0.05.  All 
statistical calculations will be completed using SAS® Version 9.4 or above. 
8.1 
COVARIATES 
The primary efficacy analyses of change in 6MWD at Week 16 will be adjusted for Baseline 
6MWD (as a continuous variable).  For sensitivity analyses of the primary efficacy endpoints 
and the secondary/exploratory endpoints with continuous variables, the baseline measure will 
always be the covariate. 
8.2 
EXAMINATION OF SUBGROUPS 
For primary efficacy endpoints of change in 6MWD at Week 16, subgroup analyses will be 
performed. These subgroups will include:  
 Etiology of ILD (Idiopathic Interstitial Pneumonia [IIP], Chronic Hypersensitivity 
Pneumonitis [CHP], Occupational, CPFE, Connective Tissue Disease [CTD], and 
Other) 
 Baseline walk categories (≤350 meters versus >350 meters, ≤ median baseline 6MWD 
versus > median baseline 6MWD) 
 ILD disease severity as measured by Baseline DLCO (<40% predicted versus ≥40% 
predicted) 


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 Sex (male versus female) 
 Pulmonary Vascular Resistance (PVR) (<4 versus ≥4 Wood Units [WU]) 
 Age group (<65 years of age, 65 to <80 years of age, and ≥80 years of age) 
 Study drug dose at Week 16 (0 to 3 breaths, 4 to 6 breaths, 7 to 9 breaths, and 10 to 12 
breaths) 
No Type 1 error adjustments will be performed for these subgroup analyses. 
8.3 
PREMATURE DISCONTINUATION AND MISSING DATA 
8.3.1 
Missing Data Handling for 6MWD 
For the analysis of 6MWD, subjects may not have completed the treatment with study drug 
prior to the Week 16 visit for the following reasons: death, progressive disease, AE, 
withdrawal of consent by the subject, protocol violation, loss to follow-up, termination of 
study by the sponsor, or withdrawal for other reasons.  Every attempt must be made to 
perform all efficacy assessments immediately prior to premature termination of study drug or 
withdrawal from the study.  In addition, subjects still receiving study drug may be too 
critically ill to perform the 6MWT, resulting in missing data for that assessment. 
Every effort should be made to complete all scheduled study assessments for all randomized 
subjects.  Although attempts will be made to continue to collect data after termination of 
study drug, these data are being collected for sensitivity analyses and descriptive purposes 
only.  Assessments performed after treatment unblinding or more than 24 hours after the last 
dose of study drug will not be included in the main analyses of peak 6MWD. 
For subjects whose peak 6MWD measures at Week 4, Week 8, Week 12, or Week 16 are 
missing, the missing value will be imputed as described in Table 8-1. 
Table 8-1 
Imputation Rules for Peak 6MWD 
Reason for missing 6MWD measure 
Imputation 
Death (all causes) 
Worst score (0 meters) 
Clinical worsening event  
Worst score (0 meters) 
Too ill to perform 6MWT 
Worst score (0 meters) 
All other reasons 
Last (peak) Observation Carried Forward 
(LOCF) 
Abbreviations: 6MWD, 6-Minute Walk Distance; 6MWT, 6-Minute Walk Test. 


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For subjects whose trough 6MWD measures at Week 15 are missing, the missing values will 
be imputed as described in Table 8-2. 
Table 8-2 
Imputation Rules for Trough 6MWD 
Reason for missing 6MWD measure 
Imputation 
Death (all causes) 
Worst score (0 meters) 
Clinical worsening 
Worst score (0 meters) 
Too ill to perform 6MWT 
Worst score (0 meters) 
All other reasons 
Baseline Observation Carried Forward (BOCF) 
Abbreviations: 6MWD, 6-Minute Walk Distance; 6MWT, 6-Minute Walk Test, BOCF, Baseline observation carried 
forward. 
8.3.2 
Missing Data Handling for Other Efficacy Assessments 
For the secondary endpoints of NT-proBNP, the missing value at Week 16 will be imputed 
using LOCF.  If the NT-proBNP measure at Baseline is missing, the change from Baseline 
will not be calculated.  The subject will not be included in the analyses. 
For exploratory endpoints of SGRQ, biomarkers, and DSP, the missing values will not be 
imputed, and all analyses will be based on the observed cases. 
8.4 
MULTIPLE COMPARISONS AND MULTIPLICITY 
The primary efficacy endpoint of change in 6MWD measured at peak exposure from Baseline 
to Week 16 will be tested at alpha level 0.05.  If the primary efficacy endpoint is statistically 
significant at alpha level 0.05, the statistical tests for secondary efficacy endpoints will be 
performed. 
To control the Type 1 error rate, the secondary efficacy endpoints will be tested using a 
hierarchical (fixed-sequence) testing procedure.  The change from Baseline in peak 6MWD at 
Week 12 will be tested at a 2-sided Type 1 error rate of 0.05.  The subsequent tests for change 
from Baseline in NT-proBNP at Week 16, and then the change from Baseline in trough 
6MWD at Week 15, will be tested sequentially only if the preceding test is statistically 
significant. 


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8.5 
DERIVED AND TRANSFORMED DATA 
Time to clinical worsening will be evaluated as an exploratory endpoint from the time to 
randomization until 1 of the following criteria are met: 
 Hospitalization due to a cardiopulmonary indication 
 Decrease in 6MWD >15% from Baseline directly related to disease under study at 2 
consecutive visits and at least 24 hours apart 
 Death (all causes) 
 Lung transplantation 
Time to clinical worsening is calculated as described in Table 8-3. 
Table 8-3 
Derivation of Time to Clinical Worsening 
Parameter 
Scenario 
Formula 
Status 
Time to 
clinical 
worsening 
(weeks) 
Subjects with clinical 
worsening event 
reported 
= (Worsening date – Randomization date +1)/7 
0 (event) 
Subjects who died 
during the study 
= (Death date – Randomization date +1)/7 
0 (event) 
Subjects without 
clinical worsening 
event during the 
study 
= (Last assessment date – Randomization date +1)/7 
1 
(censored) 
Subjects discontinued 
from the study 
prematurely 
= (Last assessment date – Randomization date +1)/7 
1 
(censored) 
 
For subjects with clinical worsening due to decrease from Baseline in 6MWD, a confirmatory 
6MWT should be conducted.  The event time is based on the date of the confirmatory 6MWT.  
If the confirmatory 6MWT is not conducted, the event time is then based on the date of the 
first 6MWT. 


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Distance Saturation Product (DSP) is 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. 
Adjustments to the QT intervals will be calculated as follows: 
Parameter 
Formula 
QTc (Bazett) 
= Q‑T/√60/HR 
QTc (Fridericia) 
= Q‑T/√60/HR
3
 
Abbreviations: HR, Heart rate; QTc, Q-T interval corrected for heart rate; Q-T, Electrocardiographic interval from 
beginning of QRS complex to end of the T wave.  
8.6 
ASSESSMENT WINDOWS 
For any data summarized by scheduled visit, an analysis visit window will be used.  The 
scheduled visits, as recorded on the eCRFs, and the corresponding target days and study day 
intervals are specified in Table 8-4.  The analysis visit window will be derived based on the 
information specified in Table 8-4. 
In the protocol, the visit window for Week 4, Week 8, Week 12, and Week 16 is ±5 days and 
the visit window for the Week 15 visit is ±5 days and at least 24 hours prior to Week 16 
6MWT.  In order to allow slotting of discontinuation visits and visits outside the planned 
schedule, the visit windows have been expanded for analysis purposes for Week 4, Week 8, 
Week 12, and Week 16.  The nominal study visit identified as Week 15 in the eCRF will be 
used for the Week 15 visit provided it is at least 24 hours prior to Week 16 6MWT or there is 
no Week 16 visit. 


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Table 8-4 
Assessment Windows for Scheduled Visits 
Visit 
Target  
Study Day 
Study Day Interval 
ECGs, SGRQ: 
Baseline 
1 
Study Day 1 (prior to the date of the first 
dose) 
Week 16 
113 
1 < Study Day 
PFTs, Clinical laboratory assessments and NT-proBNP: 
Baseline 
1 
Study Day 1 (prior to the first dose) 
Week 8 
57 
1 < Study Day  71 
Week 16 
113 
99 < Study Day 
Peak 6MWT: 
Baseline 
1 
Study Day 1 (prior to the first dose) 
Week 4 
29 
1 < Study Day  43 
Week 8 
57 
43 < Study Day  71 
Week 12 
85 
71 < Study Day  99 
Week 16 
113 
99 < Study Day 
Trough 6MWT: 
Week 15 
106 
Nominal study visit and at least 24 hours 
prior to Week 16 6MWT or no Week 16 
visit 
Vital signs, Pulse oximetry: 
Baseline 
1 
Study Day 1 (prior to the first dose) 
Week 4 
29 
1 < Study Day  43 
Week 8 
57 
43 < Study Day  71 
Week 12 
85 
71 < Study Day  99 
Week 15 
106 
Nominal study visit and at least 24 hours 
prior to Week 16 6MWT or no Week 16 
visit 
Week 16 
113 
99 < Study Day 
Note: Study Day = (Assessment Date) − (First Dosing Date) +1 
Abbreviations: 6MWT, 6-Minute Walk Test; ECG, Electrocardiogram; NT-proBNP, N-Terminal pro-brain natriuretic 
peptide; PFT, Pulmonary function test. 
Multiple Evaluations within the Same Analysis Window 
After all the observations have been slotted based on the table above, if there are multiple 
valid observations for an assessment within an assigned analysis visit window, only 1 of these 
observations will be used for summary statistics and analyses.  The observation to be used is 
determined using the following hierarchy (in decreasing order): 


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 The observation closest to the target study day 
 The later observation if 2 observations are equally close to the target study day 
For missing values where the LOCF algorithm is applied, it is always the last valid 
observation on treatment carried forward, even though this might not be the observation 
obtained by the above hierarchy and used in the summaries by visit window. 
9 
STUDY POPULATION 
Unless otherwise specified, all efficacy analyses will be performed on the ITT population and 
all safety analyses will be based on the Safety population.  In the ITT population, the 
treatment assignment is based on the assignment upon randomization.  In the Safety 
population, the treatment assignment is based on the actual treatment the subject received. 
The comparability between the 2 treatment groups will be checked for demographic and 
baseline characteristics.  The p-values from Fisher’s exact test (for discrete variables) or 
Group t-test or Wilcoxon rank sum test (for continuous variables) will be included on 
summaries but are not intended to be used to test formal hypotheses.  For these comparisons, 
missing or unknown values will be excluded from the calculations. 
9.1 
SUBJECT ACCOUNTABILITY 
All subjects’ disposition information will be listed by individual subject number, including 
the analysis population the subjects belong to, premature study drug discontinuation status, 
primary reason for premature study drug discontinuation, premature study discontinuation 
status, primary reason for premature study discontinuation, number of days on the study drug, 
and enrollment in the open label extension study (RIN-PH-202). 
The listing of subject accountability will include the dates of informed consent and 
randomization, the first study drug dose, last study drug dose, and last assessment dates and 
times, and the last dose and assessment weeks.  Whether subjects received the study drug, 
whether subjects completed the Weeks 4, 8, 12, 15, 16 assessments, and study discontinuation 
status will be summarized. 


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Information regarding whether each subject is included in each analysis population (see 
Section 6) will be listed.  If a subject is not included in a particular analysis population, the 
reason for exclusion will be noted on the listing.  Also noted on the listing will be the 
randomized treatment assignment and the actual treatment subjects have received.  The 
summary will include the frequency and percentage of all subjects in each analysis 
population. 
The stratification information used in the random assignment of subjects to treatment group 
(from the central randomization database) will be listed, including date and time of 
randomization and Baseline 6MWD category (≤350 meters versus >350 meters).  Status of 
the treatment blind, and if broken, date/time of blind broken will be listed.  The number of 
subjects in each stratum will be summarized by treatment group and overall. 
9.2 
PROTOCOL DEVIATIONS 
The status of the entry criteria will be listed for all subjects.  The listing will include the date 
of the initial screening assessment, whether all eligibility criteria were met (Yes/No), and a 
list of any specific entry criteria not met.  This listing will also include the protocol version 
that the subject was enrolled under.  Entry criteria violations will be summarized by treatment 
group and overall. 
Additional protocol deviations will be documented throughout the study.  All 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’.  Protocol deviations will be listed, including the date of the deviation, the type of 
deviation, the severity of the deviation (Major/Minor), and a description of the deviation.  The 
protocol deviations will also be summarized by treatment group and overall. 
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATION 
9.3.1 
Demographics 
All demographic data will be listed for all subjects, including assessment date, date of birth, 
country, age, sex, ethnicity, race, weight, height, and body mass index (BMI).  Age, age 
category (<65 years of age, 65 to <80 years of age, and ≥80 years of age), sex, ethnicity, race, 


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height, weight, and BMI will be summarized by treatment group and overall.  The summary 
will include p-values (2-sided) from Fisher’s exact test (for age category, sex, ethnicity, and 
race) and group t-test or Wilcoxon rank sum test (for age, weight, height, and BMI) 
comparing treatment groups. 
9.3.2 
Baseline Characteristics 
Baseline characteristics will include the Baseline 6MWD, Baseline NT-proBNP, and 
hemodynamic parameters.  Hemodynamic parameters, measured by the right heart 
catheterization (RHC), will include PVR, pulmonary artery pressure mean (PAPm), 
pulmonary capillary wedge pressure (PCWP), and details concerning vasodilator testing will 
be listed and summarized. 
9.3.3 
Medical History and PH-ILD History 
All significant past or ongoing medical conditions will be listed for all subjects.  The listing 
will include the Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
(SOC) and preferred term (PT) for each condition listed, and whether the condition is ongoing 
at Randomization.  These medical conditions will be summarized by PT within each SOC. 
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 IIP 
subcategory), date of confirmatory computed tomography (CT) scan, whether ILD diagnosis 
confirmed with a lung biopsy, and if so, the date of lung biopsy. 
The current ILD diagnosis (ILD category) and IIP subcategory, time since PH diagnosis, and 
whether ILD diagnosis was confirmed via lung biopsy will be summarized by treatment group 
and overall.  The summary will include p-values (2-sided) from Fisher’s exact test (for current 
ILD diagnosis) or Wilcoxon rank sum test (for time since diagnosis) comparing treatment 
groups. 
9.3.4 
Concomitant Medications 
All concomitant medications specified on the eCRF will be mapped to a standard name using 
the World Health Organization Drug Dictionary (WHO-DD). 


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The standard name 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 at 
randomization), date discontinued (or indication that drug was ongoing at end of study), and 
the condition(s) treated/indication(s).  If a subject received no medications, this will be 
indicated on the listing.  Summary of concomitant medications present at Baseline and 
summary of concomitant medications added during the study will include the frequency and 
percentage of subjects in each treatment group receiving each drug (by coded standard name). 
10 
EFFICACY ANALYSES 
Except where otherwise noted, all efficacy analyses will only be performed on the ITT 
population (see Section 6). 
10.1 
PRIMARY EFFICACY MEASURES 
10.1.1 
Primary Efficacy Analyses 
10.1.1.1 
Hypothesis 
The primary efficacy endpoint of peak 6MWD assesses if inhaled treprostinil will increase the 
distance traversed in the peak 6MWT at Week 16 over placebo in subjects with PH-ILD.  The 
null and alternative hypotheses are: 
𝐻0: 𝜇1 = 𝜇2 
𝐻𝑎: 𝜇1 ≠𝜇2, 
where µ1 and µ2 are the median change from Baseline in 6MWD of the inhaled treprostinil 
and placebo treatment groups, respectively. 
10.1.1.2 
Primary Efficacy Analysis 
All 6MWT data will be listed for all subjects.  For each scheduled assessment, this listing will 
include the date test was performed (or date test was intended to be performed if subject is 
unable to attempt the test), start time of the test, nominal time point, last treatment dose, hours 
from last treatment dose to 6MWT start, if walk was attempted, total distance walked (in 
meters), whether subject received oxygen during the test, amount of supplemental oxygen, 
and any circumstances that adversely affected the walk (if any) including reason for not 


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attempting test (if any).  The trough 6MWT measure will also be indicated.  In addition, a 
listing of 6MWD with imputed values will be included for both peak and trough 6MWD data. 
For the primary efficacy analysis, the effect of inhaled treprostinil versus placebo on change 
in peak 6MWD at Week 16 will be evaluated via analysis of covariance (ANCOVA).  Change 
from Baseline in peak 6MWD is the dependent variable, and treatment and Baseline 6MWD 
are covariates in this ANCOVA model.  Least squares means and standard errors for each 
treatment group, the least squares mean difference and its standard error, as well as a 95% 
confidence interval for the treatment group difference and p-value for treatment group 
comparison will be calculated from the ANCOVA model.  This methodology will be carried 
out as follows: 
1. Walk distances obtained after study drug termination or unblinding will be excluded 
(as described in Section 8). 
2. Imputation rules in Table 8-1 will be applied. 
3. The LOCF algorithm will be applied. 
4. ANCOVA will be conducted based on the pseudo SAS code: 
proc glm; 
   class Treatment; 
   model DistC = Treatment Dist0; 
run; 
where DistC is the change from Baseline in peak 6MWD at Week 16 and Dist0 is the baseline 
measure of the 6MWD. 
If the ANCOVA assumptions are violated, the primary efficacy analysis will be based on 
non-parametric analysis of covariance within the framework of the extended 
Cochran-Mantel-Haenszel test (Koch 1990, Koch 1998, Stokes 2000).  Specifically, a 
Cochran-Mantel-Haenszel mean score test will be used on the standardized mid-ranks (ie, 
overall rank divided by the number of ranks +1, or “modified ridit” scores) of the residuals 
from an ordinary least squares regression with change from Baseline in peak 6MWD at 
Week 16 as a linear function of distance walked at Baseline (as a continuous variable).  This 
methodology will be carried out as follows: 


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1. Walk distances obtained after study drug termination or unblinding will be excluded 
(as described in Section 8). 
2. Imputation rules in Table 8-1 will be applied. 
3. Calculate ranks. The pseudo SAS code is as follows: 
proc rank nplus1 ties=mean out=ranks; 
   var DistC Dist0; 
run; 
where DistC is the change from Baseline in peak 6MWD at Week 16 and Dist0 is the 
baseline measure of the 6MWD. 
4. Linear regression model will be fit using the rank values generated above.  The pseudo 
SAS code is as follows: 
proc reg data=ranks noprint; 
   model DistC=Dist0; 
   output out=residual r=resid; 
run; 
where DistC is the rank value of the change from Baseline in peak 6MWD at Week 16 
and Dist0 is the rank value of the baseline measure of the 6MWD. 
5. A mean score test, using the values of the residuals as scores, compares the treatment 
groups.  Cochran-Mantel-Haenszel mean score statistic and p-value will be calculated, 
using the NOPRINT and CMH2 options in the TABLES statement of the FREQ 
procedure of SAS.  The pseudo SAS code is as follows: 
proc freq data=residual; 
   tables Treatment*Resid / noprint cmh2; 
run; 
where Treatment indicates the randomized treatment group, and Resid represents the 
residuals obtained from the above linear regression models. 
In addition to the p-value from the non-parametric method described above, the Wilcoxon 
rank sum test and the Hodges-Lehmann estimate of median difference (as an estimate of 
location shift between 2 treatment groups for the placebo-controlled treatment effect) will be 
provided.  The Wilcoxon rank sum test and the Hodges-Lehmann estimate can be obtained 
through the following pseudo SAS code: 
proc npar1way hl Wilcoxon; 
     class treatment; 
     var DistC; 
run; 
where DistC is the change from Baseline in peak 6MWD at Week 16. 


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10.1.1.3 
Sensitivity and Subgroup Analyses 
In order to analyze walk distances at each scheduled assessment, values for missing or 
excluded assessments up to and including Week 16 will be imputed according to rules 
described in Section 8.3.1. 
To further support the robustness and assess the sensitivity of the primary efficacy analysis of 
change in peak 6MWD at Week 16 (provided that the primary analysis yields significant 
results), the above non-parametric and parametric analyses and summaries will be repeated 
using each of the following modifications (as data permit): 
 The Per-protocol population will be used instead of the ITT population 
 Missing data imputation using the LOCF method (based on peak values) 
 Missing data imputation using the last rank carried forward (LRCF) method (based on 
peak values) (O’Brien 2005) 
 Using only the observed values without imputation 
 Including data collected after termination of the study drug 
 ITT population excluding subjects with a reported exacerbation within 3 days of the 
Week 16 peak 6MWT measure 
 Stratified by ILD etiology categories (IIP, CHP, Occupational, CPFE, and Other) 
 Stratified by Baseline 6MWD categories (≤350 meters versus >350 meters, ≤median 
baseline 6MWD versus > median baseline 6MWD) 
 Stratified by Baseline DLCO percent predicted (<40% versus ≥40%) 
 Stratified by Baseline pulmonary vascular resistance (PVR) (<4 versus ≥4 WU) 
 Stratified by sex (male versus female) 
 Stratified by age group (<65 years of age, 65 to <80 years of age, and ≥80 years of 
age) 
 Stratified by study drug dose at Week 16 (0 to 3 breaths, 4 to 6 breaths, 7 to 9 breaths, 
and 10 to 12 breaths). 
A longitudinal data analysis using mixed model repeated measurement (MMRM) will also be 
performed to estimate the treatment difference in change in peak 6MWD at Week 16.  The 
MMRM will include the change from Baseline in peak 6MWD as the dependent variable, 
treatment, week, and treatment by week interaction as fixed effects, and Baseline 6MWD as a 
covariate.  An unstructured variance/covariance structure shared across treatment groups will 
be used to model the within-subject errors. 


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An additional sensitivity analysis will be performed for percent change from Baseline to 
Week 16 in peak 6MWD using the same approach as the primary analysis method where the 
percent change from Baseline is calculated as 
peak 6MWD at Week 16−Baseline 6MWD
Baseline 6MWD
X (100%). 
In addition, the impact of Baseline hemodynamics and Baseline PFTs, including PVR, PAPm, 
PCWP, FEV1, FVC, TLC, and DLCO as continuous variables, on peak 6MWD, will be 
explored using the regression approach. 
10.2 
SECONDARY EFFICACY MEASURES 
Secondary efficacy endpoints include the following: 
 Change in peak 6MWD from Baseline to Week 12 
 Change in plasma concentration of NT-proBNP from Baseline to Week 16 
 Change in trough 6MWD from Baseline to Week 15 
As specified in Section 8.4 above, the hierarchical (fixed-sequence) testing procedure will be 
employed to control the overall alpha level at 0.05. 
10.2.1 
Change in Peak 6MWD at Week 12 
The methodology for primary efficacy analysis of change in peak 6MWD at Week 16 will 
also be carried out for the Week 12 assessment, as described above in Section 10.1.1.2. 
10.2.2 
Change in NT-proBNP at Week 16 
The efficacy endpoint of change in NT-proBNP assesses if inhaled treprostinil decreases the 
level of NT-proBNP at Week 16 over placebo in subjects with PH-ILD.  The null and 
alternative hypotheses are: 
𝐻0: 𝜇1 = 𝜇2 
𝐻𝑎: 𝜇1 ≠𝜇2, 
where µ1 and µ2 are the median change from Baseline to Week 16 in NT-proBNP of the 
inhaled treprostinil and placebo treatment groups, respectively. 


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The NT-proBNP values will be listed for all subjects, including the nominal time point, 
collection date/time, normal range and “High/Low” flag.  The values and their respective 
changes from Baseline will be summarized for each assessment.  The difference between 
treatment groups for the change from Baseline to Week 16 will be tested using the analysis of 
covariance with change from Baseline in NT-proBNP as the dependent variable, treatment as 
the fixed effect, and Baseline NT-proBNP as the covariate.  The pseudo SAS code is as 
follows: 
proc glm; 
   class treatment; 
   model BNP_C=Treatment BNP_B; 
run; 
where BNP_C is the change from Baseline to Week 16 in NT-proBNP and BNP_B is the NT-
proBNP at Baseline. 
If assumptions (normality and equal variance) for the parametric test are violated, the 
nonparametric Wilcoxon rank-sum test will be used.  For subjects who do not have 
NT-proBNP measurements at Week 16, the LOCF imputation will be used.  The analyses will 
also be performed for the data without imputation for the missing measures. 
As an exploratory analysis, the NT-proBNP at Week 8 will be analysed using the same 
method as the NT-proBNP at Week 16. 
10.2.3 
Change in Trough 6MWD at Week 15 
The methodology for primary efficacy analysis of change in peak 6MWD described in 
Section 10.1.1.2 will also be carried out for the change in trough 6MWD from Baseline to 
Week 15.  Missing trough 6MWD will be imputed as described in Table 8-2 in Section 8.3.1.  
The analysis will be repeated to include only subjects with trough 6MWD at Week 15 (ie, 
missing trough 6MWD at Week 15 is not imputed). 


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10.3 
EXPLORATORY EFFICACY MEASURES 
Exploratory efficacy endpoints include the following parameters: 
 Change in peak 6MWD from Baseline to Week 4 
 Change in peak 6MWD from Baseline to Week 8 
 Change in quality of life as measured by SGRQ from Baseline to Week 16 
 Time to clinical worsening will be evaluated as an exploratory endpoint from the time 
to randomization until 1 of the following criteria are met: 
a. Hospitalization due to a cardiopulmonary indication 
b. Decrease in 6MWD >15% from Baseline directly related to disease under study, at 
2 consecutive visits and at least 24 hours apart 
c. Death (all causes) 
d. Lung transplantation 
 Change in DSP from Baseline to Week 16 
10.3.1 
Change in Peak 6MWD at Weeks 4 and 8  
The methodology for primary efficacy analysis of change in peak 6MWD described in 
Section 10.1.1.2 will also be carried out for the assessments obtained at Week 4 and Week 8. 
10.3.2 
Change in SGRQ at Week 16 
The responses to the SGRQ questionnaire at Baseline and Week 16 will be converted to the 
Total score and 3 domain scores according to the SGRQ manual (Jones 2002).  Scores for 
Total and each domain will range from 0 to 100, with higher scores indicating more 
limitations.  Both individual item responses as well as calculated scores will be listed.  The 
change from Baseline for the Total and 3 domain scores (Symptoms, Activity, and Impacts) 
will be calculated. 
The Total score and for the 3 domain scores as well as their changes from Baseline will be 
summarized by treatment group using descriptive statistics. 
For the Total score and each of the 3 domain scores, treatment differences (inhaled treprostinil 
vs. placebo) will be tested by using analysis of covariance with change from Baseline as the 
dependent variable, treatment as a fixed effect, and baseline score as the covariate.  The 
analyses will be based on the observed data with no imputation. 


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The pseudo SAS code is as follows: 
proc glm;  
   class treatment; 
   model Score_C=Treatment Score_B; 
run; 
where Score_C is the change from Baseline in Total score or each of the 3 domain scores and 
Score_B is the corresponding score at Baseline. 
10.3.3 
Time to Clinical Worsening 
 Data on the clinical worsening assessment page of the eCRF will be used to determine 
clinical worsening status.  Investigator-reported clinical worsening events including 
the date (study day) of the event, category of the clinical worsening event, Baseline 
6MWD, first 6MWT details, and second 6MWT details will be listed.  The time to 
clinical worsening will be calculated according to the rules described in Table 8-3 in 
Section 8.5. 
The number and percentage of subjects with any clinical worsening and with each category of 
clinical worsening will be summarized by treatment group.  Time to clinical worsening will 
be summarized by treatment group 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 at risk (sample size), estimated median 
duration, and a 95% confidence interval for the median duration for each treatment group.  
The log-rank test, adjusted for Baseline 6MWD category, will be used to calculate the p-value 
for treatment differences in the ITT population. 
The SAS Procedure LIFETEST will be used.  The pseudo SAS statements are listed below: 
proc lifetest; 
   time TimeToWorsening*Censor_Status(1); 
   strata B_6MWD / group = Treatment test=all; 
run; 
where B_6MWD denotes the categorical Baseline 6MWD variable (≤350 meters versus 
>350 meters). 


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In addition, the Cox proportional hazards model will be fit to obtain the hazard ratio and its 
associated 95% confidence interval.  The model will include treatment and Baseline 6MWD 
as explanatory variables.  The SAS procedure PHREG will be used.  The pseudo SAS 
statements are listed below: 
proc phreg; 
   class Treatment; 
   model TimeToWorsening*Censor_Status(1) = Treatment Dist0 
              / risklimits alpha=0.05 ties=efron; 
   assess var=Dist0 ph; 
run; 
where Dist0 denotes the Baseline 6MWD variable (continuous).  If it is determined that the 
proportional hazards assumption does not hold for Baseline 6MWD, a stratified analysis will 
be conducted.  The above SAS code will be amended to remove Dist0 from the model 
statement and add the ‘strata B_6MWD;’ statement. 
If the proportional hazards assumption does not hold for the Cox model, the restricted mean 
survival time (RMST) and its associated standard error will be calculated for each treatment 
group at Week 16 (Royston 2013).  A 95% confidence interval will be constructed for the 
difference in RMST between the 2 treatment groups at Week 16. 
10.3.4 
Change in DSP 
The DSP will be calculated, and DSP results will be included in the data listing for pulse 
oximetry.  DSP values and their respective changes from Baseline to Week 16 will be 
summarized by treatment group.  The difference between treatment groups for the change 
from Baseline to Week 16 will be tested using analysis of covariance with change from 
Baseline in DSP as the dependent variable, treatment as a fixed effect, and Baseline DSP 
measure as the covariate.  The analyses will be based on the observed data with no 
imputation. 


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The pseudo SAS code is as follows: 
proc glm;  
   class treatment; 
   model DSP_C=Treatment DSP_B; 
run; 
where DSP_C is the change from Baseline to Week 16 in DSP (m%) and DSP_B is DSP at 
Baseline. 
In addition, the DSP at Week 4, Week 8, and Week 12 will each be analyzed in the same way 
as the DSP at Week 16. 
11 
HEALTH OUTCOMES 
11.1 
QUALITY OF LIFE MEASURES 
Quality of life was assessed using SGRQ.  The analyses of SGRQ are described in 
Section 10.3.2. 
11.2 
RESOURCE UTILIZATION MEASURES 
Hospitalizations and hospitalizations related to cardiopulmonary indications are collected 
during the study.  The analysis is discussed in Section 12.6.2. 
12 
SAFETY ANALYSES 
All safety analyses will be performed only on the Safety population (see Section 6). 
12.1 
EXTENT OF EXPOSURE 
All study drug dosing will be listed for all subjects.  The listing will include initial dose 
(number of breaths for each session and number of breaths for the day) and date of this initial 
dose and dose and date of each subsequent dose change.  Dosing at Weeks 4, 8, 12, 15, and 16 
will be summarized for subjects still receiving study drug at each of these assessments.  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 is used 
for summarization.  Summary of overall duration of exposure will be included as well as the 


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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. 
12.2 
ADVERSE EVENTS 
All AEs will be coded to the appropriate PT and SOC using MedDRA.  AEs will be listed by 
treatment group including all details recorded on the eCRF plus an indicator of whether the 
event was treatment-emergent.  The AE listings will include the AE verbatim term and its 
corresponding PT and SOC. 
The AE summaries will be limited to include only treatment-emergent AEs.  Treatment-
emergent AEs are those AEs with onset date equal to or after the start date of the study drug.  
The non-treatment-emergent AEs (the AEs occur after signing the informed consent form but 
before receiving study drug) will be listed but not included in summary tables. 
All summaries will include the number and percentage of subjects experiencing each type of 
adverse event and the total number of each type of adverse event, in order of overall 
frequency and/or SOC.  Serious adverse events (SAE) and non-serious AEs will also be 
summarized by SOC and 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. 
Adverse events possibly or probably related to study drug will be summarized.  An AE 
summary by severity (mild, moderate, and severe) will also be provided. 
Separate listings and summary tables will be provided for all SAEs, AEs leading to the 
discontinuation of study drug, and all deaths during the study (if data permit).  For listing of 
deaths, information for all subjects who die during the study period from the randomization to 
the end of study (including 30 days after the last study treatment dosing) will be included. 


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12.3 
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. 
The SpO2 will be summarized by treatment group, visit, and time point (pre-walk, during 
walk, and post-walk).  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. 
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 treatment group. 
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 the treatment group.  Supplemental oxygen 
level at rest at each visit and the corresponding changes from Baseline will be summarized by 
treatment group. 
Heart rate will be summarized by treatment group, 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. 


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12.4 
PULMONARY FUNCTION TESTS 
The PFT parameters include: 
 Forced expiratory volume in 1 second (FEV1) 
 Forced vital capacity (FVC) 
 Total lung capacity (TLC) 
 Lung diffusion capacity (DLCO) 
Only pre-bronchodilator values will be recorded on eCRF and will be listed.  All PFT 
parameters and their change from baseline values will be summarized by treatment group and 
visit. 
For FEV1 results, the number and percentage of subjects with FEV1 decreasing more than 
20% from Baseline at any post-Baseline Visit will be summarized by treatment group. 
12.5 
CLINICAL LABORATORY EVALUATIONS 
Blood samples will be taken at Screening and/or Baseline, Week 8, and Week 16.  All 
samples will be sent to a central laboratory for evaluation of clinical chemistry and 
hematology. 
12.5.1 
Clinical Chemistry 
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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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 treatment group. 
For each parameter, the frequency and percentage of subjects within each treatment group 
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. 
12.5.2 
Hematology 
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. 
Numeric values of these parameters at each visit and their corresponding changes from 
Baseline will be summarized by treatment group. 
For each parameter, the frequency and percentage of subjects within each treatment group 
who have “Low,” “Normal,” or “High” Baseline values, then subsequently have “Low,” 
“Normal,” or “High” follow-up values at each assessment will be presented in a shift 
summary. 


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12.5.3 
Pregnancy Test 
Females of childbearing potential will undergo a urine pregnancy test at Screening followed 
by urine pregnancy tests at Baseline and every subsequent scheduled study visit.  All 
pregnancy tests will be performed at study sites.  Pregnancy status during the study will be 
listed. 
12.6 
OTHER SAFETY MEASURES 
12.6.1 
Electrocardiograms 
All ECG assessments will be listed for all subjects.  This listing will include the heart rate, the 
ECG interval from the beginning of QRS complex to end of the T wave (Q-T interval), the 
QT interval corrected for heart rate (QTc) (calculated using formulas by both Bazett and 
Fridericia as described in Section 8.4), the time between P wave and beginning of QRS 
complex in ECG (P-R interval), the electrocardiographic wave (QRS) duration, ECG results 
(Normal/Abnormal), whether there were clinically significant changes from Screening visit, 
whether abnormalities were present, and details and comments on any abnormalities.  The 
ECG results at Baseline and changes at Week 16 will be descriptively summarized by 
treatment group.  In addition, for QTc intervals calculated using both the Bazett and Fridericia 
methods, the number and percent of subjects with values ≥500 msec and the number and 
percent of subjects with changes from Screening of <30 msec, 30 to <60 msec, and ≥60 msec 
will be presented.  Additionally, each abnormality will be summarized by number and 
percentage of subjects reporting at each visit by treatment group. 
12.6.2 
Hospitalizations 
Details for all hospitalizations will be listed.  Number of hospitalizations for cardiopulmonary 
indications and total duration of hospitalization for cardiopulmonary indications will be 
summarized for each treatment group as well as overall number of hospitalizations and total 
duration regardless of indication. 
12.6.3 
Vital Signs 
All vital sign assessments will be listed for all subjects.  This listing will include height, 
weight, body mass index (BMI), heart rate, systolic and diastolic blood pressures, respiratory 


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rate, and temperature.  The vital sign results at each assessment and changes for each 
post-Baseline assessment will be descriptively summarized by treatment group. 
12.6.4 
Exacerbations of Underlying Lung Disease 
Exacerbation of underlying lung disease is defined as an acute, clinically significant, 
respiratory deterioration characterized by evidence of new widespread alveolar abnormality.  
Number of subjects with exacerbation of underlying lung disease will be summarized for each 
treatment group and included in the overall AE summary table.  A listing of these events will 
also be provided. 
13 
PHARMACOKINETICS 
No pharmacokinetic measures will be assessed in this study. 
14 
REFERENCES 
Jones PW.  Interpreting thresholds for a clinically significant change in health status in asthma 
and COPD.  Eur Respiratory J.  2002;19:398–404. 
Koch GG, Carr GJ, Amara IA, et al.  Categorical data analysis.  In Berry DA ed. Statistical 
Methodology in the Pharmaceutical Sciences.  New York, NY: Marcel Dekker Inc.; 
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Koch GG, Tangen CM, Jung JW, et al.  Issues for covariance analysis of dichotomous and 
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O’Brien PC, Zhang D, Bailey KR. Semi-parametric and non-parametric methods for clinical 
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15 
LIST OF TABLES, LISTINGS AND FIGURES 
15.1 
LIST OF TABLES 
Table Number 
Table Title 
14.1.1 
Summary of Subject Accountability 
14.1.2 
Summary of Analysis Population Information 
14.1.3 
Summary of Demographic Data 
14.1.4 
Summary of Baseline Characteristics 
14.1.5 
Summary of PH-ILD History 
14.1.6.1 
Summary of Entry Criteria Violations 
14.1.6.2 
Summary of Protocol Deviations 
14.1.7 
Summary of Randomization Information 
14.1.8 
Summary of Medical History  
14.1.9 
Summary of Concomitant Medications Ongoing at Baseline 
14.1.10 
Summary of Concomitant Medications Added During the Study  
14.1.11 
Summary of Study Drug Dosing and Exposure 
14.1.12 
Summary of Study Drug Treatment Compliance  
14.2.1.1 
Summary and Analysis of Peak 6MWD (meter) at Week 16 – Primary 
Efficacy Endpoint  
14.2.1.2 
Summary and Analysis of Peak 6MWD (meter) at Week 16 – Per Protocol 
Population 
14.2.1.3 
Summary and Analysis of Peak 6MWD (meter) at Week 16 with LOCF 
Imputation for Missing Data 
14.2.1.4 
Summary and Analysis of Peak 6MWD (meter) at Week 16 with LRCF 
Imputation for Missing Data 
14.2.1.5 
Summary and Analysis of Peak 6MWD (meter) at Week 16 with No 
Imputation for Missing Data 
14.2.1.6 
Summary and Analysis of Peak 6MWD (meter) at Week 16 Including Data 
Collected after Termination of Study Drug  
14.2.1.7 
Summary and Analysis of Peak 6MWD (meter) at Week 16 Excluding 
Subjects with a Reported Exacerbation within 3 Days of the Week 16 
6MWD Measure  
14.2.1.8 
Analysis of Peak 6MWD (meter) at Week 16 Using Mixed Model Repeated 
Measurement (MMRM)  
14.2.1.9 
Summary and Analysis of Percent Change from Baseline to Week 16 in 
Peak 6MWD  
14.2.1.10 
Summary and Analysis of Peak 6-Minute Walk Distance (meter) at Week 
16 by ILD Etiology Category 
14.2.1.11.1 
Summary and Analysis of Peak 6MWD (meter) at Week 16 by Baseline 
6MWD Category (≤350 meters versus >350 meters) 
14.2.1.11.2 
Summary and Analysis of Peak 6MWD (meter) at Week 16 by Baseline 
6MWD Category (≤baseline median meters versus>baseline median 
meters) 


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Table Number 
Table Title 
14.2.1.12 
Summary and Analysis of Peak 6MWD (meter) at Week 16 by Baseline 
DLCO Percent Predicted  
14.2.1.13 
Summary and Analysis of Peak 6MWD (meter) at Week 16 by Baseline 
PVR 
14.2.1.14 
Summary and Analysis of Peak 6MWD (meter) at Week 16 by Sex 
14.2.1.15 
Summary and Analysis of Peak 6MWD (meter) at Week 16 by Age Group 
14.2.1.16 
Summary and Analysis of Peak 6MWD (meter) at Week 16 by Study Drug 
Dose at Week 16 
14.2.1.17 
Summary of Effects of Baseline Hemodynamics and Baseline PFTs on 
Peak 6MWD by Week 
14.2.2.1 
Summary and Analysis of Peak 6MWD (meter) at Week 12 – Secondary 
Efficacy Endpoint 
14.2.2.2 
Summary and Analysis of Peak 6MWD (meter) at Weeks 4 and 8 
14.2.3.1 
Summary and Analysis of NT-proBNP (pg/mL) Data at Week 16 – 
Secondary Efficacy Endpoint  
14.2.3.2 
Summary and Analysis of NT-proBNP (pg/mL) Data at Week 16 – with 
Observed Case 
14.2.3.3 
Summary and Analysis of NT-proBNP (pg/mL) Data at Week 8  
14.2.3.4 
Summary and Analysis of NT-proBNP (pg/mL) Data at Week 8 with 
Observed Case 
14.2.4.1 
Summary and Analysis of Trough 6MWD (meter) at Week 15 – Secondary 
Efficacy Endpoint 
14.2.4.2 
Summary and Analysis of Trough 6MWD (meter) at Week 15 with 
Observed Case 
14.2.5.1 
Summary and Analysis of Clinical Worsening Events  
14.2.5.2 
Summary of Hospitalization Information 
14.2.6.1 
Summary and Analysis of SGRQ Total Score 
14.2.6.2 
Summary and Analysis of SGRQ Symptoms Score 
14.2.6.3 
Summary and Analysis of SGRQ Activity Score 
14.2.6.4 
Summary and Analysis of SGRQ Impacts Score 
14.2.7 
Summary and Analysis of Distance Saturation Product (DSP) (m%) 
14.3.1.1 
Overall Summary of Adverse Events and Exacerbations of Underlying 
Lung Diseases 
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 
List of Deaths 
14.3.2.2 
List of Serious Adverse Events 
14.3.4.1 
Summary of SpO2 (%) Measured by Pulse Oximetry 
14.3.4.2 
Categorical Summary of SpO2 (%) Measured by Pulse Oximetry 
14.3.4.3 
Summary of Heart Rate (beats/min) by Pulse Oximetry 
14.3.4.4 
Summary of Supplemental Oxygen Use 
14.3.4.5 
Summary of Supplemental Oxygen (L/min) 
14.3.4.6 
Summary of Pulmonary Function Test Results 
14.3.4.7 
Summary of Subjects with ≥20% Decrease in FEV1 from Baseline 
14.3.4.8.1 
Summary of Laboratory Data – Clinical Chemistry 
14.3.4.8.2 
Summary of Clinical Chemistry Shift from Baseline 
14.3.4.8.3 
Summary of Laboratory Data – Hematology 
14.3.4.8.4 
Summary of Hematology Shift from Baseline 
14.3.4.9 
Summary of Vital Signs 
14.3.4.10.1 
Summary of Electrocardiogram Parameters 
14.3.4.10.2 
Summary of Electrocardiogram Categorical Results 
 
15.2 
LIST OF LISTINGS 
Listing Number 
Listing Title 
16.2.1.1 
Subject Dispositions 
16.2.1.2 
Subject Accountability 
16.2.2 
Protocol Deviations 
16.2.3.1 
Subject Randomization 
16.2.3.2 
Analysis Population Information 
16.2.3.3 
Entry Criteria 
16.2.4.1 
Demographics 
16.2.4.2 
PH-ILD History 
16.2.4.3 
Medical History 
16.2.4.4 
Concomitant Medications 
16.2.5 
Study Drug Dosing 
16.2.6.1 
6-Minute Walk Test 
16.2.6.2 
6MWT Information with Imputed Data – Peak 6MWD 
16.2.6.3 
6MWT Information with Imputed Data – Trough 6MWD 
16.2.6.4 
Plasma NT-proBNP (pg/mL) 


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Listing Number 
Listing Title 
16.2.6.5 
Clinical Worsening Events 
16.2.6.6 
The St. George’s Hospital Respiratory Questionnaire  
16.2.6.7 
The St. George’s Hospital Respiratory Questionnaire Score by Domain 
16.2.6.8 
Hospitalizations 
16.2.6.9 
Death Records 
16.2.6.10 
RHC and Hemodynamic Measures 
16.2.7.1 
Adverse Events 
16.2.7.2 
Serious Adverse Events 
16.2.7.3 
Adverse Events Leading to Discontinuation of Study Drug 
16.2.7.4 
Exacerbations of Underlying Lung Disease 
16.2.8.1 
Pulse Oximetry and DSP 
16.2.8.2 
Supplemental Oxygen 
16.2.8.3 
Pulmonary Function Test Results 
16.2.8.4 
Laboratory Results – Clinical Chemistry 
16.2.8.5 
Laboratory Results – Hematology 
16.2.8.6 
Pregnancy Status 
16.2.8.7 
Vital Signs 
16.2.8.8 
ECG Results 
 
15.3 
LIST OF FIGURES 
Figure Number 
Figure Title 
14.2.1 
Mean Change from Baseline in Peak 6MWD (meter) by Visit  
14.2.2 
Mean Change from Baseline in Peak 6MWD (meter) at Week 16 by Inhaled 
Treprostinil Dose at Week 16 
14.2.3 
Forest Plot on Subgroup Analyses of Peak 6MWD (meter) at Week 16 
14.2.4 
Kaplan-Meier Plot of Time to Clinical Worsening Events