Clinical trial NCT03496623
Conditions: Pulmonary Hypertension Chronic Obstructive Pulmonary Disease
Keywords: Pulmonary Hypertension COPD Inhaled Treprostinil 6-Minute Walk Test Tyvaso
Sponsor: United Therapeutics
Start date: 2018-05-08; Completion date: 2022-10-13
Enrollment: 188 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this study is to demonstrate the efficacy of inhaled treprostinil compared to placebo in improving exercise ability as measured by change from baseline in 6-Minute Walk Distance (6MWD) following 12 weeks of active treatment in participants with PH-COPD.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled, 34-week, cross-over study, with a Treatment Period of approximately 26 weeks under the Original Crossover Design or, if applicable, a 21-week parallel study, with a Treatment Period of approximately 14 weeks under the Contingent Parallel Design.

Arms: arm 1: Inhaled treprostinil delivered via an ultrasonic nebulizer with a target dosing regimen of 12 breaths (72 micrograms \[mcg\]) 4 times daily (QID) arm 2: Placebo delivered via an ultrasonic nebulizer for QID administration
Interventions: intervention 1: Inhaled treprostinil solution intervention 2: Placebo solution
Intervention descriptions: intervention 1: Treprostinil inhalation solution intervention 2: Placebo solution

Protocol documents:
Prot_000.pdf: 
United Therapeutics Corp. 
RIN-PH-304 Protocol Amendment 4 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 20 October 2020 
CONFIDENTIAL 
Page 1 
A Phase 3, Randomized, Placebo-controlled, Double-blind, Adaptive 
Study to Evaluate the Safety and Efficacy of Inhaled Treprostinil in 
Patients with Pulmonary Hypertension due to Chronic Obstructive 
Pulmonary Disease (PH-COPD) 
IND Number 70,362 
Protocol RIN-PH-304 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
12 January 2018 
Amendment 1 Date: 
30 January 2018 
Amendment 2 Date: 
28 August 2018 
Amendment 3 Date: 
04 October 2019 
Amendment 4 Date: 
20 October 2020 
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. © 2020 United Therapeutics Corporation 
NCT #: NCT03496623


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LIST OF CONTACTS FOR STUDY 
Study Sponsor 
 
 
 
Sponsor’s Medical Monitor 
United Therapeutics Corp. 
 
 
 
 
Telephone: 
 
Mobile: 
 
Email: 
 
Study Conducted by 
Lung Biotechnology PBC 
 
 
 
 
  
Telephone: 
  
Mobile: 
 
Email:
 
 
 
  
Telephone: 
  
Mobile: 
 
Email: 
 
 
 
 
Telephone: 
  
Mobile: 
 
Email: 
 
Clinical Laboratory 
Covance Laboratories Inc. 
 
 
CT Imaging Laboratory 
Applied Chest Imaging Laboratory,  
Department of Radiology and Medicine 
Brigham and Women’s Hospital 
  
 
Email: 
 
Digital Health Technology 
THREAD 
 
 
Telephone: 
 
Email: 
 
SAE Reporting 
UTC Global Product Safety and Pharmacovigilance 
 
 
Fax: 
 
Email: 
 


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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled, “A Phase 3, Randomized, Placebo-controlled, 
Double-blind, Adaptive Study to Evaluate the Safety and Efficacy of Inhaled Treprostinil in 
Patients with Pulmonary Hypertension due to Chronic Obstructive Pulmonary Disease 
(PH-COPD),” Amendment 4, dated 20 October 2020 and agree to abide by all provisions set 
forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Guideline for Good 
Clinical Practice (GCP) and applicable Food and Drug Administration (FDA) 
regulations/guidelines set forth in 21 Code of Federal Regulations Parts 50, 54, 56, and 312 and 
any local regulations per country. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of United Therapeutics Corp. 
I also have read the current Clinical Investigator’s Brochure for inhaled treprostinil and 
acknowledge that review of the information contained in the Clinical 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 (EC)/Institutional Review Board (IRB) 
approval documents have been obtained. 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 


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PROTOCOL SYNOPSIS 
Title: A Phase 3, Randomized, Placebo-controlled, Double-blind, Adaptive Study to Evaluate 
the Safety and Efficacy of Inhaled Treprostinil in Patients with Pulmonary Hypertension due 
to Chronic Obstructive Pulmonary Disease (PH-COPD) 
Study Phase: 3 
Indication: Inhaled treprostinil (Tyvaso®) is a prostacyclin vasodilator being studied for the 
treatment of pulmonary hypertension due to chronic obstructive pulmonary disease 
(PH-COPD; World Health Organization [WHO] Group 3) to improve exercise ability. 
Primary Objective: To demonstrate the efficacy of inhaled treprostinil compared to placebo 
in improving exercise ability as measured by change from baseline in 6-Minute Walk Distance 
(6MWD) following 12 weeks of active treatment in subjects with PH-COPD. 
Secondary 
Objective(s): 
To assess the effect of inhaled treprostinil compared to placebo after 
12 weeks of active treatment on the following: 
1. Change in moderate to vigorous physical activity (MVPA) as 
measured by actigraphy 
2. Change in overall activity as measured by actigraphy 
3. Change in Borg dyspnea score from baseline 
4. Change in 6MWD/Borg dyspnea composite score from baseline 
5. Change in quality of life (QOL) from baseline as measured by 
St. George’s Respiratory Questionnaire (SGRQ) and the University of 
California San Diego Shortness of Breath Questionnaire 
(UCSD SOBQ) 
6. Change in plasma concentration of N-Terminal pro-brain natriuretic 
peptide (NT-proBNP) from baseline 
7. Change in patient global assessment (PGA) 
Safety 
Objective(s): 
To assess the safety of inhaled treprostinil compared to placebo on the 
following: 
1. Adverse events (AEs) 
2. Clinical laboratory assessments 
3. Electrocardiograms (ECGs) 
4. Physical examination (PE) findings 
5. Oxygenation 
6. Pulmonary function tests (PFTs) 
7. Vital sign measurements 
8. At-home spirometry 


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Exploratory 
Objectives: 
 
 
 
 
 
 
 
 
 
Study Design: This is a multicenter, randomized, double-blind, placebo-controlled, 34-week, 
crossover study with a Treatment Period of approximately 26 weeks under the Original 
Crossover Design or, if applicable, a 21-week parallel study with a Treatment Period of 
approximately 14 weeks under the Contingent Parallel Design. 
Sample Size: Approximately 136 subjects will be randomized at approximately 80 US and 
international sites in the Original Crossover Design.  If the study is adapted to the 
Contingent Parallel Design, approximately 314 subjects will be randomized at 
approximately 100 US and international sites. 
Summary of Subject Eligibility Criteria: 
Inclusion 
Criteria: 
Subjects who meet the following criteria may be included in the study: 
1. Voluntarily gives informed consent to participate in the study. 
2. Males and females 18 years of age and above at the time of informed 
consent. 
a) Females of childbearing potential (defined as less than 1 year 
postmenopausal and not surgically sterile) must agree to practice 
abstinence or use 2 highly effective methods of contraception 
(defined as a method of birth control that results in a less than 1% 
per year failure rate, such as approved hormonal contraceptives, 
barrier methods [condom or diaphragm] used with a spermicide, or 
an intrauterine device) for the duration of study treatment and for 
48 hours after discontinuing study drug.  Subjects must have 
negative pregnancy tests at Screening Visit 1 (urine [prior to the 
first dose of study drug] and serum) and the Baseline Visit (urine 
[Study Week 1]). 
b) Males with a partner of childbearing potential must agree to use a 
barrier method (condom) with a spermicide for the duration of 
treatment and for at least 48 hours after discontinuing study drug. 
3. Diagnosis of PH-COPD (WHO Group 3). 


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4. Clinical diagnosis of COPD per the Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) diagnostic criteria (2020) and 
documented spirometry parameters measured during Screening Visit 1 
(prior to start of low dose inhaled treprostinil), as follows: 
a) Forced expiratory volume in 1 second (FEV1) <80% predicted 
b) FEV1/Forced vital capacity (FVC) <70 
5. Resting saturation peripheral capillary oxygenation (SpO2) ≥90% during 
Screening Visit 1, with or without supplemental oxygen, and 
supplemental oxygen cannot exceed 10 L/min by any mode of delivery. 
6. A 6MWD ≥100 meters during Screening Visit 1 (prior to start of low 
dose inhaled treprostinil). 
7. Willing to undergo right heart catheterization (RHC) during Screening 
Visit 1.  A RHC performed within 12 months prior to the start of 
Screening Visit 1 is acceptable for determining eligibility, even if done 
without oxygen or vasodilator challenge, and a repeat RHC is not 
required.  The following parameters must be documented for eligibility: 
a) Pulmonary vascular resistance (PVR) ≥4 Wood units 
b) Pulmonary artery wedge pressure (PAWP) or left ventricular 
end-diastolic pressure (LVEDP) of <15 mmHg 
c) Pulmonary artery pressure mean (PAPm) of ≥30 mmHg 
8. Must be on a stable and optimized dose of chronic COPD medications 
for ≥30 days prior to the start of Screening Visit 1 and remain on the 
same dose throughout the Screening Period. 
9. Can communicate effectively with study personnel and is considered 
reliable, willing, and likely to be cooperative with protocol requirements, 
including attending all study visits, in the opinion of the Investigator. 
Exclusion 
Criteria: 
Subjects who meet the following criteria are excluded from the study: 
1. A diagnosis of either pulmonary arterial hypertension (PAH) or 
pulmonary hypertension (PH) due to reasons other than COPD, 
including, but not limited to, chronic thromboembolic PH or acute/recent 
deep vein thrombosis or pulmonary embolism, untreated or inadequately 
treated obstructive sleep apnea, connective tissue disease (including, but 
not limited to, systemic sclerosis/scleroderma or systemic lupus 
erythematosus), sarcoidosis, human immunodeficiency virus-1 infection, 
and other conditions under WHO Group 1, 2, 4, and 5 classifications. 
2. A confirmed diagnosis of idiopathic pulmonary fibrosis, combined 
pulmonary fibrosis and emphysema, diffuse parenchymal lung disease, 
or interstitial lung disease, based on chest CT imaging during Screening 
Visit 1.  A chest CT performed within 6 months prior to the start of 
Screening Visit 1 is acceptable for determining eligibility and a repeat 
assessment is not required.  A redacted CT scan report (from Screening 
Visit 1 or dated within 6 months prior) should be provided to the 


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Sponsor’s Medical Monitor with the Pre-Baseline Review Form to 
confirm eligibility. 
3. Received any Food and Drug Administration (FDA)-approved 
medication for the treatment of PAH (ie, prostacyclin, prostacyclin 
receptor agonist, endothelin receptor antagonist [ERA], 
phosphodiesterase type 5 inhibitor [PDE5-I], or soluble guanylate 
cyclase [sGC] stimulator) at Screening Visit 1 and thereafter, except if 
received for acute vasoreactivity testing. 
4. Previous diagnosis of homozygous alpha-1 antitrypsin deficiency. 
5. Any prior intolerance to inhaled prostanoid therapy. 
6. Inability to tolerate low dose inhaled treprostinil and/or follow dosing 
regimen during the Screening Period (pre-randomization). 
7. Unwilling or unable to use Sponsor-provided devices (actigraph, 
spirometer, or smart device). 
8. Evidence of clinically significant left-sided heart disease (including, but 
not limited to, left ventricular ejection fraction <40%, left ventricular 
hypertrophy) or clinically significant cardiologic conditions, such as 
congestive heart failure, coronary artery disease, or valvular heart 
disease.  NOTE: Subjects with abnormal left ventricular function 
attributable to the effects of right ventricular overload will not be 
excluded, but a discussion with and approval by the Sponsor’s Medical 
Monitor is required. 
9. Any exacerbation of COPD (including hospitalization or outpatient 
therapy) or active pulmonary or upper respiratory infection from 30 days 
prior to start of Screening Visit 1 through the Baseline Visit.  This is 
defined as worsening of respiratory symptoms that required treatment 
with corticosteroids and/or antibiotics. 
10. Initiation of pulmonary rehabilitation within 12 weeks prior to start of 
Screening Visit 1 or, in the opinion of the Investigator, pulmonary 
rehabilitation is likely to be needed during the Treatment Period. 
11. Any form of congenital heart disease (repaired or unrepaired) other than 
a patent foramen ovale. 
12. Any musculoskeletal disorder (ie, severe arthritis of the lower limbs 
which limits ambulation, recent hip or knee joint replacement, artificial 
leg) or any other condition that would likely be the primary limitation to 
ambulation. 
13. Use of any other investigational drug or device within 30 days prior to 
the start of Screening Visit 1. 
14. Any other clinically significant illness or abnormal laboratory value(s) 
measured during the Screening Period that, in the opinion of the 
Investigator, might adversely affect the interpretation of the study data or 
safety of the subject. 


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Drug Dosage and Formulation: 
• Active Study Drug: Inhaled treprostinil solution (0.6 mg/mL, 6 mcg/breath), 4 times daily 
(QID) during waking hours. 
• Placebo Study Drug: Placebo inhalation solution, QID during waking hours. 
All subjects will be given low dose inhaled treprostinil during the Screening Period.  After 
randomization, study drug will be initiated based on randomized treatment assignment and 
dose adjustments will be based on subject tolerability at the discretion of the Investigator.  
Study drug doses should be maximized to tolerability throughout the study and dose 
escalations (additional 1 breath QID) can occur approximately every 3 days with a target 
dosing regimen of 12 breaths QID or the maximum tolerated dose. 
Control Group: Placebo 
Route of Administration: Inhaled 
Procedures: This adaptive study will be initiated as an Original Crossover Design.  Two 
separate missing data checks will occur and will result in study design adjustment decisions.  
The following adaptation strategies will be used: 
Adaptation 1: 
At approximately 75% of subjects randomized, a blinded interim analysis will be performed to 
assess the extent of missing primary efficacy endpoint data at the end of Treatment Period 2 
(Study Week 25).  The outcome of the analysis will inform a decision for the study to 
continue as the Original Crossover Design or switch to the Contingent Parallel Design, as 
follows: 
• If data presence ≥85% for 6MWD or actigraphy data at the end of Treatment Period 2 
(Study Week 25), the study will continue as planned under the Original Crossover 
Design. 
• If data presence <85% for both 6MWD and actigraphy data at the end of Treatment 
Period 2 (Study Week 25), the study will switch to the Contingent Parallel Design. 
Adaptation 1 will assess the amount of missing exercise ability data due to subject dropout or 
otherwise lack of measurement (regardless of onsite or remote) and the outcome will be 
whether the study continues to completion as the Original Crossover Design or the 
Contingent Parallel Design. 
Adaptation 2: 
Will assess the amount of missing exercise ability data potentially due to the COVID-19 
pandemic interfering with onsite measurements.  At the conclusion of the study, a blinded 
analysis will be performed to assess the extent of missing primary efficacy endpoint data (ie, 
6MWD data).  If the absence of 6MWD data in the Treatment Period, combined across 
subjects, treatment periods, and key visits (Baseline and Study Week 12) to be used for the 
final primary endpoint analysis would likely lead to an underpowered study or yield 


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indeterminate results, a contingent primary endpoint will be used for the final primary 
endpoint analysis.  Such a contingency may include an imputation of missing 6MWD data 
from actigraphy measurements or the use of actigraphy measurements alone rather than 
6MWD for the primary endpoint analysis.  This adaptation intends that the 6MWD is to be 
used as the primary efficacy endpoint for this study, except in the case where onsite 
measurements for the 6MWD are not reasonably available, and will occur regardless of 
Adaptation 1 (ie, for either the Original Crossover Design or the Contingent Parallel 
Design).  The contingent primary endpoint definition and analysis strategy will be specified 
a priori with details fully documented in the Statistical Analysis Plan prior to the unblinding of 
the study. 
Original Crossover Design: 8 study visits will be conducted: Screening Visit 1, Screening 
Visit 2 (upon completion of low dose inhaled treprostinil), and 6 visits during Treatment 
Periods 1 and 2 (Study Weeks 1, 6, 12, 14, 19, & 25). 
Contingent Parallel Design (if applicable): 5 study visits will be conducted: Screening 
Visit 1, Screening Visit 2 (upon completion of low dose inhaled treprostinil), and 3 visits 
during the Treatment Period (Study Weeks 1, 6, & 12). 
Screening Visit 1 assessments may be spread over multiple days and include initiation of low 
dose inhaled treprostinil in both the Original Crossover Design and the Contingent Parallel 
Design.  Subjects will be issued Sponsor-provided actigraphy, spirometry, and smart devices 
during Screening Visit 1 at the time of treatment initiation to measure at-home activity and 
FEV1/FVC.  Subjects will be provided proper training on the use of these devices at that time.  
Subjects who are intolerant of therapy (as determined by the Investigator), unable to follow 
the dosing regimen, or noncompliant with actigraphy, at-home spirometry, or smart device use 
during the Screening Period will be ineligible for randomization and deemed screen failures.  
Subjects may be re-screened (see Section 3.1). 
Screening and randomization visits must occur onsite.  All attempts should be made to have 
onsite study visits thereafter.  With written Sponsor approval, subjects may have telemedicine 
visits in lieu of onsite visits after randomization in both the Original Crossover Design and 
the Contingent Parallel Design, if the conduct of an onsite study visit poses a safety risk due 
to the COVID-19 pandemic.  See Section 7.4 for the telemedicine visit assessments. 
After randomization, study drug dosing will be adjusted to tolerability at the discretion of the 
Investigator.  Study drug dose escalations (additional 1 breath QID) can occur approximately 
every 3 days with a target dosing regimen of 12 breaths QID or the maximum tolerated dose.  
Subjects will be contacted at least weekly by telephone during study drug titration and as 
needed thereafter to provide dosing instructions, assess tolerance to study drug, AEs, device 
issues, and changes in concomitant medications.  Subjects will also be contacted by phone 
mid-week during the Washout Period(s) to monitor AEs and safety. 
An Early Termination (ET) visit will be conducted for subjects who discontinue treatment 
prior to the end of Treatment Period 2 (Study Week 25) in the Original Crossover Design or, 
if applicable, prior to the end of the Treatment Period (Study Week 12) in the Contingent 


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Parallel Design.  All assessments planned for the applicable final study visit will be 
conducted during the ET Visit. 
Key Screening Activities: 
• A chest CT scan to evaluate Exclusion Criterion #2 must be performed during the 
Screening Period.  If a chest CT scan was performed within 6 months prior to Screening 
Visit 1, a repeat assessment is not required.  A redacted CT scan report should be 
provided to the Sponsor’s Medical Monitor with the Pre-Baseline Review Form to 
confirm eligibility. 
• An RHC to evaluate Inclusion Criterion #7 must be performed during the Screening 
Visit 1.  If an RHC was performed within 12 months prior to Screening Visit 1, a repeat 
assessment is not required.  For sites seeking guidance on the RHC and 
oxygen/vasodilator challenge, information is offered as a guide in the Study Procedures 
Manual, which is provided separately. 
• Training on and treatment with low dose inhaled treprostinil to assess tolerability and 
ability to follow the dosing regimen. 
• 
Training on at-home use of actigraphy, spirometry, and smart devices. 
Key Study Activities:  
• Pregnancy test: Females of childbearing potential will undergo urine (prior to the first 
dose of study drug) and serum pregnancy tests during Screening Visit 1 followed by a 
confirmatory urine pregnancy test at Study Week 1.  Serum pregnancy tests will be 
administered at all other scheduled visits. 
• A 6-Minute Walk Test (6MWT) will be conducted during Screening Visit 1 and Study 
Weeks 1, 6, 12, 14, 19, & 25 or ET in the Original Crossover Design, or if applicable, 
Screening Visit 1 and Study Weeks 1, 6, & 12 or ET in the Contingent Parallel Design. 
• Borg dyspnea score assessment will be conducted immediately after each 6MWT. 
• Pulse oximetry will be conducted continuously prior to, during, and following each 
6MWT. 
• Blood for NT-proBNP and clinical laboratory assessments will be obtained during 
Screening Visits 1 and 2 and Study Weeks 1, 6, 12, 14, 19, & 25 or ET in the Original 
Crossover Design, or if applicable, Screening Visits 1 and 2 and at Study Weeks 1, 6, 
& 12 or ET in the Contingent Parallel Design. 
• PFTs will be conducted during Screening Visit 1 and Study Weeks 1, 6, 12, 14, 19, & 
25 or ET in the Original Crossover Design, or if applicable, Screening Visit 1 and 
Study Weeks 1, 6, & 12 or ET in the Contingent Parallel Design. 
• Physical activity as measured by actigraphy will be assessed continuously from the time 
of low dose inhaled treprostinil initiation through the end of the study with the exception 
of certain activities of daily living (eg, bathing) or when the actigraph is being charged. 
• FEV1 and FVC data as measured by spirometry will be assessed at Study Weeks 1, 6, 
12, 14, 19, & 25 or ET in the Original Crossover Design, or if applicable, Study 


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Weeks 1, 6, & 12 or ET in the Contingent Parallel Design.  Spirometry should be 
performed by the subject at home during the allowable window for each study visit. 
• QOL assessments: SGRQ and UCSD SOBQ will be completed at Study Weeks 1, 6, 12, 
14, 19, & 25 or ET in the Original Crossover Design, or if applicable, Study Weeks 1, 
6, & 12 or ET in the Contingent Parallel Design.  Training on at-home completion of 
these QOL assessments will be done after randomization. 
• PGA will be completed on the Sponsor-provided smart device at Study Weeks 1, 6, 12, 
14, 19, & 25 or ET in the Original Crossover Design, or if applicable, Study Weeks 1, 
6, & 12 or ET in the Contingent Parallel Design.  Training on at-home completion of 
the PGA will be done as appropriate. 
• An ECG will be conducted during Screening Visit 1 and Study Weeks 1, 6, 12, 14, 19, 
& 25 or ET in the Original Crossover Design, or if applicable, Screening Visit 1 and 
Study Weeks 1, 6, & 12 or ET in the Contingent Parallel Design. 
• 
 
 
 
 
 
• 
 
 
 
• 
 
 
Statistical Considerations: This study is an adaptive study initiated as a crossover study (the 
Original Crossover Design).  However, due to the uncertainty of clinical benefit with inhaled 
treprostinil exposure in PH-COPD subjects and the ongoing COVID-19 pandemic, there is a 
possibility of treatment discontinuations and/or missing data due to COVID-19 impeding 
onsite visits, which may render estimates for efficacy outcomes inefficient or biased, thus an 
automatic switch to the Contingent Parallel Design or use of an alternative primary endpoint 
has been incorporated in this protocol.  The protocol specifies the algorithm to seamlessly 
transition to a parallel-group design (Contingent Parallel Design) if the degree of missing 
data subsequent to subject treatment crossover is not tolerable for primary analysis.  Similarly, 
this protocol specifies that the primary endpoint may be modified if the COVID-19 pandemic 
prevents onsite visits and data collection for the intended 6MWD primary endpoint data.  
Evaluations of missing data will be performed in a blinded fashion at the conclusion of the 
study, irrespective of actual efficacy outcomes and any information regarding efficacy 
outcomes prior to crossover and, as such, will not impact the Type I error rate. 
Original Crossover Design: a 2x2 crossover design will have 90% power to detect a 
placebo-corrected mean change from baseline difference of 30 meters, assuming that the 
standard deviation of differences is 85 meters and using a 2-group t-test with a 0.01 two-sided 
significance level with a sample size of 124 subjects (62 in each sequence group).  To account 


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for a discontinuation rate of approximately 10%, the total sample size will be approximately 
136 subjects. 
Contingent Parallel Design: a parallel-group study designed to use an allocation ratio of 1:1 
between inhaled treprostinil and placebo, a sample size of 266 subjects (133 per treatment) 
that 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.  To account for a discontinuation rate of 
approximately 15%, the total sample size will be approximately 314 subjects. 
Sponsor: 
United Therapeutics Corp. 
 
 
 
Study 
Conducted 
by: 
Lung Biotechnology PBC 
 


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LIST OF ABBREVIATIONS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
BP 
Blood pressure 
COPD 
Chronic obstructive pulmonary disease 
CT 
Computed tomography 
DLCO 
Diffusion capacity for carbon monoxide 
DNA 
Deoxyribonucleic acid 
DSMC 
Data Safety Monitoring Committee 
DSP 
Distance saturation product 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
ERA 
Endothelin receptor antagonist 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LVEDP 
Left ventricular end-diastolic pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MVPA 
Moderate to vigorous physical activity 
NT-proBNP 
N-Terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
PAH 
Pulmonary arterial hypertension 
PAPm 
Pulmonary artery pressure mean 
PAWP 
Pulmonary artery wedge pressure 
PDE5-I 
Phosphodiesterase type 5 inhibitor 


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PE 
Physical examination 
PFT 
Pulmonary function test 
PGA 
Patient global assessment 
PH 
Pulmonary hypertension 
PH-COPD 
Pulmonary hypertension due to chronic obstructive pulmonary disease 
PVR 
Pulmonary vascular resistance 
QID 
4 times daily 
QOL 
Quality of life 
QRS 
Electrocardiographic wave 
RHC 
Right heart catheterization 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sGC 
Soluble guanylate cyclase 
SGRQ 
St. George’s Respiratory Questionnaire 
SpO2 
Saturation peripheral capillary oxygenation 
TLC 
Total lung capacity 
UCSD SOBQ 
University of California San Diego Shortness of Breath Questionnaire 
US 
United States 
UTC 
United Therapeutics Corporation 
V/Q 
Ventilation/perfusion 
WHO 
World Health Organization 
 


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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ............................................................................................3 
PROTOCOL SYNOPSIS ..............................................................................................................4 
LIST OF ABBREVIATIONS .....................................................................................................13 
TABLE OF CONTENTS ............................................................................................................15 
Table of In-Text Tables ...............................................................................................................18 
1 BACKGROUND AND RATIONALE .................................................................................19 
1.1 
DEFINITION OF CLINICAL PROBLEM ....................................................................19 
1.2 
INHALED TREPROSTINIL BACKGROUND ............................................................19 
1.2.1 
General Pharmacology ................................................................................................19 
1.2.2 
General Toxicology ......................................................................................................20 
1.2.3 
Clinical Experience ......................................................................................................21 
1.3 
RATIONALE FOR DEVELOPMENT OF INHALED TREPROSTINIL IN 
DISEASE/CONDITION ...................................................................................................22 
1.4 
CLINICAL HYPOTHESIS ..............................................................................................22 
2 OBJECTIVES ........................................................................................................................24 
2.1 
PRIMARY OBJECTIVE .................................................................................................24 
2.2 
SECONDARY OBJECTIVES .........................................................................................24 
2.3 
SAFETY OBJECTIVES ...................................................................................................24 
2.4 
EXPLORATORY OBJECTIVES ...................................................................................24 
3 EXPERIMENTAL PLAN .....................................................................................................25 
3.1 
STUDY DESIGN ...............................................................................................................25 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ...................................................29 
3.2.1 
Original Crossover Design Schedule of Times and Events ......................................29 
3.2.2 
Contingent Parallel Design (if Applicable) Schedule of Times and Events ............33 
3.3 
CLINICAL ASSESSMENTS ...........................................................................................37 
3.3.1 
Efficacy ..........................................................................................................................37 
3.3.1.1 
St. George's Respiratory Questionnaire and the University of California 
San Diego Shortness of Breath Questionnaire .......................................................37 
3.3.1.2 
Patient Global Assessment (PGA) ...........................................................................38 
3.3.1.3 
N-Terminal Pro-brain Natriuretic Peptide ............................................................38 
3.3.1.4 
6-Minute Walk Test ..................................................................................................38 
3.3.1.5 
Borg Dyspnea Score ..................................................................................................39 
3.3.1.6 
Actigraphy .................................................................................................................39 
3.3.2 
Safety .............................................................................................................................40 
3.3.2.1 
Medical History and Demographics ........................................................................40 
3.3.2.2 
Physical Examinations..............................................................................................40 
3.3.2.3 
Vital Signs ..................................................................................................................41 
3.3.2.4 
12-Lead Electrocardiogram .....................................................................................41 
3.3.2.5 
Clinical Laboratory Assessments ............................................................................41 


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3.3.2.6 
Pulmonary Function Tests .......................................................................................43 
3.3.2.7 
At-home Spirometry .................................................................................................43 
3.3.2.8 
Computed Tomography Imaging (Required) ........................................................44 
3.3.2.9 
Oxygenation - Pulse Oximetry .................................................................................44 
3.3.2.10 
Adverse Events ..........................................................................................................45 
3.3.2.11 
Concomitant Medications ........................................................................................45 
3.3.2.12 
Weekly Telephone Contact ......................................................................................46 
3.3.2.13 
Telemedicine Visits ...................................................................................................46 
3.3.3 
Optional Substudies .....................................................................................................46 
3.3.3.1 
 ...................................................................................................46 
3.3.3.2 
 ..................................................................................................47 
3.3.3.3 
 .........................................................47 
3.4 
NUMBER OF SITES ........................................................................................................48 
3.5 
NUMBER OF SUBJECTS ...............................................................................................48 
3.6 
ESTIMATED STUDY DURATION ...............................................................................48 
4 SUBJECT ELIGIBILITY .....................................................................................................49 
4.1 
INCLUSION CRITERIA .................................................................................................49 
4.2 
EXCLUSION CRITERIA ................................................................................................50 
4.3 
PRESCRIBED THERAPY ..............................................................................................51 
5 SUBJECT ENROLLMENT ..................................................................................................52 
5.1 
TREATMENT ASSIGNMENT .......................................................................................52 
5.2 
RANDOMIZATION .........................................................................................................52 
5.3 
BLINDING ........................................................................................................................53 
6 DRUGS AND DOSING (OR TREATMENT PROCEDURES) ........................................53 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE ........................................53 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT ............................................54 
6.3 
COMPLIANCE .................................................................................................................55 
7 EXPERIMENTAL PROCEDURES ....................................................................................55 
7.1 
SCREENING PERIOD ....................................................................................................55 
7.1.1 
Screening Visit 1 (Study Weeks -9 to -3) ....................................................................55 
7.1.2 
Screening Visit 2 (Study Week -2) ..............................................................................56 
7.2 
WASHOUT PERIODS .....................................................................................................57 
7.2.1 
(Study Week -1 and Study Week 13) ..........................................................................57 
7.3 
TREATMENT PERIODS ................................................................................................57 
7.3.1 
Study Week 1 Visit (Baseline Visit) ............................................................................57 
7.3.2 
Study Weeks 6 and 19 Visits ........................................................................................58 
7.3.3 
Study Week 14 Visit .....................................................................................................59 
7.3.4 
Study Weeks 12 and 25 Visits ......................................................................................60 
7.4 
TELEMEDICINE VISITS ...............................................................................................61 
7.5 
EARLY TERMINATION VISIT ....................................................................................61 
7.6 
ACCESS TO OPEN-LABEL STUDY .............................................................................62 


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8 STUDY TERMINATION .....................................................................................................62 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ..............................................................62 
8.1.1 
Criteria for Withdrawal from Study Drug ................................................................62 
8.1.2 
Criteria for Subject Withdrawal from Study ............................................................63 
8.2 
CRITERIA FOR TERMINATING THE STUDY .........................................................63 
8.3 
CRITERIA FOR DISCONTINUING A SITE ...............................................................63 
9 ADVERSE EVENT REPORTING ......................................................................................64 
9.1 
DEFINITIONS ..................................................................................................................64 
9.1.1 
Adverse Event ...............................................................................................................64 
9.1.2 
Serious Adverse Event .................................................................................................64 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ............................................................65 
9.3 
FOLLOW UP OF ADVERSE EVENTS .........................................................................65 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ..............................65 
9.4.1 
Serious Adverse Event Reporting ...............................................................................65 
9.4.2 
Pregnancy Reporting ...................................................................................................66 
9.5 
SAFETY REPORTS .........................................................................................................66 
10 STATISTICAL CONSIDERATIONS .................................................................................66 
10.1 DATA PROCESSING ......................................................................................................67 
10.2 SAMPLE SIZE ..................................................................................................................67 
10.2.1 
Adaptive Design Procedures .......................................................................................69 
10.3 ANALYSIS PLAN .............................................................................................................70 
10.3.1 
Primary Efficacy Endpoint .........................................................................................71 
10.3.2 
Alternate Primary Efficacy Endpoint ........................................................................71 
10.3.3 
Secondary Efficacy Endpoint(s) ..................................................................................71 
10.3.4 
Safety Analyses .............................................................................................................72 
10.3.5 
Exploratory Analyses ...................................................................................................72 
10.4 INTERIM ANALYSIS .....................................................................................................73 
10.5 OTHER ANALYSES ........................................................................................................73 
10.6 DATA LISTINGS AND SUMMARIES ..........................................................................73 
10.7 DATA SAFETY MONITORING COMMITTEE .........................................................73 
11 PACKAGING AND FORMULATION ...............................................................................74 
11.1 STUDY SUPPLIES ...........................................................................................................74 
11.1.1 
Actigraphy, Spirometry, and Smart Devices .............................................................74 
11.2 CONTENTS OF STUDY DRUG .....................................................................................74 
11.2.1 
Study Drug (Active and Placebo) ................................................................................74 
11.2.2 
Study Inhalation Device ...............................................................................................75 
11.3 LABELING ........................................................................................................................75 
11.3.1 
Study Drug (Active and Placebo) ................................................................................75 
11.3.2 
Study Inhalation Device ...............................................................................................75 
11.4 STORAGE AND HANDLING OF STUDY DRUG .......................................................75 
11.5 SUPPLY AND RETURN OF STUDY DRUG AND DEVICES ...................................76 


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11.6 DRUG AND DEVICE ACCOUNTABILITY .................................................................76 
12 REGULATORY AND ETHICAL OBLIGATION.............................................................77 
12.1 US FDA OR APPLICABLE REGULATORY REQUIREMENTS .............................77 
12.2 INFORMED CONSENT REQUIREMENTS ................................................................77 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ..............................................................................................................................77 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ...............................................78 
12.5 SUBJECT CONFIDENTIALITY....................................................................................78 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS .......................................................79 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .................................79 
13.2 STUDY DOCUMENTATION AND STORAGE ...........................................................79 
13.3 STUDY MONITORING AND DATA COLLECTION ................................................79 
13.4 QUALITY ASSURANCE .................................................................................................80 
14 REFERENCES .......................................................................................................................81 
15 APPENDICES ........................................................................................................................84 
15.1 PROCEDURE FOR 6-MINUTE WALK TEST ............................................................84 
15.2 MODIFIED BORG DYSPNEA SCALE .........................................................................86 
15.3 ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (EXAMPLE) ........................87 
15.4 UNIVERSITY OF CALIFORNIA SAN DIEGO SHORTNESS OF BREATH 
QUESTIONNAIRE (EXAMPLE) ...................................................................................93 
15.5 PATIENT GLOBAL ASSESSMENT (EXAMPLE) ......................................................96 
15.6 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS ......97 
 
Table of In-Text Tables 
Table 3-1 
Original Crossover Design Overall Schedule of Times and Events ......................29 
Table 3-2 
Contingent Parallel Design Overall Schedule of Times and Events ......................33 
Table 3-3 
Clinical Chemistry and Hematology Parameters ...................................................42 
Table 6-1 
Sample Inhaled Treprostinil Dose Escalation Table ..............................................54 
 


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1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
Pulmonary hypertension (PH) is defined as an elevation in pulmonary arterial pressure and 
pulmonary vascular resistance (PVR).  The World Health Organization (WHO) classifies PH due 
to lung diseases and/or hypoxemia as WHO Group 3 PH (Simonneau 2019).  This classification 
includes PH due to chronic obstructive pulmonary disease (PH-COPD). 
Chronic obstructive pulmonary disease (COPD) is the most common parenchymal lung disease 
associated with WHO Group 3 PH (Simonneau 2013, Shino 2013).  Reports on the prevalence of 
PH in COPD are variable (ranging from 30% to 70% with a pulmonary artery pressure mean 
[PAPm] >20 mmHg) depending on the definition of PH and severity of COPD (Minai 2010).  
The proportion of patients having COPD with severe PH (PAPm ≥35 mmHg) was reported at 
13.5% (Thabut 2005) and 5.8% (Chaouat 2005).  The survival rate at 5 years in COPD patients 
with PH (PAPm >25 mmHg) ranges from 20% to 36% compared with 62% to 66% in COPD 
patients with normal PAPm (Burger 2009, Chaouat 2005, Oswald-Mammosser 1995). 
Potential mechanisms for PH-COPD include vasoconstriction secondary to hypoxia in the 
pulmonary vasculature, smooth muscle proliferation and vascular remodeling resulting in 
narrowing of the vascular lumen, and reduction in the total number of pulmonary vessels 
(Chaouat 2008).  Pulmonary hypertension typically appears with severe airflow limitation and is 
associated with hypoxemia.  Pulmonary hypertension due to COPD is most commonly mild to 
moderate in severity (PAPm 25 to 35 mmHg) (McLaughlin 2009, Klinger 2016, Seeger 2013).  
A small subset of patients with COPD develop severe PH (PAPm >35 mmHg) despite absence of 
major airflow limitation (Chaouat 2008, Weitzenblum 2009, Zakynthinos 2011).  A PAPm 
>35 mmHg in patients with COPD is associated with rapid deterioration and increased mortality 
(Zakynthinos 2011). 
1.2 
INHALED TREPROSTINIL BACKGROUND 
1.2.1 
General Pharmacology 
Treprostinil, 2-[[(1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-
hydroxyoctyl]-1Hbenz[f]inden-5-yl]oxy]acetic acid, is a chemically stable tricyclic analogue of 
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The pharmacology of treprostinil is well-characterized and approved for the treatment of 
pulmonary arterial hypertension (PAH) following either the subcutaneous, intravenous, 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 induces concentration dependent relaxation of rabbit isolated 
pre-contracted mesenteric arteries and inhibits 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 (US), 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 
General Toxicology 
A well-defined clinical safety profile exists for treprostinil sodium; acute toxicity studies, 
repeat-dose toxicity studies, reproductive toxicity studies, and genotoxicity studies have been 
performed in both rats and dogs and support the chronic administration to patients (Remodulin® 
Package Insert 2014).  The toxicokinetic profile of treprostinil was also evaluated in acute and 
repeat-dose toxicity studies of up to 13 weeks in duration in rodents and dogs, which supported 
the chronic administration of inhaled treprostinil to patients.  In addition, a 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 maintenance dose of 54 mcg.  Refer to the Inhaled Treprostinil Investigator’s Brochure for 
a full description of nonclinical data. 


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1.2.3 
Clinical Experience 
A series of acute and chronic investigator-initiated clinical studies were conducted with inhaled 
treprostinil to optimize the formulation for inhalation; determine dose response, tolerability, and 
safety; and 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 3 study (TRIUMPH-I) was conducted to 
assess the safety and efficacy of inhaled treprostinil in combination with approved PAH 
therapies.  Two hundred 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 12 breaths (6 to 
72 mcg) 4 times daily (QID) 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 was 
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. 


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These data support the durability of improvement in 6MWD obtained with inhaled treprostinil as 
demonstrated during the double-blind phase of the study.  Therapeutic benefit was also noted 
with improvements in the Borg dyspnea score, NYHA Functional Classification, and quality of 
life (QOL).  Survival was robust with 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 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 
RATIONALE FOR DEVELOPMENT OF INHALED TREPROSTINIL IN 
DISEASE/CONDITION 
Currently, there are no approved therapies for the treatment of PH-COPD.  Since this condition 
is associated with increased mortality compared to patients with COPD alone, PH management is 
vital for improving overall survival and decreasing associated PH-related symptoms 
(Klinger 2016). 
Pulmonary arterial hypertension (WHO Group 1 PH) has similar disease mechanisms to 
PH-COPD (ie, vasoconstriction, smooth muscle cell proliferation, vascular remodeling), which 
suggests that PAH-specific therapies, specifically vasodilators, may be valuable treatments for 
PH-COPD.  Approved therapies for PAH include endothelin receptor antagonists (ERAs), 
phosphodiesterase type 5 inhibitors (PDE5-Is), soluble guanylate cyclase (sGC) stimulators, 
prostacyclin receptor agonists, and prostacyclin analogs.  These therapies work to treat PAH 
through multiple mechanisms with vasodilation being a primary mode of action.  Preliminary 
evidence in several small PH-COPD studies of PAH-specific therapies supports this hypothesis 
and suggests that a systematic evaluation of this treatment strategy is warranted (Klinger 2016). 
1.4 
CLINICAL HYPOTHESIS 
There is unclear evidence for clinical benefit in PH-COPD with the use of oral vasodilators, such 
as ERAs, PDE5-Is, and sGC stimulators. 


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This may be attributed to worsening of the ventilation/perfusion (V/Q) ratio as a result of 
systemic vasodilation.  In PH-COPD, the presence of local hypoxia results in vasoconstriction, 
which helps to distribute the blood flow to better-ventilated portions of the lung and improves 
the V/Q ratio.  The administration of systemic vasodilators in the treatment of PH-COPD is 
thought to confound this mechanism, resulting in worsening gas exchange, despite reported 
improvements in hemodynamic parameters (Archer 1996, Blanco 2010, Stolz 2008).  In contrast, 
inhaled vasodilators are expected to directly target the more ventilated portion of the lungs in 
patients with PH-COPD, minimizing the risk of V/Q mismatch and allowing for improvements 
in exercise capacity (Seeger 2013). 
Inhaled treprostinil (Tyvaso) is approved and registered as an effective inhaled prostacyclin 
treatment for PAH with an acceptable safety profile.  Treprostinil is a stable tricyclic benzindene 
analogue of the naturally occurring prostacyclin, PGI2 (epoprostenol).  Prostacyclins are known 
to lower pulmonary artery pressure, increase cardiac output without affecting the 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.  Hence, the mechanism of action of treprostinil is theorized to be 
multifactorial, with the major pharmacological actions of treprostinil being direct vasodilation of 
pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. 
Several early phase studies have evaluated the use of inhaled prostacyclin analogs in patients 
with PH-COPD (Klinger 2016).  In small observational studies evaluating the administration of 
inhaled treprostinil in patients with PH-COPD, trends to improvement in 6MWD were noted, 
with other measures of blood gases showing inconsistent results (Malik 2013, Agarwal 2015, 
Anderson 2017, Bajwa 2017, Faria-Urbina 2018).  The reported improvements in exercise ability 
and preserved oxygenation seen in the above preliminary studies suggest that inhaled treprostinil 
can be well tolerated and potentially effective in the PH-COPD patient population. 


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2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to demonstrate the efficacy of inhaled treprostinil 
compared to placebo in improving exercise ability as measured by change from baseline in 
6MWD following 12 weeks of active treatment in subjects with PH-COPD. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are to assess the effect of inhaled treprostinil compared to 
placebo after 12 weeks of active treatment on the following: 
1. Change in moderate to vigorous physical activity (MVPA) as measured by actigraphy 
2. Change in overall activity as measured by actigraphy 
3. Change in Borg dyspnea score from baseline 
4. Change in 6MWD/Borg dyspnea composite score from baseline 
5. Change in QOL from baseline as measured by St. George’s Respiratory Questionnaire 
(SGRQ) and the University of California San Diego Shortness of Breath Questionnaire 
(UCSD SOBQ) 
6. Change in plasma concentration of N-Terminal pro-brain natriuretic peptide 
(NT-proBNP) from baseline 
7. Change in patient global assessment (PGA) 
2.3 
SAFETY OBJECTIVES 
The safety of inhaled treprostinil in comparison to placebo will be evaluated on the following: 
1. AEs 
2. Clinical laboratory assessments 
3. Electrocardiograms (ECGs) 
4. Physical examination (PE) findings 
5. Oxygenation 
6. PFTs 
7. Vital sign measurements 
8. At-home spirometry 
2.4 
EXPLORATORY OBJECTIVES 
 
 


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3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled, 34-week, crossover study 
with a Treatment Period of approximately 26 weeks under the Original Crossover Design or, if 
applicable, a 21-week parallel study with a Treatment Period of approximately 14 weeks under 
the Contingent Parallel Design.  All randomized subjects will be treated with active drug and 
placebo in the Original Crossover Design or, if applicable, active drug or placebo in the 
Contingent Parallel Design. 
Screening and randomization visits must occur onsite.  All attempts should be made to have 
onsite study visits thereafter.  With written Sponsor approval, subjects may have telemedicine 
visits in lieu of onsite visits after randomization, in both the Original Crossover Design and the 
Contingent Parallel Design, if the conduct of an onsite study visit poses a safety risk due to the 
COVID-19 pandemic.  See Section 7.4 for the telemedicine visit assessments. 
The study will consist of the following periods: 
Screening Period: During Screening Visit 1, prospective subjects (such as those having prior 
echocardiogram findings of right ventricular systolic pressure >40 mmHg and/or evidence of 
right ventricular hypertrophy or dysfunction) who sign the Informed Consent Form (ICF) will 
generally undergo all non-invasive screening assessments to evaluate eligibility as listed in the 
inclusion/exclusion criteria.  Potentially eligible subjects will undergo right heart catheterization 
(RHC), which should include a vasodilator test and oxygen challenge, if possible.  For sites 
seeking guidance on the RHC and oxygen/vasodilator challenge, information is offered as a 
guide in the Study Procedures Manual, which is provided separately. 


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If RHC results are available from a test performed within the previous 12 months (even if done 
without oxygen or vasodilator challenge), a repeat RHC during Screening Visit 1 is not needed. 
A window of up to 6 weeks is permitted to complete all assessments required for Screening 
Visit 1, including the start of low dose inhaled treprostinil.  Prospective subjects meeting all 
eligibility criteria will be provided with and trained on inhalation of study drug using the Tyvaso 
Inhalation System and begin low dose (3 breaths QID) inhaled treprostinil for a minimum of 
14 days (maximum of 18 days) to ensure tolerability and compliance.  Subjects will be issued 
Sponsor-provided actigraphy, spirometry, and smart devices during Screening Visit 1 at the time 
of low dose inhaled treprostinil initiation for measurement of at-home activity and forced 
expiratory volume in 1 second (FEV1)/forced vital capacity (FVC).  Subjects will be given 
training on the at-home use of these devices, as well as Instructions for Use.  At Screening 
Visit 2, subjects will return to the study site following completion of low dose inhaled 
treprostinil exposure to undergo scheduled assessments and return unused study drug.  Subjects 
who are intolerant of therapy (as determined by the Investigator), unable to follow the dosing 
regimen, or noncompliant with actigraphy, at-home spirometry, or smart device use during the 
Screening Period will be ineligible for randomization and deemed screen failures. 
Re-screening: Subjects may be re-screened.  The study-specific RHC performed during 
Screening Visit 1 is valid for up to 12 months and should not be repeated if a subject is 
re-screened unless written approval is first obtained from the Sponsor’s Medical Monitor. 
Original Crossover Design: 
Washout Period - Washout 1: During Washout 1 (Study Week -1), prospective subjects will 
refrain from the use of inhaled treprostinil for a minimum of 7 days (maximum of 14 days) 
preceding entry into the Treatment Period 1 Baseline Visit (Study Week 1).  Subjects will be 
contacted by telephone mid-week in Washout Period 1 to monitor safety. 
Treatment Period 1: Eligible subjects approved by the Sponsor’s Medical Monitor will undergo 
Treatment Period 1 Baseline Visit assessments (Study Week 1), be assigned to a treatment group 
based on the randomization schedule, and receive study drug.  Target dosing with study drug 
(after titration) will be 12 breaths QID or to maximum tolerated dose. 


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Two additional study visits to the study site will be conducted after the Treatment Period 1 
Baseline Visit to complete study assessments (Study Weeks 6 & 12).  Subjects will be contacted 
weekly by telephone during study drug titration (until 12 breaths QID or the maximum tolerated 
dose is achieved) and as needed thereafter to provide dosing instructions and to assess tolerance 
to study drug, AEs, and changes in concomitant medications. 
Washout Period - Washout 2: Subjects will refrain from the use of study drug for a minimum 
of 7 days (maximum of 14 days) after the Treatment Period 1 Week 12 Visit (Study Week 12) 
and preceding entry into Treatment Period 2 (Study Week 14).  Subjects will be contacted by 
telephone mid-week in Washout Period 2 to monitor safety. 
Treatment Period 2: Subjects will undergo Treatment Period 2 Baseline Visit assessments 
(Study Week 14), be provided treatment based on the randomization schedule, and receive study 
drug for this period.  Target dosing with study drug (after titration) will be 12 breaths QID or to 
the maximum tolerated dose.  Two additional study visits to the study site (Study Weeks 19 & 
25) will be conducted after the Treatment Period 2 Baseline Visit (Study Week 14) to complete 
study assessments.  Subjects will be contacted weekly by telephone during study drug titration 
(until 12 breaths QID or the maximum tolerated dose is achieved) and as needed thereafter to 
provide dosing instructions and to assess tolerance to study drug, AEs, and changes in 
concomitant medications.  At the completion of Treatment Period 2 (Study Week 25), subjects 
will be offered enrollment in the open-label extension study, RIN-PH-305.  If the Sponsor adapts 
the study to the Contingent Parallel Design, any subject in Treatment Period 2 at that time will 
be asked to return to the site for an Early Termination (ET) Visit and will be offered enrollment 
in the open-label extension study, RIN-PH-305. 
Contingent Parallel Design (If Applicable): 
Washout Period: During Washout (Study Week -1), prospective subjects will refrain from the 
use of inhaled treprostinil for a minimum of 7 days (maximum of 14 days) preceding entry into 
the Baseline Visit (Study Week 1).  Subjects will be contacted by telephone mid-week in the 
Washout Period to monitor safety. 


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Version Date 20 October 2020 
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Treatment Period: Eligible subjects that have undergone the previously described Screening 
Period and are approved by the Sponsor for enrollment will undergo Baseline Visit assessments 
(Study Week 1), be assigned to a treatment group based on the randomization schedule, and 
receive study drug.  Target dosing with study drug (after titration) will be 12 breaths QID or to 
the maximum tolerated dose.  Two additional study visits to the study site will be conducted after 
the Baseline Visit to complete study assessments (Study Weeks 6 & 12).  Subjects will be 
contacted weekly by telephone during study drug titration (until 12 breaths QID or the maximum 
tolerated dose is achieved) and as needed thereafter to provide dosing instructions and to assess 
tolerance to study drug, AEs, and changes in concomitant medications.  At the completion of the 
Treatment Period (Study Week 12), subjects will be offered enrollment in the open-label 
extension study, RIN-PH-305. 
Early Termination: An ET Visit will be conducted for subjects who end participation in the 
study prior to the completion of Treatment Period 2 (Study Week 25) in the Original Crossover 
Design or, if applicable, prior to the end of the Treatment Period (Study Week 12) in the 
Contingent Parallel Design.  All assessments planned for the applicable final study visits will 
be conducted during the ET Visit. 
 
 
 
 


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Lung Biotechnology PBC 
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Version Date 20 October 2020 
CONFIDENTIAL 
Page 29 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
3.2.1 
Original Crossover Design Schedule of Times and Events 
Table 3-1 
Original Crossover Design Overall Schedule of Times and Events 
Study Proceduresa 
Screening Perioda 
Washout 
Perioda 
Treatment Period 1 
Washout 
Perioda 
Treatment Period 2 
 
Screening 
Visit 1 
Screening 
Visit 2 
Washout 1 Baseline 
Visit 
Week 6 
Visit 
Week 12 
Visit 
Washout 2 Baseline 
Visit 
Week 19 
Visit 
Week 25 
Visit 
Early 
Termination 
Study Week 
-9 to -3 
-2 
-1  
1 
6 
12 
13 
14 
19 
25 
N/A 
Study Day 
-63 to -22  -8 (or -4) 
-7 to -1a 
1 
42±3 
84±3 
85 to 91a 
92±3 
133±3 
175±3 
N/A 
Site Visit 
X 
X 
N/A 
X 
X 
X 
N/A 
X 
X 
X 
X 
Informed Consent 
Xu 
 
 
 
 
 
 
 
 
 
 
Demographics 
Xu 
 
 
 
 
 
 
 
 
 
 
Medical History 
Xu 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationv,x 
Xu 
X 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
Vital Signsb,v,x 
Xu 
X 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
12-Lead ECGb,v,x 
Xu 
 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
Clinical Laboratory 
Assessmentsx 
Xu 
X 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
NT-proBNPc,x 
Xu 
X 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
Pregnancy Testd,x 
Xu 
 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
6MWTe,x 
Xu 
 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
Actigraphyw 
X 
X 
X 
X 
X 
X 
X 
Xu 
X 
X 
X 
Pulse Oximetryf,x 
Xu 
 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
Borg Dyspnea 
Scoreg,x 
Xu 
 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
PFTsh,x 
Xu 
 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
At-home spirometryy 
X 
X 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
CT Scani 
Xu 
 
 
 
 
 
 
 
 
 
 


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Version Date 20 October 2020 
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Study Proceduresa 
Screening Perioda 
Washout 
Perioda 
Treatment Period 1 
Washout 
Perioda 
Treatment Period 2 
 
Screening 
Visit 1 
Screening 
Visit 2 
Washout 1 Baseline 
Visit 
Week 6 
Visit 
Week 12 
Visit 
Washout 2 Baseline 
Visit 
Week 19 
Visit 
Week 25 
Visit 
Early 
Termination 
Study Week 
-9 to -3 
-2 
-1  
1 
6 
12 
13 
14 
19 
25 
N/A 
Study Day 
-63 to -22  -8 (or -4) 
-7 to -1a 
1 
42±3 
84±3 
85 to 91a 
92±3 
133±3 
175±3 
N/A 
Site Visit 
X 
X 
N/A 
X 
X 
X 
N/A 
X 
X 
X 
X 
RHCj 
Xu 
 
 
 
 
 
 
 
 
 
 
Study Drug and 
Dosing Instructions  
X 
 
 
X 
X 
 
 
X 
X 
 
 
Drug Administration 
at Site 
Xk 
 
 
Xx 
Xx 
Xx 
 
Xx 
Xx 
Xx 
 
Device Trainingk 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medicationsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weekly Contactn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
QOLo 
 
 
 
Xu 
X 
X 
 
Xu 
X 
X 
X 
PGAz 
 
 
 
X 
X 
X 
 
Xu 
X 
X 
X 
Subject Eligibility 
Xu 
X 
 
Xu 
 
 
 
 
 
 
 
Pre-Baseline Review 
Formp 
 
X 
 
 
 
 
 
 
 
 
 
Randomizationq 
 
 
 
X 
 
 
 
 
 
 
 
Drug/Device 
Accountabilityx 
 
X 
 
 
X 
X 
 
 
X 
X 
X 


United Therapeutics Corp. 
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Lung Biotechnology PBC 
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Version Date 20 October 2020 
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Page 31 
Study Proceduresa 
Screening Perioda 
Washout 
Perioda 
Treatment Period 1 
Washout 
Perioda 
Treatment Period 2 
 
Screening 
Visit 1 
Screening 
Visit 2 
Washout 1 Baseline 
Visit 
Week 6 
Visit 
Week 12 
Visit 
Washout 2 Baseline 
Visit 
Week 19 
Visit 
Week 25 
Visit 
Early 
Termination 
Study Week 
-9 to -3 
-2 
-1  
1 
6 
12 
13 
14 
19 
25 
N/A 
Study Day 
-63 to -22  -8 (or -4) 
-7 to -1a 
1 
42±3 
84±3 
85 to 91a 
92±3 
133±3 
175±3 
N/A 
Site Visit 
X 
X 
N/A 
X 
X 
X 
N/A 
X 
X 
X 
X 
6MWT, 6-Minute Walk Test; AE, adverse event; CT, computed tomography; DLCO, diffusion capacity for carbon monoxide; DNA, deoxyribonucleic acid; ECG, electrocardiogram; eCRF, 
electronic Case Report Form; ET, early termination; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, heart rate; N/A, not applicable; NT-proBNP, N-Terminal 
pro-brain natriuretic peptide; PFT, pulmonary function test; PGA, patient global assessment; QOL, quality of life; RHC, right heart catheterization; RNA, ribonucleic acid; SAE, serious 
adverse event; SGRQ, St. George’s Respiratory Questionnaire; SpO2, saturation peripheral capillary oxygenation; TLC, total lung capacity; UCSD SOBQ, University of California San 
Diego Shortness of Breath Questionnaire  
a  Sites may schedule non-invasive screening assessments, RHC, and study drug start on different days to facilitate scheduling.  However, study drug exposure in the Screening Period must 
be for a minimum of 14 days (maximum of 18 days) and washout must be for a minimum of 7 days (maximum 14 days).  If deemed necessary, per the clinical judgement of the site staff 
or Investigator, subjects may be asked to return to the study site for an unscheduled visit to assess their status.  This visit may require blood draws, vital signs, and/or review of 
concomitant medications.  Any assessments performed at an unscheduled visit should be recorded in the source documents and reported in the appropriate eCRF pages. 
b  Vital signs and ECG must be performed after a 5-minute period of rest (seated rest for vital signs).  No other procedures should be conducted during the rest period.  When possible, vital 
signs should be collected prior to the 6MWT.  Height will be measured and recorded only during Screening Visit 1. 
c  Blood for the NT-proBNP assessment must be drawn prior to conducting the 6MWT and dosing of study drug during Screening Visit 1 and Study Weeks 1 & 14 in the Original 
Crossover Design or during Screening Visit 1 and Study Week 1 in the Contingent Parallel Design. 
d For females of childbearing potential.  Urine (prior to the first dose of study drug) and serum pregnancy tests at Screening Visit 1 and a urine pregnancy test at Study Week 1.  Serum 
pregnancy tests will be performed at all other scheduled visits. 
e  The Screening Visit 1 6MWTs must precede open-label treprostinil dosing.  The 6MWT at Study Week 1 must be performed after randomization, but before administration of study drug, 
and the 6MWT at Study Week 14 must be performed before administration of study drug.  All other post-randomization 6MWTs will be performed between 10 and 60 minutes after study 
drug has been administered at the study site.  Prior to the start of each 6MWT, the subject should rest (seated) for at least 10 minutes.  Subjects receiving supplemental oxygen during any 
pre-randomization 6MWT must continue to receive the same flow rate at all subsequent 6MWT assessments.  The supplemental oxygen flow rate must be recorded at each study visit, as 
applicable.  If the site or subject has implemented protective measures against COVID-19, all subsequent 6MWT assessments should be made in a generally consistent manner. 
f  Pulse oximetry to be performed continuously prior to, during, and following each 6MWT.  Pulse oximetry will include the measurement of SpO2 and HR.  The SpO2 and HR obtained 
immediately prior to and immediately following completion of the 6MWT will be recorded in the source documents and eCRF.  The lowest recorded SpO2 obtained during each 6MWT 
(and associated HR) will be recorded in the source documents and eCRF. 
g  See Appendix 15.2.  The subject should be asked to rate their maximal breathlessness during the 6MWT. 
h PFTs will include the evaluation of FEV1, FVC, TLC, and DLCO.  TLC and DLCO will be assessed only when clinically feasible.  PFTs should be conducted either before the 6MWT or 
after recovering from the 6MWT.  If the PFTs are done both pre-bronchodilator and post-bronchodilator administration, only the post-bronchodilator treatment values will be recorded. 
i  This CT scan is required for Exclusion Criterion #2.  A chest CT scan performed within 6 months prior to the start of Screening Visit 1 is acceptable and a repeat assessment is not 
required. 


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Version Date 20 October 2020 
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j  The RHC procedure details are provided in the Study Procedures Manual, but the RHC may be omitted if it was performed within 12 months of the start of Screening Visit 1, even if 
vasodilator test and/or oxygen challenge were not completed.  Results from a previous RHC should be added to source records and entered in the eCRF.  RHC parameters, including 
PAPm, PVR, and PAWP (or LVEDP), and if available, pressures with and without oxygen, and vasodilator response are to be recorded. 
k  If all study eligibility criteria are met, dosing instructions and device training will occur, followed by administration of study drug.  The subject must remain at the study site for 
observation at least 1 hour after the first dose of study drug is administered during Screening Visit 1. 
l  All AEs/SAEs will be documented from the time of informed consent until the time screen failure is documented, study completion, or ET.  All AEs/SAEs should be followed as outlined 
in Section 9.3. 
m  The amount of supplemental oxygen (L/min) required at rest will be assessed at all scheduled visits and recorded on the concomitant medication eCRF.  
n  At least weekly telephone contact is required during study drug titration (until 12 breaths QID or the maximum tolerated dose is achieved) and as needed thereafter.  Face-to-face 
interaction may replace the telephone contact on the weeks where onsite study visits occur, and the information can be obtained during the onsite visit.  During the Washout Periods, the 
telephone contact will occur mid-week between study visits.  A copy of the telephone contact sheets must be kept in the subject’s source documentation. 
o  After randomization, site staff will provide subjects paper copies of the QOL questionnaires and training on at-home completion, in the event telemedicine visits are needed thereafter.  
Site staff should only use the paper copies of the questionnaires provided by the Sponsor.  The SGRQ and UCSD SOBQ QOL assessments that are completed by the subject at home will 
be returned to the site as instructed by the site staff. 
p  Sites should complete the Pre-Baseline Review Form, confirm tolerability and compliance of study drug during the Screening Period, and request the Sponsor’s Medical Monitor to 
review subject eligibility and allow randomization.  Subject randomization will not be possible until the Pre-Baseline Review Form (and supporting documentation) is complete and the 
Sponsor’s Medical Monitor approves the subject. 
q  Once all entry criteria have been met and the randomized treatment assigned, the first dose of study drug (3 breaths) will be inhaled at the study site. 
u  This assessment to be performed before study drug is administered.  
v  Any clinically significant changes from Screening Visit 1 should be reported as AEs. 
w Subjects will be issued a Sponsor-provided actigraph (activity monitor) during Screening Visit 1 at the time of low dose inhaled treprostinil initiation to measure daily at-home physical 
activity.  Subjects will be required to wear the device continuously from this visit through the end of the study, with the exception of certain activities of daily living (eg, bathing) or when 
the actigraph is being charged.  Subjects will be given specific instructions on how to perform actigraphy, in addition to a copy of the Instructions for Use.  Assessment of proper use and 
data capture should be performed by the site staff at all scheduled visits. 
x    Applicable only if an onsite study visit. 
y Subjects will be issued a Sponsor-provided spirometry device during Screening Visit 1 at the time of low dose inhaled treprostinil initiation for at-home capture of FEV1 and FVC data.  
Subjects will be given specific instructions on how to perform the spirometry assessment, in addition to a copy of the Instructions for Use.  Subjects will be asked to perform the 
spirometry assessment at home during the allowable window for each study visit.  Subjects are encouraged to complete the activity ahead of their scheduled visit.  If spirometry is not 
performed prior to a visit, the subject should perform the spirometry assessment during the visit.  Assessment of proper use and data capture should be performed by the site staff at all 
scheduled visits. 
z Subjects will use the Sponsor-provided smart device for at-home capture of PGA data at Study Weeks 1, 6, 12, 14, 19, & 25 or ET in the Original Crossover Design, or if applicable, 
Study Weeks 1, 6, & 12 or ET in the Contingent Parallel Design.  Subjects will be asked to perform the PGA at the same time as the at-home spirometry assessment at all applicable 
visits.  Subjects are encouraged to complete the activity ahead of their scheduled visit.  If the PGA is not performed prior to a visit, the subject should perform the PGA during the visit.  
Assessment of proper use and data capture should be performed by the site staff at all applicable visits. 


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Lung Biotechnology PBC 
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Version Date 20 October 2020 
CONFIDENTIAL 
Page 33 
3.2.2 
Contingent Parallel Design (if Applicable) Schedule of Times and Events 
Table 3-2 
Contingent Parallel Design Overall Schedule of Times and Events 
Study Proceduresa 
Screening Perioda 
Washout 
Perioda 
Treatment Period  
 
Screening Visit 1 
Screening Visit 2 
Washout  
Baseline Visit 
Week 6 
Visit 
Week 12 
Visit 
Early Termination 
Study Week 
-9 to -3 
-2 
-1  
1 
6 
12 
N/A 
Study Day 
-63 to -22  
-8 (or -4) 
-7 to -1 
1 
42±3 
84±3 
N/A 
Site Visit 
X 
X 
N/A 
X 
X 
X 
X 
Informed Consent 
Xu 
 
 
 
 
 
 
Demographics 
Xu 
 
 
 
 
 
 
Medical History 
Xu 
 
 
 
 
 
 
Physical Examinationv,x 
Xu 
X 
 
Xu 
X 
X 
X 
Vital Signsb,v,x 
Xu 
X 
 
Xu 
X 
X 
X 
12-Lead ECGb,v,x 
Xu 
 
 
Xu 
X 
X 
X 
Clinical Laboratory Assessmentsx 
Xu 
X 
 
Xu 
X 
X 
X 
NT-proBNPc,x 
Xu 
X 
 
Xu 
X 
X 
X 
Pregnancy Testd,x 
Xu 
 
 
Xu 
X 
X 
X 
6MWTe,x 
Xu 
 
 
Xu 
X 
X 
X 
Actigraphyw 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetryf,x 
Xu 
 
 
Xu 
X 
X 
X 
Borg Dyspnea Scoreg,x 
Xu 
 
 
Xu 
X 
X 
X 
PFTsh,x 
Xu 
 
 
Xu 
X 
X 
X 
At-home spirometryy 
X 
X 
 
Xu 
X 
X 
X 
CT Scani 
Xu 
 
 
 
 
 
 
RHCj 
Xu 
 
 
 
 
 
 
Study Drug and Dosing 
Instructions  
X 
 
 
X 
X 
 
 


United Therapeutics Corp. 
 RIN-PH-304 Protocol Amendment 4 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 20 October 2020 
CONFIDENTIAL 
Page 34 
Study Proceduresa 
Screening Perioda 
Washout 
Perioda 
Treatment Period  
 
Screening Visit 1 
Screening Visit 2 
Washout  
Baseline Visit 
Week 6 
Visit 
Week 12 
Visit 
Early Termination 
Study Week 
-9 to -3 
-2 
-1  
1 
6 
12 
N/A 
Study Day 
-63 to -22  
-8 (or -4) 
-7 to -1 
1 
42±3 
84±3 
N/A 
Site Visit 
X 
X 
N/A 
X 
X 
X 
X 
Drug Administration at Site 
Xk 
 
 
Xx 
Xx 
Xx 
 
Device Trainingk 
X 
 
 
 
 
 
 
Adverse Eventsl 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medicationsm 
X 
X 
X 
X 
X 
X 
X 
Weekly Contactn 
X 
X 
X 
X 
X 
X 
 
QOLo 
 
 
 
Xu 
X 
X 
X 
PGAz 
 
 
 
X 
X 
X 
X 
Subject Eligibility 
Xu 
X 
 
Xu 
 
 
 
Pre-Baseline Review Formp 
 
X 
 
 
 
 
 
Randomizationq 
 
 
 
X 
 
 
 
Drug/Device Accountabilityx 
 
X 
 
 
X 
X 
X 
6MWT, 6-Minute Walk Test; AE, adverse event; CT, computed tomography; DLCO, diffusion capacity for carbon monoxide; DNA, deoxyribonucleic acid; ECG, electrocardiogram; eCRF, 
electronic Case Report Form; ET, early termination; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, heart rate; N/A, not applicable; NT-proBNP, N-Terminal 
pro-brain natriuretic peptide; PFT, pulmonary function test; PGA, patient global assessment; QOL, quality of life; RHC, right heart catheterization; RNA, ribonucleic acid; SAE, serious 
adverse event; SGRQ, St. George’s Respiratory Questionnaire; SpO2, saturation peripheral capillary oxygenation; TLC, total lung capacity; UCSD SOBQ, University of California San 
Diego Shortness of Breath Questionnaire 
a  Sites may schedule non-invasive screening assessments, RHC, and study drug start on different days to facilitate scheduling.  However, study drug exposure in the Screening Period must 
be for a minimum of 14 days (maximum of 18 days) and washout must be for a minimum of 7 days (maximum 14 days).  If deemed necessary, per the clinical judgement of the site staff 
or Investigator, subjects may be asked to return to the study site for an unscheduled visit to assess their status.  This visit may require blood draws, vital signs, and/or review of 
concomitant medications.  Any assessments performed at an unscheduled visit should be recorded in the source documents and reported in the appropriate eCRF pages. 
b  Vital signs and ECG must be performed after a 5-minute period of rest (seated rest for vital signs).  No other procedures should be conducted during the rest period.  When possible, vital 
signs should be collected prior to the 6MWT.  Height will be measured and recorded only during Screening Visit 1. 


United Therapeutics Corp. 
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Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 20 October 2020 
CONFIDENTIAL 
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c Blood for the NT-proBNP assessment must be drawn prior to conducting the 6MWT and dosing of study drug during Screening Visit 1 and Study Weeks 1 & 14 in the Original 
Crossover Design or during Screening Visit 1 and Study Week 1 in the Contingent Parallel Design. 
d For females of childbearing potential.  Urine (prior to the first dose of study drug) and serum pregnancy tests at Screening Visit 1 and a urine pregnancy test at Study Week 1.  Serum 
pregnancy tests will be performed at all other scheduled visits. 
e  The Screening Visit 1 6MWTs must precede open-label treprostinil dosing.  The 6MWT at Study Week 1 must be performed after randomization, but before administration of study drug.  
All other post-randomization 6MWTs will be performed between 10 and 60 minutes after study drug has been administered at the study site.  Prior to the start of each 6MWT, the subject 
should rest (seated) for at least 10 minutes.  Subjects receiving supplemental oxygen during any pre-randomization 6MWT must continue to receive the same flow rate at all subsequent 
6MWT assessments.  The supplemental oxygen flow rate must be recorded at each study visit, as applicable.  If the site or subject has implemented protective measures against 
COVID-19, all subsequent 6MWT assessments should be made in a generally consistent manner. 
f  Pulse oximetry to be performed continuously prior to, during, and following each 6MWT.  Pulse oximetry will include the measurement of SpO2 and HR.  The SpO2 and HR obtained 
immediately prior to and immediately following completion of the 6MWT will be recorded in the source documents and eCRF.  The lowest recorded SpO2 obtained during each 6MWT 
(and associated HR) will be recorded in the source documents and eCRF. 
g  See Appendix 15.2.  The subject should be asked to rate their maximal breathlessness during the 6MWT. 
h  PFTs will include the evaluation of FEV1, FVC, TLC, and DLCO.  TLC and DLCO will be assessed only when clinically feasible.  PFTs should be conducted either before the 6MWT or 
after recovering from the 6MWT.  If the PFTs are done both pre-bronchodilator and post-bronchodilator administration, only the post-bronchodilator treatment values will be recorded. 
i  This CT scan is required for Exclusion Criterion #2.  A chest CT scan performed within 6 months prior to the start of Screening Visit 1 is acceptable and a repeat assessment is not 
required. 
j  The RHC procedure details are provided in the Study Procedures Manual, but the RHC may be omitted if it was performed within 12 months of the start of Screening Visit 1, even if 
vasodilator test and/or oxygen challenge were not completed.  Results from a previous RHC should be added to source records and entered in the eCRF.  RHC parameters, including 
PAPm, PVR, and PAWP (or LVEDP), and if available, pressures with and without oxygen, and vasodilator response are to be recorded. 
k  If all study eligibility criteria are met, dosing instructions and device training will occur, followed by administration of study drug.  The subject must remain at the study site for 
observation at least 1 hour after the first dose of study drug is administered during Screening Visit 1. 
l  All AEs/SAEs will be documented from the time of informed consent until the time screen failure is documented, study completion, or ET.  All AEs/SAEs should be followed as outlined 
in Section 9.3. 
m  The amount of supplemental oxygen (L/min) required at rest will be assessed at all scheduled visits and recorded on the concomitant medication eCRF. 
n  At least weekly telephone contact is required during study drug titration (until 12 breaths QID or the maximum tolerated dose is achieved) and as needed thereafter.  Face-to-face 
interaction may replace the telephone contact on the weeks where onsite study visits occur, and the information can be obtained during the onsite visit.  During the Washout Period, the 
telephone contact will occur mid-week between study visits.  A copy of the telephone contact sheets must be kept in the subject’s source documentation. 
o  After randomization, site staff will provide subjects paper copies of the QOL questionnaires and training on at-home completion, in the event telemedicine visits are needed thereafter.  
Site staff should only use the paper copies of the questionnaires provided by the Sponsor.  The SGRQ and UCSD SOBQ QOL assessments that are completed by the subject at home will 
be returned to the site as instructed by the site staff. 
p  Sites should complete the Pre-Baseline Review Form, confirm tolerability and compliance of study drug during the Screening Period, and request the Sponsor’s Medical Monitor to 
review subject eligibility and allow randomization.  Subject randomization will not be possible until the Pre-Baseline Review Form (and supporting documentation) is complete and the 
Sponsor’s Medical Monitor approves the subject. 
q  Once all entry criteria have been met and the randomized treatment assigned, the first dose of study drug (3 breaths) will be inhaled at the study site. 
u  This assessment to be performed before study drug is administered. 


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Lung Biotechnology PBC 
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Version Date 20 October 2020 
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v  Any clinically significant changes from Screening Visit 1 should be reported as AEs. 
w Subjects will be issued a Sponsor-provided actigraph (activity monitor) during Screening Visit 1 at the time of low dose inhaled treprostinil initiation to measure daily at-home physical 
activity.  Subjects will be required to wear the device continuously from this visit through the end of the study, with the exception of certain activities of daily living (eg, bathing) or when 
the actigraph is being charged.  Subjects will be given specific instructions on how to perform actigraphy, in addition to a copy of the Instructions for Use.  Assessment of proper use and 
data capture should be performed by the site staff at all scheduled visits. 
x  Applicable only if an onsite study visit. 
y Subjects will be issued a Sponsor-provided spirometry device during Screening Visit 1 at the time of low dose inhaled treprostinil initiation for at-home capture of FEV1 and FVC data.  
Subjects will be given specific instructions on how to perform the spirometry assessment, in addition to a copy of the Instructions for Use.  Subjects will be asked to perform the 
spirometry assessment at home during the allowable window for each study visit.  Subjects are encouraged to complete the activity ahead of their scheduled visit.  If spirometry is not 
performed prior to a visit, the subject should perform the spirometry assessment during the visit.  Assessment of proper use and data capture should be performed by the site staff at all 
scheduled visits. 
z 
 Subjects will use the Sponsor-provided smart device for at-home capture of PGA data at Study Weeks 1, 6, 12, 14, 19, & 25 or ET in the Original Crossover Design, or if applicable, 
Study Weeks 1, 6, & 12 or ET in the Contingent Parallel Design.  Subjects will be asked to perform the PGA at the same time as the at-home spirometry assessment at all applicable 
visits.  Subjects are encouraged to complete the activity ahead of their scheduled visit.  If the PGA is not performed prior to a visit, the subject should perform the PGA during the visit.  
Assessment of proper use and data capture should be performed by the site staff at all applicable visits. 
 


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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
The efficacy of inhaled treprostinil compared to placebo will be evaluated on the following 
parameters: change in 6MWD measured at peak exposure (defined as 10 to 60 minutes after 
dosing) after 12 weeks of treatment, change in MVPA as measured by actigraphy, change in 
overall activity as measured by actigraphy, change in Borg dyspnea score from baseline, change 
in 6MWD/Borg dyspnea composite score from baseline, change in QOL from baseline as 
measured by SGRQ and the UCSD SOBQ, change in plasma concentration of NT-proBNP from 
baseline, and change in PGA. 
3.3.1.1 
St. George's Respiratory Questionnaire and the University of California San 
Diego Shortness of Breath Questionnaire 
The SGRQ is designed to measure impact on overall health, daily life, and perceived wellbeing 
in subjects.  A copy of the SGRQ can be found in Appendix 15.3. 
The UCSD SOBQ is a 24-item dyspnea questionnaire that asks subjects to rate themselves from 
0 (none at all) to 5 (maximum or unable to do because of shortness of breath) in 2 areas, 1) how 
short of breath they are while performing various activities (21 items), and 2) how much 
shortness of breath limits them in their daily lives (3 items) (Eakin 1998).  Scores range from 
0 to 120, with higher scores indicating greater shortness of breath.  A copy of the UCSD SOBQ 
can be found in Appendix 15.4. 
Both questionnaires will be completed at Study Weeks 1, 6, 12, 14, 19, & 25 or ET in the 
Original Crossover Design, or if applicable, Study Weeks 1, 6, & 12 or ET in the Contingent 
Parallel Design. 
After randomization, site staff will provide subjects paper copies of the QOL questionnaires and 
training on at-home completion, in the event telemedicine visits are needed thereafter.  Site staff 
should only use the paper copies of the questionnaires provided by the Sponsor.  The SGRQ and 
UCSD SOBQ QOL assessments completed by the subject at home will be returned to the site as 
instructed by the site staff. 


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3.3.1.2 
Patient Global Assessment (PGA) 
The PGA is a being used to rate subject fatigue and shortness of breath.  Subjects will use the 
Sponsor-provided smart device for at-home capture of PGA data at Study Weeks 1, 6, 12, 14, 19, 
& 25 or ET in the Original Crossover Design, or if applicable, Study Weeks 1, 6, & 12 or ET in 
the Contingent Parallel Design.  Subjects will be asked to perform the PGA at the same time as 
the at-home spirometry assessment at all applicable visits.  Subjects are encouraged to complete 
the activity ahead of their scheduled visit.  If the PGA is not performed prior to a visit, the 
subject should perform the PGA during the visit.  Assessment of proper use and data capture 
should be performed by the site staff at all applicable visits.  A copy of the PGA can be found in 
Appendix 15.5. 
3.3.1.3 
N-Terminal Pro-brain Natriuretic Peptide 
NT-proBNP is a biomarker associated with changes in right heart morphology and function 
(Fijalkowska 2006).  Blood will be collected for assessment of NT-proBNP at all scheduled 
study visits.  Blood must be drawn prior to conducting the 6MWT and prior to study drug dosing 
during Screening Visit 1 and Study Weeks 1 & 14 in the Original Crossover Design, or if 
applicable, during Screening Visit 1 and Study Week 1 in the Contingent Parallel Design. 
In the event of Sponsor-approved telemedicine visits, NT-proBNP sample collection will not be 
performed. 
3.3.1.4 
6-Minute Walk Test 
The 6MWT is a validated and reliable measure of exercise ability 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 described 
in Appendix 15.1. 
Prior to the start of each 6MWT, the subject must rest (seated) for at least 10 minutes.  The 
6MWT must be performed prior to study drug dosing during Screening Visit 1 and Study Weeks 
1 & 14 in the Original Crossover Design or during Screening Visit 1 and Study Week 1 in the 
Contingent Parallel Design.  At all other visits, 6MWTs will be performed between 10 and 
60 minutes after study drug has been administered at the study site. 


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Pulse oximetry is to be performed continuously prior to, during, and following each scheduled 
6MWT, as outlined in Section 3.3.2.9. 
Similarly, if the site or subject has implemented protective measures against COVID-19 (eg, use 
of an alternative 6MWT testing area or use of personal protective equipment [mask, face shield, 
etc]) during the pre-randomization 6MWT, all subsequent 6MWT assessments should be made 
in a generally consistent manner. 
In the event of Sponsor-approved telemedicine visits, the 6MWT assessment will not be 
performed, but the subject will continue to wear an actigraph and maintain normal activity. 
3.3.1.4.1 
Supplemental Oxygen Use During the 6-Minute Walk Test 
Subjects receiving supplemental oxygen during the pre-randomization 6MWTs must continue to 
receive the same flow rate at all subsequent 6MWT assessments.  The supplemental oxygen flow 
rate must be recorded at each study visit, as applicable.  Supplemental oxygen therapy must not 
be introduced for subjects after randomization, unless there is an urgent medical need in the 
clinical judgement of the Investigator; however, if supplemental oxygen therapy is started 
post-randomization, the flow should be consistent for all subsequent tests. 
3.3.1.5 
Borg Dyspnea Score  
The Borg dyspnea score is a 0 to 10 scale rating of the level of dyspnea experienced during the 
6MWT and is administered immediately following the 6MWT.  Scores range from 0 (no 
shortness of breath) to 10 (maximal shortness of breath).  A copy of the Borg dyspnea scale can 
be found in Appendix 15.2. 
In the event of Sponsor-approved telemedicine visits, the Borg dyspnea score assessment will not 
be performed. 
3.3.1.6 
Actigraphy 
Subjects will be issued a Sponsor-provided actigraph (activity monitor) during Screening Visit 1 
at the time of low dose inhaled treprostinil initiation for measurement of daily at-home physical 
activity.  A variety of physical activity parameters, including overall activity, non-sedentary 
activity, and MVPA will be measured via this wrist-worn medical grade physical activity 
monitor.  The screening data will be used to establish a baseline level of physical activity.  


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Subjects will be asked to wear the actigraph continuously throughout the study with the 
exception of certain activities of daily living (eg, bathing) and when the device is being charged.  
Subjects will be given specific instructions on how to use the actigraph.  In addition, subjects 
will receive a copy of the Instructions for Use.  Assessment of proper use and data capture 
should be performed by the site staff at all scheduled visits. 
3.3.2 
Safety 
The safety of inhaled treprostinil compared to placebo will be evaluated on the following 
parameters: AEs, PE findings, vital sign measurements, ECGs, clinical laboratory assessments, 
PFTs, at-home spirometry, CT (required), concomitant medications, and oxygenation. 
3.3.2.1 
Medical History and Demographics 
A complete medical history (inclusive of PH-COPD) including demographics will be collected 
pre-dose during Screening Visit 1.  Any known changes to the medical history prior to 
randomization should be recorded in the subject source documents and in the electronic Case 
Report Form (eCRF).  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 also.  Any significant changes in the 
subject’s medical condition throughout the course of the study must also be documented in the 
subject’s source documents and in the eCRF. 
3.3.2.2 
Physical Examinations 
A complete PE will be conducted by appropriate study personnel (as documented on the 
Delegation of Authority Log) at all study visits.  Any clinically significant changes from 
Screening Visit 1 should be reported as AEs.  The physical examination must be performed prior 
to study drug dosing during Screening Visit 1 and at Study Weeks 1 & 14 in the Original 
Crossover Design or during Screening Visit 1 and at Study Week 1 in the Contingent Parallel 
Design.  Any significant changes in PE findings throughout the course of the study must be 
documented in the subject’s source documents and in the eCRF. 
In the event of Sponsor-approved telemedicine visits, the PE assessment will not be performed. 


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3.3.2.3 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure (BP), HR, respiratory rate (RR), and 
weight.  Height will be measured and recorded only during Screening Visit 1.  Vital signs will be 
assessed at all study visits after at least 5 minutes of rest (seated).  No other measurements or 
procedures should be performed during the rest period.  Vital signs must be assessed prior to 
dosing during Screening Visit 1 and at Study Week 1 & 14 in the Original Crossover Design or 
during Screening Visit 1 and at Study Week 1 in the Contingent Parallel Design.  When 
possible, vital signs should be collected prior to the 6MWT.  Any clinically significant changes 
from Screening Visit 1 should be reported as AEs. 
In the event of Sponsor-approved telemedicine visits, the vital sign assessment will not be 
performed. 
3.3.2.4 
12-Lead Electrocardiogram 
A 12-lead ECG will be recorded (following at least 5 minutes of rest) during Screening Visit 1 
and at study visits at Study Weeks 1, 6, 12, 14, 19, & 25 or ET in the Original Crossover 
Design, or if applicable, Screening Visit 1 and at study visits at Study Weeks 1, 6, & 12 or ET in 
the Contingent Parallel Design.  No other measurements or procedures should be performed 
during the rest period.  The ECG assessment must be performed prior to dosing during Screening 
Visit 1 and at Study Weeks 1 & 14 in the Original Crossover Design or during Screening 
Visit 1 and at Study Week 1 in the Contingent Parallel Design.  Recordings should include lead 
II as a rhythm strip and contain at least 5 electrocardiographic wave (QRS) complexes.  
Parameters to be collected include rhythm, HR, PR interval, QT interval, QRS duration, and any 
clinically significant abnormalities.  Any clinically significant changes from Screening Visit 1 
should be reported as AEs. 
In the event of Sponsor-approved telemedicine visits, the 12-lead ECG assessment will not be 
performed. 
3.3.2.5 
Clinical Laboratory Assessments 
Clinical laboratory assessments will be performed at all study visits.  Blood must be drawn prior 
to study drug dosing during Screening Visit 1 and at Study Weeks 1 & 14 in the Original 
Crossover Design or during Screening Visit 1 and at Study Week 1 in the Contingent Parallel 


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Design.  The results of all clinical laboratory tests performed during the Screening Period (prior 
to randomization) must be assessed by the Investigator to determine subject eligibility to 
participate prior to randomization and starting study drug. 
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 subject 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. 
In the event of Sponsor-approved telemedicine visits, the clinical laboratory assessments will not 
be performed. 
3.3.2.5.1 
Clinical Chemistry and Hematology 
Blood will be collected to assess for treatment-emergent changes in clinical chemistry and 
hematological laboratory parameters.  Table 3-3 provides the values to be obtained. 
Table 3-3 
Clinical Chemistry and Hematology Parameters 
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 
 
3.3.2.5.2 
Pregnancy Testing 
Females of childbearing potential will undergo urine (prior to the first dose of study drug) and 
serum pregnancy tests during Screening Visit 1, followed by a confirmatory urine pregnancy test 
at the Study Week 1 Visit (prior to randomization).  Serum pregnancy tests will be performed at 
Study Weeks 6, 12, 14, 19, & 25 or ET in the Original Crossover Design, or if applicable, 
during study visits at Study Weeks 6 & 12 or ET in the Contingent Parallel Design.   


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Pregnancy testing must be performed prior to study drug dosing during Screening Visit 1 and 
Study Weeks 1 & 14 in the Original Crossover Design, or during Screening Visit 1 and Study 
Week 1 in the Contingent Parallel Design.  A positive pregnancy test will result in subject 
withdrawal from study drug, but the subject will be encouraged to continue participation in the 
study and complete all study visits.  See Section 9.4.2 for information related to the reporting and 
following of pregnancies. 
In the event of Sponsor-approved telemedicine visits, serum pregnancy tests will not be 
performed. 
3.3.2.6 
Pulmonary Function Tests 
Pulmonary function testing will be performed during Screening Visit 1 and at Study Weeks 1, 6, 
12, 14, 19, & 25 or ET in the Original Crossover Design, or if applicable, at Study Weeks 1, 6, 
& 12 or ET in the Contingent Parallel Design.  Pulmonary function testing should be conducted 
either before the 6MWT or after recovery from the 6MWT at all study visits.  Pulmonary 
function testing should be conducted prior to study drug dosing during Screening Visit 1 and 
Study Weeks 1 & 14 in the Original Crossover Design or during Screening Visit 1 and Study 
Week 1 in the Contingent Parallel Design.  If the PFTs are done both pre-bronchodilator and 
post-bronchodilator administration, only the post-bronchodilator values will be recorded.  The 
following parameters will be recorded (absolute values and % predicted): FEV1, FVC, total lung 
capacity (TLC), and diffusion capacity for carbon monoxide (DLCO) uncorrected for 
hemoglobin and lung volume; TLC and DLCO will be assessed only when clinically feasible. 
In the event of Sponsor-approved telemedicine visits, PFTs will not be assessed. 
3.3.2.7 
At-home Spirometry 
Subjects will be issued a Sponsor-provided spirometry device during Screening Visit 1 at the 
time of low dose inhaled treprostinil initiation for at-home capture of FEV1 and FVC data.  
Subjects will be given specific instructions on how to perform the spirometry assessment.  In 
addition, subjects will receive a copy of the Instructions for Use.  Subjects will be asked to 
perform the spirometry assessment at home during the allowable window for each study visit.  
Subjects are encouraged to complete the activity ahead of their scheduled visit. 


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If spirometry is not performed prior to a visit, the subject should perform the spirometry 
assessment during the visit.  Assessment of proper use and data capture should be performed by 
the site staff at all scheduled visits. 
3.3.2.8 
Computed Tomography Imaging (Required) 
A CT scan should be performed prior to study drug dosing during Screening Visit 1 of the 
Original Crossover Design or during Screening Visit 1 in the Contingent Parallel Design to 
exclude disqualifying lung conditions, such as idiopathic pulmonary fibrosis, combined 
pulmonary fibrosis and emphysema, diffuse parenchymal lung disease, and interstitial lung 
disease.  A chest CT scan performed within 6 months prior to the start of Screening Visit 1 is 
acceptable for determining eligibility and a repeat scan is not required.  A redacted CT scan 
report (from Screening Visit 1 or dated within 6 months prior) supporting the exclusion criterion 
should be provided to the Sponsor’s Medical Monitor with the Pre-Baseline Review Form to 
confirm eligibility. 
3.3.2.9 
Oxygenation - Pulse Oximetry 
Oxygenation via pulse oximetry will be assessed continuously prior to, during, and following 
each scheduled 6MWT assessment.  Pulse oximetry will include the collection of saturation 
peripheral capillary oxygenation (SpO2) and HR.  The SpO2 and HR obtained immediately prior 
to and immediately following completion of the 6MWT will be recorded in the subject’s source 
documents and the eCRF.  In addition, the lowest recorded SpO2 (and associated HR) obtained 
during each 6MWT will be recorded in the subject’s source documents and the eCRF. 
A Sponsor-approved pulse oximeter model will be recommended and reimbursed by the 
Sponsor, if necessary, to maintain consistency and facilitate documentation of oxygen 
saturations.  In the event a 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, so long 
as the same device is used for all subsequent testing conducted for that subject.  This must be a 
recording oximeter that captures continuous HR and oxygenation data that can be downloaded 
and reviewed. 
In the event of Sponsor-approved telemedicine visits, the oxygenation assessment will not be 
performed. 


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3.3.2.10 
Adverse Events 
Adverse events will be recorded throughout the course of the study from the time each subject 
signs the ICF until the time a screen failure is documented, study completion (Study Week 25 in 
the Original Crossover Design, or Study Week 12 in the Contingent Parallel Design), or ET.  
Subjects will be questioned for AEs/SAEs at each scheduled study visit and during all telephone 
contacts, including the Washout Period(s).  Subjects will also be instructed to voluntarily report 
all AEs/SAEs throughout the study as warranted. 
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 SAEs should be followed until resolution, death, or the subject is lost to follow-up, even if 
they are ongoing more than 30 days after completion of the final study visit or ET. 
All AEs/SAEs that occur while the subject is in the study will be recorded as instructed in this 
protocol.  Section 9 and Appendix 15.6 provide definitions and guidelines for recording 
AEs/SAEs. 
3.3.2.11 
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 in the 
eCRF. 
3.3.2.11.1 
Supplemental Oxygen Use at Rest 
The amount of supplemental oxygen (L/min) required at rest will be assessed at all scheduled 
visits and recorded in the subject source documents and on the concomitant medication eCRF.  
Supplemental oxygen therapy should not be introduced after randomization, unless there is a 
medical need in the clinical judgement of the Investigator; however, if supplemental oxygen 
therapy is started post-randomization, the flow should be consistent for all subsequent tests 
where oxygen is required at rest. 


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3.3.2.12 
Weekly Telephone Contact 
Weekly telephone contact is required during study drug titration (in the Screening and Treatment 
Periods), the Washout Period(s), and as needed thereafter to provide dosing instructions and to 
assess tolerance to study drug, AEs, and changes in concomitant medications.  During the 
Washout Period(s), the telephone contact will occur mid-week between study visits. 
Subjects will also be directed to call the study site coordinator or Investigator at any time to 
discuss study-related issues of concern (AEs, symptoms, tolerability, device issues, etc).  
Face-to-face interaction may replace telephone contact on the weeks where onsite study visits 
occur and the information can be obtained during the onsite visit.  All telephone contact with 
subjects must be recorded in the subject’s source documents and captured in the eCRF. 
3.3.2.13 
Telemedicine Visits 
With written Sponsor approval, subjects may have telemedicine visits in lieu of onsite visits after 
randomization in both the Original Crossover Design and the Contingent Parallel Design, if 
the conduct of an onsite study visit poses a safety risk due to the COVID-19 pandemic.  The 
following assessments are to be completed during telemedicine visits: compliance with all 
study-related items (questionnaires, study drug, actigraphy, spirometry), AEs, and concomitant 
medications (see Section 7.4). 
3.3.3 
Optional Substudies 
 
 
 
 
 
 
 
 
 
  
  


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3.4 
NUMBER OF SITES 
Approximately 80 US and international sites that treat COPD subjects will be identified and 
recruited for this study in Original Crossover Design, or if applicable, approximately 100 US 
and international sites will be identified and recruited for this study in the Contingent Parallel 
Design. 
3.5 
NUMBER OF SUBJECTS 
The total sample size will be approximately 136 subjects in the Original Crossover Design, or if 
applicable, approximately 314 subjects in the Contingent Parallel Design. 
3.6 
ESTIMATED STUDY DURATION 
In the Original Crossover Design, subjects will undergo 26 weeks of treatment (over a 34-week 
period) as follows: at least 2 weeks of low dose (3 breaths QID) inhaled treprostinil treatment 
during the Screening Period (a minimum of 14 days and a maximum of 18 days if needed to 


U nite d T her a pe utics C or p.  
 RI N -P H -3 0 4 Pr ot oc ol A me n d me nt 4  
L u n g Bi otec h n ol o g y P B C  
I n h ale d Tre pr osti nil 
Versi o n D ate 2 0 Oct o ber 2 0 2 0  
C O N FI D E N TI A L  
P a ge 4 9  
facilitate sc he d uli n g); a n d 2 4  wee ks o n eit her acti ve or place b o, as per ra n d o mizati o n, d uri n g  
Treat me nt Peri o ds 1 a n d 2.  T here will be 2 W as h o ut P eri o ds ( n o  treat me nt) f or a mi ni m u m of 
7  da ys ( ma xi m u m of 1 4  da ys) .  Was h o ut Peri o d 1  ( St u d y Wee k -1 ) will occ ur aft er t he Scree ni n g 
P eri o d a n d Was h o ut  Peri o d 2 ( St u d y Wee k 1 3) will occ ur aft er Treat me nt Peri o d 1 . 
If a p plica bl e, s u bjects will u n der g o 1 4 wee ks of treat me nt ( o ver a 2 1 -wee k peri o d) i n t he 
C o nti n ge nt P ar allel D esi g n  as f oll o ws: at least 2 wee ks of l o w  d os e ( 3 breat hs  QI D ) i n hal e d 
tre pr osti nil treat me nt d uri n g t he Scree ni n g P eri o d (a mi ni m u m of 1 4 da ys a n d a ma xi m u m of 
1 8  da ys if n ee d e d t o facilitate sc he d uli n g) , a W as h o ut  P eri o d ( n o treat me nt) f or a mi ni m u m of 
7  da ys ( ma xi m u m 1 4  da ys) , a n d 1 2 wee ks o n eit her acti ve or pl ace b o, as per ra n d o mizati o n.  
4  
S U B J E C T E LI GI BI LI T Y  
4. 1  
I N C L U SI O N C RI T E RI A 
S u bjects w h o meet  t he f oll o wi n g criteria ma y be i ncl u de d i n t he st u d y: 
1.  V ol u ntaril y gi ves i nf or me d c o nse nt t o partici p ate i n t he st u d y.  
2.  Males a n d fe m ales 1 8 years of a ge a n d a b o ve at t h e ti me of i nf or me d c o ns e nt.  
a. Fe males of c hil d beari n g p ote ntial ( defi ne d as less t ha n 1 yea r p ost me n o pa usal a n d n ot 
s ur gic all y sterile) m ust a gree t o practice a bsti ne nce or use 2  hi g hl y effecti v e met h o ds 
of c o ntrace pti o n ( defi ne d as a met h o d of birt h c o ntr ol t hat res ults i n a less t ha n 1 % 
per year  fail ure rat e, s uc h as a p pr o ve d h or m o nal c o ntracepti ves, b arrier met h o ds 
[c o n d o m or dia p hra g m] use d wit h a s per mici de, or a n i ntra uteri n e de vice) f or t he 
d urati o n of st u d y tr eat me nt a n d f or 4 8  h o urs after disc o nti n ui n g st u d y dr u g .  S u bjects 
m ust ha ve ne gati ve pre g na nc y test s at Scree ni n g Visit 1 (uri ne [ pri or t o t he first d ose 
of st u d y dr u g ] a n d ser u m) a n d t he Baseli ne Visit ( uri ne [ St u d y Wee k 1 ]). 
b.  Males wit h a part ner of c hil d beari n g p ot e ntial m ust a gree t o use a barrier m et h o d 
(c o n d o m) wit h a s per mici de f or t he d urati o n of treat me nt a n d f or at least 4 8 h o urs 
after disc o nti n ui n g st u d y dr u g.  
3.  Dia g n osis of P H -C O P D ( W H O Gr o u p 3).  
4.  Cli nical dia g n osis of C O P D per  t he Gl o bal I nitiati ve f or C hr o nic O bstr ucti ve L u n g 
Disease ( G O L D) di a g n ostic criteria (2 0 2 0 ) a n d d o c u me nte d s pir o metr y para meters 
meas ure d d uri n g Scree ni n g Visit 1 ( pri or t o start of l o w  d ose i n hale d tre pr osti nil) , as 
f oll o ws: 
a. F E V 1 < 8 0 % pre dicte d  
b.  F E V 1/ F V C < 7 0 
5.  R esti n g S p O 2 ≥9 0 % d uri n g Scree ni n g Visit 1 , wit h or wit h o ut s u p ple me ntal o x y ge n , a n d 
s u p ple me ntal o x y ge n ca n n ot e x cee d 1 0 L/ mi n b y a n y m o de of deli ver y.  
6.  A 6 M W D ≥1 0 0  meters  d uri n g  Scree ni n g Visit 1  (pri or t o start of l o w  d ose i n hale d 
tre pr osti nil). 


U nite d T her a pe utics C or p.  
 RI N -P H -3 0 4 Pr ot oc ol A me n d me nt 4  
L u n g Bi otec h n ol o g y P B C  
I n h ale d Tre pr osti nil 
Versi o n D ate 2 0 Oct o ber 2 0 2 0  
C O N FI D E N TI A L  
P a ge 5 0  
7.  Willi n g t o u n der g o  R H C d uri n g Scree ni n g Visit 1.  A n  R H C perf or me d  wit hi n 1 2  m o nt hs  
pri or t o t he start of Scree ni n g Visit 1 is acce pta ble f or deter mi ni n g eli gi bilit y , e v e n if 
d o ne wit h o ut o x y ge n or vas o dilat or c halle n ge, a n d a re peat R H C is n ot re q uire d .  T he 
f oll o wi n g para meters m ust be d oc u me nte d f or eli gi bilit y: 
a. P V R  ≥4  W o o d u nits  
b.  P ul m o nar y arter y w e d ge press ure ( P A W P) or left ve ntric ular e n d -diast olic press ure 
( L V E D P) of ≤1 5  m m H g  
c. P A P m of ≥3 0 m m H g  
8.  M ust be o n a sta ble a n d o pti mize d d ose of c hr o nic C O P D me dicati o ns f or ≥3 0  da ys pri or 
t o t he start of Scree ni n g Visit 1  a n d re mai n o n t he sa me d ose t hr o u g h o ut t he Scree ni n g 
Peri o d . 
9.  Ca n c o m m u nicate effecti vel y wit h st u d y pers o n nel a n d is c o nsi dere d relia ble, willi n g, 
a n d li kel y t o be c o o perati ve wit h pr ot oc ol re q uir e me nts, i ncl u di n g atte n di n g all st u d y 
visits , i n t he o pi ni o n of t he I n vesti gator . 
4. 2  
E X C L U SI O N  C RI T E RI A  
S u bjects w h o meet t he f oll o wi n g  criteria are e x cl u ded  fr o m t he st u d y: 
1.  A  dia g n osis of eit her P A H or P H d ue t o reas o ns ot her t ha n C O P D , i ncl u di n g, b ut n ot 
li mite d t o, c hr o nic t hr o m b oe m b olic P H  or ac ute/rece nt dee p vei n t hr o m b osis or 
p ul m o nar y e m b olis m, u ntreate d or i n a de q uatel y tr eate d o bstr ucti ve sle e p a p nea, 
c o n necti ve tiss ue diseas e (i ncl u di n g , b ut n ot li mite d t o , s yste mic scl er osis/scler o der m a 
or s yste mic l u p us er yt h e mat os us), sarc oi d osis, h u ma n i m m u n o deficie nc y vir us -1 
i nfecti o n, a n d ot her c o n diti o ns u n der W H O Gr o u p 1, 2, 4, a n d 5 classificati o ns. 
2.  A c o nfir me d dia g n osis of i di o pat hic p ul m o nar y fi br osis , c o m bi ne d p ul m o nar y fi br osis 
a n d e m p h yse ma , diff us e pare nc h y m al l u n g dise as e , or i nterstitial l u n g dise ase, base d o n 
c hest C T i ma gi n g d uri n g Scree ni n g Visit 1 .  A c hest C T perf or me d wit hi n 6  m o nt hs 
pri or t o t he start of Scree ni n g Visit 1 is acce pta ble  f or deter mi ni n g eli gi bilit y a n d a 
re peat assess me nt is n ot re q uire d.  A re dacte d C T sca n re p or t (fr o m Scree ni n g Visit 1 or 
date d wit hi n 6  m o nt hs  pri or ) s h o ul d be pr o vi de d t o t he S p o ns or’s Me dical M o nit or wit h 
t he Pre-Baseli ne Re vie w F or m t o c o nfir m eli gi bilit y.  
3.  R ecei ve d a n y F o o d a n d Dr u g A d mi nistrati o n ( F D A )-a p pr o ve d me dicati o n f or t he 
treat me nt of P A H (ie, pr ostac ycli n, pr ostac ycli n rece pt or a g o nist, e n d ot heli n rece pt or 
a nta g o nist [ E R A], p h os p h o diesterase t y pe 5 i n hi bit or [ P D E 5 -I], or s ol u ble g ua n yl ate 
c yclase [s G C] sti m ulat or) at Scree ni n g Visit 1  a n d t herea fter, e x ce pt if recei ve d f or ac ute 
vas oreacti vit y testi n g.  
4.  P re vi o us dia g n osis of h o m oz y g o us al p ha-1 a ntitr y psi n deficie nc y.  
5.  A n y pri or i nt olera nce t o i n hale d pr osta n oi d t hera p y.  
6.  I n a bilit y t o t olerate l o w d ose i n hale d tre pr osti nil a n d/ or f oll o w d osi n g re gi me n d uri n g 
t he Scree ni n g Peri o d ( pre -ra n d o mizati o n). 
7.  U n willi n g or u na ble t o us e S p o ns or -pr o vi de d de vi ces (acti gra p h, s pir o meter, or s mart 
de vice).  


U nite d T her a pe utics C or p.  
 RI N -P H -3 0 4 Pr ot oc ol A me n d me nt 4  
L u n g Bi otec h n ol o g y P B C  
I n h ale d Tre pr osti nil 
Versi o n D ate 2 0 Oct o ber 2 0 2 0  
C O N FI D E N TI A L  
P a ge 5 1  
8.  E vi de nce of cli nicall y si g nifica nt left -si de d h eart disease (i ncl u di n g, b ut n ot li mite d t o , 
left ve ntric ular ejecti o n fracti o n < 4 0 %, l eft ve ntri c ular h y pertr o p h y) or cli nicall y 
si g nifica nt car di ol o gic c o n diti o ns, s uc h as c o n gesti ve heart fail ure, c or o nar y arter y 
disease, or val v ular heart disease .  N O T E : S u bjects wit h a b n or mal left ve ntric ular 
fu ncti o n attri b uta ble t o t he effects of ri g ht ve ntric ular o verl oa d will n ot be e x cl u de d, b ut 
a disc ussi o n wit h a n d a p pr o val b y t h e S p o ns or ’s Me dical M o nit or is re q uire d. 
9.  A n y e x acer bati o n of C O P D ( i ncl u di n g h os pitalizati o n or o ut patie nt t hera p y) or acti ve 
p u l m o nar y or u p per res pirat or y i nfecti o n fr o m 3 0  da ys pri or t o start of Scree ni n g Visit  1 
t hr o u g h t he Bas eli ne Visit.  T his is defi ne d as w orse ni n g of res pir at or y s y m pt o ms t hat 
re q uire d tr eat me nt wit h c ortic oster oi ds a n d/ or a nti bi otics. 
1 0.  I nitiati o n of p ul m o nar y re ha bilitati o n wit hi n 1 2 wee ks pri or t o start of Scree ni n g Visit  1 
or, i n t he o pi ni o n of t he I n vesti gat or, p ul m o nar y re ha bilitati o n is li kel y t o b e nee d e d 
d uri n g t he Treat me nt Peri o d.  
1 1.  A n y f or m of c o n ge nital heart diseas e (re pair e d or u nre pair e d ) ot her t h a n a pate nt 
f ora me n o v ale. 
1 2.  A n y m usc ul os kel etal dis or der (ie,  s e vere art hritis of t he l o wer li m bs w hic h li mits 
a m b ulati o n, rece nt hi p or k nee j oi nt re place me nt, artificial le g) or a n y ot her c o n diti o n 
t hat w o ul d li kel y be t he pri mar y li mitati o n t o a m b ulati o n.  
1 3.  Use of a n y ot her i n vesti gati o nal dr u g or de vice wit hi n 3 0  da ys pri or t o t he start of 
Scree ni n g Visit 1.  
1 4.  A n y ot her cli nicall y si g nifica nt ill ness or a b n or mal la b orat or y val u e(s) meas ure d d uri n g 
t he Scree ni n g Peri o d t hat, i n t he o pi ni o n of t he I nv esti gat or, mi g ht a d versel y affect t he 
i nter pretati o n of t he st u d y dat a or safet y of t he s u bject . 
4. 3  
P R E S C RI B E D T H E R A P Y  
S u bjects m ust n ot be recei vi n g a n y F D A -a p pr o ve d me dicati o n t o treat P A H (ie, pr ostac ycli n, 
pr ostac ycli n rece pt or a g o nist, E R A, P D E 5 -I, or s G C sti m ulat or) at Scree ni n g Visit 1  a n d 
t hereafter, e x ce pt if recei ve d f or ac ute vas oreacti vit y testi n g. 
S u bjects o n a c hr o nic me dicati o n f or C O P D s h o ul d be o n a sta ble a n d o pti mize d d ose f or 
≥3 0  da ys pri or t o t he start of Scree ni n g Visit 1 a n d re mai n o n t he sa me d os e t hr o u g h o ut t he 
Scree ni n g Peri o d.   After ra n d o mizati o n, s u bjects s h o ul d re mai n o n a sta ble d ose u ntil t he e n d of 
t he st u d y, as m uc h as feasi ble.  W he n a p plica ble, it is rec o m me n de d t hat st u d y dr u g b e 
a d mi nistere d after c o n c o mita nt br o nc h o dilat ors.  
S u bjects m ust n ot be partici pati n g i n a n y ot her  i n vesti gati o nal st u d y i n v ol vi n g a n i n v esti gati o nal 
dr u g  or de vic e wit hi n 3 0  da ys pri or t o start of Scree ni n g Visit 1 or d uri n g t h e st u d y. 


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Subjects may not initiate pulmonary rehabilitation within 12 weeks prior to the start of Screening 
Visit 1 through the end of the study. 
All concomitant medications taken during the conduct of the study, including supplemental 
oxygen, and those taken for AEs or other medical events, should be recorded in the subject’s 
source documents and transcribed into the eCRF.  The flow rate of supplemental oxygen should 
be recorded as outlined in Section 3.3.2.11.1. 
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
In the Original Crossover Design, which is a crossover study, approximately 136 subjects will 
receive inhaled treprostinil and placebo.  If applicable, in the Contingent Parallel Design, which 
is a parallel study (approximately 314 subjects), at least 157 subjects will receive inhaled 
treprostinil and another 157 subjects will receive placebo. 
5.2 
RANDOMIZATION 
Prior to randomization, at Screening Visit 2 (Study Week -2), site personnel should complete the 
Pre-Baseline Review Form, confirm study drug tolerability and compliance during the Screening 
Period, and request the Sponsor’s Medical Monitor review subject eligibility.  Randomization 
will not be possible until the Pre-Baseline Review Form (and supporting documentation) is 
complete and the Sponsor’s Medical Monitor confirms subject eligibility.  Subjects who are 
intolerant of therapy (as determined by the Investigator), unable to follow the dosing regimen, or 
noncompliant with actigraphy, at-home spirometry, or smart device use during the Screening 
Period will be ineligible for randomization and deemed screen failures.  Subjects may be 
re-screened (see Section 3.1). 
An Interactive Response Technology (IRT) (
) will be utilized 
for the central randomization procedure.  Sites will access the IRT and conduct the 
randomization steps if the subject is approved for the study. 
In the Original Crossover Design, subjects will be randomized to receive treatment with either 
inhaled treprostinil (6 mcg/breath, target of 12 breaths QID or the maximum tolerated dose) or 
placebo in Treatment Period 1 (at Study Week 1), followed by a crossover to the other treatment 


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in Treatment Period 2 (at Study Week 14).  There will be a Washout Period (no treatment; Study 
Week 13) for a minimum of 7 days (maximum of 14 days) between Treatment Periods 1 and 2.  
If the Sponsor adapts the study to the Contingent Parallel Design, any subject in Treatment 
Period 2 will be asked to return to the site as soon as possible to complete an ET Visit. 
In the Contingent Parallel Design (if applicable), subjects will be randomized to receive 
treatment with either inhaled treprostinil (6 mcg/breath, target of 12 breaths QID or the 
maximum tolerated dose) or placebo at Study Week 1. 
5.3 
BLINDING 
The subjects, Investigators, study site personnel, and Sponsor (United Therapeutics Corp. [UTC] 
and its designee, Lung Biotechnology PBC), with the exception of select UTC 
Pharmacovigilance and Drug Supply staff, will be blinded to the treatment assignment of the 
subject, unless unblinding is required for safety review or regulatory reporting. 
The site staff must never be unblinded to the treatment assignment of participating subjects, 
unless deemed medically necessary (see Section 6.2). 
6 
DRUGS AND DOSING (OR TREATMENT PROCEDURES) 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE 
Treprostinil for inhalation solution (0.6 mg/mL) is delivered via the Tyvaso Inhalation System, 
which emits a dose of approximately 6 mcg per breath.  Placebo will be provided as an identical 
solution for inhalation using the same Tyvaso Inhalation System.  Subjects will receive study 
drug (inhaled treprostinil or placebo) via the Tyvaso Inhalation System and will be trained on use 
of the Tyvaso Inhalation System at Screening Visit 1.  In addition, subjects will receive a copy of 
the Tyvaso Inhalation System Instructions for Use.  The first dose of study drug (3 breaths, 
18 mcg) will be inhaled at the study site, followed by at least a 1-hour observation period. 
Once informed consent has been signed, all entry criteria have been met (including Sponsor 
Medical Monitor Approval), and the randomized treatment assignment confirmed, study drug 
doses should be maximized throughout the study and dose escalations (additional 1 breath QID) 
can occur approximately every 3 days with a target dosing regimen of 12 breaths (72 mcg) QID 


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or the maximum tolerated dose.  Table 6-1 provides an example of dose escalations that can be 
followed. 
Table 6-1 
Sample Inhaled Treprostinil Dose Escalation Table 
Study Day a 
Single Dose 
Total Daily Dose 
Titrating to maximum dose of 12 breaths 
1 to 3 
3 breaths QID (18 mcg) 
72 mcg 
4 to 6 
4 breaths QID (24 mcg) 
96 mcg 
7 to 9 
5 breaths QID (30 mcg) 
120 mcg 
10 to 12 
6 breaths QID (36 mcg) 
144 mcg 
13 to 15 
7 breaths QID (42 mcg) 
168 mcg 
16 to 18 
8 breaths QID (48 mcg) 
192 mcg 
19 to 21 
9 breaths QID (54 mcg) 
216 mcg 
22 to 24 
10 breaths QID (60 mcg) 
240 mcg 
25 to 27 
11 breaths QID (66 mcg) 
264 mcg 
28 (and beyond) 
12 breaths QID (72 mcg) 
288 mcg 
QID, 4 times daily 
a Study day refers to the days on study drug, with Day 1 referring to the first dose of study drug 
The above dosing schedule is recommended as a guide only.  The Investigator may accelerate or 
decelerate the dosing titration schedule on an individual subject basis, considering subject safety, 
tolerability, and functional improvement. 
Dose changes should be conducted under appropriate medical supervision in consultation with 
the study site staff.  Telephone calls between the site staff and subject should occur prior to each 
dose adjustment, or at least weekly during titration (until 12 breaths QID or the maximum 
tolerated dose is achieved), and as needed thereafter to provide dosing instructions and to assess 
tolerance to study drug, AEs, and changes in concomitant medications.  If subjects are prescribed 
bronchodilators, study drug should be taken after. 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
The subjects, Investigators, study site personnel, and Sponsor (UTC and its designee, Lung 
Biotechnology PBC) are blinded to the treatment assignments of all subjects throughout the 
study.  Exceptions are the UTC Pharmacovigilance and Drug Supply staff (and their designated 
third-party vendors), who are unblinded for packaging and labeling of study drug and for safety 
reporting per local, national, and international regulations.  If unblinding of a subject’s treatment 
assignment is necessary for the safety of a subject, the Investigator (or Sponsor’s Medical 


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Monitor) would perform an unblinding of a subject’s treatment assignment through the IRT.  
Appropriate communication should take place between the site and the Sponsor before accessing 
the IRT to enable the unblinding. 
6.3 
COMPLIANCE 
At each study visit, all study drug returned by the subject (used and unused) will be collected and 
new study drug will be dispensed as needed.  The appropriate study personnel must document 
the number of used and unused ampoules.  To accommodate Sponsor-approved telemedicine 
visits, study drug and device supplies will be allowed to be shipped directly to the subject. 
Subject compliance with the prescribed dosage regimen will be monitored throughout the study.  
At each study visit, the subject will be asked whether they have been compliant with dosing 
instructions.  If it is determined that a subject is noncompliant with study drug, the site personnel 
must re-educate the subject on proper dosing compliance and its importance.  Continued 
noncompliance may lead to withdrawal of the subject from the study, after consultation between 
the Investigator and the Sponsor’s Medical Monitor or other Sponsor representative. 
7 
EXPERIMENTAL PROCEDURES  
The allowable window for each study visit will be ±3 days; however, where specified, the 
minimum Treatment or Washout Period must be adhered.  Refer to Section 3.2 for the Overall 
Schedule of Times and Events. 
7.1 
SCREENING PERIOD 
7.1.1 
Screening Visit 1 (Study Weeks -9 to -3) 
All procedures may be conducted over a 6-week period to facilitate scheduling.  The following 
assessments for Screening Visit 1 are required prior to dosing with study drug: 
• Informed consent 
• Demographics 
• Medical history, including PH-COPD history 
• PE 
• Vital signs: height, weight, RR, HR, and BP (following at least 5 minutes of seated rest 
and collected prior to 6MWT); no other measurements or procedures should be 
performed during the rest period 
• 12-lead ECG (following at least 5 minutes of rest) 


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• Blood draws for NT-proBNP and clinical laboratory parameters 
• 
 
• Urine (prior to the first dose of study drug) and serum pregnancy tests for females of 
childbearing potential 
• 6MWT and, if applicable, documentation of supplemental oxygen requirement 
• Pulse oximetry (performed continuously prior to, during, and following the 6MWT) 
• Borg dyspnea score immediately following the 6MWT 
• PFTs (performed either before the 6MWT or after recovering from the 6MWT, if 
applicable) 
• Chest CT scan; if performed within 6 months prior to the start of Screening Visit 1 a 
repeat assessment is not required.  A redacted CT scan report should be provided to the 
Sponsor’s Medical Monitor with the Pre-Baseline Review Form to confirm eligibility. 
• Review inclusion/exclusion criteria 
• RHC; an RHC obtained within 12 months prior to the start of Screening Visit 1 is 
acceptable for determining eligibility, even if done without oxygen or vasodilator 
challenge, and a repeat RHC is not required. 
If all study eligibility criteria are met, dosing instructions and Tyvaso Inhalation device training 
will occur, followed by administration of study drug.  The subject must remain at the study site 
for at least 1 hour after the first dose of study drug for observation.  The following assessments 
should be completed after dosing: 
• Assess for AEs 
• Assess for changes in concomitant medications 
• Issue the Sponsor-provided actigraphy, spirometry, and smart devices and provide 
training on use of the devices 
• Subjects will be called weekly during the Screening Period and directed to call the study 
site coordinator or Investigator at any time to discuss study-related issues of concern 
(AEs, symptoms, tolerability, device issues, etc) 
Re-screening: Subjects may be re-screened.  The study-specific RHC performed during 
Screening Visit 1 is valid for up to 12 months and should not be repeated if the subject is being 
re-screened unless written approval is first obtained from the Sponsor’s Medical Monitor. 
7.1.2 
Screening Visit 2 (Study Week -2)  
• PE 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest and 
collected prior to 6MWT); no other measurements or procedures should be performed 
during the rest period 


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• Blood draws for NT-proBNP and clinical laboratory parameters 
• Collect study drug from subject and complete drug/device accountability 
• Assess for AEs 
• Assess for changes in concomitant medications 
• Confirm study drug tolerability and compliance during the Screening Period 
• Review inclusion/exclusion criteria and confirm study eligibility 
• Complete the Pre-Baseline Review Form for Sponsor’s Medical Monitor review and 
approval if subject tolerates drug and meets all other eligibility criteria 
• Confirm proper use and capture of actigraphy data 
• Confirm proper use and capture of spirometry data 
• Subjects will be directed to call the study site coordinator or Investigator at any time to 
discuss study-related issues of concern (AEs, symptoms, tolerability, etc) 
7.2 
WASHOUT PERIODS 
7.2.1 
(Study Week -1 and Study Week 13) 
At the end of Screening Visit 2 (Original Crossover Design and Contingent Parallel Design) 
and Study Week 12 (Original Crossover Design), all subjects will enter a 7-day minimum 
(14 days maximum) Washout Period. 
Subjects will be called mid-week following discharge from the site and directed to call the study 
site coordinator or Investigator at any time to discuss study-related issues of concern (AEs, 
concomitant medications, symptoms, tolerability, etc). 
7.3 
TREATMENT PERIODS 
7.3.1 
Study Week 1 Visit (Baseline Visit) 
The following baseline assessments must be performed prior to the first dose of study drug at the 
Study Week 1 Visit: 
• QOL questionnaires: SGRQ and UCSD SOBQ 
• PE 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest and 
collected prior to 6MWT); no other measurements or procedures should be performed 
during the rest period 
• 12-lead ECG (following at least 5 minutes of rest) 
• Blood draws for clinical laboratory parameters and NT-proBNP (NT-proBNP sample 
must be drawn prior to 6MWT) 
• 
 


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• 
 
 
• 
 
 
 
• Reconfirm inclusion/exclusion criteria 
• Confirm Sponsor’s Medical Monitor approval to randomize subject 
• Urine pregnancy test for females of childbearing potential 
• Randomization using IRT 
• PFTs (must be done after randomization either before the 6MWT or after recovery from 
the baseline 6MWT) 
• 6MWT (conducted post randomization; following at least 10 minutes of seated rest) and, 
if applicable, documentation of supplemental oxygen requirement 
• Pulse oximetry (performed continuously prior to, during, and following the 6MWT) 
• Borg dyspnea score immediately following 6MWT 
• Confirm proper use and capture of actigraphy data 
• Confirm proper use and capture of spirometry data 
• Collect PGA and provide training on at-home completion of the PGA 
After the above assessments are completed, the following should be conducted: 
• Provide and administer study drug, including dosing instructions 
• Assess for AEs 
• Assess for changes in concomitant medications 
• Provide paper QOL questionnaires and training on at-home completion in the event 
telemedicine visits are needed 
• Weekly telephone contact 
7.3.2 
Study Weeks 6 and 19 Visits 
The following assessments are to be completed during Study Weeks 6 & 19 in the Original 
Crossover Design, or if applicable, Study Week 6 in the Contingent Parallel Design: 
• QOL questionnaires: SGRQ and UCSD SOBQ 
• PE 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest and 
collected prior to 6MWT); no other measurements or procedures should be performed 
during the rest period 
• 12-lead ECG (following at least 5 minutes of rest) 
• Blood draws for clinical laboratory parameters and NT-proBNP (NT-proBNP sample 
must be drawn prior to 6MWT) 


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• Serum pregnancy test for females of childbearing potential 
• Administer study drug at the study site 
• 6MWT (to be conducted between 10 to 60 minutes after study drug administration and 
following at least 10 minutes of seated rest) and, if applicable, documentation of 
supplemental oxygen requirement 
• Pulse oximetry (performed continuously prior to, during, and following the 6MWT) 
• Borg dyspnea score immediately following the 6MWT 
• PFTs (performed before the 6MWT or after recovery from the 6MWT) 
• Confirm proper use and capture of actigraphy data 
• Confirm proper use and capture of spirometry data 
• Confirm proper use and capture of PGA data 
• Provide study drug and assess drug/device accountability 
• Assess for AEs 
• Assess for changes in concomitant medications 
• Weekly telephone contact 
7.3.3 
Study Week 14 Visit 
The following assessments are to be completed prior to the first dose of study drug during Study 
Week 14 in the Original Crossover Design only: 
• QOL questionnaires: SGRQ and UCSD SOBQ 
• PE 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest and 
collected prior to 6MWT); no other measurements or procedures should be performed 
during the rest period 
• 12-lead ECG (following at least 5 minutes of rest) 
• Blood draws for clinical laboratory parameters and NT-proBNP (NT-proBNP sample 
must be drawn prior to 6MWT) 
• Serum pregnancy test for females of childbearing potential 
• 
 
• 
 
• 
 
• 6MWT (following at least 10 minutes of seated rest) and, if applicable, documentation of 
supplemental oxygen requirement  
• Pulse oximetry (performed continuously prior to, during, and following the 6MWT) 
• Borg dyspnea score immediately following the 6MWT 
• PFTs (performed before the 6MWT or after recovery from the 6MWT) 


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• Confirm proper use and capture of actigraphy data 
• Confirm proper use and capture of spirometry data 
• Confirm proper use and capture of PGA data 
After the above assessments are completed, the following should be performed: 
• Provide and administer study drug, including dosing instructions 
• Assess for AEs 
• Assess for changes in concomitant medications 
• Weekly telephone contact 
7.3.4 
Study Weeks 12 and 25 Visits 
The following assessments are to be completed during Study Weeks 12 & 25 in the Original 
Crossover Design or, if applicable, Study Week 12 in the Contingent Parallel Design: 
• QOL questionnaires: SGRQ and UCSD SOBQ 
• PE 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest and 
collected prior to 6MWT); no other measurements or procedures should be performed 
during the rest period 
• 12-lead ECG (following at least 5 minutes of rest) 
• Blood draws for clinical laboratory parameters and NT-proBNP (NT-proBNP sample 
must be drawn prior to 6MWT) 
• Serum pregnancy test for females of childbearing potential 
• 
 
• 
 
• 
 
• Administer study drug at the study site 
• 6MWT (conducted between 10 to 60 minutes after study drug administration and 
following at least 10 minutes of seated rest) and, if applicable, documentation of 
supplemental oxygen requirement 
• Pulse oximetry (performed continuously prior to, during, and following the 6MWT) 
• Borg dyspnea score immediately following the 6MWT 
• PFTs (performed before the 6MWT or after recovery from the 6MWT) 
• Confirm proper use and capture of actigraphy data 
• Confirm proper use and capture of spirometry data 
• Confirm proper use and capture of PGA data 
• Provide study drug and assess drug/device accountability 


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• Assess for AEs 
• Assess for changes in concomitant medications 
• Weekly telephone contact 
At the end of Study Week 25 in the Original Crossover Design, or if applicable, Study Week 12 
in the Contingent Parallel Design, subjects will be terminated from the study.  Subjects who 
meet all eligibility criteria will be offered enrollment in the open-label extension study, 
RIN-PH-305. 
7.4 
TELEMEDICINE VISITS 
With written Sponsor approval, subjects may have telemedicine visits in lieu of onsite visits after 
randomization in both the Original Crossover Design and the Contingent Parallel Design, if 
the conduct of an onsite study visit poses a safety risk due to the COVID-19 pandemic.  The 
following assessments will be performed during the telemedicine visits: 
• Confirm completion of paper QOL questionnaires: SGRQ and UCSD SOBQ 
• Confirm proper use and capture of actigraphy data 
• Confirm proper use and capture of spirometry data 
• Confirm proper use and capture of PGA data 
• Confirm receipt of study drug resupply and dosing of study drug 
• Assess for AEs 
• Assess for changes in concomitant medications 
7.5 
EARLY TERMINATION VISIT 
If the subject permanently discontinues study drug prior to Study Week 25 in the Original 
Crossover Design, or if applicable, Study Week 12 in the Contingent Parallel Design, for any 
reason, the subject should be encouraged to remain in the study and complete all visits up to and 
including the ET Visit. 
If a decision is made to terminate a subject early from the study, the following assessments 
should be conducted as soon as possible and prior to study drug discontinuation, if possible: 
• QOL questionnaires: SGRQ and UCSD SOBQ 
• PE 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest and 
collected prior to 6MWT); no other measurements or procedures should be performed 
during the rest period 


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• 12-lead ECG (following at least 5 minutes of rest) 
• Blood draws for clinical laboratory parameters and NT-proBNP (NT-proBNP sample 
must be drawn prior to 6MWT) 
• Serum pregnancy test for females of childbearing potential 
• 
 
• 
 
• 
 
• 6MWT (if possible, to be conducted between 10 to 60 minutes after the most recent dose 
of study drug and following at least 10 minutes of seated rest) and, if applicable, 
documentation of supplemental oxygen requirement 
• Pulse oximetry (performed continuously prior to, during, and following the 6MWT) 
• Borg dyspnea score immediately following the 6MWT 
• PFTs (performed before the 6MWT or after recovery from the 6MWT) 
• Confirm capture of actigraphy data 
• Confirm capture of spirometry data 
• Confirm capture of PGA data 
• Verify study drug/device accountability 
• Assess for AEs 
• Assess for changes in concomitant medications 
7.6 
ACCESS TO OPEN-LABEL STUDY 
Subjects who meet all eligibility criteria will be offered enrollment in the open-label extension 
study, RIN-PH-305. 
8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
Investigators and site staff should encourage subjects to continue participation in the study and 
complete all study procedures and study visits as indicated by the study protocol, unless subjects 
provide written withdrawal of consent from the study. 
8.1.1 
Criteria for Withdrawal from Study Drug 
Subject discontinuation from study drug does not mean discontinuation from the study.  Subjects 
may voluntarily withdraw from study drug for any reason or the study drug may be withdrawn 
by the Investigator to protect subject safety.  If a subject is withdrawn from study drug, the 
subject will be encouraged to actively continue to return for all study visits per the study protocol 


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and the Investigator will continue all reasonable efforts to obtain subject data.  The primary 
reason for withdrawal from study drug should be documented in the subject’s eCRF.  If 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 follow up, or for 30 days if the AE extends beyond the final visit.  If a 
subject discontinues study drug prematurely due to an SAE, the subject should be followed until 
resolution, death, or the subject is lost to follow-up, even if they are ongoing more than 30 days 
after completion of the final visit. 
A positive pregnancy test will result in subject withdrawal from study drug, but the subject will 
be encouraged to continue participation in the study and complete all study visits.  See 
Section 9.4.2 for information related to the reporting and following of pregnancies. 
8.1.2 
Criteria for Subject Withdrawal from Study 
Subjects may voluntarily withdraw from the study at any time for any reason after completing a 
formal and written withdrawal of consent.  A withdrawal of consent would preclude data 
collection regarding that subject after the date that the withdrawal of consent was documented.  
The date that consent was withdrawn should be documented in the subject’s eCRF. 
8.2 
CRITERIA FOR TERMINATING THE STUDY 
The study may be stopped at any time if, in the opinion of 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 unanticipated in nature, 
severity, or frequency.  The Sponsor reserves the right to discontinue the study for any reason at 
any time. 
8.3 
CRITERIA FOR DISCONTINUING A SITE 
The study may also be terminated at a given site if any of the following occur: 
• The Investigator elects to discontinue the study. 
• The Sponsor elects to discontinue the study at the site. 
• Applicable regulations are not observed. 
• The protocol is repeatedly violated or critical violations are documented. 
• Changes in personnel or facilities adversely affect performance of the study. 


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9 
ADVERSE EVENT REPORTING  
All AEs/SAEs that occur while the subject is participating in the study will be recorded as 
instructed in this protocol (see Section 9.2). 
9.1 
DEFINITIONS 
9.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
9.1.2 
Serious Adverse Event 
An SAE is an AE that results in any of the following outcomes: 
• Death 
• Life-threatening event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
In addition, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and require medical/surgical intervention to prevent any of the 
outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or abuse. 
Life-threatening means that the subject was at immediate risk of death from the event as it 
occurred.  It does not mean that the event, had it occurred in a more severe form, might have 
caused death. 


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9.2 
DOCUMENTATION OF ADVERSE EVENTS 
All AEs will be documented from the time of informed consent until the time screen failure is 
documented, study completion, or early termination.  An AE 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 15.6 for 
definitions).  Where possible, AEs should be recorded using standard medical terminology.  If 
several signs or symptoms are clearly related to a medically defined diagnosis or syndrome, the 
diagnosis or syndrome should be recorded on the eCRF page, not the individual signs and 
symptoms. 
9.3 
FOLLOW UP OF ADVERSE EVENTS 
All AEs should be followed until either resolution (or return to normal or baseline values), until 
they are judged by the Investigator to no longer be clinically significant, or for at least 30 days if 
the AE extends beyond the final visit. 
All SAEs should be followed until resolution, death, or the subject is lost to follow-up, even if 
they are ongoing more than 30 days after completion of the final visit. 
Supplemental measurements and/or evaluations may be necessary to fully investigate the nature 
and/or causality of an AE.  This may include additional laboratory tests, diagnostic procedures, 
or consultation with other healthcare professionals.  The applicable eCRF pages should be 
updated with any new or additional information, as appropriate. 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
9.4.1 
Serious Adverse Event Reporting 
Sites should enter all available initial and follow-up SAE information into the eCRF (primary 
method) within 24 hours of awareness of the information, regardless of causality or 
expectedness.  The SAE information will be transmitted directly from the eCRF into the safety 
database (Argus).  If the site is unable to enter the SAE information into the eCRF within 
24 hours of awareness, the alternative method is to email a paper SAE Report Form to 
 or fax it to 
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Any information submitted on a paper SAE Report Form must also be entered into the eCRF by 
the study site as soon as possible thereafter.  Any subject source documents related to the SAE 
(eg, hospital discharge summary, treatment records, death certificate, diagnostic test results) 
should be emailed to 
.  The Investigator or Sponsor (if appropriate) must 
also notify their Institutional Review Board (IRB), Independent Ethics Committee (IEC), and/or 
other local equivalent body of the reported SAE, including any follow-up information.  Copies of 
each report and documentation of IEC/IRB/local equivalent body notification and receipt will be 
kept in the Investigator study file. 
9.4.2 
Pregnancy Reporting 
Both female and male subjects must be instructed to contact the Investigator immediately if they 
suspect they or their partner became pregnant while participating in this study.  Any pregnancy 
that occurs during the study must be reported to the Sponsor via email 
 
or fax 
 using the Pregnancy Notification and Outcome Form within 24 hours 
of awareness.  All pregnancies, including those of a male subject’s female partner, must be 
followed until outcome.  A pregnancy is not an AE/SAE.  If there is an abnormal pregnancy 
outcome, a spontaneous abortion, an elective termination for medical reasons, or a congenital 
anomaly in the offspring, the pregnancy outcome becomes an AE/SAE. 
9.5 
SAFETY REPORTS 
In accordance with national regulations, the Sponsor will notify the appropriate regulatory 
authority(ies) and all participating Investigators of any AE that is considered possibly 
attributable to study drug and is both serious and unexpected.  The Investigator must report these 
AEs to their IRB or EC in accordance with applicable national regulations and guidelines set 
forth by the IRB or EC. 
10 
STATISTICAL CONSIDERATIONS 
This section briefly describes the planned statistical analyses.  A complete description of the 
methodology will be specified in the Statistical Analysis Plan (SAP), which will be finalized 
prior to database lock.  Any changes in the statistical methods described in this protocol that 
occur prior to database lock will be documented in the SAP and will not require a protocol 
amendment. 


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10.1 
DATA PROCESSING 
The study eCRF is the primary data collection instrument for the study.  All data requested on 
the eCRF must be recorded following the eCRF completion guidelines to be provided to site 
personnel.  Subject data will be entered in the eCRF for all subjects who sign an ICF until study 
completion or study discontinuation by appropriate site staff.  Data recorded in the eCRF should 
be consistent with source documents.  A representative from the Sponsor will verify eCRF data 
fields against source documentation per the established monitoring plan. 
All data transmitted from the site will be reviewed by the Sponsor and data clarification requests 
may be generated in the eCRF, as appropriate.  The eCRF screens are to be reviewed by the 
Investigator for completeness and accuracy.  The Investigator must electronically sign each 
subject’s eCRF to signify their approval of the data.  The Investigator will be required to re-sign 
an eCRF if changes are made by the site after the Investigator initially signs the eCRF.  The 
clinical database will be final when all outstanding queries have been resolved and all data 
management quality assurance procedures are complete. 
Additional data resulting from actigraphy, spirometry, and PGA will be transmitted to the 
Sponsor from the respective vendors during the study and at study completion.  These data will 
be reviewed by the Sponsor accordingly, but will not be recorded in the eCRF.  These data will 
be merged into the clinical database after completion of the study. 
10.2 
SAMPLE SIZE 
This is an adaptive design study that will be initiated as a crossover study (the Original 
Crossover Design).  However, due to the uncertainty of clinical benefit with inhaled treprostinil 
exposure in PH-COPD subjects and the ongoing COVID-19 pandemic, there is a possibility of 
treatment discontinuations and/or missing data due to COVID-19 impeding onsite visits, which 
may render estimates for efficacy outcomes inefficient or biased, thus an automatic switch to the 
Contingent Parallel Design or an alternative primary endpoint that has been incorporated in this 
study protocol.  The protocol specifies the algorithm to seamlessly transition to a parallel-group 
design (Contingent Parallel Design) if the degree of missing data subsequent to subject 
treatment crossover is not tolerable for primary analysis.   


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Similarly, this protocol specifies the algorithm to switch the primary endpoints to measurements 
conducted remotely if the COVID-19 pandemic prevents onsite visits and data collection for the 
intended primary endpoint data.  Evaluations of missing data will be performed in a blinded 
fashion at the conclusion of the study, irrespective of actual efficacy outcomes and any 
information regarding efficacy outcomes prior to crossover and, as such, will not impact the 
Type I error rate (FDA Guidance 2019).  Section 10.2.1 presents the adaptation procedures to be 
employed for this protocol. 
The Original Crossover Design is a 2x2 crossover study designed to have 90% power to detect 
a placebo-corrected mean change from baseline difference of 30 meters, assuming that the 
standard deviation of differences is 85 meters and using a 2-group t-test with a 0.01 two-sided 
significance level, with a sample size of 124 subjects (62 in each sequence group).  To account 
for a discontinuation rate of approximately 10%, the total sample size will be approximately 
136 subjects.  
Based on published data using actigraphy as an outcome measure in studies conducted in the 
pulmonary hypertension population (Gonzalez-Saiz 2018; Nathan 2020), reasonable statistical 
power (80%; 2-sided alpha of 0.05) can be assumed for approximately 90 evaluable subjects 
when the observed improvement is in excess of 6%-8% for overall activity or 20-25% or greater 
for moderate to vigorous activity.  Nathan (2019) provides that the clinically meaningful 
difference observed in their study was 5% to 10% for overall activity and 20% for MVPA, with a 
clinically meaningful difference range in studies of COPD patients from 11% to 29%. 
The Contingent Parallel Design is a parallel-group study designed to use an allocation ratio of 
1:1 between inhaled treprostinil and placebo, with a sample size of 266 subjects (133 per 
treatment) that 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.  To account for a discontinuation rate of 
approximately 15%, the total sample size will be approximately 314 subjects. 


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10.2.1 
Adaptive Design Procedures 
This adaptive study will be initiated as an Original Crossover Design.  Two separate missing 
data checks will occur and will result in study design adjustment decisions.  The following 
adaptation strategies will be used: 
Adaptation 1: 
At approximately 75% of subjects randomized, a blinded interim analysis will be performed to 
assess the extent of missing primary efficacy endpoint data at the end of Treatment Period 2 
(Study Week 25).  The outcome of the analysis will inform a decision for the study to continue 
as the Original Crossover Design or switch to the Contingent Parallel Design as follows: 
• If data presence ≥85% for 6MWD or actigraphy data at the end of Treatment Period 2 
(Study Week 25), the study will continue as planned under the Original Crossover 
Design. 
• If data presence <85% for both 6MWD and actigraphy data at the end of Treatment 
Period 2 (Study Week 25), the study will switch to the Contingent Parallel Design. 
Adaptation 1 will assess the amount of missing exercise ability data due to subject dropout or 
otherwise lack of measurement (regardless of onsite or remote) and the outcome will be whether 
study continues to completion as the Original Crossover Design or the Contingent Parallel 
Design. 
Adaptation 2: 
Will assess the amount of missing exercise ability data potentially due to the COVID-19 
pandemic interfering with onsite measurements.  At the conclusion of the study, a blinded 
analysis will be performed to assess the extent of missing primary efficacy endpoint data (ie, 
6MWD data).  If the absence of 6MWD data in the Treatment Period of the study, combined 
across subjects, treatment periods, and key visits (Baseline and Study Week 12) to be used for 
the final primary endpoint analysis would likely lead to an underpowered study or yield 
indeterminate results, a contingent primary endpoint will be used for the final primary endpoint 
analysis.  Such a contingency may include an imputation of missing 6MWD data from 
actigraphy measurements or the use of actigraphy measurements alone rather than 6MWD for 
the primary endpoint analysis.   


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This adaptation intends that the 6MWD is to be used as the primary efficacy endpoint for this 
study, except in the case where onsite measurements for the 6MWD are not reasonably available 
and will occur regardless of Adaptation 1 (ie, for either the Original Crossover Design or the 
Contingent Parallel Design).  The contingent primary endpoint definition and analysis strategy 
will be specified a priori with details fully documented in the SAP prior to the unblinding of the 
study. 
As outlined in Section 8.2, the Sponsor reserves the right to discontinue the study for any reason, 
at any time. 
10.3 
ANALYSIS PLAN 
Statistical analyses will be performed using 2-sided tests.  A 0.05 significance level will be used 
in all tests of treatment differences.  In addition, for labeling purposes only, the experiment-wise 
Type I error will be controlled to a maximum of 5%.  A gatekeeper strategy may be employed 
such that any secondary endpoints or subset analyses will be considered for statistical 
significance only if the primary endpoint is statistically significant.  The Type I family-wise error 
rate will be controlled at the 0.05 level of significance. 
Data will be summarized by treatment group (and by visit when applicable).  For parameters 
measured at baseline, the outcome variables of interest are the changes from baseline. 
Summary statistics will include the mean, N, standard deviation, median, minimum, maximum, 
the 25th and 75th percentile values for continuous variables, and frequencies and percentages for 
categorical variables. 
The SAP will specify the details of the models to be used for the efficacy, safety, and exploratory 
analyses.  All statistical analyses will be performed by the Sponsor’s biostatistics department 
personnel (or appropriate designees) using SAS®, Version 9.3 or higher or other validated 
software. 
The Full Analysis Population will be defined as all subjects randomized into the study who 
receive at least 1 dose of study drug; all 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 population, unless otherwise specified. 


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The Safety Population will be defined as all subjects enrolled into the study who receive 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 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in 6MWD measured at peak exposure (defined as 
10 to 60 minutes after dosing) after 12 weeks of study drug treatment.  The primary endpoint 
analysis will evaluate the difference in baseline-corrected 6MWDs between active and placebo 
conditions.  The primary endpoint analysis will test the hypothesis of an improvement in 
baseline-corrected 6MWDs for active compared to placebo conditions as administered to 
subjects with PH-COPD.  The primary null hypothesis to be tested is that there are no differences 
in the baseline-corrected 6MWDs between active and placebo conditions. 
A mixed-effect model repeated measure will be used to estimate the treatment effect.  The 
magnitude of treatment effect will be estimated across the 12-week conditions between 
2 treatment groups and the test of the Week 12 treatment effect will be produced using contrasts. 
Sensitivity analyses to support the primary endpoint analysis will be conducted to examine 
robustness of results under various assumptions underlying the analysis (eg, normality, effects of 
dropout). 
10.3.2 
Alternate Primary Efficacy Endpoint 
The analysis strategy will be specified a priori with details fully documented in the SAP prior to 
the unblinding of the study.  
10.3.3 
Secondary Efficacy Endpoint(s) 
The effect of inhaled treprostinil after 12 weeks of treatment will be formally tested on the 
following secondary efficacy endpoints: 
1. Change in MVPA as measured by actigraphy 
2. Change in overall activity as measured by actigraphy 
3. Change in Borg dyspnea score from baseline 
4. Change in 6MWD/Borg dyspnea composite score from baseline 
5. Change in QOL from baseline as measured by SGRQ and UCSD SOBQ 


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6. Change in plasma concentration of NT-proBNP from baseline  
7. Change in PGA 
Hypothesis testing of secondary efficacy endpoints will be conducted using a gatekeeper 
strategy, such that any secondary endpoints will be considered for statistical significance only if 
the primary endpoint is statistically significant.  Under closed testing procedures, the Type I 
family-wise error rate will be controlled at the 0.05 level of significance.  The SAP will detail the 
specific analyses and methods for testing of secondary efficacy endpoints. 
10.3.4 
Safety Analyses 
The safety of inhaled treprostinil compared to placebo will be evaluated on the following 
parameters: AEs, clinical laboratory assessments, ECGs, PE findings, oxygenation, PFTs, vital 
sign measurements, and at-home spirometry. 
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 Period.  Summary statistics will be calculated for measured values and 
changes from baseline values.  Treatment-emergent changes in clinical laboratory evaluations, 
ECGs, oxygenation, PFTs, at-home spirometry, and vital sign measurements will be summarized 
by treatment group.  No inferential analyses are planned on these safety endpoints. 
10.3.5 
Exploratory Analyses 
 
 
 
 
 
 


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10.4 
INTERIM ANALYSIS 
An interim analysis is planned in a blinded fashion, at approximately 75% of subjects 
randomized, to assess the extent of missing primary efficacy endpoint data at the end of 
Treatment Period 2.  The outcome of this analysis will inform a decision for the study to 
continue with the Original Crossover Design or switch to the Contingent Parallel Design.  
Full details of the adaptation procedures are specified in Section 10.2.1. 
A single interim efficacy analysis will be conducted when at least 75% of the subjects (ie, 
~100 subjects) have completed the 26-week Treatment Period, data are available for both 
Treatment Period 1 and Period 2 6MWD evaluations, and if the expected time to randomize the 
final (136th) subject is greater than 3 months.  The expected time to randomize will be based on 
the average recruitment rate for the prior 6 months.  This plan will allow early stopping for 
convincing evidence of benefit if recruitment is slow.  A non-binding futility analysis will be 
conducted at the same time.  The results of these analyses will be provided to the independent 
Data Safety Monitoring Committee (DSMC) by the independent external consultant for their 
review and recommendation.  The DSMC Charter and SAP will contain the approach for 
projecting recruitment, as well as formal criteria for the interim analyses for efficacy and futility.  
The Sponsor will remain fully blinded throughout this process.  
10.5 
OTHER ANALYSES 
Other analyses may be conducted based on available study data.  Details for any other planned 
statistical analyses will be specified in the SAP. 
10.6 
DATA LISTINGS AND SUMMARIES 
All scientifically relevant data gathered in this study will be presented in summary tables and 
listings in the clinical study report. 
10.7 
DATA SAFETY MONITORING COMMITTEE 
A DSMC will be established for the study, including physicians knowledgeable in the treatment 
of PH-COPD.  Throughout the course of the study, the DSMC will meet on a regular basis to 
monitor the safety of the study.  Meetings will occur as outlined in the DSMC charter.   


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The DSMC will be unblinded to individual subject treatment allocation during the review 
process.  All analyses will be prepared by an independent external consultant and reviewed only 
by the DSMC, as defined in the DSMC charter.  The Sponsor will only have access to blinded 
study data during this process. 
11 
PACKAGING AND FORMULATION 
11.1 
STUDY SUPPLIES 
11.1.1 
Actigraphy, Spirometry, and Smart Devices 
The Sponsor will supply sufficient quantities of actigraphy, spirometry, and smart devices to 
begin enrollment in the study.  The devices will be supplied using standard packaging labeled 
with the study number, accompanied by the Instructions for Use.  Site staff will dispense these 
devices to eligible subjects during Screening Visit 1 at the time of low dose inhaled treprostinil 
initiation. 
If a device is defective or suspected to be defective and the issue cannot be resolved via 
troubleshooting, the site should complete the Product Complaint Form provided in the Study 
Procedures Manual, return the form to the Sponsor within 24 hours, and follow any additional 
instructions provided by the Sponsor.  As indicated in the Study Procedures Manual, a new 
device will be issued to the subject. 
11.2 
CONTENTS OF STUDY DRUG  
11.2.1 
Study Drug (Active and Placebo) 
The Sponsor will supply active study drug (treprostinil inhalation solution, 0.6 mg/mL) and 
placebo study drug as a clear liquid in 2.9-mL ampoules.  Each ampoule will provide for a single 
day of treatment across the QID dosing.  The ampoules will be packaged in groups of 4, sealed in 
aluminum foil pouches.  During Screening Visit 1, subjects will be supplied cartons containing 
5 pouches per carton to last the 2-week assessment of tolerability and follow the QID dosing 
regimen in the Screening Period.  After randomization, subjects will be supplied cartons 
containing 12 pouches per carton. 
If a study drug is believed to be suspect by site staff or a subject, the site should complete the 
Product Complaint Form provided in the Study Procedures Manual, return the form to the 
Sponsor within 24 hours, and follow any additional instructions provided by the Sponsor. 


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11.2.2 
Study Inhalation Device 
The Sponsor will supply the 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 Tyvaso Inhalation System Instructions for Use. 
Subjects will receive 2 Tyvaso Inhalation Systems during Screening Visit 1 at the time of low 
dose inhaled treprostinil initiation.  In addition, the subjects will be provided with the appropriate 
number of plastic device accessories at each study visit.  Damaged devices should be replaced as 
needed during the study. 
If a device is defective or suspected to be defective and the issue cannot be resolved via 
troubleshooting, the site should complete the Product Complaint Form provided in the Study 
Procedures Manual, return the form to the Sponsor within 24 hours, and follow any additional 
instructions provided by the Sponsor.  As indicated in the Study Procedures Manual, a new 
device will be issued to the subject. 
The Investigator or designee will give subjects further instructions regarding the return of the 
Tyvaso Inhalation Systems at the completion of this study. 
11.3 
LABELING 
11.3.1 
Study Drug (Active and Placebo) 
The foil pouch and the outer carton will each be labeled with the same information and sent to 
the study site.  At a minimum, the study drug outer packaging (pouch and carton) will be labeled 
to clearly display the product name, study number, kit identification number, expiry date, 
Sponsor’s name and address, Instructions for Use, and storage information (subject to regulatory 
requirements in each study region or country). 
11.3.2 
Study Inhalation Device 
The Tyvaso Inhalation System and accessories and will be supplied using standard packaging 
labeled with the study number. 
11.4 
STORAGE AND HANDLING OF STUDY DRUG 
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.  


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The ampoules must be kept in the foil pouch to protect from light.  Subjects should be instructed 
that once the foil pouch is opened, the study drug should be used within 7 days.  See the study 
drug label for information on use and storage of the product. 
Study drug will be stored at the site in a securely locked cabinet or enclosure with appropriate 
temperature monitoring.  Access should be strictly limited to the Investigators and their 
designees.  Investigators or their designees may not provide study drug to any individual not 
participating in this protocol. 
11.5 
SUPPLY AND RETURN OF STUDY DRUG AND DEVICES 
Study sites will be supplied with a sufficient quantity of study drug to begin enrollment in the 
study.  At each study visit, all study drug previously dispensed to a subject should be returned to 
the study site, including all used and unused ampoules. 
In the event of Sponsor-approved telemedicine visits, study drug and device accessories may be 
sent to subjects via mail. 
Subjects should return all Sponsor-provided devices and any remaining study drug to the study 
site at the end of the study (withdrawal, discontinuation, termination, or completion). 
In the event of Sponsor-approved telemedicine visits, the Sponsor-provided devices and study 
drug may be returned to the study site via mail. 
11.6 
DRUG AND DEVICE ACCOUNTABILITY 
The Investigator is responsible for study drug/device accountability and reconciliation overall 
and on a per subject basis.  Accountability records are to be maintained during the study, and 
these records include, but are not limited to, the amount of study drug/device received from the 
Sponsor, the amount dispensed to each subject, and the amount of used/unused study drug/device 
returned to the site from the subject. 
At each applicable visit, site personnel will: 
• Collect and document all study drug/device returned by the subject (both used and 
unused). 
• Assess study drug compliance using the dosing instructions given to the subject since the 
previous study visit and the amount of study drug returned. 


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• Re-educate the subject about the importance of following the prescribed dosing regimen 
(if compliance is low). 
Once a Sponsor’s representative confirms drug/device accountability for a completed subject, 
used and unused study drug can either be destroyed onsite locally and a destruction certification 
placed in the subject’s file, or alternately, the study drug can be shipped to the 
Sponsor-designated location for destruction. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
US FDA OR APPLICABLE REGULATORY REQUIREMENTS 
The study will be conducted in accordance with International Council for Harmonisation (ICH), 
Good Clinical Practices (GCP) guidelines, and all applicable national regulations.  The Sponsor 
will obtain the required approval from each national regulatory authority to conduct the study.  
During the conduct of the study, an annual safety report will be compiled by the Sponsor for 
submission to those regulatory authorities and IRBs/IECs that require it.  Any additional national 
reporting requirements specified by the applicable regulations, regulatory authorities, or IRB/IEC 
will also be fulfilled during the conduct of the study. 
12.2 
INFORMED CONSENT REQUIREMENTS 
Before a subject is enrolled in the study, the Investigator or their 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/IEC-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 records. 
The subject should also be informed that if they wish to withdraw from the study any time, a 
written withdrawal of consent will be required.  
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
Prior to study initiation at each site, the Investigator will obtain approval for the study from an 
appropriate IRB/IEC and provide the Sponsor or designee with a copy of the approval letter.  
The IRB/IEC must also review and approve the study site ICF and any other written information 
provided to the subject prior to enrollment, as well as any advertising materials used for subject 


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recruitment.  Copies of the ICF and advertising materials must be forwarded to the Sponsor or 
designee for review before submission to the IRB/IEC 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/IEC approval of these amended documents prior to 
implementation.  Copies of the IRB/IEC correspondence and approval letters must be sent to the 
Sponsor or designee. 
During the conduct of the study, an annual progress report will be compiled by the Sponsor for 
submission to those IRBs/IECs 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/IEC standard procedures.  Additional 
updates will also be provided in accordance with the IRB/IEC’s standard procedures. 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical study, the following documents will be provided to the 
site: Investigator’s Brochure, protocol, ICF, budget agreement, and eCRF. 
The site will be required to provide the following documents to UTC’s designee (Lung 
Biotechnology PBC) prior to study start: signature page of the protocol, Form FDA 1572, 
Financial Disclosure Form, IRB/IEC Composition and Roster, IRB/IEC protocol and informed 
consent approval letters, and Curriculum Vitae of study staff listed on the 1572. 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  UTC, Lung Biotechnology 
PBC, the FDA or other regulatory bodies, and the IRB/IEC governing this study may inspect the 
medical records of any subject involved in this study.  The Investigator may release subject 
medical records to employees or agents of the Sponsor, the IRB/IEC, 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 or any other 
personal information, such as medical record number, any national identification number, etc. 


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13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially adversely affect the safety of participating subjects 
or that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, duration of therapy, assessment variables, the number of subjects treated, or 
subject selection criteria may be made only after consultation between UTC, its designee, Lung 
Biotechnology PBC, and the Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory 
authorities and IRB/IEC prior to implementation. 
A report documenting study termination must also be submitted to and acknowledged by the 
appropriate IRB/IEC for each study site. 
At the end of the study, where applicable, a final report will be provided to the local regulatory 
agencies. 
13.2 
STUDY DOCUMENTATION AND STORAGE 
In accordance with federal/national regulations, the 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 UTC or its designee, Lung 
Biotechnology PBC, before any disposal or change in location of study records. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
In accordance with federal/national regulations, ICH, and GCP guidelines, monitors for UTC or 
its designee, Lung Biotechnology PBC, will periodically contact the site and conduct onsite or 
remote 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 
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13.4 
QUALITY ASSURANCE 
The Sponsor is responsible for ensuring that the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, GCP guidelines, and applicable 
regulatory requirements. 
The Sponsor or a contracted representative of the Sponsor may conduct a quality assurance audit 
of this study.  If such an audit occurs, the Investigator agrees to allow the auditor direct access to 
all relevant study documents and source data and to allocate time to discuss findings and any 
relevant issues.  In addition, this study is subject to an audit by the relevant Regulatory 
Authorities.  If such a regulatory inspection occurs, the Investigator agrees to allow the inspector 
direct access to all relevant study documents and source data. 


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14 
REFERENCES 
Agarwal M, Waxman AB.  Inhaled treprostinil in Group-3 pulmonary hypertension.  J Heart 
Lung Transplant.  2015;34(4 Suppl):S343.  [abstract] 
Anderson JW, Robinson J, Abbott C, et al.  TAPIT treatment of pulmonary hypertension 
associated COPD with inhaled treprostinil: an open label, pilot study.  Am J Respir Crit Care 
Med.  2017;195:A6906.  [abstract] 
Archer SL, Mike D, Crow J, et al.  A placebo-controlled trial of prostacyclin in acute respiratory 
failure in COPD.  Chest.  1996;109(3):750-755. 
Bajwa AA, Shujaat A, Patel M, et al.  The safety and tolerability of inhaled treprostinil in 
patients with pulmonary hypertension and chronic obstructive pulmonary disease.  Pulm Circ.  
2017;7(1):82-88. 
Benza RL, Seeger W, McLaughlin VV, et al.  Long-term effects of inhaled treprostinil in 
patients with pulmonary arterial hypertension: the Treprostinil Sodium Inhalation Used in the 
Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension.  J 
Heart Lung Transplant.  2011;30(12):1327-1333. 
Blanco I, Gimeno E, Munoz PA, et al.  Hemodynamic and gas exchange effects of sildenafil in 
patients with chronic obstructive pulmonary disease and pulmonary hypertension.  Am J Respir 
Crit Care Med.  2010;181(3):270-278. 
Burger CD.  Pulmonary hypertension in COPD: a review and consideration of the role of arterial 
vasodilators.  COPD.  2009;6(2):137-144. 
Channick RN, Olschewski H, Seeger W, et al.  Safety and efficacy of inhaled treprostinil as add-
on therapy to bosentan in pulmonary arterial hypertension.  J Am Coll of Cardiol.  
2006;48(7):1433-1437. 
Chaouat A, Bugnet AS, Kadaoui N, et al.  Severe pulmonary hypertension and chronic 
obstructive pulmonary disease.  Am J Respir Crit Care Med.  2005;172(2):189-194. 
Chaouat A, Naeije R, Weitzenblum E.  Pulmonary hypertension in COPD.  Eur Respir J.  
2008;32(5):1371-1385. 
Eakin EG, Resnikoff PM, Prewitt LM et. al.  Validation of a new dyspnea measure: the UCSD 
Shortness of Breath Questionnaire.  Chest.  1998;113(3):619-624. 
Faria-Urbina, Oliveira RKF, Agarwal M, et al.  Inhaled treprostinil in pulmonary hypertension 
associated with lung disease.  Lung.  2018;196(2):139-146. 
Food and Drug Administration.  Guidance for Industry: Adaptive design clinical trials for drugs 
and biologics.  Washington, DC: U.S. Dept of Health and Human Services; 2019. 
Fijalkowska A, Kurzyna M, Torbicki A, et al.  Serum N-terminal brain natriuretic peptide as a 
prognostic parameter in patients with pulmonary hypertension.  Chest.  2006;129(5):1313-1321. 
Global Initiative for Chronic Obstructive Lung Disease, Inc.  Pocket guide to COPD diagnosis, 
management, and prevention: a guide for health care professionals 2020 report. 
González-Saiz L, Santos-Lozano A, Fiuza-Luces C, et al.  Physical activity levels are low in 
patients with pulmonary hypertension. Annal Transl Med. 2018; 6(11): 205.  


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Holland AE, Spruit MA, Troosters T, et al.  An official European Respiratory Society/American 
Thoracic Society technical standard: field walking tests in chronic respiratory disease.  Eur 
Respir J.  2014;44(6):1428-1446. 
Klinger JR.  Group III pulmonary hypertension: pulmonary hypertension associated with lung 
disease: epidemiology, pathophysiology, and treatments.  Cardiol Clin.  2016;34(3):413-433.  
Malik N, Patel G, Tandon R.  Clinical outcomes in patients with Group III associated pulmonary 
hypertension on prostacyclin therapy.  Am J Respir Crit Care Med.  2013;187:A2272.  [abstract] 
McLaughlin VV, Archer SL, Badesch DB, et al.  ACCF/AHA 2009 expert consensus document 
on pulmonary hypertension: a report of the American College of Cardiology Foundation Task 
Force on Expert Consensus Documents and the American Heart Association: developed in 
collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., 
and the Pulmonary Hypertension Association.  Circulation. 2009;119(16):2250-2294. 
McLaughlin VV, Benza RL, Rubin LJ, et al.  Addition of inhaled treprostinil to oral therapy for 
pulmonary arterial hypertension: a randomized controlled clinical trial.  J Am Coll Cardiol.  
2010;55(18):1915-1922. 
Minai OA, Chaouat A, Adnot S.  Pulmonary hypertension in COPD: epidemiology, significance, 
and management: pulmonary vascular disease: the global perspective.  Chest.  2010;137(6 
Suppl):39S-51S.  
Nathan SD, Flaherty KR, Glassberg MK, et al.  Actigraphy as a clinically meaningful endpoint 
to detect change after treatment with iNO (30 mcg/kg-IBW/hr) in patients at risk of Pulmonary 
Hypertension associated with Pulmonary Fibrosis (poster). 2019;PVRI – Bellerophon 
Therapeutics. 
Nathan, SD, Flaherty KR, Glassberg MK, et al.  A Randomized, double-blind, placebo-
controlled study to assess the safety and efficacy of pulsed, inhaled nitric oxide (iNO) at a dose 
of 30 mcg/kg-IBW/hr (iNO 30) in subjects at risk of Pulmonary Hypertension associated with 
Pulmonary Fibrosis (PH-PF) receiving Oxygen Therapy.  Chest. 2020: 21;S0012-
3692(20)30327-5. doi: 10.1016/j.chest.2020.02.016. 
Oswald-Mammosser M, Weitzenblum E, Quoix E, et al.  Prognostic factors in COPD patients 
receiving long-term oxygen therapy.  Importance of pulmonary artery pressure.  Chest.  
1995;107(5):1193-1198. 
Remodulin (treprostinil) Injection Package Insert.  Research Triangle Park, NC: United 
Therapeutics Corp.; December 2014. 
Seeger W, Adir Y, Barbera JA, et al.  Pulmonary hypertension in chronic lung diseases.  J Am 
Coll Cardiol.  2013;62(25 Suppl):D109-D116. 
Shino MY, Lynch JP 3rd, Saggar R, et al.  Pulmonary hypertension complicating interstitial lung 
disease and COPD.  Semin Respir Crit Care Med.  2013;34(5):600-619. 
Simonneau G, Gatzoulis MA, Adatia I, et al.  Updated clinical classification of pulmonary 
hypertension.  J Am Coll Cardiol.  2013;62(25 Suppl):D34-D41. 
Simonneau G, Montani D, Celermajer DS, et al.  Haemodynamic definitions and updated clinical 
classification of pulmonary hypertension.  Eur Respir J. 2019;53(1):1801913.  Published 2019 
Jan 24. doi:10.1183/13993003.01913-2018. 


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Stolz D, Rasch H, Linka A, et al.  A randomized, controlled trial of bosentan in severe COPD.  
Eur Respir J.  2008;32(3):619-628. 
Thabut G, Dauriat G, Stern JB, et al.  Pulmonary hemodynamics in advanced COPD candidates 
for lung volume reduction surgery or lung transplantation.  Chest.  2005;127(5):1531-1536. 
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. 
Weitzenblum E, Chaouat A, Canuet M, et al.  Pulmonary hypertension in chronic obstructive 
pulmonary disease and interstitial lung diseases.  Semin Respir Crit Care Med.  2009;30(4):458-
470. 
Zakynthinos E, Daniil Z, Papanikolaou J, et al.  Pulmonary hypertension in COPD: 
pathophysiology and therapeutic targets.  Curr Drug Targets.  2011;12(4):501-513. 


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15 
APPENDICES 
15.1 
PROCEDURE FOR 6-MINUTE WALK TEST 
General Procedures: 
The 6MWT should be administered consistently at each study site throughout the study.  The 
administration of the test and specifications of the testing area should be generally consistent 
with the American Thoracic Society guidelines and the usual practice of the study site.  If the 
subject was assessed at baseline using oxygen therapy, then all 6MWTs during the study must be 
conducted with the same oxygen flow rate and mode of administration.  Similarly, if the baseline 
assessment was conducted without oxygen therapy, then subsequent assessments should also be 
conducted without oxygen therapy.  Before each 6MWT, the subject should rest (seated) for at 
least 10 minutes. 
The area used for the 6MWT should be premeasured at approximately 30 meters in length (but 
no shorter than 15 meters [16 yards or 50 feet] 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, they may stand or sit and then begin again when 
they are sufficiently rested, but the clock will continue to run.  At the end of 6 minutes, the tester 
will call “stop where you are” while simultaneously stopping the watch, and then measure the 
distance walked.   
Instructions to the Subject: 
Subjects will be instructed that the preceding meal should be light.  Subjects should be told to 
wear comfortable clothing and sneakers or comfortable walking shoes.   
The person administering the test will use the following exact dialogue with the subject: 
“The purpose of this test is to find out how far you can walk in 6 minutes.  You will start from 
this point and follow the hallway to the marker (eg, chair) at the end, turn around and walk back.  
When you arrive back at the starting point you will go back and forth again.   


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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 
MODIFIED BORG DYSPNEA SCALE 
Immediately following the 6MWT, the person administering the test will obtain a rating of 
dyspnea using the Borg dyspnea scale.  The person will use the following dialogue:  
“I would like to use the following scale to indicate the maximal shortness of breath you had 
during the walk test (indicate the Borg dyspnea scale).  If there was no shortness of breath at all 
you would point to 0; if the shortness of breath was not very great you would choose from 0.5 to 
2; if you were somewhat more short of breath you would select 3; and if the breathing was 
getting very difficult, you would choose 4 to 9, depending on just how hard it was; 10 represents 
the greatest shortness of breath you have ever experienced in your life.  If one of the numbers 
does not exactly represent how short of breath you are, then you can choose a fraction between.  
For example, if you had shortness of breath somewhere between 4 and 5, you could choose 4.5.”  
Perceived Breathlessness (Borg Scale)  
0  
NOTHING AT ALL  
0.5 
VERY VERY SLIGHT (just noticeable)  
1  
VERY SLIGHT  
2  
SLIGHT  
3  
MODERATE  
4  
SOMEWHAT SEVERE  
5  
SEVERE  
6  
7  
VERY SEVERE  
8  
9  
VERY VERY SEVERE (almost maximum)  
10 
MAXIMUM 


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15.3 
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (EXAMPLE) 


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15.4 
UNIVERSITY OF CALIFORNIA SAN DIEGO SHORTNESS OF BREATH 
QUESTIONNAIRE (EXAMPLE) 
 


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15.5 
PATIENT GLOBAL ASSESSMENT (EXAMPLE) 
Question 1: “Over the past week, on average, how many times has fatigue limited your ability 
to do what you wanted?” 
• All of the time 
• Several times per day 
• At least once a day 
• 3 or more times per week, but not every day 
• 1-2 times per week 
• Less than once a week 
• Never over the past week 
Question 2: “Over the past week, on average, how many times has shortness of breath limited 
your ability to do what you wanted?” 
• All of the time 
• Several times per day 
• At least once a day 
• 3 or more times per week, but not every day 
• 1-2 times per week 
• Less than once a week 
• Never over the past week 


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15.6 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Investigator or a designated member of their 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. 
• Mild: Discomfort noticed, but no disruption to daily activity 
• Moderate: Discomfort sufficient to disrupt normal daily activity 
• Severe: Inability to work or perform normal daily activity 


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SERIOUSNESS 
An SAE 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 hospitalizationa, 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). 
a 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 that was elective or pre-planned for a pre-existing condition and not associated 
with any deterioration in condition (eg, pre-planned operation which does not lead to 
further complications etc). 
• Treatment of an emergency, in an outpatient setting for an event not fulfilling any of the 
definitions of serious as given above and not resulting in hospital admission. 
CAUSALITY 
An estimate of causality between a specified AE and the study drug is made by the Investigator.  
Several factors should be considered when determining causality.  These factors include 
temporal relationship and response to withdrawal or reintroduction of the study drug.  
Definitions of the causality categories are as follows: 
• NOT RELATED – There is not a temporal relationship to study drug administration (too 
early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, or concurrent disease and the SAE, or any of the following: 
• An event that precedes the first administration of study drug 
• An event for which the cause is clearly related to an external event 
• Temporal relationship to study drug is atypical 
• Is readily explained by an intercurrent illness AND has an expected level of severity, 
duration, and resolution 
• An alternative explanation (concomitant drug, intercurrent illness) is likely 
• POSSIBLE – There is a reasonable causal relationship between the study drug and the 
SAE.  Dechallenge information is lacking or unclear, study drug administration was not 
modified in response to the SAE, or any of the following: 


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• Has a reasonable temporal relationship to study drug 
• The event has a plausible biological link to the activity of the study drug 
• Is unlikely to be related to an intercurrent illness or has an unexpected degree of 
severity, duration, or complication 
• PROBABLE – There is a reasonable causal relationship between the study drug and the 
SAE.  The event responds to dechallenge - the event resolves or improves with 
modification of study drug administration.  Rechallenge (the original study drug was 
restarted) is not required, or any of the following: 
• Has a reasonable temporal relationship to study drug 
• The event has a plausible biologic link to the activity of the study drug 
• Not readily explained by an intercurrent illness 
• Not readily explained by external event 
• Improves on discontinuation of study drug 
• If study drug has been discontinued, may recur or reintroduction of study drug 
ACTION TAKEN 
STUDY DRUG DOSE MODIFICATION 
• Dose Not Changed – The dose or regimen of the study drug was not changed 
• Dose Increased – The dose or regimen of study drug was increased  
• Dose Decreased – The dose or regimen of study drug was decreased 
• Drug Interrupted – Administration of the study drug was stopped temporarily 
• Drug Withdrawn – Administration of the study drug was stopped permanently and not 
restarted 
• Unknown – Changes to the administration of the study drug cannot be determined 
• Not Applicable (only used if the AE was started and resolved prior to Tyvaso dosing used 
in the study treatment periods, or for an AE that started after permanent discontinuation 
from study treatment) 
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. 


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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. 
• 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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SAP_001.pdf: 
United Therapeutics Corp. 
Statistical Analysis Plan: RIN-PH-304 
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Statistical Analysis Plan: RIN-PH-304
Study Title: 
A Phase 3, Randomized, Placebo-controlled, Double-blind, Adaptive Study 
to Evaluate the Safety and Efficacy of Inhaled Treprostinil in Patients with 
Pulmonary Hypertension due to Chronic Obstructive Pulmonary Disease 
(PH-COPD) 
Study Number: 
RIN-PH-304 
Study Phase: 
3 
Product Name: 
Inhaled Treprostinil 
Indication: 
Treatment of PH-COPD 
IND Number: 
070362 
Sponsor: 
United Therapeutics Corp. 
  
 
 
Author: 
 
Final Date: 
07 January 2022 
Version: 
2.0 
NCT #: NCT03496623


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
Table of In-Text Tables .................................................................................................................4 
ABBREVIATIONS AND DEFINITIONS ...................................................................................5 
1 PREFACE .................................................................................................................................7 
2 STUDY OBJECTIVES AND ENDPOINTS ..........................................................................9 
2.1 
OBJECTIVES .....................................................................................................................9 
2.2 
PRIMARY ENDPOINT .....................................................................................................9 
2.3 
ALTERNATIVE PRIMARY ENDPOINT .......................................................................9 
2.4 
SECONDARY EFFICACY ENDPOINTS .....................................................................10 
2.5 
SAFETY ENDPOINTS .....................................................................................................10 
2.6 
EXPLORATORY ENDPOINTS .....................................................................................11 
3 STUDY DESIGN ....................................................................................................................11 
3.1 
GENERAL DESCRIPTION ............................................................................................11 
4 SEQUENCE OF PLANNED ANALYSES ..........................................................................13 
4.1 
INTERIM ADAPTIVE ANALYSIS ................................................................................14 
4.2 
INTERIM EFFICACY ANALYSIS ................................................................................14 
4.2.1 
 ................................................................................15 
4.2.2 
Formal Criteria for Interim Efficacy Analyses .........................................................15 
4.3 
ALTERNATIVE PRIMARY ENDPOINT .....................................................................16 
4.4 
FINAL ANALYSIS ...........................................................................................................16 
5 SAMPLE SIZE CONSIDERATIONS .................................................................................16 
5.1 
PLANNED STUDY ...........................................................................................................16 
5.2 
 .........................................................................................................17 
6 ANALYSIS POPULATIONS ...............................................................................................18 
7 GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................19 
7.1 
BASELINE ........................................................................................................................20 
7.2 
CHANGE FROM BASELINE .........................................................................................20 
7.3 
STUDY DAY .....................................................................................................................20 
7.4 
COVARIATES ..................................................................................................................21 
7.5 
EXAMINATION OF SUBGROUPS ...............................................................................21 
7.6 
PREMATURE DISCONTINUATION AND MISSING DATA ...................................21 
7.7 
MULTIPLE COMPARISONS AND MULTIPLICITY ...............................................22 
8 STUDY POPULATION ........................................................................................................23 
8.1 
PATIENT ACCOUNTABILITY .....................................................................................23 
8.1.1 
Treatment Compliance ................................................................................................23 
8.1.2 
Protocol Deviations ......................................................................................................23 
8.2 
ELIGIBILITY CRITERIA ..............................................................................................23 
8.3 
OTHER DESCRIPTIONS OF STUDY POPULATION ..............................................23 
8.3.1 
Demographics ...............................................................................................................24 


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8.3.2 
Baseline Disease Characteristics .................................................................................24 
8.3.3 
Medications ...................................................................................................................25 
8.3.3.1 
Prior Medications .....................................................................................................25 
8.3.3.2 
Concomitant Medications ........................................................................................25 
8.3.4 
Medical History ............................................................................................................26 
8.3.5 
Subject Disposition .......................................................................................................26 
9 EFFICACY ANALYSES.......................................................................................................27 
9.1 
PRIMARY EFFICACY MEASURE ...............................................................................27 
9.1.1 
Hypothesis Test .............................................................................................................27 
9.1.2 
Primary Efficacy Analysis Data ..................................................................................27 
9.1.3 
Primary Efficacy Analysis ...........................................................................................28 
9.1.4 
Sensitivity Analyses ......................................................................................................29 
9.1.4.1 
Deviations from Protocol .........................................................................................29 
9.1.4.2 
Carryover Effect .......................................................................................................30 
9.1.4.3 
Multiple Imputation for Missing Data Due to Death and Too Ill to Walk ..........30 
9.1.4.4 
 .........................................31 
9.2 
ALTERNATIVE PRIMARY ENDPOINT .....................................................................32 
9.2.1 
Pre-specified Primary Endpoint Switching Algorithm .............................................32 
9.2.2 
Alternative Primary Endpoint Hypothesis Test ........................................................34 
9.2.3 
Alternative Primary Efficacy Endpoint Derivation ..................................................34 
9.2.4 
Alternative Primary Efficacy Analysis .......................................................................35 
9.2.5 
Alternative Primary Endpoint Sensitivity Analyses .................................................35 
9.2.5.1 
 ...........................................................................................36 
9.2.5.2 
 ......................................................36 
9.3 
KEY SECONDARY EFFICACY MEASURES .............................................................37 
9.3.1 
Actigraphy .....................................................................................................................37 
9.3.1.1 
Overall Activity .........................................................................................................37 
9.3.1.2 
Moderate to Vigorous Physical Activity .................................................................39 
9.3.1.3 
Actigraphy Analyses .................................................................................................39 
9.3.2 
Borg Dyspnea Score .....................................................................................................40 
9.3.3 
6MWD and Borg Dyspnea Composite Score .............................................................40 
9.3.4 
NT-proBNP ...................................................................................................................42 
9.4 
OTHER SECONDARY EFFICACY MEASURES .......................................................42 
9.4.1 
St. George’s Respiratory Questionnaire ....................................................................42 
9.4.2 
University of California San Diego Shortness of Breath Questionnaire .................43 
9.4.3 
 ....................................................................43 
9.4.4 
Patient Global Assessment ...........................................................................................44 
9.5 
EXPLORATORY EFFICACY MEASURES .................................................................44 
10 SAFETY ANALYSES ...........................................................................................................44 
10.1 EXTENT OF EXPOSURE ...............................................................................................45 


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10.2 ADVERSE EVENTS .........................................................................................................45 
10.2.1 
Severity of Adverse Event ............................................................................................45 
10.2.2 
Relationship to Study Treatment ................................................................................46 
10.2.3 
Action Taken with Study Treatment ..........................................................................46 
10.2.4 
Outcome of Treatment Emergent Adverse Event .....................................................46 
10.2.5 
Summary of Treatment Emergent Adverse Events ..................................................46 
10.3 DEATHS ............................................................................................................................47 
10.4 PHYSICAL EXAM ...........................................................................................................47 
10.5 CLINICAL LABORATORY EVALUATIONS .............................................................48 
10.6 VITAL SIGNS ...................................................................................................................49 
10.7 ELECTROCARDIOGRAM EVALUATIONS ..............................................................49 
10.8 PULMONARY FUNCTION TESTS ..............................................................................49 
10.9 
 .............................................................................................50 
10.10 OXYGENATION ..............................................................................................................50 
10.10.1 Pulse Oximetry .............................................................................................................50 
11 REFERENCES .......................................................................................................................51 
12 APPENDICES ........................................................................................................................53 
12.1 LIST OF TABLES ............................................................................................................53 
12.2 LIST OF LISTINGS .........................................................................................................54 
12.3 LIST OF FIGURES ..........................................................................................................54 
12.4 CONTINGENT PARALLEL DESIGN ANALYSIS PLAN .........................................55 
12.4.1 
Study Design .................................................................................................................55 
12.4.2 
Interim Efficacy Analysis ............................................................................................55 
12.4.3 
General Considerations For Data Analyses ...............................................................56 
12.4.4 
Covariates .....................................................................................................................57 
12.4.5 
Primary Efficacy Measure ...........................................................................................57 
12.4.6 
Secondary Efficacy Measures .....................................................................................61 
12.4.7 
Safety Analyses .............................................................................................................61 
 
Table of In-Text Tables 
Table 10-1 
Clinical Laboratory Parameters .............................................................................48 
 


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ABBREVIATIONS AND DEFINITIONS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
BMI 
Body mass index 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DLCO 
Diffusion capacity of lung for carbon monoxide 
DSMC 
Data Safety Monitoring Committee 
DSP 
Distance saturation product 
ECG 
Electrocardiogram 
FAS 
Full Analysis Population 
FCS 
Fully conditional specification  
FEF 
Forced expiratory flow 
FEV1 
Forced expiratory volume in 1 second 
FEV6 
Forced expiratory volume in 6 seconds 
FVC 
Forced vital capacity 
HR 
Heart rate 
ICF 
Informed Consent Form 
LS 
Least Square  
MAR 
Missing at random 
MET 
Metabolic equivalent task 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures  
mPAP 
Mean pulmonary artery pressure  
MVPA 
Moderate to vigorous physical activity 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
PEF 
Peak expiratory flow 
PFT 
Pulmonary function test 
PGA 
Patient global assessment 
PH 
Pulmonary hypertension 
PH-COPD 
Pulmonary hypertension due to chronic obstructive pulmonary disease 
PR 
Electrocardiographic wave of P-R interval 
PT 
Preferred Term 
PVR 
Pulmonary vascular resistance 
QID 
4 times daily 
QOL 
Quality of life 
QRS 
Electrocardiographic wave of QRS interval 
QT 
Electrocardiographic wave of QT interval 
RHC 
Right heart catheterization 
RVSP 
Right ventricular systolic pressure 


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SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SGRQ 
St. George’s Respiratory Questionnaire 
SOC 
System Organ Class 
SpO2 
Saturation peripheral capillary oxygenation 
TLC 
Total lung capacity 
UCSD SOBQ 
University of California San Diego Shortness of Breath Questionnaire 
WHO 
World Health Organization 
 


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1 
PREFACE 
This plan provides further details of the planned analyses for Study RIN-PH-304 as presented in 
the study protocol.  Based on the original Study Protocol RIN-PH-304 dated 12 January 2018 
and the subsequent study protocol amendments (latest version study protocol Amendment 4 
dated 20 October 2020), it provides further details of the planned analyses described 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).  
The RIN-PH-304 study is an adaptive study with a (fully blinded) decision for design 
modification based on enrollment and missing data metrics.  This SAP pre-specifies analyses 
under the original design, as described in the study protocol (and associated amendments).  To 
address the adaptive design feature of this study for a Contingent Parallel Design, as defined by 
the criteria in Section 10.2.1 of the study protocol, this SAP has been formally amended to 
provide analytic plans and details for the Contingent Parallel Design in Appendix 12.4.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In light of the missing data arising from COVID-19, this SAP incorporates the ability to invoke a 
new definition for the primary endpoint based on a fully blinded assessment for missing data.  
This SAP defines the decision rules, data handling, and analyses for the updated definition of the 


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primary endpoint.  In general, the amount of missing 6MWD data potentially due to the COVID-
19 pandemic interfering with onsite measurements will define if adaptation is necessary.  At the 
conclusion of the study, a blinded analysis will be performed to assess the extent of missing 
primary efficacy endpoint data (ie, 6MWD data).  If the absence of 6MWD data, combined 
across subjects, treatment periods, and key visits (Baseline and Study Week 12) to be used for 
the final primary endpoint analysis would likely lead to an underpowered study or yield 
indeterminate results, an alternate primary endpoint will be used for the final primary endpoint 
analysis (see Section 9.2).  This adaptation intends that the 6MWD is to be used as the primary 
efficacy endpoint for this study, except in the case where onsite measurements for the 6MWD 
are not available, and will occur regardless of Adaptation 1 (ie, for either the Original Crossover 
Design or the Contingent Parallel Design).   
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
OBJECTIVES 
The primary objective of this study is to demonstrate the efficacy of inhaled treprostinil 
compared to placebo in improving exercise ability as measured by change from baseline in 
6MWD following 12 weeks of active treatment in subjects with pulmonary hypertension due to 
chronic obstructive pulmonary disease (PH-COPD). 
All secondary, safety, and exploratory objectives can be found in Section 2 of the study protocol.  
2.2 
PRIMARY ENDPOINT 
The primary efficacy endpoint for this study is the change in 6MWD from Baseline to Week 12 
in subjects with PH-COPD.  
2.3 
ALTERNATIVE PRIMARY ENDPOINT 
An alternative primary efficacy endpoint of 6MWD/MVPA ranks will replace the change in 
6MWD from Baseline to Week 12 if pre-specified rules (see Section 9.2 of this SAP for further 
details of the alternative primary endpoint and Section 9.3.1.2 for details regarding MVPA 
derivation).  


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2.4 
SECONDARY EFFICACY ENDPOINTS 
The secondary efficacy endpoints are the comparison for the effect of inhaled treprostinil versus 
placebo after 12 weeks of active treatment. Specifically: 
• Change in MVPA as measured by actigraphy from Baseline to Week 12 
• Change in overall activity as measured by actigraphy from Baseline to Week 12 
• Change in Borg dyspnea score from Baseline to Week 12  
• Change in 6MWD/Borg dyspnea composite score from Baseline to Week 12 
• Change in quality of life (QOL) measured by the St. George’s Respiratory Questionnaire 
(SGRQ) and the University of California San Diego Shortness of Breath Questionnaire 
(UCSD SOBQ) from Baseline to Week 12 
• Change in plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) 
levels from Baseline to Week 12 
• Change in PGA from Baseline to Week 12. 
2.5 
SAFETY ENDPOINTS 
The safety of inhaled treprostinil will be evaluated compared to placebo on the following 
parameters in comparison to placebo: 
• AEs 
• Clinical laboratory parameters 
• Electrocardiograms (ECGs) 
• Physical examination (PE) findings 
• Oxygenation 
• Pulse oximetry (saturation of peripheral capillary oxygenation [SpO2]) 
• Supplemental oxygen requirement (L/min) 
• Pulmonary function tests (PFTs) 
• Forced expiratory volume in 1 second (FEV1) 
• Forced vital capacity (FVC) 
• Total lung capacity (TLC) 
• Diffusion capacity of lung for carbon monoxide (DLCO) 
• Vital sign measurements  
• At-home spirometry. 


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2.6 
EXPLORATORY ENDPOINTS 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
STUDY DESIGN 
3.1 
GENERAL DESCRIPTION 
This is a multicenter, randomized, double-blind, placebo-controlled, 34-week, crossover study of 
inhaled treprostinil (Tyvaso® [treprostinil] Inhalation Solution) in males and females 18 years or 
older diagnosed with WHO Group 3 pulmonary hypertension (PH) associated with chronic 
obstructive pulmonary disease (COPD).  Subject eligibility will be based on the inclusion and 
exclusion criteria described in Section 4 of the protocol.  
Approximately 136 eligible subjects will be randomized with half of the subjects receiving 12 
weeks of active study drug (Period 1) then 12 weeks of placebo (Period 2) and the other half 
receiving 12 weeks of placebo (Period 1) then 12 weeks of active study drug (Period 2).  Under 
the original study design, all randomized subjects will be treated with both active study drug and 
placebo. 


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The study will consist of the following periods: 
Screening Period: At Screening Visit 1, prospective subjects (defined as having prior 
echocardiogram findings of right ventricular systolic pressure [RVSP] >40 mmHg and/or 
evidence of right ventricular hypertrophy or dysfunction), who sign the Informed Consent 
Form (ICF) will generally undergo all non-invasive screening assessments to evaluate 
eligibility, as listed in the inclusion/exclusion criteria.  Potentially eligible subjects will 
undergo a right heart catheterization (RHC), including a vasodilator test and oxygen 
challenge, if possible, to confirm eligibility.  If RHC results are available from a test 
performed within the previous 12 months (even if done without oxygen or vasodilator 
challenge), a repeat RHC during Screening Visit 1 is not needed.  A window of up to 6 weeks 
is permitted to complete all assessments required for Screening Visit 1, including the start of 
low dose inhaled treprostinil.  Prospective subjects meeting all eligibility criteria will be 
provided with and trained on inhalation of study drug using the Tyvaso Inhalation System 
and begin low dose (3 breaths QID) inhaled treprostinil for a minimum of 14 days (maximum 
of 18 days) to ensure tolerability and compliance.  Subjects will be issued Sponsor-provided 
actigraphy, spirometry, and smart devices during Screening Visit 1 at the time of low dose 
inhaled treprostinil initiation for measurement of at-home activity and FEV1/FVC.  Subjects 
will be given training on the at-home use of these devices, as well as Instructions for Use.  At 
Screening Visit 2, subjects will return to the study site following completion of low dose 
inhaled treprostinil exposure to undergo scheduled assessments and return unused study drug.  
Subjects who are intolerant of therapy (as determined by the Investigator), unable to follow 
the dosing regimen, or noncompliant with actigraphy, at-home spirometry, or smart device 
use during the Screening Period will be ineligible for randomization and deemed screen 
failures. 
Washout Period - Washout 1: During Washout 1 (Study Week -1), prospective subjects 
will refrain from the use of inhaled treprostinil for a minimum of 7 days (maximum of 14 
days) preceding entry into the Treatment Period 1 Baseline Visit (Study Week 1).  Subjects 
will be contacted by telephone mid-week in Washout Period 1 to monitor safety. 


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Treatment Period 1: Eligible subjects approved by the Sponsor’s Medical Monitor will 
undergo Treatment Period 1 Baseline Visit assessments (Study Week 1), be assigned to a 
treatment group based on the randomization schedule, and receive study drug.  Target dosing 
with study drug (after titration) will be 12 breaths QID or to maximum tolerated dose.  Two 
additional study visits to the study site will be conducted after the Treatment Period 1 
Baseline Visit to complete study assessments (Study Weeks 6 and 12).  Subjects will be 
contacted weekly by telephone during study drug titration (until 12 breaths QID or the 
maximum tolerated dose is achieved) and as needed thereafter to provide dosing instructions 
and to assess tolerance to study drug, AEs, and changes in concomitant medications. 
Washout Period - Washout 2: Subjects will refrain from the use of study drug for a 
minimum of 7 days (maximum of 14 days) after the Treatment Period 1 Week 12 Visit 
(Study Week 12) and preceding entry into Treatment Period 2 (Study Week 14).  Subjects 
will be contacted by telephone mid-week in Washout Period 2 to monitor safety. 
Treatment Period 2: Subjects will undergo Treatment Period 2 Baseline Visit assessments 
(Study Week 14), be provided treatment based on the randomization schedule, and receive 
study drug for this period.  Target dosing with study drug (after titration) will be 12 breaths 
QID or to the maximum tolerated dose.  Two additional study visits to the study site (Study 
Weeks 19 and 25) will be conducted after the Treatment Period 2 Baseline Visit (Study 
Week 14) to complete study assessments.  Subjects will be contacted weekly by telephone 
during study drug titration (until 12 breaths QID or the maximum tolerated dose is achieved) 
and as needed thereafter to provide dosing instructions and to assess tolerance to study drug, 
AEs, and changes in concomitant medications.  At the completion of Treatment Period 2 
(Study Week 25), subjects will be offered enrollment in the open-label extension study, RIN-
PH-305. 
4 
SEQUENCE OF PLANNED ANALYSES 
In brief, the specified primary endpoint for this study is 6MWD, which is a validated and reliable 
measure of exercise ability in patients with chronic respiratory diseases.  Subjects perform the 
test at the clinical site following published guidelines and tests are conducted by trained 
personnel.  For further details regarding the 6MWT and 6MWD, please see the study protocol.  


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The alternative primary endpoint for this study is a combined and standardized rank for 6MWD 
and MVPA, which is a measurement of subjects’ time spent in moderate to vigorous activity 
during the course of daily living.  The study protocol provides further detail about actigraphy and 
Section 9.3 of this SAP gives information about how blinded assessments will occur, the 
handling of data for actigraphy and MVPA, etc.  
4.1 
INTERIM ADAPTIVE ANALYSIS 
Under the Original Crossover Design, at approximately 75% of subjects randomized, a blinded 
interim analysis will be performed to assess the extent of missing data for the primary analysis 
for the crossover design.  The outcome of the analysis will inform a decision for the study to 
continue as the Original Crossover Design or switch to the Contingent Parallel Design as 
follows: 
• If data presence ≥85% for 6MWD or actigraphy data at the end of Treatment Period 2 
(Study Week 25), the study will continue as planned under the Original Crossover 
Design. 
• If data presence <85% for both 6MWD and actigraphy data at the end of Treatment 
Period 2 (Study Week 25), the study will switch to the Contingent Parallel Design. 
The goal of this assessment is to determine the amount of missing data due to subject dropout or 
otherwise lack of measurement (regardless of onsite or remote) and the outcome will be whether 
study continues to completion as the Original Crossover Design or the Contingent Parallel 
Design. Should there be a switch to the Contingent Parallel Design, the analysis plan described 
in Appendix 12.4 will be followed.  
4.2 
INTERIM EFFICACY ANALYSIS 
A single interim efficacy analysis will be conducted when 75% of the subjects (ie, ~100 subjects) 
have completed the 26-week Treatment Period if both of the following criteria are met: a) the 
expected time to randomize the final (136th) subject is greater than 3 months; b) at least 90% of 
the 6MWD data is present for both Period 1: Baseline and Week 12 and Period 2: Baseline and 
Week 12 for these subjects.  The projected time to randomize will be based on the average 
recruitment rate for the prior 6 months.  This plan will allow early stopping for efficacy if 
recruitment is slow enough to warrant an interim review and if the data are sufficiently complete.  


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A non-binding futility analysis will also be conducted as part of the interim analysis.  Analyses 
will be conducted for the primary endpoint of 6MWD per Section 9.1.  Analyses will use the 
entire Full Analysis Population (FAS), including all available data for subjects who may be still 
ongoing in the study.  The independent external statistical consultant will provide the results of 
these analyses to the independent Data Safety Monitoring Committee (DSMC) for their review 
and recommendation.  The Sponsor will remain fully blinded throughout this process. 
The DSMC Charter will contain more specific details regarding the processes for the interim 
analyses for efficacy and futility, such as timelines for data lock, information transfer and 
communications.  However, the following approaches will be taken for projecting recruitment 
and the criteria for the interim analyses for efficacy. 
4.2.1 
 
 
 
 
 
 
 
  
 
 
 
  
4.2.2 
Formal Criteria for Interim Efficacy Analyses  
If conducted, the interim analysis will apply a 2-sided alpha level of 0.010 (75% information 
fraction), and at the final analysis at a 2-sided alpha of 0.022 with the overall Type I error rate at 
2-sided alpha of 0.05.  Efficacy boundaries for early stopping of the study for efficacy are based 
                                                 
1 Subjects who were active in the treatment periods of this protocol as of 13 March 2020 will be assessed on a case-by-case basis 
by the Sponsor for inclusion of populations for adaptive, interim, and final analyses.  All decisions will be documented and 
presented in the clinical study report. 


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on a Lan-DeMets spending function, with an O’Brien-Fleming boundary (GD-INFO; EAST®, 
Cytel, Version 6.5).  The corresponding non-binding futility boundary is provided as p-value less 
than or equal to 0.227 for the interim analysis (Lan-DeMets: O’Brien-Fleming). 
4.3 
ALTERNATIVE PRIMARY ENDPOINT  
To address the possibility of missing data arising from COVID-19, this SAP incorporates the 
ability to determine a new definition for the primary endpoint based on a fully blinded 
assessment for missing data.  Section 9.2 of the SAP defines the decision rules, data handling, 
and analyses for the alternative definition of the primary endpoint.  In general, the amount of 
missing 6MWD data potentially due to the COVID-19 pandemic interfering with onsite 
measurements will define whether adaptation is necessary.  At the conclusion of the study, a 
blinded analysis will be performed to assess the extent of missing primary efficacy endpoint data 
(ie, 6MWD data).  If the absence of 6MWD data in the Treatment Period, combined across 
subjects, treatment periods, and key visits (Baseline and Study Week 12) to be used for the final 
primary endpoint analysis would likely lead to an underpowered study or yield indeterminate 
results, an alternative primary endpoint will be used for the final primary endpoint analysis (see 
Section 9.2 for decision rules).  The 6MWD is to be used as the primary efficacy endpoint for 
this study, except in the case where onsite measurements for the 6MWD are not practically 
available, and will occur independently of Adaptation 1 (ie, for either the Original Crossover 
Design or the Contingent Parallel Design).   
4.4 
FINAL ANALYSIS 
The final analysis is planned after all subjects have completed treatment or withdrawn from the 
study, the study database is locked, and the randomization codes have been revealed.  All 
statistical analyses will be performed by the Sponsor’s biostatistics department personnel (or 
appropriate designees) using SAS®, Version 9.4 (or higher) or other validated software. 
5 
SAMPLE SIZE CONSIDERATIONS 
5.1 
PLANNED STUDY 
The Original Crossover Design is a 2x2 crossover study designed to have 90% power to detect 
a placebo-corrected mean change from baseline difference of 30 meters, assuming that the 


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standard deviation of differences is 85 meters2 and using a 2-group t-test with a 0.01 2-sided 
significance level, with a sample size of 124 subjects (62 in each sequence group).  To account 
for a discontinuation rate of approximately 10%, the total sample size will be approximately 
136 subjects.  
The Contingent Parallel Design is a parallel-group study designed to use an allocation ratio of 
1:1 between inhaled treprostinil and placebo, with a sample size of 266 subjects (133 per 
treatment) that 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.  To account for a discontinuation rate of 
approximately 15%, the total sample size will be approximately 314 subjects. Should there be a 
switch to the Contingent Parallel Design, the analysis plan described in Appendix 12.4 will be 
followed. 
5.2 
 
 
 
 
  
 
 
 
 
 
 
 
 
                                                 
2 Note. Due to the smaller sample size expected for the crossover design a more conservative standard deviation of 
the difference (85 meters) was assumed (compared to 75 meters for a parallel design).  


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6 
ANALYSIS POPULATIONS 
This study has the following 4 analysis populations3: 
• Randomized Population (RAND): All subjects randomized to the study.  Tabulations for 
disposition of subjects will be generated from this population. 
• Full Analysis Population (FAS): All randomized subjects who received at least 1 dose of 
study treatment (treprostinil or placebo).  All subjects will be counted in the group to 
which they were randomized, regardless of the study treatment they were given.  All 
efficacy analyses will be performed on this population, unless otherwise specified. 
• Per-Protocol Analysis Population (PPROT): All randomized subjects who are included in 
the FAS but 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 Analysis Population will be reviewed at a blinded data 
review meeting and documented prior to the database lock and the study unblinding.  
• Safety Population (SAFETY): All enrolled subjects who received at least 1 dose of 
treprostinil, during low dose run-in, or study treatment (treprostinil or placebo) during the 
randomized portion of the study.  All Safety Population subjects will be counted in the 
group corresponding to the study treatment received, regardless of randomized 
                                                 
3 Subjects who were active in the treatment periods of this protocol as of 13 March 2020 will be assessed on a case-by-case basis 
by the Sponsor for inclusion of populations for adaptive, interim, and final analyses.  All decisions will be documented and 
presented in the clinical study report.  


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assignment.  All safety analyses will be performed on this Safety Population, unless 
otherwise specified. 
A summary table presenting the number and percentages of subjects for each analysis population 
will be presented by treatment group.  Subjects who are excluded from any analysis population 
will be listed with reason for exclusion.  The Sponsor must approve this list before treatment is 
unblinded and thus before performing final analyses. 
7 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Given the crossover design utilized for this study, efficacy and safety summary tables will follow 
the general format that baseline and post-baseline data will be presented by the assigned 
treatment condition when those data are observed during the treatment period.  Treatments will 
be labeled as “Treprostinil” and “Placebo” to correspond with the assigned treatment condition.  
Any efficacy and safety data that are collected during the washout period between Periods 1 and 
2 will be presented for the assigned treatment condition from Period 1.  Any follow-up data 
collected after Period 2, while on this study, will be assigned to Period 2.  Subjects who are not 
retained will not be replaced during the study.  
For continuous variables, the summary statistics will include the mean, standard deviation, 
median, lower quartile, upper quartile, minimum, and maximum.  Statistics will be expressed 
using the level of precision in which the variable was collected.  For discrete variables, 
summaries will include the frequency and percent in each category.  Whenever practical, 
categories of discrete variables will be ordered and labeled as they appear in the case report form 
(CRF), and all categories represented on the CRF will be included in summaries, even when they 
do not apply to any patients in the study. 
For data collected on a fixed schedule, the nominal time point will be used for summarization. 
Evaluations from Unscheduled Visits are to be mapped to Scheduled Visits to the extent possible 
per the protocol-specified windows.  Repeat or redundant observations within an assessment 
window and observations that do not fall within any predefined assessment window will be 
excluded from summaries.  If an evaluation is repeated, such as to confirm an observed aberrant 
laboratory value, the analyses will use the later value if within the protocol-specified window.  


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Unless otherwise specified, all final statistical tests will be 2-sided at alpha level 0.05 if the 
interim analysis is not conducted, and 0.022, if conducted.  All tables will be presented in 
landscape format.  For practical reasons, the point size may be reduced to (but not less than) 7 
point for tables that contain too much information to fit into a single page. SAS® version 9.4 or 
higher will be used.  The Sponsor’s Biostatistics Department will analyze the efficacy and safety 
data.  
7.1 
BASELINE 
Given the crossover design utilized for this study, Periods 1 and 2 each have a different baseline 
for efficacy measurements: Period 1: Day 1 and Period 2: Week 14.  With the exception of 
actigraphy measurements, the baseline value will be defined as the non-missing value 
immediately prior to dosing with study drug for Period 1: Day 1 and Period 2: Week 14.  The 
baseline period for actigraphy measurements will be the last 7 days during the washout period 
prior to the day of dosing on Day 1 and Week 14.  In the event that the washout period is less 
than 7 days then only the non-dosing days will be used to derive a baseline average.  
For safety evaluations, the baseline will be defined as the last evaluation closest, but prior to, the 
first dose of study drug during the low dose run-in period.  
7.2 
CHANGE FROM BASELINE 
For parameters measured at baseline, the variables of interest are the change from baseline of the 
original measurements.  Unless otherwise specified, all changes from baseline (for all variables 
where this is applicable) will be calculated as follows: 
Change from baseline = Post baseline – baseline 
7.3 
STUDY DAY 
Study day will be calculated relative to first dose of study drug (Day 1), after randomization. 
Specifically: 
Study day before dosing = (Date of occurrence – Date of first dose of study drug). 
Study day on or after dosing = (Date of occurrence – Date of first dose of study drug) + 1. 


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7.4 
COVARIATES 
Efficacy analyses will include the assigned treatment sequence and period order as covariates.  
Change from baseline analyses will include the baseline measurement as a continuous covariate.  
7.5 
EXAMINATION OF SUBGROUPS 
Primary and secondary efficacy analyses will be conducted on the FAS.  Subgroup analyses will 
be performed to explore the efficacy of treprostinil in different subject populations.  The 
subgroups will include, but not be limited to: 
• age (<65, ≥65 years); 
• sex (males, females); 
• race (White, Black or African-American, Asian, American Indian or Alaskan Native, 
Native Hawaiian or Other Pacific Islander); 
• ethnicity (Hispanic or Latino, non-Hispanic or Latino); 
• age at WHO Group 3 PH-COPD diagnosis (date of diagnosis minus date of birth, in 
years, by quartiles); 
• pulmonary vascular resistance (PVR; during screening, in quartiles); 
• mean pulmonary artery pressure (mPAP; during screening, in quartiles); 
• baseline (Day 1) 6MWD (≤350 meters versus >350 meters);  
• baseline (Day 1) Borg dyspnea score (in quartiles). 
Unless otherwise prespecified, continuous covariates will be presented by quartiles.  
Comparative results will be presented using point estimates and associated 95% CIs both in 
tables and forest plots.  Because the study was not designed to have high power for small or even 
moderate sized subgroups, these analyses will be considered exploratory.  No Type 1 error 
adjustments will be performed for these subgroup analyses. 
7.6 
PREMATURE DISCONTINUATION AND MISSING DATA 
Investigators and site staff are to encourage all subjects to continue their participation in the 
study and complete all study procedures and study visits as indicated by the study protocol 
unless the subject provides a written withdrawal of consent from the study.  A subject’s 
discontinuation from study drug does not mean discontinuation from the study.  If study drug is 
discontinued for a randomized subject, the subject will be encouraged to actively continue to 


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return for all study visits per the study protocol, and the Investigator will continue all reasonable 
efforts to obtain the subject’s data.   
Patients may not complete the full treatment periods for the following reasons: death, lost to 
follow-up, study terminated by Sponsor, COVID-19 truncation, or withdrawal of consent.  All 
available data from all patients will be used as detailed in this analysis plan.  In addition, subjects 
may be too ill to perform assessments, such as the 6MWT or Borg, resulting in missing data for 
that assessment. 
Methods for imputation and handling missing data, when applicable, will be described in the 
sections for the particular outcome. 
7.7 
MULTIPLE COMPARISONS AND MULTIPLICITY 
A gatekeeper strategy will be employed to address multiple comparisons.  Secondary endpoints 
will be formally tested only if the primary endpoint is statistically significant.  If the primary 
analysis of treprostinil vs placebo change from Baseline to Week 12 is statistically significant at 
a 2-sided alpha level of 0.05, showing superiority of treprostinil over placebo, then the secondary 
endpoints will be formally tested. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  


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Other secondary endpoints, including change in QOL, based on the SGRQ and UCSD SOBQ, 
and PGA will not have formal statistical testing. 
8 
STUDY POPULATION 
8.1 
PATIENT ACCOUNTABILITY 
8.1.1 
Treatment Compliance 
At each study 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 within the interactive voice/web response system. 
Subject compliance with the prescribed dosage regimen will be monitored throughout the study.  
If it is determined that a subject is not compliant with study drug, the site personnel must re-
educate the subject on proper dosing compliance and its importance.  
Treatment compliance will be presented as a table summarizing the counts and summary 
statistics for used and unused ampoules by the assigned treatment. 
8.1.2 
Protocol Deviations 
Significant protocol deviations occurring during the study, either critical or major, that could 
impact the completeness, accuracy, and/or reliability of the study data or that may affect a 
subject's rights, safety, or wellbeing will be determined by the Sponsor (which will be completed 
prior to database lock) and will be presented for all subjects randomized. 
8.2 
ELIGIBILITY CRITERIA 
Males and females, 18 years of age and above at the time of informed consent, who have been 
diagnosed with WHO Group 3 PH associated with COPD are eligible for randomization to this 
study.  A full list of inclusion and exclusion criteria can be found in the study protocol, Sections 
4.1 and 4.2. 
8.3 
OTHER DESCRIPTIONS OF STUDY POPULATION 
All summaries of baseline information will be based on the full analysis set population, unless 
otherwise noted. 


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8.3.1 
Demographics 
Descriptive statistics will be presented overall based on the overall population for the following 
demographic data collected prior to randomization: 
• age (in years); 
• age (<65, ≥65 years); 
• sex (males, females); 
• race (White, Black or African-American, Asian, American Indian or Alaskan Native, 
Native Hawaiian or Other Pacific Islander); 
• ethnicity (Hispanic or Latino, non-Hispanic or Latino); 
• baseline (Screening Visit 1 and Day 1) weight (in kg); 
• baseline (Screening Visit 1) height (in m); 
• baseline (Screening Visit 1 and Day 1) Body mass index (BMI) (in kg/m2);  
• country of clinical site (USA, Israel, Argentina).  
8.3.2 
Baseline Disease Characteristics 
Descriptive statistics will be presented overall based on the randomized population for the 
following disease characteristics collected prior to randomization: 
• age of WHO Group 3 PH-COPD diagnosis (date of diagnosis minus date of birth, in 
years, by quartiles);  
• years of PH-COPD (date for the start of low dose run-in minus date of diagnosis, in 
years, by quartiles);  
• baseline (Day 1) 6MWD;  
• baseline (Day 1) Borg dyspnea score;  
• baseline (Day 1) 6MWD and Borg dyspnea composite score;  
• baseline (Days -7 to -1) actigraphy: average minutes of overall activity and MVPA;  
• baseline (Day 1) SGRQ score; 
• baseline (Day 1) UCSD SOBQ score; 
• baseline (Day 1) plasma concentration of NT-proBNP; 
• baseline (Screening Visit 1 and Day 1) FEV1; 
• baseline (Screening Visit 1 and Day 1) FEV1/FVC; 
• lowest recorded SpO2 during baseline (Screening Visit 1 and Day 1) 6MWT; 
• baseline (Day 1) PGA: categorical percentages and average scale value for fatigue and 
shortness of breath;  
• baseline (Day 1) DSP;  


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• supplemental oxygen use and flow rate (in L/min) with 6MWT at baseline (Screening 
Visit 1 and Day 1); 
• At-home spirometry values at baseline (Day 1). 
8.3.3 
Medications 
Prescription or nonprescription medications (including vitamins and herbal products) will be 
coded using the most recent version of the WHO-Drug Global Dictionary prior to the data base 
lock. 
Medications will be summarized overall and by assigned treatment - 1 for prior medications and 
1 for concomitant medications.  The number and percentage of subjects with any medication will 
be summarized by decreasing order of incidence.  The number and percentage of subjects who 
have taken a medication within a primary drug category will be summarized by cohort under that 
drug category by the most specific level available.   
For these summaries, a subject taking the same medication multiple times will only be counted 
once for the corresponding most specific level available.  Similarly, a subject who took multiple 
medications within the same drug category will be counted only once for that drug category.  
Prior and concomitant medications will be presented in alphabetical order of drug category; 
within each drug category, the most specific level available for drugs will be presented in 
decreasing order of incidence. 
8.3.3.1 
Prior Medications 
All medications or therapies reported before the first dose of treprostinil (during low dose run-in) 
are defined as prior medications and will be summarized overall and by assigned treatment. 
8.3.3.2 
Concomitant Medications 
Any medication or therapy initiated after, or corresponding with, the first dose of treprostinil 
(during low dose run-in) will be considered a concomitant medication.  These medications will 
be presented using the same structure as prior medications.  Tabulations will allow occurrences 
during low dose run-in and blinded treatment to be assessed (eg, low dose treprostinil, 
treprostinil treated, any treprostinil, placebo treated). 


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8.3.4 
Medical History 
Medical history identified prior to ICF date will be summarized overall and by treatment.  The 
number and percentage of subjects with any occurrence will be summarized by System Organ 
Class (SOC; alphabetically) and by Preferred Term (PT) in decreasing order of incidence. 
For subjects experiencing the same medical condition multiple times, the summaries will count 
the condition only once for the corresponding PT.  Similarly, the summaries will count a subject 
with multiple medical conditions within the same SOC only once for that SOC.  SOCs will be 
tabulated alphabetically; within each SOC, PTs will be presented in decreasing order of 
incidence. 
Medical conditions are coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary.  The most recently available MedDRA version before the 
database lock date will be used to assign PTs and SOCs (the database will document the version 
at time of data lock). 
8.3.5 
Subject Disposition 
All subjects screened will be used to describe subject disposition.  The number and percentage of 
randomized subjects who completed and who discontinued (with reason for discontinuation) will 
be summarized overall and by treatment sequence at the time of discontinuation.  In addition, the 
summary table will display the number and percentage of subjects in each of the following 
groups, as well as the reason for discontinuation and treatment assigned, where applicable: 
• Screened, but never randomized; 
• Randomized, but never treated; 
• Discontinued during the first treatment phase; 
• Completed the first treatment phase and discontinued prior to the second; 
• Completed the first treatment phase and discontinued during the second treatment phase;  
• Completed the study (both treatment phases). 
A CONSORT diagram (Schulz 2010) may be used to display the disposition by treatment. 


U nite d T her a pe utics C or p.  
St atistic al A n al ysis Pl a n: RI N -P H -3 0 4  
L u n g Bi otec h n ol o g y P B C  
I n h ale d Tre pr osti nil 
0 7  J a n u ar y 2 0 2 2  Versi o n 2. 0  
C O N FI D E N TI A L  
P a ge 2 7  
9  
E F FI C A C Y A N A L Y S E S  
T he f oll o wi n g d escri b es t he pla n ne d pri mar y e n d p oi nt a nal ysis usi n g 6 M W D if t he alter nati ve 
pri mar y e n d p oi nt a nal ysis is n ot e nacte d.  F or details a b o ut t he alter nate pri mar y e n d p oi nt a n d 
a nal ysis, s ee Secti o n  9. 2 .  A ll efficac y a n al ys es will be perf or me d o n t h e F A S (see Secti o n  8 ). 
A d diti o nal s u p p orti ve a nal yses will be c o n d ucte d o n t he P P R O T, as o utli ne d bel o w.  
9. 1  
P RI M A R Y E F FI C A C Y M E A S U R E  
T he pri mar y effic ac y e n d p oi nt is t he c ha n ge i n 6 M W D meas ure d at pea k e x p os ure ( defi ne d as 1 0 
t o 6 0 mi n utes after d osi n g) after 1 2 wee ks of st u d y dr u g tr eat me nt.  T he pri mar y e n d p oi nt 
a nal ysis will e v al uate t he differe n ce i n b as eli ne-a dj uste d  6 M W Ds bet wee n acti ve a n d place b o 
c o n diti o ns.  T he pri mar y e n d p oi nt a nal ysis will test t he h y p ot he sis of a n i m pr o ve me nt i n 
b aseli ne-a dj uste d 6 M W Ds f or acti ve c o m pare d t o place b o treat me nts, as ra n d o mize d, t o s u bjects 
wit h P H -C O P D.  T he pri mar y n ull h y p ot hesis t o b e teste d is t hat t here are n o differe n ces i n t he 
b aseli ne-a dj uste d me a ns c ha n ge i n 6 M W Ds bet wee n acti ve a n d place b o treat me nt gr o u ps. 
9. 1. 1  
H y p ot hesis Test  
T he  a nal ysis of t he pri mar y effic ac y e n d p oi nt of pea k 6 M W D assesses if i n hale d tre pr osti nil will 
i ncreas e t he dista nce tr a v erse d i n t he pea k 6 M W T at Wee k 1 2 relati ve t o baseli ne c o m pare d t o 
place b o i n s u bjects wit h P H -C O P D.  T he n ull a n d alter nati ve h y p ot hes es are:  
𝐻0: 𝜇1 = 𝜇2  
𝐻𝑎: 𝜇1 >  𝜇2,  
w here μ 1 a n d μ 2 are t he baseli ne -a dj uste d c ha n ge fr o m b aseli ne i n 6 M W D of t he i n hale d 
tre pr osti nil a n d place b o treat me nts, res p ecti vel y. 
9. 1. 2  
Pri m ar y Ef fic ac y A n al ysis D at a 
T he pri mar y effic ac y a n al ysis will be base d o n all a vaila ble meas ure me nts of t he 6 M W D f or t he 
F A S as o bser ve d i n t he st u d y, wit h t he e x ce pti o n t hat for s u bjects w h os e 6 M W D meas ures at 
Wee k 6 or Wee k 1 2 of eit her Peri o d are missi n g d ue t o deat h or bei n g t o o ill t o perf or m 6 M W T, 
t he missi n g val ues will be i m p ute d as t he w orst p ossi ble sc ore ( 0 meter) a n d c ha n ge-fr o m-
baseli ne  sc ores cal c ulate d.  F or missi n g d ata d ue t o a n y ot h er reas o n, t he missi n g val ue will n ot 
be i m p ute d.  


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9.1.3 
Primary Efficacy Analysis 
Descriptive statistics showing the raw values and changes from baseline for the 6MWD will be 
presented for each scheduled visit by treatment.  Additionally, boxplots presenting the raw 
values and changes from baseline for each visit for the 6MWD may be presented. 
A mixed-effect model for repeated measures (MMRM) will be used to estimate the treatment 
effect.  The magnitude of treatment effect will be compared between the 2 treatments across the 
12-week treatment periods, and the test of the Week 12 change from baseline and difference 
between treatments will be produced using contrasts. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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Least square means for baseline adjusted 6MWD for each treatment group, difference of LS 
means between treatment groups with the associated p-value, and 95% CIs for each treatment LS 
mean and the difference in LS means will be summarized and presented. 
9.1.4 
Sensitivity Analyses 
Sensitivity analyses will be carried out to assess the effect of deviations from the study protocol, 
the carryover effect, and the impact of missing data. All analyses will be based on the data as 
described in Section 9.1.2, unless otherwise noted.  These analyses are mandatory if the primary 
endpoint analysis is statistically significant, but will otherwise be performed at Sponsor’s 
discretion.  
9.1.4.1 
Deviations from Protocol 
A “per protocol” analysis will be carried out to assess the effect of substantive deviations from 
the study protocol.  Analyses will be identical to those in Section 9.1 for the primary analysis, 
except the PPROT analysis population will be used instead of the FAS (ie, the dataset used will 
remove subjects with substantive deviations).  The test will examine the robustness of the total 
treatment effect to known departures from the protocol.  The magnitude of the treatment effect 
and significance testing will be contrasted against the results from the primary efficacy analysis.  


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If results are generally similar, then the effect of substantive deviations will be considered 
minimal.  
9.1.4.2 
Carryover Effect 
The carryover effect analysis will be performed using a 2-sided Wilcoxon Rank Sum Test on the 
sum of the changes in 6MWD for each treatment period between assigned treatment sequences.  
To determine the sum of the treatment effects, the change in the 6MWD from Baseline to Week 
12 for the active treatment and placebo will be summed for each subject.  The test will determine 
if the total treatment effect is different across assigned treatment sequence groups.  If the result is 
statistically significant, the assumption that the washout period was long enough to rule out the 
carryover effect, will be examined using the following approach: 
 
 
 
 
 
 
 
 
 
 
9.1.4.3 
Multiple Imputation for Missing Data Due to Death and Too Ill to Walk 
The primary efficacy analysis will be imputed 6MWD observations missing due to death or 
being too ill to perform 6MWT as the worst possible score (0 meters) and change scores 
calculated.  An alternative sensitivity analysis will be conducted that imputes missing 
observations due to death or being too ill to perform 6MWD to be the worst observed change 
score in all subjects plus a random error component added.  The error will be randomly drawn 
from a normal distribution with a mean of 0 and a variance equal to the residual variance 
estimated from the mixed model for observed values of change from baseline in 6MWD, 
adjusted for the same covariates and factors as pre-specified for the primary analysis.  
This analysis will be identical to those in Section 9.4 for the primary analysis, except for the use 
of the alternatively imputed data for death or being too ill to perform 6MWT as described above.  


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The test will examine the robustness of the total treatment effect to an alternative imputation 
strategy for handling missing data arising from death or being too ill to walk.   
9.1.4.4 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.2 
ALTERNATIVE PRIMARY ENDPOINT  
At the conclusion of the study, a fully blinded analysis will be performed to assess the extent of 
missing primary efficacy endpoint data (ie, 6MWD data).  If the absence of 6MWD data in the 
Treatment Period, combined across subjects, treatment periods, and key visits (Baseline and 
Study Week 12) to be used for the final primary endpoint analysis would likely lead to an 
underpowered study or yield indeterminate results, an alternative primary endpoint will be used 
for the final primary endpoint analysis.  
The alternative primary efficacy endpoint is defined as the ranked value for 6MWD measured at 
each study visit (if present and otherwise imputed for death or too ill to walk) or the ranked value 
for MVPA measured corresponding to each study visit (otherwise).  These data are termed the 
combined 6MWD/MVPA ranks data.  
 
 
 
 
  
 
  
 
 
 
 
 
The following sections present the pre-specified procedures to be followed. 
9.2.1 
Pre-specified Primary Endpoint Switching Algorithm 
At the conclusion of the study, a blinded analysis will be performed to assess the extent of 
missing primary efficacy endpoint data.  The Sponsor has estimated the power of this planned 
study at various sample sizes and determined that the minimum acceptable power (90% for a 2-
tailed alpha=0.05) occurs at approximately 88 subjects providing evaluable primary endpoint 
data.  With planned sample size of 136 evaluable subjects, if at least 65% of the 6MWD has been 


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collected (or otherwise imputed for death or too ill to walk) across subjects, periods, and key 
visits (Baseline and Week 12), the primary endpoint will remain, as planned, the 6MWD, 
regardless of actigraphy data. 
If the study completes under the Original Crossover Design, the outcome of the analysis will 
inform a decision to adopt an alternative primary efficacy endpoint of combined 6MWD/MVPA 
ranks data as follows:  
• If data presence ≥65% for 6MWD data (Study Weeks 1, 12, 14, and 25), regardless of 
data presence for actigraphy, the study will use only 6MWD data as the primary efficacy 
endpoint. 
• If data presence <65% for 6MWD data (Study Weeks 1, 12, 14, and 25) and the data 
presence for actigraphy (Study Weeks 1, 12, 14, and 25) is greater than the presence for 
the 6MWD data, the study will switch and use combined 6MWD/MVPA ranks data as 
the primary efficacy endpoint. 
• In the event that the data presence <65% for 6MWD data (Study Weeks 1, 12, 14, and 
25) and the data presence for actigraphy (Study Weeks 1, 12, 14, and 25) is equal or 
lower than the presence for the 6MWD data, the study will use only 6MWD data as the 
primary efficacy endpoint. 
If the study completes under the Contingent Parallel Design, the outcome of the analysis will 
inform a decision to adopt the alternative primary efficacy endpoint of actigraphy data as 
follows: 
• If data presence ≥65% for 6MWD data (Study Weeks 1 and 12), regardless of data 
presence for actigraphy, the study will use only 6MWD data as the primary efficacy 
endpoint. 
• If data presence <65% for 6MWD data (Study Weeks 1 and 12) and the data presence for 
actigraphy (Study Weeks 1 and 12) is greater than the presence for the 6MWD data, the 
study will switch and use combined 6MWD/MVPA ranks data as the primary efficacy 
endpoint. 
• In the event that the data presence <65% for 6MWD data (Study Weeks 1 and 12) and the 
data presence for actigraphy (Study Weeks 1 and 12) is equal or lower than the presence 
for the 6MWD data, the study will use only 6MWD data as the primary efficacy 
endpoint. 
This algorithm intends that the 6MWD is to be used as the primary efficacy endpoint for this 
study, except in the case where onsite measurements for the 6MWD are not available. 


U nite d T her a pe utics C or p.  
St atistic al A n al ysis Pl a n: RI N -P H -3 0 4  
L u n g Bi otec h n ol o g y P B C  
I n h ale d Tre pr osti nil 
0 7  J a n u ar y 2 0 2 2  Versi o n 2. 0  
C O N FI D E N TI A L  
P a ge 3 4  
9. 2. 2  
Alter n ati ve  Pri m ar y E n d p oi nt H y p ot hesis Test  
T he pri mar y effic ac y e n d p oi nt of c o m bi ne d 6 M W D/ M V P A ra n ks assesses if i n hale d  tre pr osti nil 
will i ncrease t he c o m bi ne d ra n ks at W ee k 1 2 o v er place b o i n s u bjects wit h P H -C O P D.  T he n ull 
a n d alter nati ve h y p ot h eses are:  
𝐻0: 𝜇1 = 𝜇2  
𝐻𝑎: 𝜇1 > 𝜇2,  
w here μ 1 a n d μ 2 are t he baseli ne -a dj uste d c ha n ge fr o m baseli ne i n c o m bi n e d 6 M W D/ M V P A 
ra n ks of t he i n hale d tre pr osti nil a n d place b o treat me nts, res pecti vel y. 
9. 2. 3  
Alter n ati ve  Pri m ar y Effic ac y E n d p oi nt Deri v ati o n  
T he alter nati ve pri mar y efficac y a nal ysis will be pri maril y b ase d o n all a v aila ble meas ure me nts 
of t he 6 M W D f or t he F A S , as o bser ve d i n t he st u d y.  T he prec urs or d ata fil e f or t he alter nati ve 
pri mar y efficac y data set will be t he data defi n e d i n Secti o n 9. 1. 2  (ie, all av aila ble meas ure me nts 
of t he 6 M W D as o bser ve d i n t he st u d y, wit h  val ues  missi n g d ue t o deat h or bei n g t o o ill t o 
perf or m 6 M W T  bei n g  i m p ute d as t he w orst p ossi ble sc ore of 0 m eter) .  T hese data will be 
tra nsf or me d i nt o ra n ks a n d missi n g 6 M W D data t hat were ot h er wise meas ure d f or M V P A will 
be i m p ute d f or t his a nal ysis data.  All ot her val ues  t hat are missi n g a n d n ot prese nt i n M V P A 
data will n ot be i m p ute d.   T he fi nal data res ulti n g will be t he c o m bi ne d 6 M W D/ M V P A ra n ks 
data set.  
 
  
 
 
 
  
 
 
 
 
  


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All data sets will be retained for further use in the sensitivity analyses specified below (see 
Section 9.2.5). 
9.2.4 
Alternative Primary Efficacy Analysis 
The primary efficacy analysis to be conducted will follow those specified for the planned 
primary efficacy endpoint (see Section 9.1.3) with the exception that specification of the variable 
for 6MWD (only) will be replaced with the variable created for the combined 6MWD/MVPA 
ranks.  
The Sponsor considers that the sample size is sufficiently large to rely on asymptotic theory.  
The combined data will be standardized (allowing the 2 separate data sets to be combined on the 
same scale), and the standardized ranking is a transformation towards the normal distribution.  
As such, a mixed model would be appropriate and generally expected to perform better under a 
rank transformation than an analysis based on raw values.  The Sponsor believes this is 
consistent with published literature on rank analysis of covariance (Quade 1967; Conover 1982; 
Lawson 1983) 
9.2.5 
Alternative Primary Endpoint Sensitivity Analyses 
The sensitivity analyses to be carried out for the alternative primary endpoint (the combined 
6MWD/MVPA ranks) will include those specified in Section 9.1.4.  Assessment for the effect of 
deviations from the study protocol, carryover effect, and the impact of missing data will use the 
combined 6MWD/MVPA ranks data instead of 6MWD data.  With the use of combined 


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6MWD/MVPA ranks data, sensitivity analyses will be performed to assess underlying clinical 
meaningfulness of the rank scores, and the relationship between 6MWD and actigraphy 
measurements (overall activity and MVPA).  In addition, sensitivity analyses will be performed 
with 6MWD rank data (without imputation of MVPA data), MVPA raw data (by itself, without 
6MWD data), and MVPA rank data (by itself, without 6MWD), applying the primary endpoint 
imputation approach and method of analysis.  All analyses will be based on the data, as described 
in Section 9.2.3, unless otherwise noted.  These analyses specified in this section are mandatory 
if the use of the alternative primary endpoint is triggered; otherwise will only be performed at 
Sponsor’s discretion.  
9.2.5.1 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
9.2.5.2 
  
 
 
 
 
  


U nite d T her a pe utics C or p.  
St atistic al A n al ysis Pl a n: RI N -P H -3 0 4  
L u n g Bi otec h n ol o g y P B C  
I n h ale d Tre pr osti nil 
0 7  J a n u ar y 2 0 2 2  Versi o n 2. 0  
C O N FI D E N TI A L  
P a ge 3 7  
9. 3  
K E Y  S E C O N D A R Y E F FI C A C Y M E A S U R E S  
T he f oll o wi n g s ec o n dar y e n d p oi nts will be f or mall y teste d (i n or d er) if t he pri mar y e n d p oi nt 
a nal ysis is statisticall y si g nifica nt.  Eac h will assess if i n hale d tre pr osti nil i m pr o ves t he e n d p oi nt 
at W ee k 1 2 o ver place b o i n s u bjects wit h P H -C O P D.  I m pr o ve ment is defi n e d as a decrease i n 
t he N T -pr o B N P  plas ma c o nce ntrati o n , a n i ncreas e i n M V P A,  a n i ncreas e i n o verall acti vit y, 
decrease i n B or g d ys p nea s c ore, a n d a n i ncreas e i n t he ra n k f or t h e 6 M W D a n d B or g d ys p n ea 
c o m p osite sc ore.  T h e n ull a n d alter nati ve h y p ot heses are:  
𝐻0: 𝜇1 = 𝜇2  
𝐻𝑎: 𝜇1 <  𝜇2  or 𝜇1 > 𝜇2 , de pe n de nt o n t he state d directi o n a b o ve , 
w here μ 1 a n d μ 2 are i n hale d tre pr osti nil a n d place b o treat me nts, res p ecti vel y.   
9. 3. 1  
Acti gr a p h y  
S u bjects w ore t he acti gra p h acceler o meter Ce ntre P oi nt I nsi g ht Watc h ( Acti Gra p h., Pe nsac ol a, 
F L) o n t heir n o n d o mi na nt wrist fr o m t he o nset of t he l o w d ose i n hale d tr e pr osti nil r u n -i n peri o d 
u ntil st u d y ter mi nati o n.  S u bjects were pr o vi de d a n acti gra p h at t h e ti me of t he scree ni n g r u n -i n 
visit t o esta blis h t heir baseli ne le vel of acti vit y.  T he y were as ke d t o w ear t he de vice 
c o nti n u o usl y t hr o u g h o ut t he da y, i ncl u di n g w hile slee pi n g.   P h ysical acti vit y le vels were 
c o nti n u o usl y m o nit ore d t hr o u g h o ut t he bli n de d tr eat me nt peri o d.  Meas ure me nts were n ot 
vie wa ble b y s u bject via t he watc h or ot h er wise.  
 
 
 
  
 
 
 
  
9. 3. 1. 1  
O ver all  Acti vit y  
S u m mar y e p o c h data were f urt her pr ocesse d b y Acti G ra p h t o pr o d uce dail y s u m mar y d ata of 
acti vit y.  D eri ve d fr o m t he e p oc h d ata were a g gre gate meas ures of t otal e p o c hs meas ure d i n eac h 


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day, total sleep minutes (epochs with awake flag = FALSE), total awake minutes (epochs with 
awake flag = TRUE), total non-wear minutes (epochs with wear flag = FALSE), and total wear 
minutes (epochs with wear flag = TRUE).  
 
  
 
  
Physical activities can be characterized into groupings based on their energy expenditures, 
measured in Metabolic Equivalent of Tasks (METs), as:  
 
Adapted from Nathan 2020 
These activity data were further filtered to include only activity when measured during flagged 
wear epochs.  Summary daily data were available to the Sponsor and investigative site staff 
throughout the study and a final cumulative transfer of summary data to the Sponsor is to occur 
after database lock. 
The secondary endpoint defined for analysis is the percent change in overall activity (ie, minutes 
spent in non-sedentary activity) during flagged wake epochs and calculated as absolute 


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change/baseline (eg, change overall activity [minutes]/baseline overall activity [minutes]).  Data 
will be aggregated across the 7-day baseline to produce an average baseline measurement to 
minimize day to day variability.  Similarly, the Weeks 6 and 12 endpoints will be constructed by 
averaging across the measurements on the study visit day and the measurements for the 6 days 
prior.  
9.3.1.2 
 Moderate to Vigorous Physical Activity 
The secondary endpoint defined for analysis is the percent change in MVPA (ie, minutes spent in 
moderate or vigorous activity) during flagged wake epochs and calculated as absolute 
change/baseline (eg, change MVPA [minutes]/baseline MVPA [minutes]).  Data will be 
aggregated across the 7-day baseline to produce an average baseline measurement to minimize 
diurnal variability.  Similarly, the Weeks 6 and 12 endpoints will be constructed by averaging 
across the study visit day measurement and the measurements for the 6 days prior.  
9.3.1.3 
Actigraphy Analyses 
9.3.1.3.1 
Main Analyses 
A longitudinal mixed model, similar to that used for the primary analysis of 6MWD, will be used 
to describe the change from baseline in actigraphy, percent change in overall activity and 
MVPA, separately¸ over time.  All subjects, including those who did not complete both treatment 
sequences, will be included in the model.  A contrast will be calculated for Week 12 to compare 
the treatment groups with respect to percent change.  The outcome variable will be percent 
change from baseline.  Analyses will be conducted on the FAS and the PPROT. 
9.3.1.3.2 
 
 
  
 
 
 
   


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9.3.1.3.3 
 
 
 
 
 
 
 
  
9.3.2 
Borg Dyspnea Score 
The Borg dyspnea score is an 11-point scale measuring the degree of dyspnea from 0 (no 
shortness of breath) to 10 (maximal shortness of breath).  A score of 10 will be assigned to 
subjects who died or were too ill to walk for the 6MWT.  Descriptive statistics of the raw and 
change from baseline values for Borg dyspnea score will be presented for each scheduled visit by 
treatment.  Additionally, boxplots presenting the raw values and changes from baseline for each 
visit will be presented.  The Borg dyspnea score will be treated as a continuous variable. 
A longitudinal mixed model, similar to that used for the primary analysis of 6MWT, will be used 
to describe the change from baseline in Borg dyspnea score over time.  All subjects, including 
those who did not complete both treatment sequences, will be included in the model.  A contrast 
will be calculated for Week 12 to compare the treatment groups with respect to change.  The 
outcome variable will be change from baseline.  Independent variables will be treatment, the 
subject’s baseline Borg dyspnea score, treatment sequence, visit number, and the interaction of 
visit and treatment.  Analyses will be conducted on the FAS and the PPROT. 
9.3.3 
6MWD and Borg Dyspnea Composite Score 
The intent of the 6MWT is to determine how much exercise subjects can do during the course of 
carrying out activities of daily living.  However, the capacity of subjects to function is 
determined not only by what they can do when they exert themselves to the fullest, but also by 
how they feel when they are carrying out their usual activities of daily living.  It is important not 
only to look at the distance traversed during the unencouraged 6MWT, but also the symptoms 
experienced at the end of the effort (Rao 2019).  


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The 6MWD and Borg dyspnea composite score is derived based on the results of the 6MWD and 
the Borg dyspnea scale measuring the degree of dyspnea.  The following derivation strategy will 
be employed to calculate the 6MWD and Borg dyspnea composite score: 
 
  
 
 
 
  
 
 
 
 
 
  
  
 
 
 
  
 
 
 
Descriptive statistics of the raw and change from baseline values for composite score will be 
presented for each scheduled visit by treatment.  The composite score will be treated as a 
continuous variable.  A longitudinal mixed model, similar to that used for the primary analysis of 
6MWD, will be used to describe the change from baseline in the composite score over time.  All 
subjects, including those who did not complete both treatment sequences, will be included in the 
model.  A contrast will be calculated for Week 12 to compare the treatment groups with respect 
to change.  


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9.3.4 
NT-proBNP  
Descriptive statistics of the raw values for NT-proBNP will be presented for each scheduled visit 
by treatment.  Because the parameter is highly skewed, the data will be log-transformed before 
analysis.  A mixed model will be used to describe log NT-proBNP over time.  The outcome 
variable will be the value at each time of measurement, not the change from baseline.  
Independent variables will be treatment, treatment sequence, the subject’s baseline log NT-
proBNP, visit number, and the interaction of visit and treatment.  A contrast will be calculated at 
Week 12 to compare the treatment with respect to level of the parameter. 
The contrast will be on the log scale. In order to provide summary statistics that are easily 
clinically interpretable, the estimates may be back transformed to the natural scale and the 
change from baseline may be calculated as the difference between the mean of the back-
transformed estimates and the mean of the baseline value.  
Observed values for the FAS and PPROT will be used with no imputation for missing values.  
However, if a NT-proBNP value is reported below the lower limit of quantification, half of the 
lower limit of quantification will be used for summary and analysis (eg, if the result is reported 
as ‘<51 ng/L,’ a numerical value of 25 ng/L will be used). 
9.4 
OTHER SECONDARY EFFICACY MEASURES 
9.4.1 
St. George’s Respiratory Questionnaire 
The SGRQ is a 50-item questionnaire designed to measure impact on overall health, daily life, 
and perceived wellbeing in patients with obstructive airways disease (Jones 1992).  Scores for 
the SGRQ are totaled into 3 components (symptoms, activities, impacts) as well as a total score.  
Scores weighted and expressed as a range from 0 to 100, with higher scores indicating more 
limitations.  The current established minimal important difference for SGRQ scores in an 
average COPD population is −4 units (Jorrit 2015).  Calculation of component and total scores 
are described in the manual (Jones 2009).  
Descriptive statistics for the raw and change from baseline to Week 12 values for the SGRQ the 
components and the total score will be presented for each scheduled visit by treatment.  


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Additionally, boxplots presenting the raw values and changes from baseline for each visit will be 
presented.  The SGRQ scores will be treated as a continuous variable. 
A longitudinal mixed model will be used to describe the change from baseline for the each of the 
scores over time.  All subjects, including those who did not complete both treatment sequences, 
will be included in the model.  A contrast will be calculated for Week 12 to compare the 
treatment groups with respect to change.  The outcome variable will be change from baseline.  
Independent variables will be treatment, the subject’s baseline average SGRQ score, treatment 
sequence, visit number, and the interaction of visit and treatment. 
Observed values for the FAS and PPROT will be used with no imputation for missing values.  
9.4.2 
University of California San Diego Shortness of Breath Questionnaire 
The UCSD SOBQ is a self-administered rating of dyspnea associated with activities of daily 
living (Eakin 1998).  The questionnaire contains 24 items on a 6-point scale, where 0 = “not at 
all” and 5 = “maximal or unable to do because of breathlessness” and total score are summed 
across items for a range from 0 to 120.  The current established minimal important difference for 
UCSD SOBQ scores in a chronic lung disease population is 5 units (Ries 2005).  Descriptive 
statistics of the raw and change from baseline to Week 12 values for the UCSD SOBQ score will 
be presented for each scheduled visit by treatment. 
A longitudinal mixed model will be used to describe the change from baseline in the total score 
over time.  All subjects, including those who did not complete both treatment sequences, will be 
included in the model.  A contrast will be calculated for Week 12 to compare the treatment 
groups with respect to change.  The outcome variable will be change from baseline.  Independent 
variables will be treatment, the subject’s baseline average UCSD SOBQ score, treatment 
sequence, visit number, and the interaction of visit and treatment. 
Observed values for the FAS and PPROT will be used with no imputation for missing values.  
9.4.3 
 
 


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9.4.4 
Patient Global Assessment  
The PGA is a being used to rate subject fatigue and shortness of breath.  Subjects will use the 
Sponsor-provided smart device for at-home capture of the PGA data at or just prior to each study 
visit.  Subjects will be asked to perform the PGA at the same time as the at-home spirometry 
assessment at all applicable visits.  Scores for each are on a 5-point response scale of: “never,” 
“rarely,” “sometimes,” “often,” or “always” with higher scores indicating a worse symptom 
rating.  
Descriptive statistics for the raw and change from baseline values for the PGA ratings will be 
presented for each scheduled visit by treatment.  Additionally, boxplots presenting the raw 
values and changes from baseline for each visit may be presented.  
Exploratory analyses may be conducted for PGA items to examine floor and ceiling effects, 
reliability across repeated baseline assessments, and within subgroups to further understand the 
psychometric properties of PGA measurements.  
9.5 
EXPLORATORY EFFICACY MEASURES 
Exploratory analyses will not be addressed in this SAP.  Relevant analyses conducted will be 
presented in the CSR. 
10 
SAFETY ANALYSES 
The safety of inhaled treprostinil compared to placebo will be evaluated on the following 
parameters: AEs, vital sign measurements, ECGs, clinical laboratory assessments, PFTs, 
spirometry, and oxygenation.  All safety analyses will be based on the Safety Population (see 
Section 6).  No formal inferential testing will be reported for routine safety analyses. 


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10.1 
EXTENT OF EXPOSURE 
Exposure to treprostinil and placebo will be calculated as the date of last dose minus the date of 
first dose plus 1.  If the date of last dose of study drug was missing or unknown, the return date 
of study drug will be used as an imputed date.  All analyses will be presented by treatment and 
period.  These analyses include: 
• Duration of exposure (in weeks) to each treatment 
• Number of subjects exposed by time (weekly from Baseline Visit respective to treatment) 
• Maintenance dose (in mcg QID) during the study (dose subject is maintained on after 
titration period [ie, the mode of the dose during that treatment period]). 
10.2 
ADVERSE EVENTS 
Adverse events are recorded starting from the time each subject signs the ICF until the time a 
screen failure is documented, study completion, or early termination.  All events recorded by the 
Investigators will be assigned a MedDRA PT and SOC.  The most recently available MedDRA 
version before the database lock date will be used to assign preferred terms and system organ 
classes.  All presentations will present data by treatment received at the time of the event.  
Adverse events that occur during the Washout Period following Treatment Period 1 will be 
presented as having occurred on the treatment taken by the subject during Treatment Period 1.  
Similarly, AEs that occur during post-discontinuation follow-up will be presented as having 
occurred on the treatment taken by the subject during Treatment Period 2.  Finally, AE 
tabulations will allow occurrences during low dose run-in and blinded treatment to be assessed 
(eg, low dose treprostinil, treprostinil treated, any treprostinil, placebo treated).  Non-treatment 
emergent AEs observed outside of any study drug exposure will not be presented.  
In addition, a limited number of presentations may be tabulated for AE data by both treatments 
received at the time of the event and treatment sequence, including the total rates by sequence.  
10.2.1 
Severity of Adverse Event 
The severity of AEs will be reported by the Investigator as ‘Mild,’ ‘Moderate,’ or ‘Severe.’ 


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10.2.2 
Relationship to Study Treatment 
The relationship of the event to the study drug is classified by the Investigator as ‘Not Related,’ 
‘Possible,’ or ‘Probable.’  For analytic purposes, AEs classified as ‘Probable’ or ‘Possible’ will 
be considered ‘Related.’ 
10.2.3 
Action Taken with Study Treatment 
For each AE, the Investigator classifies the action taken with the study treatment as 1 of the 
following: ‘Dose Not Changed,’ ‘Dose Increased,’ ‘Dose Decreased,’ ‘Drug Interrupted,’ ‘Drug 
Withdrawn,’ ‘Unknown,’ or ‘Not Applicable.’ 
10.2.4 
Outcome of Treatment Emergent Adverse Event 
The Investigator categorizes the outcome of each AE as 1 of the following: ‘Fatal,’ ‘Not 
Recovered/Not Resolved,’ ‘Recovered/Resolved,’ ‘Recovered/Resolved with Sequelae,’ 
‘Recovering/Resolving,’ or ‘Unknown.’ 
10.2.5 
Summary of Treatment Emergent Adverse Events 
An overall summary of AEs by treatment received at the time of the event and treatment will 
contain the following: 
• Total number of AEs, total number of subjects with at least one AE 
• Total number of related AEs, total number of subjects with at least one related AE 
• Total number of serious adverse events (SAEs), total number of subjects with at least one 
SAE 
• Total number of AEs leading to study withdrawal 
• Total number of AEs leading to treatment discontinuation. 
Table summaries of all AEs will present numbers and percentages by SOC and PT of the 
following by treatment received at the time of the event: 
• Subjects with at least one AE 
• Subjects with at least one treatment-related AE 
• Subjects with at least one SAE 
• Subjects with an AE leading to treatment discontinuation. 


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AEs will also be summarized by treatment received at the time of the event for the following: 
• AEs by severity 
• AEs by relationship to treatment 
• AEs by action taken with treatment, separately 
• Listing of all SAEs. 
Finally, a table summarizing the AEs that occurred during the pre-randomization run-in phase 
will be presented for all screened subjects.  
Adverse events will be presented in alphabetical order of SOC and by decreasing order of 
incidence of the PTs. 
For these summaries, a subject having the same AE multiple times will only be counted once for 
the corresponding PT.  Similarly, a subject who experienced multiple AEs within the same SOC 
will be counted only once for that SOC. 
A subject experiencing the same AE multiple times or at multiple severities will only be counted 
once under that PT at the worst severity rating.  Similarly, a subject who experiences the same 
AE multiple times or at multiple severities across multiple PTs within the same SOC will only be 
counted once for the worst severity rating within the SOC. 
10.3 
DEATHS 
A listing will be provided for any deaths occurring on the study.  Included in this listing, to the 
extent available, will be the subject’s age, race, sex, treatment received at the time of death, 
duration of that treatment in days, whether or not the subject received the other treatment, days 
since randomization, days since last treatment, and the cause of death. 
10.4 
PHYSICAL EXAM 
Any value the Investigator judges to be a clinically significant abnormal change after the 
subject’s consent to the study was to be recorded as an AE. 


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10.5 
CLINICAL LABORATORY EVALUATIONS 
Laboratory tests for serum electrolytes, chemistry, and hematology will be assessed at each study 
visit.  Table 10-1 provides the values that will be summarized. 
Table 10-1 
Clinical Laboratory Parameters 
Electrolyte Panel 
Chemistry Panel 
Hematology Panel 
Sodium 
Total bilirubin 
Hemoglobin 
Potassium 
Alkaline phosphatase 
Hematocrit 
Bicarbonate 
Alanine aminotransferase 
Red blood cell count 
Chloride 
Aspartate aminotransferase 
White blood cell count 
 
Urea nitrogen 
Platelet count 
 
Creatinine 
Erythrocytes Mean Corpuscular 
Volume 
 
Calcium 
 
Albumin 
 
 
Descriptive statistics for each clinical laboratory parameters (hematology, serum chemistry and 
electrolytes) will be presented by treatment group at baseline, each post-baseline assessment, and 
End of Study visits for raw data and change from respective baseline.  Additionally, summary 
statistics will be presented for the change in each parameter from the baseline visit for Treatment 
Period 1 to the Baseline Visit for Treatment Period 2. 
Post-baseline abnormal values, as defined by the normal limits, for hematology, serum 
chemistry, and electrolyte parameters will be summarized as shift tables from baseline to each 
post-baseline assessment and End of Study visits. 
Tables will contain the number and percentage of subjects by treatment received at the time of 
measurement with post-baseline categories (low, high, and normal for hematology, chemistry, 
and electrolytes) compared to the respective baseline category for each parameter.  
If data from both the central lab and a local lab is available for a given lab result, then the central 
lab value will be used in the analyses.  If data is only available from a local lab for a given lab 
result, then local lab results will be transformed to be consistent to the central lab results for the 
analyses. 


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If a value for a laboratory value is reported below the lower limit of quantification, half of the 
lower limit of quantification will be used for summary and analysis. 
10.6 
VITAL SIGNS 
Descriptive statistics for vital signs (heart rate, systolic blood pressure, diastolic blood pressure, 
respiration rate, weight, BMI) will be presented for both Baseline Visits by treatment.  
Additionally, summary statistics will be presented for the change in each parameter from the 
Baseline Visit for Treatment Period 1 to the Baseline Visit for Treatment Period 2.  The same 
statistics will also be presented for each post-baseline assessment and End of Study visits for the 
raw data and change from the respective baseline.  Any clinically significant change from 
Screening Visit 1 was to be recorded as an AE. 
10.7 
ELECTROCARDIOGRAM EVALUATIONS 
Descriptive statistics for ECG findings (sinus rhythm [present/absent], heart rate, PR interval, 
QRS duration, QT interval, interpretation [normal/abnormal]) will be presented by treatment 
group.  Continuous variables will also be presented as the raw values and change from the 
respective baseline will be presented for each post-baseline assessment by treatment received at 
the time of the visit.  Additionally, summary statistics for continuous variables will be presented 
for the change in each parameter from the Baseline Visit for Treatment Period 1 to the Baseline 
Visit for Treatment Period 2.  Whenever more than 1 ECG evaluations are recorded on the same 
day, the data summaries will use the average of these readings. 
In addition, a summary of subjects with treatment-emergent abnormal values will be presented 
by treatment received at the time of the evaluation.  Presentation will be made in order of 
decreasing incidence by type of abnormality with the number and percentage of subjects who 
experienced the type of abnormality. 
10.8 
PULMONARY FUNCTION TESTS 
Descriptive statistics will be presented by treatment group at baseline for the following 
parameters (absolute values and % predicted): FEV1, FVC, TLC, and DLCO uncorrected for 
hemoglobin and lung volume.  Additionally, descriptive statistics of the raw values and change 


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from the respective baseline will be presented for each post-baseline assessment by treatment 
received at the time of the visit. 
10.9 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.10 OXYGENATION 
10.10.1 
Pulse Oximetry 
Pulse oximetry measurements will be taken before, during, and after each 6MWT.  These 
measurements include the collection of saturation peripheral capillary oxygenation (SpO2) and 
heart rate (HR).  Descriptive statistics of raw values and the change from baseline pre-walk, 
post-walk, and the lowest recorded SpO2 (and associated HR) for each 6MWT will be presented 
by treatment received during time of assessment.  The baseline value used to compute the change 
score of each follow-up measurement will be respective of the same timeframe of the follow-up 
value (ie, pre-walk baseline used for pre-walk follow-up).  


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11 
REFERENCES 
Choi L, Liu Z, Matthews CE, et al.  Validation of Accelerometer Wear and Nonwear Time 
Classification Algorithm.  Med Sci Sports Exerc.  2011;Feb;43(2):357-364. 
Eakin EG, Resnikoff PM, Prewitt LM, et al.  Validation of a new dyspnea measure.  The UCSD 
shortness of breath questionnaire.  Chest.  1998;113(3):619-24. 
East 6 (2020).  Statistical software for the design, simulation and monitoring clinical trials.  Cytel 
Inc., Cambridge MA. 
Conover WJ, Iman RL.  Analysis of covariance using the rank transformation.  Biometrics.  
1982;38:715-724. 
Jones PW, Quirk FH, Baveystock CM, et al.  A self-complete measure for chronic airflow 
limitation - the St George's Respiratory Questionnaire.  Am Rev Respir Dis.  1992;145:1321-
1327. 
Jones PW, Ford Y.  St.George’s Respiratory Questionnaire Manual.  2009. 
Jorrit BA, Welling JE, Hartman NHT, et al.  The minimal important difference for the St 
George's Respiratory Questionnaire in patients with severe COPD.  Eur Respir J.  2015;46:1598-
1604. 
Kenward MG, Roger, JH.  Small sample inference for fixed effects from restricted maximum 
likelihood.  Biometrics.  1997;53(3):983-997.  
Lawson A.  Rank Analysis of Covariance: Alternative Approaches.  The Statistician.  
1983;32(3):331-337.  
Nathan SD, Flaherty KR, Glassberg MK, et al.  A Randomized, Double-Blind, Placebo-
Controlled Study of Pulsed, Inhaled Nitric Oxide in Subjects at Risk of Pulmonary Hypertension 
Associated With Pulmonary Fibrosis.  Chest.  2020;158(2):637-645. 
Quade D.  Rank analysis of covariance.  Journal of the American Statistical Association.  
1967;62(320):1187-1200. 
Rao Y, Zheng C, Nelsen A, et al.  Borg Dyspnea Score Adjusted Six Minute Walk Distance in 
Pulmonary Arterial Hypertension Clinical Trials.  PVRI 2019 abstract presented in Barcelona, 
Spain.  2019. 
Ries AL.  Minimally clinically important difference for the UCSD Shortness of Breath 
Questionnaire, Borg Scale, and Visual Analog Scale.  COPD: Journal of Chronic Obstructive 
Pulmonary Disease.  2005;2:105-110. 
Schulz KF, Altman DG, D. Moher.  CONSORT 2010 Statement: updated guidelines for 
reporting parallel group randomised trials.  BMC Medicine.  2010;8:18. 


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Staudenmayer J, He S, Hickey A, et al.  Methods to estimate aspects of physical activity and 
sedentary behavior from high-frequency wrist accelerometer measurements.  J Appl Physiol.  
2015;119:396-403. 
Tracy JD, Acra S, Chen KY, et al.  Identifying bedrest using 24-h waist or wrist accelerometry in 
adults.  PLoS ONE.  2018;13(3):e0194461. https://doi.org/10.1371/journal.pone.0194461. 


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12 
APPENDICES 
12.1 
LIST OF TABLES 


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12.2 
LIST OF LISTINGS 
Listings to be provided upon request.  
12.3 
LIST OF FIGURES 
 


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12.4 
CONTINGENT PARALLEL DESIGN ANALYSIS PLAN 
The RIN-PH-304 study is an adaptive study with a (fully blinded) decision for design 
modification based on enrollment and missing data metrics.  Following a formal and documented 
decision to switch from the Original Crossover Design to the Contingent Parallel Design, the 
following modifications will be applied to those sections specified in the main body of this SAP 
with the Original Crossover Design.  To minimize repetition, this section will cover only those 
sections affected by a decision to switch to the Contingent Parallel Design, that is:  
• If no modifications are required to a section in the main body of the SAP, no mention will 
be made below.  For example, Section 2 (Study Objectives and Endpoints) requires no 
modification under switch to a parallel design.  
• If a modification will be necessary, the affected section number and the replacement text 
are provided below.  The updated text will then supersede the current text in the main 
body of the SAP.  Text within an affected section that does not require modification will 
not be repeated below. 
12.4.1 
Study Design 
Section 3.1: Approximately 314 eligible subjects will be randomized to either 12 weeks of active 
study drug or 12 weeks of placebo (Treatment Period 1 only).  All subjects following the 
adaptive switch will be discharged from the study following 12 weeks of treatment.  The second 
washout (Washout Period - Washout 2) and Treatment Period 2 assessments will not be 
conducted following the adaptive switch and any previously collected Period 2 data will be 
ignored for the primary analyses.  
12.4.2 
Interim Efficacy Analysis 
Section 4.2: A single interim efficacy analysis will be conducted when 75% of the subjects (ie, 
~235 subjects) have completed the 12-week Treatment Period if both of the following criteria are 
met: a) the expected time to randomize the final (314th) subject is greater than 6 months; b) at 
least 90% of the 6MWD data is present for Period 1: Baseline and Week 12 for these subjects.  
Section 4.2.1: Prior to any planned interim analysis being performed, the following steps will be 
followed to estimate the expected time to randomize the final (314th) subject: 


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Section 4.2.2: If conducted with exactly 75% information fraction, the interim analysis will apply 
a 2-sided alpha level of 0.019, and at the final analysis at a 2-sided alpha of 0.044 with the 
overall Type I error rate at 2-sided alpha of 0.05; the actual information fraction at the time of 
the interim analysis will be used to calculate the 2-sided alpha level that will be applied.  
Efficacy boundaries for early stopping of the study for efficacy are based on an O’Brien-Fleming 
spending function (PASS 12, NCSS, Version 12.0).  There will be no corresponding futility 
boundary for the interim analysis. 
12.4.3 
General Considerations For Data Analyses 
Section 7: If the study design is changed to a parallel design, efficacy and safety summary tables 
will follow the general format that baseline and post-baseline data will be presented by the 
assigned treatment group when those data are observed.  Treatments will be labeled as 
“Treprostinil” and “Placebo” to correspond with the assigned treatment group.  
Efficacy and safety data collected after study discharge (after Period 1) will not be presented.  
Section 7.1: If the study design is changed to a parallel design for this study, only the Period 1 
baseline for efficacy measurements will be used.  Except for actigraphy measurements, the 
baseline value will be defined as the non-missing value immediately prior to dosing with study 
drug for Period 1: Day 1.  The baseline period for actigraphy measurements will be the last 7 
days during the washout period prior to the day of dosing on Day 1.  In the event that the 
washout period is less than 7 days then only the non-dosing days will be used to derive a baseline 
average.  


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12.4.4 
Covariates 
Section 7.4: Efficacy analyses will not include the assigned treatment sequence and period order 
as covariates.  Change from baseline analyses will include the baseline measurement as a 
continuous covariate.  
12.4.5 
Primary Efficacy Measure 
Section 9.1.3: Descriptive statistics showing the raw values and changes from baseline for the 
6MWT will be presented for each scheduled visit by treatment group.  
A longitudinal model with change from baseline as the outcome variable, implemented through 
SAS PROC MIXED, will be used to analyze the data.  The model will include all measurements 
of 6MWT.  Baseline average 6MWT will be a covariate.  The model will include terms for the 
interaction between visit number and treatment.  The contrast between treatment groups at Week 
12 will be calculated from the following model: 
 
 
 
 
 
 
  
 
 
  
LS means for baseline-adjusted 6MWT for each treatment group, LS means of treatment group 
differences with their associated p-values, and 95% CIs for both will be summarized and 
presented.   
The primary sensitivity analysis will incorporate control-based multiple imputation, which 
assumes that patients who stop study medication will adopt the experience in the placebo group, 


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will be used to account for missing data.  An addendum to this protocol, to be written before the 
data are unblinded, will present the SAS program to be used for the multiple imputation. 
Section 9.1.4: Sensitivity analyses will explore the extent to which multiple imputation of Week 
12 data influences the interpretation of the outcome.   
The following describe the sensitivity analysis approach using multiple imputation of the 
primary outcomes.  The analyses will be structured as follows: 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Planned sensitivity analyses will be described in an addendum to this SAP, which will be 
completed around the Blind Data Review but prior to the breaking of the study blind. 
Section 9.2.1: At the conclusion of the study, a blinded analysis will be performed to assess the 
extent of missing primary efficacy endpoint data.  The Sponsor has estimated the power of this 
planned study at various sample sizes and determined that the minimum acceptable power (80% 
for a 2-tailed alpha=0.05) occurs at approximately 200 subjects (~100 per treatment) providing 
evaluable primary endpoint data.  With a planned sample size of 314 evaluable subjects, if at 
least 65% of the 6MWD has been collected (or otherwise imputed for death or too ill to walk) 
across subjects and key visits (Baseline and Week 12), the primary endpoint will remain, as 
planned, the 6MWD, regardless of actigraphy data. 


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Section 9.2.3:  
The final data resulting will be the combined 6MWD/MVPA ranks data set. 
 
  
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.3.1.3.2: The associations between the observed change from baseline actigraphy 
measurements of MVPA and overall activity will be contrasted with the magnitude of change for 
PGA items.  Assessments will be made in an exploratory fashion and may include bivariate 
frequencies and correlations to assess the associations between activity and symptoms 
measurements made overall and between treatments (as appropriate).  A 1-category change on 
the 5-point PGA scale will be considered clinically meaningful.   


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Section 9.3.3: The 6MWD and Borg dyspnea composite score is derived based on the results of 
the 6MWD and the Borg dyspnea scale measuring the degree of dyspnea.  The following 
derivation strategy will be employed to calculate the 6MWD and Borg dyspnea composite score: 
 
  
 
 
 
  
 
 
 
  
 
  
  
 
 
 
  
 
  
 
Descriptive statistics of the raw and change from baseline values for composite score will be 
presented for each scheduled visit by treatment.  The composite score will be treated as a 
continuous variable.  A longitudinal mixed model, similar to that used for the primary analysis of 
6MWD, will be used to describe the change from baseline in the composite score over time.  A 
contrast will be calculated for Week 12 to compare the treatment groups with respect to change.  


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12.4.6 
Secondary Efficacy Measures 
Section 9.4.1: A longitudinal mixed model will be used to describe the change from baseline for 
the each of the scores over time.  A contrast will be calculated for Week 12 to compare the 
treatment groups with respect to change.  The outcome variable will be change from baseline.  
Independent variables will be treatment, the subject’s baseline average SGRQ score, treatment 
sequence, visit number, and the interaction of visit and treatment. 
Section 9.4.2: A longitudinal mixed model will be used to describe the change from baseline in 
the total score over time.  A contrast will be calculated for Week 12 to compare the treatment 
groups with respect to change.  The outcome variable will be change from baseline.  Independent 
variables will be treatment, the subject’s baseline average UCSD SOBQ score, treatment 
sequence, visit number, and the interaction of visit and treatment. 
12.4.7 
Safety Analyses 
Section 10.1: Exposure to treprostinil and placebo will be calculated as the date of last dose 
minus the date of first dose plus 1.  If the date of last dose of study drug was missing or 
unknown, the return date of study drug will be used as an imputed date.  All analyses will be 
presented by treatment. 
Section 10.2: Adverse events are recorded starting from the time each subject signs the ICF until 
the time a screen failure is documented, study completion, or early termination.  All events 
recorded by the Investigators will be assigned a MedDRA PT and SOC.  The most recently 
available MedDRA version before the database lock date will be used to assign preferred terms 
and system organ classes.  All presentations will present data by treatment received at the time of 
the event.  Non–treatment-emergent AEs observed outside of any study drug exposure will not 
be presented.  
Section 10.5: Descriptive statistics for each clinical laboratory parameter (hematology, serum 
chemistry, and electrolytes) will be presented by treatment group at baseline, each post-baseline 
assessment, and End of Study visits for raw data and change from baseline. 


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Section 10.6: Descriptive statistics for vital signs (heart rate, systolic blood pressure, diastolic 
blood pressure, respiration rate, weight, BMI) will be presented for both Baseline Visits by 
treatment.  The same statistics will also be presented for each post-baseline assessment and End 
of Study visits for the raw data and change from the respective baseline.  Any clinically 
significant change from Screening Visit 1 was to be recorded as an AE.  
Section 10.7: Descriptive statistics for ECG findings (sinus rhythm [present/absent], heart rate, 
PR interval, QRS duration, QT interval, interpretation [normal/abnormal]) will be presented by 
treatment group.  Continuous variables will also be presented as the raw values and change from 
the respective baseline will be presented for each post-baseline assessment by treatment received 
at the time of the visit.  Whenever more than one ECG evaluations are recorded on the same day, 
the data summaries will use the average of these readings.