An Open-label, Clinical Study to Evaluate the Safety and Tolerability of Treprostinil Inhalation Powder (TreT) in Subjects With Pulmonary Arterial Hypertension Currently Using Tyvaso
Phase: PHASE1
Conditions: Pulmonary Arterial Hypertension
Sponsor: United Therapeutics

TIP-PH-101 Protocol Amendment 2 
Treprostinil Inhalation Powder (TreT) 
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 
Page 1 
An Open-label, Clinical Study to Evaluate the Safety and Tolerability of 
Treprostinil Inhalation Powder (TreT) in Subjects with Pulmonary Arterial 
Hypertension Currently Using Tyvaso  
IND Number: 134,582 
Protocol TIP-PH-101 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Protocol Date: 30 January 2019 
Amendment 1: 
Amendment 2: 
08 May 2019 
02 April 2020 

United Therapeutics Corp. 
TIP-PH-101 Protocol Amendment 2 
 
Treprostinil Inhalation Powder (TreT) 
Version Date 02 April 2020 
CONFIDENTIAL 
Page 3 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “An Open-label, Clinical Study to Evaluate the Safety 
and Tolerability of Treprostinil Inhalation Powder in Subjects with Pulmonary Arterial 
Hypertension Currently Using Tyvaso,” Protocol Amendment 2 dated 02 April 2020 and agree to 
abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation Guideline for Good Clinical 
Practice and applicable Food and Drug Administration regulations/guidelines set forth in 
21 Code of Federal Regulations Parts 50, 54, 56 and 312 and any local regulations per country. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of United Therapeutics Corp.  
I also have read the current Clinical Investigator’s Brochure for Treprostinil Inhalation Powder 
and acknowledge that review of the information contained in the Clinical Investigator’s Brochure 
is a requirement for Investigators before using Treprostinil Inhalation Powder in a clinical study. 
This protocol has been received for information only and must not be implemented before all 
necessary regulatory agency and Ethics Committee/Institutional Review Board approval 
documents have been obtained. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 

United Therapeutics Corp. 
TIP-PH-101 Protocol Amendment 2 
 
Treprostinil Inhalation Powder (TreT) 
Version Date 02 April 2020 
CONFIDENTIAL 
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PROTOCOL SYNOPSIS 
Title  
An Open-label, Clinical Study to Evaluate the Safety and 
Tolerability of Treprostinil Inhalation Powder (TreT) in Subjects 
with Pulmonary Arterial Hypertension Currently Using Tyvaso 
Study Phase 
1b 
Indication 
Pulmonary arterial hypertension (WHO Group 1) 
Primary Objective 
To evaluate the safety and tolerability of Treprostinil Inhalation 
Powder (TreT) in subjects with pulmonary arterial hypertension 
(PAH) currently treated with Tyvaso® 
Secondary Objective(s) 
1. To evaluate systemic exposure and pharmacokinetics (PK) of 
treprostinil in subjects with PAH when delivered as Tyvaso 
and TreT 
2. To evaluate 6-Minute Walk Distance (6MWD) at study entry 
and after 3 weeks of treatment with TreT 
3. To evaluate long-term safety and tolerability of TreT in 
subjects with PAH previously treated with Tyvaso  
4. To evaluate subject satisfaction with and preference for 
inhaled treprostinil devices with the Preference 
Questionnaire for Inhaled Treprostinil Devices (PQ-ITD). 
5. To evaluate patient-reported PAH symptoms and impact with 
the PAH-Symptoms and Impact (PAH-SYMPACT) 
Questionnaire. 
Study Design 
This is a Phase 1b safety and tolerability single-sequence study in 
which subjects on a stable regimen of Tyvaso will switch to a 
corresponding dose of TreT.  At Baseline, subjects currently taking 
stable doses of Tyvaso (6 to 12 breaths 4 times daily [QID]) will 
take a dose of Tyvaso in the clinic and undergo PK assessments, 
safety assessments, and a 6-Minute Walk Test (6MWT).  Following 
the in-clinic assessments, subjects will switch from Tyvaso to the 
corresponding dose of TreT and take their first dose of TreT in the 
clinic.  Following 3 weeks of treatment with TreT, subjects will 
return to the clinic and receive 1 dose of TreT in clinic and undergo 
PK assessments, safety assessments, and a 6MWT as performed at 
the Baseline Visit.   
Following the Week 3 Visit, subjects will be offered the opportunity 
to participate in the Optional Extension Phase of the study.  Subjects 
who elect to discontinue TreT at the end of the Treatment Phase will 
return to the clinic in 2 weeks for an End of Study Visit.  Subjects 
who elect to enter the Optional Extension Phase will remain on TreT 
and attend follow-up study visits that will occur every 8 weeks until 
the study is terminated or the drug/device becomes commercially 
available.  If the subject discontinues TreT prematurely during the 

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Version Date 02 April 2020 
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Optional Extension Phase, he/she must return to clinic as soon as 
possible for an Early Termination Visit.   
Sample Size 
For this study, total sample size is estimated to be 45 subjects and is 
not based on power calculations. 
Summary of Subject 
Eligibility Criteria 
Inclusion Criteria: 
1. Subject voluntarily gives informed consent to participate in 
the study. 
2. Subject is aged 18 years or older at the time of signing 
informed consent. 
3. Women of childbearing potential must be nonpregnant and 
nonlactating, and will: 
a. Either abstain from intercourse (when it is in line with 
their preferred and usual lifestyle), or 
b. Use 2 medically acceptable, highly effective forms of 
contraception for the duration of study, and at least 
30 days after discontinuing TreT.  Medically 
acceptable, highly effective forms of contraception can 
include approved hormonal contraceptives (oral, 
injectable, and implantable), intrauterine devices or 
systems, and barrier methods (such as a condom or 
diaphragm) when used with a spermicide.  
4. Males with a partner of childbearing potential must use a 
condom for the duration of treatment and for at least 
48 hours after discontinuing TreT.   
5. Subject is diagnosed with PAH as defined by the following 
World Health Organization (WHO) Group 1 categories: 
a. 
Idiopathic/familial 
b. 
Associated with unrepaired or repaired congenital 
systemic-to-pulmonary shunts (repaired ≥5 years prior 
to screening) 
c. 
Associated with collagen vascular disease 
d. 
Associated with human immunodeficiency virus 
e. 
Associated with appetite suppressant/other drug or 
toxin use 
6. Subject must have started Tyvaso ≥3 months prior to the 
Baseline Visit and must currently be on a stable regimen (no 
change in dose within 30 days of Baseline Visit) of Tyvaso 
(6 to 12 breaths QID). 
7. Baseline 6MWD ≥150 m. 

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Version Date 02 April 2020 
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8. If currently receiving other approved background therapy for 
PAH (eg, endothelin receptor antagonist or 
phosphodiesterase-5-inhibitor or both), the subject must be 
on a stable dose with no additions or discontinuations for a 
minimum of 30 days prior to Screening.  
9. The subject has had evidence of forced expiratory volume in 
1 second (FEV1) ≥60% and FEV1/forced vital capacity ratio 
≥60% during the 6 months prior to enrollment. 
10. In the opinion of the Investigator, the subject is able to 
communicate effectively with study personnel, and is 
considered reliable, willing, and likely to be cooperative with 
protocol requirements, including all study visits.   
 
Exclusion Criteria: 
1. Subject is pregnant or lactating.   
2. Subject has been diagnosed with pulmonary hypertension for 
reasons other than WHO Group 1 as outlined in Inclusion 
Criterion 5 (including but not limited to portal hypertension, 
chronic thromboembolic disease, pulmonary veno-occlusive 
disease, hemolytic anemia, sarcoidosis). 
3. Subject has a history of uncontrolled sleep apnea, 
parenchymal lung disease, or hemodynamically significant 
left-sided heart disease (including but not limited to aortic or 
mitral valve disease, pericardial constriction, restrictive or 
congestive cardiomyopathy, or coronary artery disease). 
4. Subject is currently taking any other prostacyclin analogue or 
agonist, including but not limited to, selexipag, epoprostenol, 
iloprost, or beraprost; except for acute vasoreactivity testing. 
5. Subject experienced an acute exacerbation of disease or 
hospitalization for any reason within 30 days of Screening 
Visit or between Screening and Baseline. 
6. Subject is WHO Functional Class IV at Screening. 
7. Subject has used any investigational drug/device or 
participated in any other investigational study with 
therapeutic intent within 30 days prior to Screening Visit. 
8. Subject has a history of anaphylaxis, a documented 
hypersensitivity reaction, or a clinically significant 
idiosyncratic reaction to treprostinil or excipients in the 
investigational product.  

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Version Date 02 April 2020 
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9. Subject has conditions that, in the opinion of the Investigator, 
would make the subject ineligible.  
10. Subject is not able to perform inhalation maneuvers that meet 
inspiratory training criteria. 
11. Subject has a musculoskeletal disorder (eg, arthritis affecting 
the lower limbs, recent hip or knee joint replacement) or any 
disease that would likely be the primary limit to ambulation, 
or is connected to a machine that is not portable enough to 
allow for a 6MWT. 
12. Subject has had a new type of chronic therapy (including but 
not limited to oxygen, a different class of vasodilator, 
diuretic, and digoxin) for pulmonary hypertension added 
within 30 days of the Screening Phase. 
13. Initiation of pulmonary rehabilitation within 12 weeks prior 
to the Baseline Visit. 
Drug Dosage  
and Formulation 
The treatments are assigned based on current stable Tyvaso dose.  
Each subject will receive a corresponding dose of TreT for 3 weeks 
during the Treatment Phase.  
 
Study Entry 
Treatment Phase 
Tyvaso Dose 
(QID) 
TreT Dose (QID) 
Device Requirement 
6 to 7 breaths 
32 µg 
32 µg cartridge 
8 to 10 breaths 
48 µg 
48 µg cartridge 
11 to 12 breaths 
64 µg 
32 µg + 32 µg cartridges 
Control Group 
None 
Route of  
Administration 
TreT will be administered via a dry powder inhaler in 3 dose levels 
supplied as cartridges filled to provide 32 µg, 48 µg, and 64 µg of 
treprostinil.  Tyvaso inhalation solution will be administered via 
ultrasonic nebulization using the commercially available Tyvaso 
Inhalation System. 
Procedures 
Screening Phase: Prospective subjects will be assessed during the 
Screening Phase to determine eligibility for the study.  The 
Screening Visit must occur within 14 days prior to Baseline.  During 
this Screening Phase, eligible subjects will sign the Informed 
Consent form and undergo screening assessments.  Subjects who 
satisfy all eligibility criteria during the Screening Phase may return 
to the clinic at Baseline for enrollment.  If subjects are able to satisfy 
all eligibility criteria on the same day, a combined 
Screening/Baseline Visit may be conducted.  

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Treatment Phase: The Treatment Phase consists of 2 study visits to 
the clinic separated by 3 weeks of treatment with TreT.  At Baseline, 
subjects will receive 1 dose of Tyvaso in clinic and undergo PK 
assessments (at the following timepoints: 15 minutes before dose 
and 5, 10, 15, 30, 45, 90, 120, 180, 240, and 300 minutes after dose), 
safety assessments, and a 6MWT.  No additional dose of Tyvaso 
will be administered, nor will TreT be started, until after the PK 
sampling assessment is complete.  Following these assessments, 
subjects will be assigned a corresponding dose of TreT based upon 
their current stable Tyvaso dose and will receive the first dose of 
TreT in the clinic.  Each subject will receive TreT QID by oral 
inhalation for 3 weeks.  Following 3 weeks of treatment, subjects 
will return to the clinic and receive 1 dose of TreT in clinic and 
undergo PK assessments, safety assessments, and a 6MWT as 
performed at the Baseline Visit.  Questionnaires evaluating patient 
preference for inhaled treprostinil devices and patient-reported PAH 
symptoms and impact will also be administered.  At each study visit 
during the Treatment Phase, adverse events (AEs) will be assessed, 
vital signs will be recorded, and a physical examination will be 
performed.  Following the Week 3 Visit, subjects may choose to 
participate in the Optional Extension Phase of the study.  If the 
subject does not elect to participate in the Optional Extension Phase 
of the study, he/she must discontinue TreT, may resume Tyvaso, and 
must return to the clinic 2 weeks after TreT discontinuation for an 
End of Study Visit.   
Optional Extension Phase: The Optional Extension Phase will 
occur following completion of the Treatment Phase and continue 
with clinic visits every 8 weeks until the study is terminated for any 
reason or the drug/device becomes commercially available.  To be 
eligible for the Optional Extension Phase, subjects must complete 
the Treatment Phase, elect to continue TreT, and agree to attend 
follow-up visits in the clinic.  Dosing titration will be encouraged 
during the Optional Extension Phase; the dose of TreT should be 
titrated upward, as clinically tolerated, to identify a maximum stable 
dose in each subject.  Subjects who discontinue TreT must complete 
an Early Termination Visit as soon as possible. 
Statistical 
Considerations 
Plasma concentrations of treprostinil above the lower limit of 
quantitation will be used to calculate area under the curve from time 
0 to 300 minutes (AUC0-300) and maximal drug concentration (Cmax) 
for each treatment.  PK and safety parameters will be summarized 
using descriptive statistics.  The 6MWT results will also be 
summarized using descriptive statistics.  The number and percent of 
subjects with AEs will be tabulated for treatment phases by Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ 
Class and Preferred Term by relationship to treatment and severity.   

United Therapeutics Corp. 
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Version Date 02 April 2020 
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Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive 
Research Triangle Park, NC 27709 
USA  
 
 

United Therapeutics Corp. 
TIP-PH-101 Protocol Amendment 2 
 
Treprostinil Inhalation Powder (TreT) 
Version Date 02 April 2020 
CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ............................................................................................3 
PROTOCOL SYNOPSIS ..............................................................................................................4 
TABLE OF CONTENTS ............................................................................................................10 
Table of In-Text Tables ...............................................................................................................13 
Table of In-Text Figures ..............................................................................................................13 
LIST OF ABBREVIATIONS .....................................................................................................14 
1 BACKGROUND AND RATIONALE .................................................................................16 
1.1 
DEFINITION OF CLINICAL PROBLEM ....................................................................16 
1.2 
INHALED TREPROSTINIL BACKGROUND ............................................................16 
1.2.1 
Treprostinil Inhalation Powder ..................................................................................16 
1.2.1.1 
Active Pharmaceutical Ingredient: Treprostinil ....................................................17 
1.2.2 
General Toxicology ......................................................................................................17 
1.2.2.1 
Active Pharmaceutical Ingredient: Treprostinil ....................................................17 
1.2.3 
Clinical Experience ......................................................................................................18 
1.2.3.1 
Inhaled Treprostinil (Tyvaso) ..................................................................................18 
1.2.3.2 
Treprostinil Inhalation Powder ...............................................................................19 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION ...................................................................................................20 
1.4 
CLINICAL HYPOTHESIS ..............................................................................................21 
2 OBJECTIVES ........................................................................................................................21 
2.1 
PRIMARY OBJECTIVES ...............................................................................................21 
2.2 
SECONDARY OBJECTIVES .........................................................................................21 
3 EXPERIMENTAL PLAN .....................................................................................................21 
3.1 
STUDY DESIGN ...............................................................................................................21 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ...................................................25 
3.3 
CLINICAL ASSESSMENTS ...........................................................................................29 
3.3.1 
Efficacy Assessments ....................................................................................................29 
3.3.1.1 
Pharmacokinetic Assessments .................................................................................29 
3.3.1.2 
6-Minute Walk Test ..................................................................................................29 
3.3.1.3 
Preference Questionnaire for Inhaled Treprostinil Devices .................................30 
3.3.1.4 
PAH-SYMPACT Questionnaire..............................................................................30 
3.3.1.5 
Optional Biomarker and Optional Whole Genome Sequencing ..........................30 
3.3.2 
Safety and Tolerability Assessments ..........................................................................31 
3.3.2.1 
Inspiratory Criteria Assessment .............................................................................31 
3.3.2.2 
Medical History and Physical Examinations .........................................................31 
3.3.2.3 
Vital Signs ..................................................................................................................32 
3.3.2.4 
12-Lead Electrocardiogram .....................................................................................32 
3.3.2.5 
Clinical Laboratory Assessments ............................................................................32 

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3.3.2.6 
Adverse Events ..........................................................................................................33 
3.3.2.7 
Concomitant Medications ........................................................................................33 
3.3.2.8 
Periodic Telephone/Email Contact .........................................................................34 
3.4 
NUMBER OF CENTERS ................................................................................................34 
3.5 
NUMBER OF SUBJECTS ...............................................................................................34 
3.6 
ESTIMATED STUDY DURATION ...............................................................................34 
4 SUBJECT ELIGIBILITY .....................................................................................................34 
4.1 
INCLUSION CRITERIA .................................................................................................34 
4.2 
EXCLUSION CRITERIA ................................................................................................36 
4.3 
PRESCRIBED THERAPY ..............................................................................................37 
4.3.1 
Concomitant Medications ............................................................................................37 
4.3.2 
Other Treatments .........................................................................................................37 
5 SUBJECT ENROLLMENT ..................................................................................................37 
5.1 
TREATMENT ASSIGNMENT .......................................................................................37 
6 DRUGS AND DOSING .........................................................................................................38 
6.1 
DRUG DOSAGE, ADMINISTRATION, AND SCHEDULE .......................................38 
6.1.1 
Tyvaso ............................................................................................................................38 
6.1.2 
Treprostinil Inhalation Powder ..................................................................................38 
6.2 
COMPLIANCE .................................................................................................................39 
7 EXPERIMENTAL PROCEDURES ....................................................................................39 
7.1 
SCREENING VISIT .........................................................................................................39 
7.2 
BASELINE VISIT .............................................................................................................40 
7.3 
COMBINED SCREENING AND BASELINE VISIT ...................................................41 
7.4 
WEEK 3 VISIT .................................................................................................................41 
7.5 
END OF STUDY VISIT AND/OR EARLY TERMINATION VISIT .........................42 
7.6 
OPTIONAL EXTENSION PHASE Visits ......................................................................43 
7.6.1 
Week 11 Visit (Then Every 8 weeks) ..........................................................................43 
7.6.2 
TreT Dose Titration Visits ...........................................................................................43 
7.6.3 
TreT Blister Packaging ................................................................................................43 
7.7 
STUDY CONTACTS ........................................................................................................44 
8 STUDY TERMINATION .....................................................................................................44 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ..............................................................44 
8.2 
CRITERIA FOR TERMINATING THE STUDY .........................................................45 
8.3 
CRITERIA FOR DISCONTINUING THE SITE ..........................................................45 
9 ADVERSE EVENT REPORTING ......................................................................................45 
9.1 
DEFINITIONS ..................................................................................................................45 
9.1.1 
Adverse Event ...............................................................................................................45 
9.1.2 
Serious Adverse Event .................................................................................................46 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ............................................................47 
9.3 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ..............................48 

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9.4 
SAFETY REPORTS .........................................................................................................48 
9.5 
PREGNANCY ...................................................................................................................48 
10 STATISTICAL CONSIDERATIONS .................................................................................49 
10.1 DATA PROCESSING ......................................................................................................49 
10.2 SAMPLE SIZE ..................................................................................................................49 
10.3 ANALYSIS PLAN .............................................................................................................49 
10.3.1 
Pharmacokinetic Analysis ...........................................................................................49 
10.3.2 
Safety and Tolerability Analyses ................................................................................50 
10.4 INTERIM ANALYSIS .....................................................................................................50 
10.5 OTHER ANALYSES ........................................................................................................50 
10.6 DATA LISTINGS AND SUMMARIES ..........................................................................50 
11 PACKAGING AND FORMULATION ...............................................................................50 
11.1 CONTENTS OF STUDY DRUG .....................................................................................50 
11.1.1 
Study Drug ....................................................................................................................50 
11.1.2 
Study Device ..................................................................................................................51 
11.2 LABELING ........................................................................................................................51 
11.2.1 
Study Drug ....................................................................................................................51 
11.2.2 
Study Device ..................................................................................................................51 
11.3 STORAGE AND HANDLING OF CLINICAL STUDY MATERIAL .......................51 
11.4 SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL ................................52 
11.5 DRUG ACCOUNTABILITY ...........................................................................................52 
12 REGULATORY AND ETHICAL OBLIGATION.............................................................53 
12.1 US FDA REGULATORY REQUIREMENTS ...............................................................53 
12.2 INFORMED CONSENT REQUIREMENTS ................................................................53 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ..............................................................................................................................53 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ...............................................54 
12.5 SUBJECT CONFIDENTIALITY ...................................................................................54 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS .......................................................54 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .................................54 
13.2 STUDY DOCUMENTATION AND STORAGE ...........................................................55 
13.3 STUDY MONITORING AND DATA COLLECTION ................................................55 
14 REFERENCES .......................................................................................................................56 
15 APPENDICES ........................................................................................................................57 
15.1 PROCEDURES FOR A 6-MINUTE WALK TEST ......................................................57 
15.2 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS ......59 
 
 
 

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Table of In-Text Tables 
Table 3-1 
Overall Schedule of Times and Events ..................................................................25 
Table 3-2 
Schedule of Events for Dosing and Pharmacokinetic Sampling - Baseline and 
Week 3 Visit ..........................................................................................................28 
Table 3-3 
Clinical Laboratory Parameters .............................................................................33 
Table 6-1 
Treatment Phase Assignments ...............................................................................38 
Table of In-Text Figures 
Figure 1-1 
Mean Plasma Treprostinil Concentration-time Profiles after Single-dose 
Administrations of 30 µg to 180 µg Treprostinil Inhalation Powder (TreT) .........20 
Figure 3-1 
Study Flow Chart ...................................................................................................24 
 

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LIST OF ABBREVIATIONS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
AUC 
Area under the curve 
Cmax 
Maximal drug concentration 
DBP 
Diastolic blood pressure 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ERA 
Endothelin receptor antagonist 
FEV1 
Forced expiratory volume in 1 second 
FDA 
Food and Drug Administration 
FDKP 
Fumaryl diketopiperazine 
GCP 
Good Clinical Practice 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology  
IV 
Intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
PAH 
Pulmonary arterial hypertension 
PAH-SYMPACT 
Pulmonary Arterial Hypertension-Symptoms and Impact 
PDE5-I 
Phosphodiesterase type 5 inhibitor 
PE 
Physical examination 
PFT 
Pulmonary function test 
PGI2 
Prostacyclin 
PK 
Pharmacokinetic(s) 
PQ-ITD 
Preference Questionnaire for Inhaled Treprostinil Devices 
PRO 
Patient reported outcome 
QID 
4 times daily 
RR 
Respiratory rate 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
sGC 
Soluble guanylate cyclase 

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TreT 
Treprostinil Inhalation Powder 
UTC 
United Therapeutics Corporation 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
 

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1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
Pulmonary arterial hypertension (PAH), defined as an elevation in pulmonary arterial pressure 
and pulmonary vascular resistance, is a severe hemodynamic abnormality associated with a 
variety of diseases and syndromes.  Elevation in pulmonary arterial pressure causes an increase 
in right ventricular afterload, impairing right ventricular function, and ultimately leading to heart 
failure and death (Rubin 1997). 
There are 3 major factors thought to contribute to the increased pulmonary vascular resistance 
seen in this disease: vasoconstriction, remodeling of the vessel wall, and thrombosis.  There are 
several metabolic pathways which contribute to these changes that involve vasoactive mediators 
such as the vasodilators, nitric oxide and prostacyclin (PGI2), and the vasoconstrictor, 
endothelin-1.  These substances affect both vascular tone and remodeling, leading to their use as 
pharmacologic targets (Farber 2004). 
Approved pharmacotherapies for PAH in the US include intravenous (IV) PGI2 (epoprostenol 
sodium or Flolan, Veletri®); the PGI2 analogues, subcutaneous, IV, and inhaled treprostinil 
(Remodulin®, Tyvaso®), oral treprostinil diethanolamine (also referred to as treprostinil 
diolamine; Orenitram®), oral selexipag (Uptravi®), and inhaled iloprost (Ventavis®); the 
phosphodiesterase type 5 inhibitors (PDE5-Is), tadalafil (Adcirca®) and sildenafil (Revatio®); the 
oral endothelin receptor antagonists (ERAs), bosentan (Tracleer®), ambrisentan (Letairis®, 
Volibris®), and macitentan (Opsumit®); and a soluble guanylate cyclase (sGC) stimulator, 
riociguat (Adempas®). 
1.2 
INHALED TREPROSTINIL BACKGROUND 
1.2.1 
Treprostinil Inhalation Powder 
United Therapeutics Corporation (UTC) is developing a combination drug-device product which 
is comprised of a dry powder formulation of Treprostinil Inhalation Powder (TreT) and a small, 
portable, dry powder inhaler.  The dry powder contains treprostinil and an inhalation excipient, 
fumaryl diketopiperazine (FDKP), which is an excipient present in Afrezza®, an Food and Drug 
Administration (FDA)-approved drug product that is listed in the FDA Inactive Ingredient 
Database.   

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1.2.1.1 
Active Pharmaceutical Ingredient: Treprostinil 
Treprostinil, [[(1R,2R,3aS,9aS) 2,3,3a,4,9,9a hexahydro 2 hydroxy 1 [(3S) 3 hydroxyoctyl] 1H 
benz [f]inden 5 yl]oxy]acetic acid, is a chemically stable tricyclic analogue of PGI2.  The 
pharmacology of treprostinil has been extensively characterized in well-established models, all 
confirming the suitability of the drug for the treatment of PAH following either the 
subcutaneous, IV, inhaled (as treprostinil sodium), or oral (as treprostinil diethanolamine) routes 
of administration. 
The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and 
systemic arterial vascular beds and inhibition of platelet aggregation.  In vitro, treprostinil 
induced concentration-dependent relaxation of rabbit isolated, precontracted, mesenteric arteries 
and inhibition of 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.  Prostacyclins lower pulmonary 
artery pressure, increase cardiac output without affecting the heart rate (HR), and improve 
systemic oxygen transport as well as possibly reversing pulmonary artery remodeling.  There is 
also increasing evidence that the ability to block the proliferation of pulmonary artery smooth 
muscle cells may contribute, along with vasodilation, to the therapeutic effects of PGI2 in the 
treatment of PAH.  The mechanism of action is therefore likely to be multifactorial. 
1.2.2 
General Toxicology 
1.2.2.1 
Active Pharmaceutical Ingredient: Treprostinil 
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 2018, Tyvaso Package Insert 2017).   
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 for inhalation at target doses up to 5.25, 10.6, and 
34.1 µg/kg/day, which found no evidence for carcinogenic potential associated with inhaled 

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treprostinil in rats at systemic exposure levels up to 35 times the clinical exposure at the target 
maintenance dose of 54 µg.   
1.2.3 
Clinical Experience 
1.2.3.1 
Inhaled Treprostinil (Tyvaso) 
A series of acute and chronic investigator-initiated clinical studies were conducted with inhaled 
treprostinil to optimize the formulation for inhalation; determine dose response, tolerability, and 
safety; and also to evaluate safety and tolerability when combined with other PAH therapies 
(Channick 2006, Voswinckel 2006).  In the acute dosing studies, administration of inhaled 
treprostinil resulted in pulmonary vasodilation at relatively low doses.  In the chronic studies, 
administration of inhaled treprostinil resulted in sustained improvement of exercise capacity.   
A randomized, double-blind, placebo-controlled, Phase 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 m in 6MWD, and 
subjects in the placebo group had a median improvement of +3.0 m.  The Hodges-Lehmann 
placebo-corrected median change from baseline in peak 6MWD was +20.0 m (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 m (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 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 µg) 4 times daily (QID) to achieve daily doses of 24 to 288 µg.  The longest duration of 

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inhaled treprostinil exposure in the open-label study was 5.4 years and the mean duration 
2.3 years.  There were observed improvements in median 6MWD at 6, 12, 18, and 24 months of 
28, 31, 32, and 18 m, respectively.  These data support the durability of improvement in 6MWD 
obtained with inhaled treprostinil as demonstrated during the double-blind phase of the study.  
Therapeutic benefit was also noted with improvements in the Borg dyspnea score, New York 
Heart Association Functional Classification, and quality of life.  Survival was robust with 1- and 
2-year Kaplan-Meier survival estimates of 97% and 91%, respectively, for subjects that remained 
in the study.  The most frequently reported AEs during the open-label study were cough (39%), 
headache (31%), upper respiratory tract infection (22%), and nausea (22%).  There were no 
clinically significant changes in clinical chemistry or hematology parameters.  Unique findings 
that related to the inhaled route of administration, in addition to cough, were throat pain and 
throat irritation, occurring in 12% and 10% of subjects, respectively.  These events were usually 
of mild or moderate severity and transient in duration.  In a few subjects, these specific AEs were 
more pronounced as 6 subjects (3%) discontinued inhaled treprostinil due to cough, including 
1 subject (<1%) with dry throat. 
1.2.3.2 
Treprostinil Inhalation Powder 
An open-label, single ascending dose (SAD) study in healthy normal volunteers, MKC-475-001, 
was conducted to assess the safety and tolerability of TreT.  A total of 36 healthy volunteers 
were sequentially assigned to 6 cohorts (6 subjects per cohort) of ascending dose levels of TreT 
(30, 60, 90, 120, 150, and 180 µg).  Each subject received 1 dose of TreT by oral inhalation 
during the Treatment Period.  The incidence and severity of AEs were assessed and 
pharmacokinetic (PK) parameters were measured by analyzing plasma concentrations of 
treprostinil.  Bioanalysis data confirmed treprostinil plasma concentrations and exposure at 
clinically relevant concentrations when TreT is administered as a dry powder via oral inhalation.  
Treprostinil exposure, as measured by maximal drug concentration (Cmax) and area under the 
curve (AUC), increased in a linear manner with increasing dose up to 180 µg tested, which 
would correspond to a 30-breath dose of Tyvaso.   

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Figure 1-1 
Mean Plasma Treprostinil Concentration-time Profiles after Single-dose 
Administrations of 30 µg to 180 µg Treprostinil Inhalation Powder (TreT) 
 
The most frequently reported AEs overall were cough (31%) and headache (22%).  There were 
no severe AEs, serious AE (SAEs), or deaths during this study.  No AEs led to a subject’s early 
termination.  No clinically significant abnormalities on oropharyngeal examinations, clinical 
laboratory evaluations, electrocardiograms (ECGs), or PFTs (spirometry) were observed.  
Overall, TreT was safe and well tolerated as oral inhalation doses of 30, 60, 90, 120, and 150 µg.   
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION 
UTC is developing a combination drug-device product which is comprised of a dry powder 
formulation of TreT and a small, portable, dry powder inhaler.  This combination product is a 
change in dosage form for treprostinil from a solution for oral inhalation (Tyvaso) to a dry 
powder for oral inhalation.  The dry powder contains the inhalation excipient, FDKP, which is an 
excipient present in Afrezza, an FDA-approved drug product that is listed in the FDA Inactive 
Ingredient Database.  The properties of the dry powder are suitable for dosing by oral inhalation 
(eg, particle size suitable for pulmonary delivery).  The device is a reusable, breath-powered, dry 
powder inhaler that does not require software, electrical power, or cleaning.  For these reasons, it 

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is significantly smaller and more portable than the currently available inhaled prostacyclin 
therapies.  
1.4 
CLINICAL HYPOTHESIS 
This study hypothesizes that the systemic exposure, PK, and tolerability of treprostinil will be 
similar in patients with PAH when administered as TreT and Tyvaso.  
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective of this clinical study is to evaluate the safety and tolerability of TreT in 
subjects with PAH currently treated with Tyvaso. 
2.2 
SECONDARY OBJECTIVES 
A secondary objective of this clinical study is to evaluate systemic exposure and PK of 
treprostinil in subjects with PAH when delivered as Tyvaso and TreT.  Additionally, this study 
will evaluate 6MWD at study entry and after 3 weeks of treatment with TreT.  The Optional 
Extension Phase of this study will evaluate long-term safety and tolerability of TreT in subjects 
with PAH previously treated with Tyvaso.  Further, this study will evaluate subject satisfaction 
with and preference for inhaled treprostinil devices with the PQ-ITD and patient-reported PAH 
symptoms and impact with the Pulmonary Arterial Hypertension-Symptoms and Impact 
(PAH-SYMPACT®) Questionnaire. 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a Phase 1b safety and tolerability single-sequence study in which subjects on a stable 
regimen of Tyvaso will switch to a corresponding dose of TreT.  At Baseline, subjects currently 
taking stable doses of Tyvaso (6 to 12 breaths QID) will take a dose of Tyvaso in the clinic and 
undergo PK assessments, safety assessments, and a 6MWT.  Following the in-clinic assessments, 
subjects will switch from Tyvaso to the corresponding dose of TreT and take their first dose of 
TreT in the clinic.  Following 3 weeks of treatment with TreT, subjects will return to the clinic 
and receive 1 dose of TreT and undergo PK assessments, safety assessments, and a 6MWT as 
performed at the Baseline Visit.   

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Following the Week 3 Visit, subjects will be offered the opportunity to participate in the 
Optional Extension Phase of the study.  Subjects who elect to discontinue TreT at the end of the 
Treatment Phase will return to the clinic in 2 weeks for an End of Study Visit.  Subjects who 
elect to enter the Optional Extension Phase will remain on TreT and attend study visits every 
8 weeks until the study is terminated or the drug/device becomes commercially available.  If the 
subject discontinues TreT prematurely during the Optional Extension Phase, he/she must return 
to the clinic as soon as possible for an Early Termination Visit.   
Screening Phase: Prospective subjects will be assessed during the Screening Phase to determine 
eligibility for the study.  The Screening Visit must occur within 14 days prior to Baseline.  
During this Screening Phase, eligible subjects will sign the Informed Consent Form (ICF) and 
undergo screening assessments.  Subjects who satisfy all eligibility criteria during the Screening 
Phase may return to the clinic at Baseline for enrollment.  If subjects are able to satisfy all 
eligibility criteria on the same day, a combined Screening/Baseline Visit may be conducted. 
Treatment Phase: The Treatment Phase consists of 2 study visits to the clinic separated by 
3 weeks of treatment with TreT.  At Baseline, subjects will receive 1 dose of Tyvaso in the clinic 
and undergo PK assessments (at the following timepoints: 15 minutes before dose and 5, 10, 15, 
30, 45, 90, 120, 180, 240, and 300 minutes after dose), safety assessments, and a 6-Minute Walk 
Test (6MWT).  No additional dose of Tyvaso will be administered, nor will TreT be started, until 
after the PK sampling assessment is complete.  Following these assessments, subjects will be 
assigned a corresponding dose of TreT based upon their current stable Tyvaso dose and will 
receive the first dose of TreT in the clinic.  Each subject will receive TreT QID by oral inhalation 
for 3 weeks.  Following 3 weeks of treatment, subjects will return to the clinic and receive 1 dose 
of TreT in the clinic and undergo PK assessments, safety assessments, and a 6MWT as 
performed at the Baseline Visit.  Questionnaires evaluating patient preference for inhaled 
treprostinil devices and patient-reported PAH symptoms and impact will also be administered.  
At each study visit, AEs will be assessed, vital signs will be recorded, and a physical 
examination (PE), including oropharyngeal examination, will be performed.  Following the 
Week 3 Visit, subjects may choose to participate in the Optional Extension Phase of the study.  If 
the subject does not elect to participate in the Optional Extension Phase of the study, he/she must 

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discontinue TreT, may resume Tyvaso therapy, and must return to the clinic 2 weeks after TreT 
discontinuation for an End of Study Visit.  Blood samples for an optional evaluation of change in 
biomarkers (specific targets to be determined) will be collected at the Baseline Visit and Week 3 
Visit.  An additional blood sample for an optional evaluation of whole genome sequence will be 
collected at the Baseline Visit. 
Optional Extension Phase: The Optional Extension Phase will occur following completion of 
the Treatment Phase and continue with clinic visits every 8 weeks until the study is terminated 
for any reason or the drug/device becomes commercially available.  To be eligible for the 
Optional Extension Phase, subjects must complete the Treatment Phase, elect to continue TreT, 
and agree to attend follow-up visits in the clinic.  Dosing titration will be encouraged during the 
Optional Extension Phase; the dose of TreT should be titrated upward, as clinically tolerated, to 
identify a maximum stable dose in each subject.  Subjects who discontinue TreT must complete 
an Early Termination Visit as soon as possible.  A blood sample for an optional evaluation of 
change in biomarkers will be collected at the Week 51 Visit. 

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l At least weekly telephone contact is required during the 3-week Treatment Phase. During the optional extension phase, telephone contact must occur at least every 
2 weeks between Week 3 and Week 11, and must occur at least monthly after Week 11 to encourage uptitration in addition to assessing AEs and concomitant 
medications.  Contact may be replaced by a face-to-face interaction on the weeks where study visits occur and the information can be obtained during the visit.  
Subjects may be contacted via email in lieu of a telephone call.  A copy of the emails and/or telephone contact sheets must be documented in the subject’s source 
documentation.  Email should not replace direct follow-up by phone or in the clinic for clinically significant AEs or other emergent issues. 
m The PQ-ITD and PAH-SYMPACT should be completed as the first assessments during the visit before the subject completes any of the other scheduled visit 
assessments (after informed consent is obtained).  The PQ-ITD for TreT will only be administered during an Early Termination Visit if the subject discontinues during 
the 3-week Treatment Phase.  The PAH-SYMPACT will be conducted at Week 11 visit only in the Optional Extension Phase. 
n The 12-lead ECG should be recorded after at least 5 minutes of rest.  
o Only drug accountability and dosing diary will be performed at the End of Study Visit or Early Termination Visit.  
 
 

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Table 3-2 
Schedule of Events for Dosing and Pharmacokinetic Sampling - Baseline and 
Week 3 Visit 
Time Relative to Dose (minutes) 
Activitya 
-15±3 (predose) 
PK Sample 1 
0 (dose) 
Administer dose 
5±3 
PK Sample 2 
10±3 
PK Sample 3 
15±3 
PK Sample 4 
30±3 
PK Sample 5 
45±3 
PK Sample 6 
90±3 
PK Sample 7 
120±3 
PK Sample 8 
180±3 
PK Sample 9 
240±3 
PK Sample 10 
300±3 
PK Sample 11 
Abbreviations: 6MWT, 6-Minute Walk Test; PK, pharmacokinetic  
a  If the baseline 6MWT is conducted concurrently with the PK sampling, then the Week 3 6MWT must also be conducted 
concurrently with PK sampling.  If the 6MWT is conducted concurrently with the PK sampling, it should occur between 
45 to 60 minutes after the most recent dose. 

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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy Assessments 
3.3.1.1 
Pharmacokinetic Assessments 
Fifteen minutes prior to administration of the in-clinic dose of Tyvaso or TreT at the Baseline 
Visit and the Week 3 Visit, qualified study personnel, as delegated by the Investigator, will 
obtain a predose blood sample of approximately 5 mL via an indwelling IV catheter or by direct 
venipuncture.  The predose sample should occur at least 4 hours after the subject’s last dose of 
Tyvaso or TreT.  Subsequent serial blood samples of approximately 5 mL will be taken in a 
similar manner at the following timepoints (±3 minutes): 5, 10, 15, 30, 45, 90, 120, 180, 240, and 
300 minutes after Tyvaso or TreT administration (see Table 3-2).  Blood samples will be 
analyzed for treprostinil plasma concentrations. 
3.3.1.2 
6-Minute Walk Test 
The 6MWT is a validated and reliable measure of exercise capacity in patients with chronic 
respiratory diseases (Holland 2014).  This study will utilize an unencouraged 6MWT to minimize 
potential bias associated with encouragement.  All 6MWTs will be conducted by qualified, 
trained personnel in a designated 6MWT area which meets the requirements as described in 
Appendix 15.1.  Subjects who have not previously performed the 6MWT at the study site on the 
course intended for use during the study must perform a practice 6MWT at the study site at least 
1 day prior to the Baseline Visit.  Subjects will perform a peak 6MWT at Baseline to confirm 
their eligibility to participate in the study (6MWD ≥150 m per Inclusion Criterion 7).  Prior to the 
start of each 6MWT, the subject must rest (seated) for at least 10 minutes.  To assist with subject 
scheduling, the baseline 6MWT may be conducted within 24 hours prior to PK sampling (eg, 
previous day).  If the baseline 6MWT is conducted the day prior to PK sampling, then the Week 3 
6MWT must also be conducted on the day prior to PK sampling for consistency.  Peak 6MWTs 
will be conducted at study visits as specified in Table 3-1.  All 6MWTs should be conducted 
between 10 to 60 minutes after the most recent dose of Tyvaso or TreT.  If the 6MWT is 
conducted concurrently with the PK sampling, the 6MWT should occur between 45 to 60 minutes 
after the most recent dose.  Subjects receiving supplemental oxygen during the Baseline 6MWT 
should continue to receive the same flow rate at the Week 3 6MWT.  Pulmonary rehabilitation 

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may not be introduced to a subject’s treatment regimen within 12 weeks prior to Baseline through 
the Week 3 Visit.  
3.3.1.3 
Preference Questionnaire for Inhaled Treprostinil Devices 
The Preference Questionnaire for Inhaled Treprostinil Devices (PQ-ITD) will be administered at 
the Baseline Visit to assess the subject’s current use of the Tyvaso Inhalation System and at the 
Week 3 Visit or the Early Termination Visit to assess the subject’s use of the TreT Inhaler.  The 
PQ-ITD for TreT will only be administered during an Early Termination Visit if the subject 
discontinues during the 3-week Treatment Phase.  The PQ-ITD should be completed as the first 
assessment during the visit before the subject completes any of the other scheduled visit 
assessments.  Copies of the PQ-ITD (Tyvaso and TreT versions) can be found in the Study 
Reference Manual and will only be administered at study sites where available. 
3.3.1.4 
PAH-SYMPACT Questionnaire 
The PAH-SYMPACT is a patient reported outcome (PRO) questionnaire consisting of 
11 symptom and 11 impact items, which was developed based on interviews of PAH patients and 
following PRO guidance from the US Food and Drug Administration (FDA) (McCollister 2016, 
Chin 2018). 
The PAH-SYMPACT questionnaire will be administered at the Baseline Visit, Week 3 Visit, and 
the Week 11 Visit (subjects participating in the Optional Extension Phase) or the Early 
Termination Visit.  Detailed instructions on how to administer the PAH-SYMPACT to subjects 
will be provided to the sites.  A copy of the PAH-SYMPACT questionnaire can be found in the 
Study Reference Manual and will only be administered at study sites where available. 
3.3.1.5 
Optional Biomarker and Optional Whole Genome Sequencing 
For subjects consenting to the optional biomarker sample, blood will be collected for the 
evaluation of biomarkers (specific targets to be determined) at Baseline, Week 3 Visit, and at the 
Week 51 Visit for subjects participating in the Optional Extension Phase (or upon early 
termination if prior to Week 51).  These samples will be shipped to the central laboratory for 
processing and storage prior to analysis. 

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For subjects consenting to whole genome sequence analysis, a blood sample will be collected at 
Baseline.  These samples will be shipped to the central laboratory for processing and storage 
prior to analysis.  Whole genome sequences will be analyzed for genetic markers that may be 
associated with clinical response and tolerability.   
Samples for the optional biomarker and optional whole genome sequencing will be coded in a 
manner that allows them to be matched to a study site and/or a subject number, but will not carry 
personal identifiers that could be traced to a specific individual.  Complete instructions regarding 
the processing, packaging, and shipping of samples will be provided in a separate laboratory 
manual. 
3.3.2 
Safety and Tolerability Assessments 
Safety assessments include incidence and severity of reported AEs, as well as changes from 
screening in vital signs, clinical laboratory tests, ECGs, and PEs.  
3.3.2.1 
Inspiratory Criteria Assessment 
The subject’s ability to perform inhalation maneuvers will be assessed at the Screening Visit and 
the Baseline Visit.  Subjects must be able to perform inhalation maneuvers using the BluHale® 
technology that meets inspiratory training criteria.  Subjects who are not able to demonstrate 
proper technique will be considered screen failures. 
3.3.2.2 
Medical History and Physical Examinations 
A complete medical history (including pulmonary hypertension history), demographics, and PE 
(including an oropharyngeal exam) will be conducted during the Screening Visit.  Significant 
past or present illnesses, current prescription or nonprescription medications (including vitamins 
and herbal products), and history of allergies or idiosyncratic responses to drugs should be 
recorded.  Any significant changes to the subject’s medical condition and physical examination 
must be documented throughout the course of the study.  A complete PE will be conducted by 
appropriate study personnel at the Screening Visit, Baseline Visit, Week 3 Visit, and the Early 
Termination Visit.  For subjects continuing in the Optional Extension Phase, a physical exam 
will conducted at each Extension Visit.  Any clinically significant changes from Baseline noted 
during the study should be reported as AEs.  

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3.3.2.3 
Vital Signs 
Vital signs will be assessed at study visits as specified in Table 3-1.  Vital signs measured will 
include blood pressure (systolic and diastolic), HR, respiratory rate (RR), and weight.  Vital 
signs must be assessed following at least 5 minutes of rest (sitting) to ensure accurate 
measurement.  No other measurements or procedures should be performed during this 5-minute 
period.  When possible, vital signs should be collected prior to the 6MWT.  If vital signs cannot 
be obtained prior to the 6MWT, then they should be obtained after recovery from the 6MWT.  
Vital signs should also be assessed and reported in the case of abnormal clinical signs and 
symptoms.   
3.3.2.4 
12-Lead Electrocardiogram 
A 12-lead ECG will be recorded after at least 5 minutes of rest at the Baseline Visit and End of 
Study Visit or Early Termination Visit.  Recordings should include lead II as a rhythm strip and 
contain at least 5 QRS complexes.  ECG parameters to be collected include rhythm, HR, PR 
interval, QT interval, QRS duration (uncorrected), and any clinically significant abnormalities.   
3.3.2.5 
Clinical Laboratory Assessments 
Clinical laboratory assessments will be collected at the Baseline Visit, Week 3 Visit, End of 
Study Visit or Early Termination Visit, and at follow-up visits in the Optional Extension Phase 
as specified in Table 3-1.  Clinical laboratory results outside the normal reference range must be 
assessed for clinical significance by the Investigator.  Clinically significant refers to a laboratory 
value that is unusual with respect to the subject’s medical history or current health status.  
Clinically significant abnormal laboratory test values will be reported as AEs and treated and/or 
followed-up until the symptoms or values return to normal or acceptable levels, as judged by the 
Investigator.  Where appropriate, medical tests and examinations will be performed to assess and 
document resolution.   
3.3.2.5.1 
Clinical Chemistry and Hematology 
Blood for the measurement and evaluation of clinical chemistry and hematology collected at 
study visits will be used to assess for treatment-emergent changes in clinical chemistry and 
hematological laboratory parameters.  Values for the following parameters will be obtained: 

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Table 3-3 
Clinical Laboratory Parameters 
Electrolyte Panel 
Chemistry Panel 
Hematology Panel 
Bicarbonate 
Alanine aminotransferase  
Hemoglobin  
Chloride 
Aspartate aminotransferase 
Hematocrit  
Potassium 
Bilirubin (total and indirect) 
Red blood cell count  
Sodium 
Creatinine 
White blood cell count  
 
Blood urea nitrogen 
Platelet count 
3.3.2.5.2 
Pregnancy Testing 
Women of childbearing potential (WOCBP) will undergo a urine pregnancy test at study visits as 
specified in Table 3-1.  A positive pregnancy test will exclude the subject from further 
participation in the study.  Pregnant subjects who are discontinued from the study will be 
transitioned to an alternate therapy at the discretion of the Investigator. 
3.3.2.6 
Adverse Events 
AEs will be recorded throughout the course of the study from the time that each subject signs the 
ICF until the time screen failure is documented, or until the subject is either discontinued from 
the study or all End of Study Visit assessments have been completed.  Each subject will be 
questioned for AEs at each scheduled study visit.  Subjects will also be instructed to 
spontaneously report all AEs throughout the study. 
All AEs should be followed until either resolution (or return to normal or baseline values), until 
they are judged by the Investigator to no longer be clinically significant, or for at least 30 days if 
the AE extends beyond the final study visit.  All AEs meeting the criteria for serious (ie, serious 
AEs [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 (End of Study Visit 
or Early Termination Visit).  All AEs/SAEs that occur while the subject is in study will be 
recorded as instructed in this protocol. 
Sections 9 and 15.2 provide the guidelines and definitions for recording AEs.  
3.3.2.7 
Concomitant Medications 
All concomitant medications taken during the conduct of the study, including those taken for 
AEs or other medical events as well as vitamins and herbal supplements, should be recorded in 

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the subject’s source documents and captured in the electronic Case Report Form (eCRF) as 
required.   
3.3.2.8 
Periodic Telephone/Email Contact 
At least weekly telephone contact is required throughout the Treatment Phase to assess for AEs 
and concomitant medications.  During the Optional Extension Phase, telephone contact must 
occur at least every 2 weeks between Week 3 and Week 11, and must occur at least monthly 
after Week 11 to encourage uptitration in addition to assessing AEs and concomitant 
medications.  These contacts may be replaced by a face-to-face interaction on the weeks where 
study visits occur and the information can be obtained during the visit.  The subject may be 
contacted via email in lieu of a telephone call; however, email should not replace direct 
follow-up by telephone or in the clinic for clinically significant AEs or other emergent issues.  A 
copy of the emails and/or telephone contact sheets (ie, AEs reported and/or concomitant 
medication changes) must be documented in the subject’s source documentation. 
3.4 
NUMBER OF CENTERS 
This study is multicenter with approximately 15 participating study centers.   
3.5 
NUMBER OF SUBJECTS 
For this study, total sample size is estimated to be 45 subjects and is not based on power 
calculations.  
3.6 
ESTIMATED STUDY DURATION 
The mandatory portion of the study is expected to be a minimum of 5 weeks duration.  If the 
subject consents to the Optional Extension Phase of the study, the study will continue with clinic 
visits every 8 weeks until the study is terminated for any reason or the drug/device becomes 
commercially available.   
4 
SUBJECT ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
A subject is eligible for inclusion in this study if all of the following criteria apply:  
1. Subject voluntarily gives informed consent to participate in the study. 
2. Subject is aged 18 years or older at the time of signing informed consent. 

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3. WOCBP are those who have experienced menarche and who have not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or are not postmenopausal (defined as amenorrhea for at least 
12 consecutive months).  WOCBP must be nonpregnant (as confirmed by a urine 
pregnancy test at Screening prior to initiating study medication), nonlactating, and will do 
1 of the following: 
a. Abstain from intercourse (when it is in line with their preferred and usual 
lifestyle), or 
b. Use 2 medically acceptable, highly effective forms of contraception for the 
duration of study, and at least 30 days after discontinuing TreT.  Medically 
acceptable, highly effective forms of contraception can include approved 
hormonal contraceptives (oral, injectable, and implantable), intrauterine devices 
or systems, and barrier methods (such as a condom or diaphragm) when used with 
a spermicide.  
4. Males with a partner of childbearing potential must use a condom for the duration of 
treatment and for at least 48 hours after discontinuing TreT.   
5. Subject is diagnosed with PAH as defined by the following World Health Organization 
(WHO) Group 1 categories: 
a. Idiopathic/familial 
b. Associated with unrepaired or repaired congenital systemic-to-pulmonary shunts 
(repaired ≥5 years prior to screening) 
c. Associated with collagen vascular disease 
d. Associated with human immunodeficiency virus 
e. Associated with appetite suppressant/other drug or toxin use 
6. Subject must have started Tyvaso ≥3 months prior to the Baseline Visit and must 
currently be on a stable regimen (no change in dose within 30 days of Baseline Visit) of 
Tyvaso (6 to 12 breaths QID). 
7. Baseline 6MWD ≥150 m. 
8. If currently receiving other approved background therapy (eg, ERA or PDE5-I or both), 
the subject must be on a stable dose with no additions or discontinuations for a minimum 
of 30 days prior to Screening.  
9. The subject has had evidence of forced expiratory volume in 1 second (FEV1) ≥60% and 
FEV1/forced vital capacity ratio ≥60% during the 6 months prior to enrollment. 
10. In the opinion of the Investigator, the subject is able to communicate effectively with 
study personnel, and is considered reliable, willing, and likely to be cooperative with 
protocol requirements, including all study visits.   

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4.2 
EXCLUSION CRITERIA 
A subject is not eligible for inclusion in this study if any of the following criteria apply: 
1. Subject is pregnant or lactating.   
2. Subject has been diagnosed with pulmonary hypertension for reasons other than WHO 
Group 1 as outlined in Inclusion Criterion 5 (including but not limited to portal 
hypertension, chronic thromboembolic disease, pulmonary veno-occlusive disease, 
hemolytic anemia, sarcoidosis). 
3. Subject has a history of uncontrolled sleep apnea, parenchymal lung disease, or 
hemodynamically significant left-sided heart disease (including but not limited to aortic 
or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, 
or coronary artery disease). 
4. Subject is currently taking any other prostacyclin analogue or agonist, including but not 
limited to selexipag, epoprostenol, iloprost, or beraprost; except for acute vasoreactivity 
testing. 
5. Subject experienced an acute exacerbation of disease or hospitalization for any reason 
within 30 days of the Screening Visit or between Screening and Baseline. 
6. Subject is WHO Functional Class IV at Screening. 
7. Subject has used any investigational drug/device or participated in any other 
investigational study with therapeutic intent within 30 days prior to the Screening Visit. 
8. Subject has a history of anaphylaxis, a documented hypersensitivity reaction, or a 
clinically significant idiosyncratic reaction to treprostinil or excipients in the 
investigational product.  
9. Subject has conditions that, in the opinion of the Investigator, would make the subject 
ineligible. 
10. Subject is not able to perform inhalation maneuvers that meet inspiratory training criteria. 
11. Subject has a musculoskeletal disorder (eg, arthritis affecting the lower limbs, recent hip 
or knee joint replacement) or any disease that would likely be the primary limit to 
ambulation, or is connected to a machine that is not portable enough to allow for a 
6MWT. 
12. Subject has had a new type of chronic therapy (including but not limited to oxygen, a 
different class of vasodilator, diuretic, and digoxin) for pulmonary hypertension added 
within 30 days of the Screening Phase. 
13. Initiation of pulmonary rehabilitation within 12 weeks prior to the Baseline Visit. 

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4.3 
PRESCRIBED THERAPY 
Subject must have started Tyvaso ≥3 months prior to the Baseline Visit and must currently be on 
a stable regimen (no change in dose within 30 days of Baseline Visit) of Tyvaso (6 to 12 breaths 
QID).  Subjects must not be receiving any other prostacyclin analogue or agonist, including but 
not limited to selexipag, epoprostenol, iloprost, or beraprost, except for Tyvaso within 30 days 
prior to the Baseline Visit (unless used for acute vasoreactivity testing) until study termination.  
Subjects on any other FDA-approved PAH background therapy (eg, ERA, PDE5-I, and/or sGC 
stimulator) must be on a stable and optimized dose for ≥30 days prior to the Baseline Visit.  
Subjects may not newly initiate or discontinue PAH background therapy from the Screening 
Phase through the Week 3 Visit.  
4.3.1 
Concomitant Medications 
All concomitant medications taken during the conduct of the study, including those taken for 
AEs or other medical events as well as vitamins and herbal therapies, should be recorded in the 
subject’s source documents and transcribed into the eCRF as required.  
4.3.2 
Other Treatments 
Subjects may not initiate pulmonary rehabilitation within 12 weeks prior to Baseline through the 
Week 3 Visit. 
5 
SUBJECT ENROLLMENT 
All subjects who sign the ICF will be assigned a subject number consisting of the site number 
followed by an unique consecutive number within each site. 
5.1 
TREATMENT ASSIGNMENT 
Subjects will be assigned treatment with TreT based on current Tyvaso regimen as detailed in 
Section 6.1.2.  An Interactive Response Technology (IRT) will be utilized to assign each subject 
the appropriate study drug for the 3-week Treatment Phase and the Optional Extension Phase.   

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6 
DRUGS AND DOSING 
6.1 
DRUG DOSAGE, ADMINISTRATION, AND SCHEDULE 
6.1.1 
Tyvaso 
Treprostinil for inhalation solution (0.6 mg/mL) is delivered via ultrasonic nebulization using the 
commercially available Tyvaso Inhalation System, which emits a dose of approximately 6 µg per 
breath.  All subjects will receive their current dose of Tyvaso in the clinic at the Baseline Visit 
for the 6MWT and PK sampling. 
6.1.2 
Treprostinil Inhalation Powder  
During the Treatment Phase, TreT will be supplied in single-use cartridges that contain either 
32 µg or 48 µg of treprostinil per cartridge. All subjects will initiate TreT at a dose 
corresponding to their current Tyvaso regimen per Table 6-1.  Subjects will be trained on 
inhalation of TreT using the inhaler device.  Detailed instructions for the use of this device will 
be provided to all study subjects.  In addition, all subjects will receive a copy of the TreT 
Instructions for Use. 
Table 6-1 
Treatment Phase Assignments 
Study Entry 
Treatment Phase 
Tyvaso Dose (QID) 
TreT Dose (QID) 
Device Requirement 
6 to 7 breaths 
32 µg 
32 µg cartridge 
8 to 10 breaths 
48 µg 
48 µg cartridge 
11 to 12 breaths 
64 µg 
32 µg + 32 µg cartridges 
Abbreviations: QID, 4 times daily; TreT, Treprostinil Inhalation Powder  
 
A single-use cartridge is manually inserted into the dry powder inhaler, which is a proprietary, 
breath-activated, reusable, dry powder inhaler that will deliver TreT to the lungs.  Powder is 
discharged from the inhaler when the subject inhales.  Each subject will be trained on inhalation 
technique prior to the first dose of TreT in clinic.  Additionally, subjects must be able to perform 
inhalation maneuvers using the BluHale technology that meets inspiratory training criteria.  
Subjects who are not able to demonstrate proper technique will be considered screen failures.  
At the end of the Treatment Phase, subjects will be offered the opportunity to continue therapy 
with TreT or resume Tyvaso therapy.  If the subject continues therapy with TreT during the 
Optional Extension Phase, the dose of TreT should be titrated upward, as clinically tolerated, to 

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identify a maximum stable dose in each subject.  During the Optional Extension Phase, a 64 µg 
cartridge strength may be dispensed as appropriate to meet dosing requirements.  Dose titration 
may start at the Week 3 Visit after all study assessments have been completed and subject agrees 
to participate in the Optional Extension Phase.  
6.2 
COMPLIANCE 
Each subject will be provided with a dosing diary in order to record dosing information from 
Baseline Visit through End of Study Visit.  Subjects will be asked to return the completed dosing 
diary, all used and unused TreT cartridges, and all TreT inhalers to each scheduled study visit.  
At each visit, all TreT cartridges and inhalers returned by the subject (used and unused) will be 
collected and new TreT cartridges and inhalers will be dispensed.  The appropriate study 
personnel must document the number of used and unused cartridges and determine if the 
appropriate amount of TreT cartridges remain based on the dose of TreT prescribed.  
Subject compliance with the prescribed dosage regimen will be monitored throughout the study.  
At each study visit, the subject will be asked whether he or she has been compliant with dosing 
instructions.  If it is determined that a subject is not compliant with TreT, then site personnel 
must re-educate the subject on proper doing compliance and its importance.  Continued 
noncompliance during any phase of the study may lead to withdrawal of the subject from the 
study after consultation between the Investigator and the Sponsor.  
7 
EXPERIMENTAL PROCEDURES 
Assessments during the study will be performed according to Table 3-1.  Screening may begin 
up to 14 days prior to the Baseline Visit.  If subjects are able to satisfy all eligibility criteria on 
the same day, a combined Screening/Baseline Visit may be conducted.   
7.1 
SCREENING VISIT 
The recommended sequence of assessments for the Screening Visit is as follows: 
 Informed consent 
 Inclusion/exclusion review 
 If necessary to satisfy inclusion criterion #9, procedures may be performed to provide 
evidence of FEV1 ≥60% and FEV1/forced vital capacity ratio ≥60%. 
 Inspiratory criteria assessment 

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 Demographics 
 Medical history (including PH history) 
 Physical exam 
 Vital signs (following at least 5 minutes of rest) including weight, RR, HR, systolic blood 
pressure (SBP), and diastolic blood pressure (DBP) 
 Urine pregnancy test for WOCBP 
 Practice 6MWT (only required if the subject has not previously performed a 6MWT at 
the study site on the study course; must precede the baseline 6MWT by at least 1 day; to 
be conducted following at least 10 minutes of rest [sitting])  
 AE assessment  
 Concomitant medications 
 
7.2 
BASELINE VISIT  
Baseline Visit activities will include the following: 
 Administration of PQ-ITD (Tyvaso Inhalation System assessment) 
 Administration of PAH-SYMPACT Questionnaire 
 Confirmation of inclusion/exclusion criteria  
 Inspiratory criteria assessment 
 Physical examination  
 Vital signs (following at least 5 minutes of rest); including weight, RR, HR, SBP, and 
DBP 
 Urine pregnancy test for WOCBP 
 Blood draws for clinical laboratory parameters 
 Collection of blood sample for evaluation of biomarkers (optional) 
 Collection of blood sample for evaluation of whole genome sequence (optional) 
 12-lead ECG (following at least 5 minutes of rest) 
 In-clinic dose of Tyvaso 
 Peak 6MWT (should be conducted between 10 to 60 minutes after the most recent dose 
and following at least 10 minutes of rest [sitting]; if the 6MWT is conducted concurrently 
with the PK sampling, the 6MWT should occur between 45 to 60 minutes after the most 
recent dose; to assist with subject scheduling, the baseline 6MWT may be conducted 
within 24 hours prior to PK sampling [eg, previous day]) 
 PK blood samples (see Table 3-2 for specific timepoints; the first sample is a predose 
sample and should occur at least 4 hours after the subject’s last dose of Tyvaso) 
 AE assessment  
 Concomitant medications 
 Dosing instructions/dosing diary/TreT accountability 
 First dose of TreT 

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7.3 
COMBINED SCREENING AND BASELINE VISIT  
If subjects are able to satisfy all eligibility criteria on the same day, a combined 
Screening/Baseline Visit may be conducted.  The recommended sequence of assessments for the 
Combined Screening and Baseline Visit is as follows: 
 Informed consent 
 Administration of PQ-ITD (Tyvaso Inhalation System assessment) 
 Administration of PAH-SYMPACT Questionnaire 
 Inclusion/exclusion review 
 Inspiratory criteria assessment 
 Demographics 
 Medical history (including PH history) 
 Physical exam 
 Vital signs (following at least 5 minutes of rest) including weight, RR, HR, SBP, and 
DBP 
 Blood draws for clinical laboratory parameters 
 Collection of blood sample for evaluation of biomarkers (optional) 
 Collection of blood sample for evaluation of whole genome sequence (optional) 
 Urine pregnancy test for WOCBP 
 12-lead ECG (following at least 5 minutes of rest) 
 In-clinic dose of Tyvaso 
 Peak 6MWT (should be conducted to confirm eligibility and prior to enrollment; should 
be conducted between 10 to 60 minutes after the most recent dose and following at least 
10 minutes of rest [sitting]; if the 6MWT is conducted concurrently with the PK 
sampling, the 6MWT should occur between 45 to 60 minutes after the most recent dose; 
to assist with subject scheduling, the baseline 6MWT may be conducted within 24 hours 
prior to PK sampling [eg, previous day]) 
 PK blood samples (see Table 3-2 for specific timepoints; the first sample is a predose 
sample and should occur at least 4 hours after the subject’s last dose of Tyvaso) 
 AE assessment  
 Concomitant medications 
 Dosing instructions/dosing diary/TreT accountability 
 First dose of TreT 
7.4 
WEEK 3 VISIT 
Week 3 Visit activities will include the following: 
 Administration of PQ-ITD (TreT assessment) 

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 Administration of PAH-SYMPACT Questionnaire 
 Physical examination 
 Urine pregnancy test for WOCBP 
 Vital signs (following at least 5 minutes of rest); including weight, RR, HR, SBP, and 
DBP 
 Blood draws for clinical laboratory parameters 
 Collection of blood sample for evaluation of biomarkers (optional) 
 In-clinic dose of TreT 
 Peak 6MWT (should be conducted between 10 to 60 minutes after the most recent dose 
and following at least 10 minutes of rest [sitting]; if the 6MWT is conducted concurrently 
with the PK sampling, the 6MWT should occur between 45 to 60 minutes after the most 
recent dose) 
 PK blood samples (see Table 3-2 for specific timepoints; the first sample is a predose 
sample and should occur at least 4 hours after the subject’s last dose of TreT) 
 Dosing instructions/dosing diary/TreT accountability 
 AE assessments  
 Concomitant medications 
7.5 
END OF STUDY VISIT AND/OR EARLY TERMINATION VISIT 
If a subject elects to discontinue TreT at the end of the Treatment Phase, an End of Study Visit 
must be completed within 2 weeks (±3 days).  If a subject is discontinued from the study 
prematurely, an Early Termination Visit should be completed as soon as possible.  Subjects who 
permanently discontinue TreT are encouraged to undergo premature termination assessments 
prior to discontinuing TreT or as close as possible to the last dose of TreT.  The following 
activities will be performed: 
 Administration of PQ-ITD (TreT assessment; only for subjects that discontinue during 
the 3-week Treatment Phase) 
 Administration of PAH-SYMPACT Questionnaire 
 Physical examination  
 Vital signs (following at least 5 minutes of rest), including weight, RR, HR, SBP, and 
DBP 
 Urine pregnancy test for WOCBP 
 Blood draws for clinical laboratory parameters 
 12-lead ECG (following at least 5 minutes of rest) 
 Peak 6MWT (should be conducted between 10 to 60 minutes after the most recent dose 
and following at least 10 minutes of rest [sitting]) 

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 Dosing diary/TreT accountability 
 AE assessment 
 Concomitant medications 
7.6 
OPTIONAL EXTENSION PHASE VISITS 
Subjects who choose to continue TreT and enter the Optional Extension Phase will complete 
study visits every 8 weeks.  The assessments performed during the Optional Extension Phase 
will alternate as follows. 
7.6.1 
Week 11 Visit (Then Every 8 weeks) 
Beginning on Week 11, the following assessments will be performed every 8 weeks: 
 Administration of PAH-SYMPACT Questionnaire (Week 11 only) 
 Physical examination 
 Vital signs (following at least 5 minutes of rest), including weight, RR, HR, SBP, and 
DBP 
 Urine pregnancy test for WOCBP 
 Blood draws for clinical laboratory parameters 
 Peak 6MWT (should be conducted between 10 to 60 minutes after the most recent dose 
and following at least 10 minutes of rest [sitting]) 
 Collection of blood sample for evaluation of biomarkers (optional) (Week 51 only) 
 Dosing instructions/dosing diary/TreT accountability 
 AE assessments  
 Concomitant medications 
7.6.2 
TreT Dose Titration Visits 
Dose titration will be encouraged during the Optional Extension Phase; the dose of TreT should 
be titrated upward, as clinically tolerated, to identify a maximum stable dose in each subject.  
Titration may occur at a scheduled Extension Visit, or may occur at an unscheduled visit as 
deemed clinically appropriate by the Investigator. 
7.6.3 
TreT Blister Packaging 
Once available, study drug will be provided as blister packages during the Optional Extension 
Phase.  Subjects who are enrolled in the Optional Extension Phase will attend their subsequent 
Extension Visit as scheduled and will be resupplied with the blister-packaged study drug in place 
of the investigational foil pouch packaging.  A 64 µg cartridge will be made available in addition 

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to the 32 µg and 48 µg cartridges, and may be dispensed as appropriate to meet dosing 
requirements.  Once a subject is receiving study drug in the blister packaging, subsequent 
Extension Visits will occur every 8 weeks. 
7.7 
STUDY CONTACTS 
At least weekly telephone contact is required throughout the Treatment Phase to assess for AEs 
and concomitant medications.  During the Optional Extension Phase, telephone contact must 
occur at least every 2 weeks between Week 3 and Week 11, and must occur at least monthly 
after Week 11 to encourage uptitration in addition to assessing AEs and concomitant 
medications.  These contacts may be replaced by a face-to-face interaction on the weeks where 
study visits occur and the information can be obtained during the visit.  The subject may be 
contacted via email in lieu of a telephone call; however, email should not replace direct 
follow-up by telephone or in the clinic for clinically significant AEs or other emergent issues.  A 
copy of the emails and/or telephone contact sheets (ie, AEs reported and/or concomitant 
medication changes) must be documented in the subject’s source documentation.  
8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A subject may voluntarily withdraw or be withdrawn from the study and/or TreT by the 
Investigator at any time for reasons including, but not limited to, the following: 
 The subject wishes to withdraw from further participation. 
 A serious or life-threatening AE occurs or the Investigator considers that it is necessary to 
discontinue TreT to protect the safety of the subject. 
 The subject consistently deviated from the protocol. 
 The subject has a lung transplant. 
 The subject becomes pregnant. 
 The subject’s behavior is likely to undermine the validity of his/her results.  
If a subject is discontinued from the study prematurely, the Investigator must provide an 
explanation in the eCRF and an Early Termintion Visit should be completed as soon as possible.  
If TreT has been administered, the Investigator should make every effort to perform all 
scheduled evaluations prior to discharge.  In the event that a subject discontinues TreT 
prematurely due to an AE, the subject will be followed until either the Investigator determines 

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that the AE has resolved, it is no longer considered clinically significant, the subject is lost to 
further follow-up, or for 30 days if the AE extends beyond the final visit. 
If a subject withdraws consent from either the optional biomarker and/or whole genome 
sequencing and/or requests sample destruction, the investigator must document the request and 
inform the Sponsor.  The Sponsor will only keep data that are collected or generated up to the 
point at which consent to use the sample is withdrawn by the subject.  Withdrawal of consent 
from the optional biomarker and/or optional whole genome sequencing does not affect consent to 
participate in any part of the analysis for which the subject has not withdrawn consent, nor does 
it affect consent to participate in the main clinical study. 
8.2 
CRITERIA FOR TERMINATING THE STUDY 
The study may be stopped at any time if, in the opinion of the Investigator and/or Sponsor, 
continuation of the study represents a serious medical risk to the subjects or if the drug/device 
becomes commercially available.  This may include, but is not limited to, the presence of 
serious, life-threatening, or fatal AEs or AEs that are unacceptable in nature, severity, or 
frequency.  The Sponsor reserves the right to discontinue the study for any reason at any time.  
8.3 
CRITERIA FOR DISCONTINUING THE SITE 
The study may also be terminated at a given center if: 
 The Investigator elects to discontinue the study 
 The Sponsor elects to discontinue the study at the site 
 US FDA, European, or other national regulations are not observed 
 The protocol is violated 
 Changes in personnel or facilities adversely affect performance of the study. 
9 
ADVERSE EVENT REPORTING 
9.1 
DEFINITIONS 
9.1.1 
Adverse Event  
An AE is any untoward medical experience occurring to a subject during the clinical study 
whether or not it is related to the study drug.   

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An AE may include any of the following: 
 An intercurrent illness, injury, or any other concomitant impairment of the subject’s 
health, as well as abnormal laboratory findings if deemed to have clinical significance.  
 A worsening of existing symptom or condition or post-treatment events that occur as a 
result of protocol-mandated procedures (eg, exacerbation of a pre-existing illness 
following the start of the study or an increase in frequency or intensity of a pre-existing 
episodic event or condition).  
Thus, no causal relationship with the study drug is implied by the use of the term “adverse 
event.” 
An AE does not include the following: 
 Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
however, the condition for which the surgery is required may be an AE. 
 Planned surgical measures permitted by the study protocol and the condition(s) leading to 
these measures are not AEs. 
 Day-to-day fluctuations of pre-existing disease or conditions present or detected at the 
start of the study that do not worsen. 
 Situations where an untoward medical occurrence has not occurred (eg, hospitalizations 
for cosmetic elective surgery, social and/or convenience admissions). 
All AEs will be documented from the time of informed consent until the time screen failure is 
documented, or until the subject is either discontinued from the study or all End of Study Visit 
assessments have been completed. 
9.1.2 
Serious Adverse Event  
An SAE is an AE occurring during the clinical study that results in any of the following 
outcomes: 
 Death 
 A life-threatening AE 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
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 1 of the 

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outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug abuse. 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred.  It does not mean that the event, had it occurred in a more 
severe form, might have caused death. 
9.2 
DOCUMENTATION OF ADVERSE EVENTS 
An AE or SAE occurring during the study must be documented in the subject’s source 
documents and on the appropriate eCRF page.  Information relating to the AE, such as onset and 
cessation date and times, intensity, seriousness, relationship to study drug, and outcome, is also 
to be documented in the eCRF (see Section 9 and Appendix 15.2 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. 
All AEs should be followed until either resolution (or return to normal or baseline values), until 
they are judged by the Investigator to no longer be clinically significant, or for at least 30 days if 
the AE extends beyond the final visit.  All SAEs that occur during the study will be followed 
until resolution, death, or the subject is lost to follow-up even if they are ongoing more than 
30 days after completion of the final visit.  Supplemental measurements and/or evaluations may 
be necessary to investigate fully the nature and/or causality of an AE or SAE.  This may include 
additional laboratory tests, diagnostic procedures, or consultation with other healthcare 
professionals.  The eCRF pages should be updated with any new or additional information as 
appropriate. 
The inhaler to be used in this clinical study is identical in all aspects, including function, to the 
inhaler of the FDA-approved Afrezza drug-device combination product except for minor 
changes (these changes do not change drug delivery device performance).  Any device 
complications associated with the use of the inhaler reported by the subject/health professional 
will be forwarded by UTC to the device manufacturer according to the specified timeline. 

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9.3 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
Sites should enter initial or follow-up SAE information regardless of causality or expectedness 
into the Sponsor’s Electronic Data Capture (EDC) system (primary method) within 24 hours of 
awareness of SAE.  The SAE will be directly transmitted from the EDC system to the Argus 
Safety Database.  If the site is unable to enter the SAE electronically into the EDC system, the 
alternative for reporting is submitting the paper SAE Report Form via email to 
 or fax to 
 within 24 hours of awareness.  If the paper 
SAE Report Form is submitted, the site will also be required to enter the SAE data into the EDC 
system.  SAE source documents (eg, hospital discharge summary or death certificate) will be 
submitted by the site via email 
 or fax 
.  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 Clinical 
Investigator’s study file. 
9.4 
SAFETY REPORTS 
In accordance with national regulations, the Sponsor will notify the appropriate regulatory 
authority(ies) and all participating Investigators of any AE that is considered to be possibly 
attributable to study drug and is both serious and unexpected.  The Investigator must report these 
AEs to their IRB or Ethics Committee (EC) in accordance with applicable national regulations 
and guidelines set forth by the IRB or EC. 
9.5 
PREGNANCY 
If a study subject becomes pregnant during participation in this clinical study, site staff must 
notify the Sponsor within 24 hours of learning of the pregnancy by completing the Pregnancy 
Notification and Outcome Form and submitting via fax or e-mail to Global Drug Safety at UTC 
) and withdraw the subject from the study.  The 
United Therapeutics Global Drug Safety department will follow up with the Investigator to 
ensure appropriate data are provided regarding the outcome of the pregnancy, and to ask the 
Investigator to update the Pregnancy Notification Form.  Pregnancy only becomes an AE/SAE if 

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there is an abnormal outcome, a spontaneous abortion, an elective termination for medical 
reasons, or a congenital anomaly in the offspring.  
10 
STATISTICAL CONSIDERATIONS 
10.1 
DATA PROCESSING 
The results of assessments will be transcribed into an eCRF for each subject who signs an ICF 
until study completion, or study discontinuation for any reason.  A representative from the 
sponsor will verify eCRF data fields against source documentation.  All data transmitted from 
the site will be reviewed and entered into a quality assured computerized database.  Data 
clarifications will be generated, and the database will be edited as appropriate.  The eCRF 
screens are to be reviewed by the Investigator for completeness and accuracy.  The Investigator 
must electronically sign each subject’s eCRF to signify his/her approval of the data.  The 
Investigator will be required to re-sign an eCRF if changes are made to a subject’s eCRF by the 
site after the Investigator initially signs the eCRF.  The database will be final when all 
outstanding queries have been resolved and all data management quality assurance procedures 
are complete. 
10.2 
SAMPLE SIZE 
Total sample size is planned to be 45 subjects.  No formal sample size calculation has been 
conducted.  
10.3 
ANALYSIS PLAN 
All PK and safety data will be listed and summarized in tables.   
10.3.1 
Pharmacokinetic Analysis 
PK parameters of treprostinil (Cmax, time of maximal plasma concentration, t½, and AUC from 
time 0 to 300 minutes [AUC0-300]) will be obtained from the resulting plasma drug concentration-
time data.  Plasma concentrations of treprostinil above the lower limit of quantitation will be 
used to calculate AUC0-300 and Cmax for each treatment.  PK parameters will be compared 
between Tyvaso and TreT and among all dose levels.  PK parameters will be summarized using 
descriptive statistics. 

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10.3.2 
Safety and Tolerability Analyses 
The Safety Population will be defined as all subjects in the study who received at least 1 dose of 
TreT in the Treatment Phase.  Safety analyses will be performed on the Safety Population.  All 
AEs recorded by the Investigators will be assigned Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Terms by the Sponsor for reporting purposes. 
The number and percent of subjects with AEs for each Treatment Phase will be tabulated by 
MedDRA System Organ Class and Preferred Term by relationship to treatment and severity.  
ECG and clinical laboratory test results will be summarized in shift tables.  The original values 
and the changes from baseline in vital signs, laboratory parameters, and 6MWT results will be 
summarized with descriptive statistics.  
10.4 
INTERIM ANALYSIS 
Interim analyses are not planned for this study.  
10.5 
OTHER ANALYSES 
Exploratory analyses may be conducted based on available study data. 
10.6 
DATA LISTINGS AND SUMMARIES 
All data gathered in this study will be presented in summary tables and listings in the clinical 
study report. 
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG  
11.1.1 
Study Drug 
The Sponsor will supply study medication, TreT, as unit-dose cartridges.  During the Treatment 
Phase of the study, 32 and 48 µg cartridges will be supplied in investigational foil pouches in 
cartons.  One carton will contain 33 cartridges to provide 7 days of medication and 5 additional 
cartridges in the event the subject loses or damages a cartridge.  Each carton will contain 
1 strength of study medication.  
During the Optional Extension Phase, the Sponsor will supply TreT cartidges in cartons with 
blister packaging.  Each carton will contain 1 strength of study medication.  During the Optional 

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Extension Phase, a 64 µg cartridge may be dispensed to meet dosing requirements as 
appropriate. 
11.1.2 
Study Device 
The sponsor will supply dry powder inhalers that will be used in combination with the study drug 
cartridges.  Each inhaler will be packaged individually in a clear plastic overwrap which will 
then be packaged in groups of 5 per carton.  The inhaler will be provided with the instructions 
for use to assist the subjects in loading the cartridge and using the device properly. 
Each subject will receive 1 carton of inhalers for the 3-week Treatment Phase of the study.  
Additional inhalers will be supplied for subjects remaining in the Optional Extension Phase. 
11.2 
LABELING  
11.2.1 
Study Drug 
The primary packaging and outer carton will be labeled with but not limited to the product name, 
study number, kit identification number, date of manufacture, Sponsor’s name and address, 
strength, and storage information (subject to regulatory requirements in each study region).   
11.2.2 
Study Device 
Inhalers will be packaged in cartons, each containing 5 inhalers.  The carton will be labeled with 
but not limited to the protocol name, study number, kit identification number, storage conditions, 
and the Sponsor’s name and address. 
11.3 
STORAGE AND HANDLING OF CLINICAL STUDY MATERIAL 
TreT will be supplied in individual cartridges packaged in sealed foil pouches during the 
Treatment Phase, and as blister packs during the Optional Extension Phase, once available.  TreT 
should be stored at 2°C to 8°C (36°F to 46°F) prior to dispensing.  Once dispensed to study 
subjects, TreT cartridges should be stored and used as directed by the study site.  Cartridges 
should not be removed from their packaging until just prior to use (inhalation). 
TreT inhalers are to be stored at ambient temperature during distribution and in-use period. 

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11.4 
SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL 
Study sites will be supplied with a sufficient quantity of TreT cartridges and inhalers to begin 
enrollment in the study.  An IRT will be utilized to assign each subject the appropriate study 
drug for the 3-week Treatment Phase and the Optional Extension Phase.   
At each study visit for the duration of the study, all used and unused inhalers dispensed to a 
subject should be returned to the study site.  During the Treatment Phase, all used and unused 
TreT cartridges should be returned to the study site.  During the Optional Extension Phase, all 
blister packaging must be returned to the study site and used cartridges may be discarded after 
use. 
11.5 
DRUG ACCOUNTABILITY 
The Investigator is responsible for TreT accountability and reconciliation overall and on a 
per-subject basis.  Drug accountability records are to be maintained during the study, and these 
records include, but are not limited to the amount of TreT received from the Sponsor, the amount 
dispensed to each subject, and the amount of used/unused TreT returned to the site by the 
subject. 
At each visit, site personnel will: 
 Collect and document all inhalers and all TreT cartridges and/or blister packaging 
returned by the subject (both used and unused). 
 Compute study drug compliance using the dosing instructions given to the subject since 
the previous study visit and the amount of TreT cartridges and/or blister packaging 
returned. 
 Re-educate the subject about the importance of following the prescribed dosing regimen 
(if compliance is low). 
 
Once a representative from the Sponsor is able to confirm drug accountability for a completed 
subject, TreT cartidges and/or blister packaging will be returned to a Sponsor-designated 
location for destruction and/or destroyed onsite per institutional policy.  All used and unused 
inhalers will be collected by the Sponsor for additional testing.  In the event of device 
malfunction, at any point during the study, the inhalers should be returned to the Sponsor.   

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12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
US FDA REGULATORY REQUIREMENTS 
The study will be conducted in accordance with International Council for Harmonisation (ICH) 
and Good Clinical Practice (GCP) guidelines and all applicable national regulations.  The 
Sponsor will obtain the required approval from the FDA to conduct the study.  During the 
conduct of the study, an annual safety report will be compiled by the Sponsor for submission to 
the FDA and IRBs/ECs that require it.  Any additional FDA reporting requirements, as specified 
by the FDA or IRB/EC, will also be fulfilled during the conduct of the study. 
12.2 
INFORMED CONSENT REQUIREMENTS 
Before a subject is enrolled in the study, the Investigator or his/her designees must explain the 
purpose and nature of the study, including potential benefits and risks and all study procedures to 
the subject.  The subject must sign and date an IRB/EC-approved ICF prior to the conduct of any 
study-related activities.  A copy of the signed consent form will be given to the subject, and the 
original will be retained in the study site’s records. 
12.3 
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 with a copy of the approval letter.  The IRB/IEC 
must also review and approve the study site’s ICF and any other written information provided to 
the subject prior to enrollment, as well as any advertising materials used for subject recruitment.  
Copies of the ICF and advertising materials must be forwarded to the Sponsor for review before 
submission to the IRB/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. 
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. 

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A written summary of the study will be provided by the Investigator to the IRB/IEC following 
study completion or termination according to the IRB or 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, at a minimum, the following documents will be 
provided to the site:  Investigator’s Brochure, clinical study protocol, ICF, Budget Agreement, 
and access to the eCRF. 
At a minimum, the site will be required to provide the following documents to UTC or designee 
prior to study start:  Signature page of the protocol, Form FDA 1572, Financial Disclosure 
Form(s), 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, 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 the subject’s 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. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially 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 or its designee and the 
Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory 
authorities and IRB/IEC prior to implementation. 

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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, 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 before any disposal or change 
in location of study records. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
In accordance with federal regulations, ICH, and GCP guidelines, monitors for UTC or its 
designee will periodically contact the site and conduct on-site visits.  During these visits, the 
monitor will at a minimum confirm ethical treatment of subjects, assess study progress, review 
data collected, conduct source document verification, verify drug accountability periodically, and 
identify any issues requiring resolution.   
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and his/her staff to the monitor to discuss any findings or any relevant 
issues. 

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14 
REFERENCES 
ATS Statement:  Guidelines for the six-minute walk test.  Am J Respir Crit Care Med.  
2002;166:111-117. 
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. 
Chin KM, Gomberg-Maitland M, Channick RN, et al.  Psychometric validation of the Pulmonary 
Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire: results of the 
SYMPHONY trial.  Chest.  2018;154(4):848-861. 
Farber H and Loscalzo J.  Mechanisms of disease:  Pulmonary arterial hypertension.  N Engl J 
Med.  2004;3511(16):1655-1665. 
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. 
McCollister D, Shaffer S, Badesch DB, et al.  Development of the Pulmonary Arterial 
Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported 
outcome instrument for PAH.  Respir Res.  2016;17(1):72. 
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. 
Remodulin [package insert].  Research Triangle Park, NC: United Therapeutics Corporation; 
2018. 
Rubin LJ.  Primary pulmonary hypertension. N Engl J Med.  1997;336:111-117. 
Tyvaso [package insert].  Research Triangle Park, NC: United Therapeutics Corporation; 2017. 
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.

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15 
APPENDICES 
15.1 
PROCEDURES FOR A 6-MINUTE WALK TEST 
General Procedures 
The 6MWT should be administered by the same tester at each study site throughout the study, 
whenever possible.  The administration of the test and specifications of the testing area should be 
generally consistent with the American Thoracic Society guidelines and the usual practice of the 
investigative site (ATS Statement 2002).  Subjects receiving supplemental oxygen during the 
Baseline 6MWT must continue to receive the same flow rate at the Week 3 6MWT.   
The area used for the 6MWT should be pre-measured at approximately 30 m in length and at 
least 2 to 3 m in width.  There must be no turns or significant curves to the 6MWT area.  The 
length should be marked with gradations to ensure the accurate measurement of the distance 
walked.  The area should be well ventilated.  The tester may be at the starting end of the corridor 
or at the midpoint of the corridor with a stop-watch.  Intermittent rest periods are allowed if the 
subject can no longer continue.  If the subject needs to rest briefly, he/she may stand or sit and 
then begin again when he/she is sufficiently rested but the clock will continue to run.  The 
subject may use ambulatory aids if needed.  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.  
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.” 

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After these instructions are given to the subject, the person administering the test will then ask: 
“Do you have any questions about the test?” 
The person administering the test will then start the test by saying the following to the subject: 
“Are you ready?” 
“Start when I say ‘GO.’” 
The person administering the test will tell the subject the time at each minute by saying: 
“You have 5 minutes to go.” 
“You have 4 minutes to go.” 
“You have 3 minutes to go.” 
“You have 2 minutes to go.” 
“You have 1 minute to go.” 
At 6 minutes, the person administering the test will tell the subject:  
“Stop where you are.” 
No other instruction or encouragement will be given during the test.  Eye contact with the subject 
should be avoided during the test. 
 
 

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

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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 hospitalization, is a congenital abnormality (offspring of subject), or is 
medically significant (important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent 1 of the outcomes listed in this definition). 
Hospitalizations that would not be considered SAEs include those for: 
 Routine treatment or monitoring of the study indication not associated with any 
deterioration in condition (eg, hospitalization for a routine right heart catheterization). 
 Treatment which was elective or pre-planned, for a pre-existing condition not associated 
with any deterioration in condition (eg, pre-planned operation which does not lead to 
further complications, etc). 
 Treatment of an emergency, in an outpatient setting for an event not fulfilling any of the 
definitions of serious as given above and not resulting in hospital admission. 
CAUSALITY 
An estimate of causality between a specified AE and the study drug is made by the Investigator.  
Several factors should be considered when determining causality.  These factors include 
temporal relationship and response to withdrawal or reintroduction of the study drug.  
Definitions of the causality categories are as follows: 
 NOT RELATED – There is not a temporal relationship to study drug administration (too 
early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, or concurrent disease and the SAE, or any of the following: 
 An event that precedes the first administration of study drug 
 An event for which the cause is clearly related to an external event 
 Temporal relationship to study drug is atypical 
 Is readily explained by an intercurrent illness AND has an expected level of severity, 
duration, and resolution 
 An alternative explanation (concomitant drug, intercurrent illness) is likely 
 POSSIBLE – There is a reasonable causal relationship between the study drug and the 
SAE.  Dechallenge information is lacking or unclear, study drug administration was not 
modified in response to the SAE, or any of the following: 

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 Has a reasonable temporal relationship to study drug 
 The event has a plausible biological link to the activity of the study drug 
 Is unlikely to be related to an intercurrent illness or has an unexpected degree of 
severity, duration, or complication 
 PROBABLE – There is a reasonable causal relationship between the study drug and the 
SAE.  The event responds to dechallenge—the event resolves or improves with 
modification of study drug administration.  Rechallenge (the original study drug was 
restarted) is not required, or any of the following: 
 Has a reasonable temporal relationship to study drug 
 The event has a plausible biologic link to the activity of the study drug 
 Not readily explained by an intercurrent illness 
 Not readily explained by external event 
 Improves on discontinuation of study drug 
 If study drug has been discontinued, may recur or reintroduction of study drug 
ACTION TAKEN 
STUDY DRUG DOSE MODIFICATION* 
 Dose Not Changed – The dose or regimen of the study drug was not changed. 
 Dose Increased – The dose or regimen of study drug was increased.  
 Dose Decreased – The dose or regimen of study drug was decreased. 
 Drug Interrupted – Administration of the study drug was stopped temporarily. 
 Drug Withdrawn – Administration of the study drug was stopped permanently and not 
restarted. 
 Unknown – Changes to the administration of the study drug cannot be determined. 
 Not Applicable  
NOTE:  Only the last study drug action should be recorded in the eCRF.  For example, if the 
study drug is withdrawn and then the decision is made to restart, the dose modification of “Drug 
interrupted” should be reported on the SAE form. 
OUTCOME 
 Fatal – The study subject died. 
 Not Recovered/Not Resolved – The AE was ongoing at the time of death or at the time 
the subject was lost to follow up. 
 Recovered/Resolved – The AE resolved. 
 Recovered/Resolved with Sequelae – The AE is considered resolved; however, there is 
residual sequelae.  Some events do not return to baseline, such as metastasis or 
progression of disease; however, once these events are determined by the Investigator to 

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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.