An Open-Label Extension Study of Inhaled Treprostinil in Patients With Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (PH-COPD)
Phase: PHASE3
Conditions: Pulmonary Hypertension, Chronic Obstructive Pulmonary Disease
Sponsor: United Therapeutics

United Therapeutics Corp. 
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 1 
An Open-Label Extension Study of Inhaled Treprostinil in Patients 
with Pulmonary Hypertension due to Chronic Obstructive Pulmonary 
Disease (PH-COPD) 
IND Number 70,362 
Protocol RIN-PH-305 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
05 September 2018 
Amendment 1 Date: 
18 October 2019 
Amendment 2 Date: 
29 January 2021 
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. 
© 2021 United Therapeutics Corporation
NCT #: NCT03794583

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 2 
LIST OF CONTACTS FOR STUDY 
Study Sponsor: 
 
 
 
Sponsor’s Medical Monitor: 
United Therapeutics Corp. 
 
 
 
 
 
Telephone: 
 
Email: 
 
Study Conducted by: 
Lung Biotechnology PBC 
 
 
 
 
Telephone: 
 
Mobile: 
 
Email: 
 
 
  
Telephone: 
  
Mobile: 
 
Email: 
 
 
 
 
Telephone: 
  
Mobile: 
 
Email:
 
Clinical Laboratory: 
Covance Laboratories Inc. 
 
 
Digital Health Technology: 
THREAD 
 
Telephone: 
 
Email: 
 
SAE Reporting: 
United Therapeutics Corp. Global Product Safety & 
Pharmacovigilance 
  
 
Email: 
 
Fax: 
 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 3 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled, “An Open-Label Extension Study of Inhaled 
Treprostinil in Patients with Pulmonary Hypertension due to Chronic Obstructive Pulmonary 
Disease (PH-COPD),” Amendment 2, dated 29 January 2021 and agree to abide by all provisions 
set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Guideline for Good 
Clinical Practice (GCP) and applicable Food and Drug Administration (FDA) 
regulations/guidelines set forth in 21 Code of Federal Regulations Parts 50, 54, 56, and 312 and 
any local regulations per country. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of United Therapeutics Corp. 
I also have read the current Clinical Investigator’s Brochure for inhaled treprostinil and 
acknowledge that review of the information contained in the Clinical Investigator’s Brochure is a 
requirement for Investigators before using inhaled treprostinil in a clinical study. 
 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 4 
PROTOCOL SYNOPSIS 
Title: 
An Open-Label Extension Study of Inhaled Treprostinil in Patients with 
Pulmonary Hypertension due to Chronic Obstructive Pulmonary Disease 
(PH-COPD) 
Phase: 
3 
Indication: 
PH-COPD 
Primary 
Objective: 
To evaluate the long-term safety and tolerability of inhaled treprostinil in 
subjects with PH-COPD. 
Secondary 
Objective: 
To evaluate the long-term efficacy of inhaled treprostinil in subjects with 
PH-COPD. 
Exploratory 
Objective: 
 
 
Design: 
This is a multicenter, open-label extension study for eligible subjects 
who completed Study RIN-PH-304. 
Estimated 
Duration: 
3 years 
Sample Size:  
Approximately 136 subjects from Study RIN-PH-304 in the Original 
Crossover Design or approximately 314 subjects if the Contingent 
Parallel Design is applied. 
Summary of Subject Eligibility Criteria: 
Inclusion 
Criteria: 
Subjects who meet the following criteria may be included in the study: 
1. Voluntarily gives informed consent to participate in the study. 
2. Completed Study RIN-PH-304. 
3. Females of childbearing potential (defined as less than 1 year 
postmenopausal and not surgically sterile) must agree to practice 
abstinence or use 2 highly effective methods of contraception 
(defined as a method of birth control that results in a less than 1% per 
year failure rate, such as an approved hormonal contraceptive, barrier 
method [condom or diaphragm] with a spermicide, or an intrauterine 
device) for the duration of study treatment and for 48 hours after 
discontinuing study drug. 
4. Males with a partner of childbearing potential must agree to use a 
barrier method (condom) with a spermicide for the duration of 
treatment and for at least 48 hours after discontinuing study drug. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 5 
Exclusion 
Criteria: 
Subjects who meet the following criteria are excluded from the study: 
1. Pregnant or lactating. 
2. Prematurely discontinued Study RIN-PH-304. 
3. Intolerant to inhaled prostanoid therapy. 
4. Unwilling or unable to use Sponsor-provided devices (actigraph, 
spirometer, or smart device). 
5. Scheduled to receive another investigational drug, device, or therapy 
during the course of this study. 
6. Any other clinically significant illness or abnormal laboratory value 
that, in the opinion of the Investigator, might adversely affect the 
interpretation of the study data or subject safety. 
Drug Dosage, 
Route, and 
Formulation: 
Inhaled treprostinil solution (0.6 mg/mL, 6 mcg/breath), 4 times daily 
(QID) during waking hours. 
Subjects will initiate inhaled treprostinil at a dose of 3 breaths QID 
during waking hours.  Study drug doses should be titrated to a target 
dosing regimen of 15 breaths QID or the maximum tolerated dose.  Dose 
titrations can occur as rapidly as possible (as directed by the 
Investigator). 
Control Group: 
None 
Procedures: 
Subjects cannot begin this open-label extension study until all procedures 
from Study RIN-PH-304 are complete.  The Enrollment Visit for this 
study will occur on the same day as the final visit for Study RIN-PH-
304. 
At the Enrollment Visit, subjects will receive a new actigraph and 
continue to use their Sponsor-provided spirometry and smart devices 
from Study RIN-PH-304 until Quarterly Visit 4 (Year 1) or the 
Discontinuation Visit (whichever occurs first). 
After the Enrollment Visit, subjects will have assessments at Week 6 and 
Quarterly thereafter for up to 3 years.  Telephone contact will occur 
weekly during dose titration and then monthly for the remainder of the 
study to assess tolerability, adverse events, concomitant medications, 
drug/device compliance, and any other study-related issues, as described 
in Section 7.4. 
Given the uncertainty of clinical benefit of novel inhaled treprostinil in 
PH-COPD and the ongoing COVID-19 pandemic, a high rate of 
discontinuations and/or missing data are both possible. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 6 
All attempts should be made to have onsite clinic visits, but subjects 
may have telemedicine visits in lieu of onsite visits, as described in 
Section 7.5. 
Safety Assessments: 
• Adverse events, physical examinations, vital signs, 12-lead 
electrocardiograms, clinical laboratory assessments, pulmonary 
function tests, at-home spirometry, and oxygenation will be collected 
to evaluate the long-term safety and tolerability of inhaled 
treprostinil. 
Efficacy Assessments: 
• N-terminal pro-brain natriuretic peptide, 6-Minute Walk Distance, 
Borg dyspnea score, patient global assessment, and physical activity 
(actigraphy) will be collected to evaluate the long-term efficacy of 
inhaled treprostinil. 
Exploratory Assessments: 
• 
 
 
 
 
Statistical 
Considerations: 
All safety and efficacy data will be summarized in tables and listings and 
analyzed for trends over time.  No formal hypothesis testing is planned. 
Sponsor: 
United Therapeutics Corp. 
 
  
Study Conducted 
by: 
Lung Biotechnology PBC 
 
 
 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 7 
TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ............................................................................................3 
PROTOCOL SYNOPSIS ..............................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................7 
Table of In-Text Tables .................................................................................................................9 
LIST OF ABBREVIATIONS .....................................................................................................10 
1 BACKGROUND AND RATIONALE .................................................................................11 
2 OBJECTIVES ........................................................................................................................11 
2.1 
PRIMARY OBJECTIVE .................................................................................................11 
2.2 
SECONDARY OBJECTIVE ...........................................................................................11 
2.3 
EXPLORATORY OBJECTIVE......................................................................................11 
3 EXPERIMENTAL PLAN .....................................................................................................11 
3.1 
STUDY DESIGN ...............................................................................................................11 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ...................................................13 
3.3 
CLINICAL ASSESSMENTS ...........................................................................................16 
3.3.1 
Demographics and Medical History ...........................................................................16 
3.3.2 
Safety .............................................................................................................................16 
3.3.2.1 
Physical Examination ...............................................................................................16 
3.3.2.2 
Vital Signs ..................................................................................................................16 
3.3.2.3 
12-Lead Electrocardiogram .....................................................................................17 
3.3.2.4 
Clinical Laboratory Assessments ............................................................................17 
3.3.2.5 
Pulmonary Function Tests .......................................................................................18 
3.3.2.6 
At-home Spirometry .................................................................................................18 
3.3.2.7 
Oxygenation - Pulse Oximetry .................................................................................19 
3.3.2.8 
Adverse Events ..........................................................................................................19 
3.3.2.9 
Concomitant Medications ........................................................................................20 
3.3.3 
Efficacy ..........................................................................................................................20 
3.3.3.1 
N-Terminal Pro-brain Natriuretic Peptide ............................................................20 
3.3.3.2 
6-Minute Walk Test ..................................................................................................21 
3.3.3.3 
Borg Dyspnea Score ..................................................................................................21 
3.3.3.4 
Patient Global Assessment .......................................................................................22 
3.3.3.5 
Actigraphy .................................................................................................................22 
3.3.4 
Exploratory ...................................................................................................................22 
3.3.4.1 
 ...............................................................................22 
3.3.5 
Telephone Contact ........................................................................................................23 
3.4 
NUMBER OF SITES ........................................................................................................23 
3.5 
NUMBER OF SUBJECTS ...............................................................................................23 
3.6 
ESTIMATED STUDY DURATION ...............................................................................23 
4 SUBJECT ELIGIBILITY .....................................................................................................24 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 8 
4.1 
INCLUSION CRITERIA .................................................................................................24 
4.2 
EXCLUSION CRITERIA ................................................................................................24 
4.3 
PRESCRIBED THERAPY ..............................................................................................25 
5 SUBJECT ENROLLMENT ..................................................................................................25 
5.1 
TREATMENT ASSIGNMENT .......................................................................................25 
6 DRUGS AND DOSING (OR TREATMENT PROCEDURES) ........................................25 
6.1 
DRUG DOSAGE, ADMINISTRATION, AND SCHEDULE .......................................25 
6.2 
COMPLIANCE .................................................................................................................26 
7 EXPERIMENTAL PROCEDURES ....................................................................................27 
7.1 
ENROLLMENT VISIT ....................................................................................................27 
7.2 
WEEK 6 VISIT .................................................................................................................28 
7.3 
QUARTERLY VISITS .....................................................................................................29 
7.4 
TELEPHONE CONTACTS .............................................................................................30 
7.5 
TELEMEDICINE VISITS ...............................................................................................30 
7.6 
UNSCHEDULED VISIT ..................................................................................................31 
7.7 
DISCONTINUATION VISIT ..........................................................................................31 
8 STUDY TERMINATION .....................................................................................................32 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ..............................................................32 
8.2 
CRITERIA FOR STUDY TERMINATION ..................................................................32 
8.3 
CRITERIA FOR SITE DISCONTINUATION .............................................................33 
9 ADVERSE EVENT REPORTING ......................................................................................33 
9.1 
DEFINITIONS ..................................................................................................................33 
9.1.1 
Adverse Event ...............................................................................................................33 
9.1.2 
Serious Adverse Event .................................................................................................33 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ............................................................34 
9.3 
FOLLOW-UP OF ADVERSE EVENTS ........................................................................34 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ..............................35 
9.4.1 
Serious Adverse Event Reporting ...............................................................................35 
9.4.2 
Pregnancy Reporting ...................................................................................................35 
9.5 
SAFETY REPORTS .........................................................................................................36 
10 STATISTICAL CONSIDERATIONS .................................................................................36 
10.1 DATA PROCESSING ......................................................................................................36 
10.2 SAMPLE SIZE ..................................................................................................................37 
10.3 ANALYSIS PLAN .............................................................................................................37 
10.3.1 
Safety Analyses .............................................................................................................37 
10.3.2 
Efficacy Analyses ..........................................................................................................37 
10.3.3 
Exploratory Analyses ...................................................................................................37 
10.4 INTERIM ANALYSIS .....................................................................................................37 
10.5 OTHER ANALYSES ........................................................................................................38 
10.6 DATA LISTINGS AND SUMMARIES ..........................................................................38 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 9 
11 PACKAGING AND FORMULATION ...............................................................................38 
11.1 STUDY SUPPLIES ...........................................................................................................38 
11.1.1 
Actigraphy, Spirometry, and Smart Devices .............................................................38 
11.2 CONTENTS .......................................................................................................................38 
11.2.1 
Study Drug ....................................................................................................................38 
11.2.2 
Study Inhalation Device ...............................................................................................39 
11.3 LABELING ........................................................................................................................39 
11.3.1 
Study Drug ....................................................................................................................39 
11.3.2 
Study Inhalation Device ...............................................................................................39 
11.4 STORAGE AND HANDLING OF STUDY DRUG .......................................................39 
11.5 SUPPLY AND RETURN OF STUDY DRUG AND DEVICES ...................................40 
11.6 DRUG AND DEVICE ACCOUNTABILITY .................................................................40 
12 REGULATORY AND ETHICAL OBLIGATIONS ..........................................................41 
12.1 US FDA OR APPLICABLE REGULATORY REQUIREMENTS .............................41 
12.2 INFORMED CONSENT REQUIREMENTS ................................................................41 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ..............................................................................................................................41 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ...............................................42 
12.5 SUBJECT CONFIDENTIALITY....................................................................................42 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS .......................................................43 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .................................43 
13.2 STUDY DOCUMENTATION AND STORAGE ...........................................................43 
13.3 STUDY MONITORING AND DATA COLLECTION ................................................43 
13.4 QUALITY ASSURANCE .................................................................................................44 
14 REFERENCES .......................................................................................................................45 
15 APPENDICES ........................................................................................................................46 
15.1 PROCEDURE FOR 6-MINUTE WALK TEST ............................................................46 
15.2 MODIFIED BORG DYSPNEA SCALE .........................................................................48 
15.3 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS ......49 
15.4 PATIENT GLOBAL ASSESSMENT (EXAMPLE) ......................................................53 
 
Table of In-Text Tables 
Table 3-1 
Overall Schedule of Times and Events ..................................................................13 
Table 3-2 
Clinical Chemistry and Hematology ......................................................................18 
Table 6-1 
Sample Inhaled Treprostinil Dose Escalation ........................................................26 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 10 
LIST OF ABBREVIATIONS 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
BP 
Blood pressure 
COPD 
Chronic obstructive pulmonary disease 
DLCO 
Diffusion capacity for carbon monoxide 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
PE 
Physical examination 
PFT 
Pulmonary function test 
PGA 
Patient global assessment 
PH 
Pulmonary hypertension 
PH-COPD 
Pulmonary hypertension due to chronic obstructive pulmonary disease 
QID 
4 times daily 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SpO2 
Saturation peripheral capillary oxygenation 
TLC 
Total lung capacity 
 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 11 
1 
BACKGROUND AND RATIONALE 
Currently, there are no approved therapies for the treatment of pulmonary hypertension due to 
chronic obstructive pulmonary disease (PH-COPD).  Since this condition is associated with 
increased mortality compared to patients with chronic obstructive pulmonary disease (COPD) 
alone, pulmonary hypertension (PH) management is vital for improving overall survival and 
decreasing PH-related symptoms (Klinger 2016). 
This open-label extension study will evaluate the safety of continued therapy with inhaled 
treprostinil in subjects who completed the randomized, placebo-controlled, double-blind, 
adaptive study, RIN-PH-304.  This study hypothesizes that the long-term safety findings will be 
similar to those observed in Study RIN-PH-304. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective is to evaluate the long-term safety and tolerability of inhaled treprostinil in 
subjects with PH-COPD. 
2.2 
SECONDARY OBJECTIVE 
The secondary objective is to evaluate the long-term efficacy of inhaled treprostinil in subjects 
with PH-COPD. 
2.3 
EXPLORATORY OBJECTIVE 
 
 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a multicenter, open-label extension study for subjects who completed Study RIN-PH-304.  
Subjects who provide informed consent for this study on or prior to the final visit for Study 
RIN-PH-304 may participate, provided all other eligibility criteria are met.  The Enrollment Visit 
for RIN-PH-305 will occur on the same day as the final visit for Study RIN-PH-304.  Study-
related procedures and initiation of study drug cannot begin until all final visit procedures for 
Study RIN-PH-304 are complete. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 12 
All subjects will initiate inhaled treprostinil at a dose of 3 breaths (18 mcg) 4 times daily (QID) 
during waking hours.  Dose titrations should occur as rapidly as possible (as directed by the 
Investigator) with a target dosing regimen of 15 breaths (90 mcg) QID or the maximum tolerated 
dose.  Dosing can be adjusted to tolerability for any dose-related adverse events (AEs).  
Telephone contact will occur weekly during dose titration and monthly thereafter to assess study 
drug tolerability, AEs, concomitant medications, drug/device compliance, and any other study-
related issues, as described in Section 7.4. 
Study visits will occur at Enrollment, Week 6, and Quarterly thereafter for up to 3 years.  At the 
Enrollment Visit, subjects will receive a new actigraph and continue to use their 
Sponsor-provided spirometry and smart devices from Study RIN-PH-304 for assessment of 
activity, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), fatigue, and 
shortness of breath until Quarterly Visit 4 (Year 1) or the Discontinuation Visit (whichever 
occurs first). 
Given the uncertainty of clinical benefit of novel inhaled treprostinil in PH-COPD and the 
ongoing COVID-19 pandemic, a high rate of discontinuations and/or missing data are both 
possible.  All attempts should be made to have onsite clinic visits, but subjects may have 
telemedicine visits in lieu of onsite visits, as described in Section 7.5.  
The study may be terminated at any time by the Sponsor for reasons that may include, but are not 
limited to, commercial availability of inhaled treprostinil for PH-COPD and Sponsor termination 
of the development of the indication for PH-COPD. 
A schedule of study visits and assessments is presented in Table 3-1. 
 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 13 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
Table 3-1 
Overall Schedule of Times and Events 
Study Procedures 
Treatment Phase 
Enrollment Visita 
Week 6 Visitc 
(±3 days) 
Quarterly Visitsc 
(±14 days) 
Discontinuation Visitm 
Informed Consent 
X 
 
 
 
Subject Eligibility 
X 
 
 
 
Demographics and Medical History 
Xa 
 
 
 
Physical Examinationr 
Xa 
X 
X 
X 
Vital Signse,r 
Xa 
X 
X 
X 
12-Lead ECGe,r 
Xa 
X 
X 
X 
Clinical Laboratory Assessmentsr 
Xa 
X 
X 
X 
NT-proBNPn,r 
Xa 
X 
X 
X 
Pregnancy Testd,r 
Xa 
X 
X 
X 
PFTsi,r 
Xa 
X 
X 
X 
Pulse Oximetryh,r 
Xa 
X 
X 
X 
6MWTg,r 
Xa 
X 
X 
X 
Borg Dyspnea Scoref,r 
Xa 
X 
X 
X 
Actigraphyo 
X 
X 
X 
X 
At-home Spirometryp 
X 
X 
X 
X 
PGAq 
X 
X 
X 
X 
Dispense Study Drug/Dosing Instructions 
X 
X 
X 
 
Drug Administration at Study Siter 
X 
X 
X 
X 
Drug/Device Accountability 
 
X 
X 
X 
Adverse Eventsk,l 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
Telephone Contactj 
 
X 
X 
X 
Discontinuation Form 
 
 
 
Xm 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 14 
6MWT, 6-Minute Walk Test; AE, adverse event; BP, blood pressure; eCRF, electronic Case Report Form; DLCO, diffusion capacity for carbon monoxide; ECG, electrocardiogram; FEV1, 
forced expiratory volume in 1 second; FVC, forced vital capacity; HR, heart rate; NT-proBNP, N-terminal pro-brain natriuretic peptide; PE, physical examination; PFT, pulmonary 
function test; PGA, patient global assessment; PH, pulmonary hypertension; RR, respiratory rate; SpO2, saturation peripheral capillary oxygenation; TLC, total lung capacity 
a  The following assessments - demographics, medical history, PE, vital signs, 12-lead ECG, clinical laboratory assessments, NT-proBNP, PFTs, pulse oximetry (oxygenation), 6MWT, and 
Borg dyspnea score - will be performed at the final visit for Study RIN-PH-304 and along with the corresponding eCRF data entry, do not need to be repeated at the Enrollment Visit for 
RIN-PH-305.  Assessments to be performed prior to initiation of study drug include a urine pregnancy test for females of childbearing potential and the collection of biomarkers for 
consented subjects who did not provide blood in Study RIN-PH-304.  If the Enrollment Visit is done via telemedicine, study drug and a new actigraph will be shipped from the study site 
directly to subjects and subjects should begin study drug and actigraphy assessments as soon as they arrive. 
b  
 
   
c  The visit window for the Week 6 Visit is ±3 days; the visit window for all Quarterly Visits is ±14 days.  Study visits are scheduled based on the date of enrollment in RIN-PH-305 
(eg, 6, 13, 26, 39, 52 weeks after the Enrollment Visit).  An unscheduled visit may occur at any time and involve any of the procedures deemed appropriate by the Investigator. 
d For females of childbearing potential, a urine pregnancy test should be done at the Enrollment Visit (prior to study drug administration) and serum pregnancy tests at all other visits.  
e  Vital signs (weight, RR, HR, and BP) and ECG are to be performed after a 5-minute period of seated rest.  No other measurement or procedure should be performed during this 5-minute 
rest period.  When possible, vital signs and ECGs should be collected prior to the 6MWT. 
f  See Appendix 15.2.  The subject should be asked to rate their maximal breathlessness during the 6MWT immediately following the 6MWT. 
g  See Appendix 15.1.  All 6MWTs performed after enrollment will be conducted following at least 10 minutes of seated rest and between 10 to 60 minutes after study drug administration.  
The 6MWT will be conducted by qualified, trained staff in a designated 6MWT area.  Subjects receiving supplemental oxygen during any 6MWT should continue to receive the same 
flow rate at all subsequent 6MWTs.  The supplemental oxygen flow rate (L/min) must be recorded at each study visit, as applicable. 
h  Pulse oximetry will be performed continuously prior to, during, and immediately following each 6MWT.  Pulse oximetry will include the measurement of SpO2 and HR.  The SpO2 and 
HR obtained immediately prior to and immediately following completion of the 6MWT will be recorded in the eCRF.  In addition, the lowest recorded SpO2 and associated HR obtained 
during each 6MWT will be recorded in the eCRF. 
i 
PFTs will include the evaluation of FEV1, FVC, TLC, and DLCO.  TLC and DLCO will be assessed only when clinically feasible.  When possible, PFTs should be performed prior to the 
6MWT.  If PFTs cannot be performed prior to the 6MWT, they should be performed after recovery from the 6MWT.  If PFTs are done both pre- and post-bronchodilator use, only the 
post-bronchodilator values will be recorded. 
j  At least weekly telephone contact is required throughout the dose titration period and monthly thereafter for the remainder of the study to assess study drug tolerability, AEs, concomitant 
medications, drug/device compliance, and any other study-related issues.  Subjects will also be directed to call the study site at any time to discuss any issues of concern (AEs, 
symptoms, concomitant medications, tolerability, etc).  Face-to-face interaction may replace telephone contact for the weeks/months where onsite visits occur and the information can be 
obtained during the visit.  All telephone contact must be documented on telephone contact sheets and kept in the subject’s source documents.   
k  AEs that are ongoing from Study RIN-PH-304 should be recorded as continuing in RIN-PH-305 and followed as instructed in Section 3.3.2.8. 
l  AEs that are ongoing at study discontinuation in RIN-PH-305 should be followed as instructed in Section 3.3.2.8.  
m  A Discontinuation Visit will be required if the subject cannot be seen at the clinic during a regularly scheduled visit (ie, Week 6 or Quarterly Visit) given the pre-specified visit windows 
for these study visits.  If possible, the subject should remain on study drug until completion of the discontinuation procedures.  The study site should complete a Discontinuation Form at 
the end of the subject’s participation in the study, regardless of the visit type. 
n  Blood for NT-proBNP assessment must be drawn prior to the 6MWT and study drug administration. 
o Subjects will receive a new Sponsor-provided actigraph (activity monitor) at the Enrollment Visit for measurement of daily at-home physical activity.  Subjects will be asked to wear the 
device continuously up to Quarterly Visit 4 (Year 1) or the Discontinuation Visit (whichever occurs first) with the exception of certain activities of daily living (eg, bathing) or when the 
actigraph is being charged.  Assessment of proper use and data capture should be performed by the study site staff at all scheduled visits. 
p Subjects will use their Sponsor-provided spirometry device from Study RIN-PH-304 for at-home capture of FEV1 and FVC data.  Subjects will be asked to perform the spirometry 
assessment at home during the allowable window for each study visit up to Quarterly Visit 4 (Year 1) or the Discontinuation Visit (whichever occurs first).  Subjects are encouraged to 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 15 
complete the activity ahead of their scheduled visit.  If spirometry is not performed prior to a visit, the subject should perform the spirometry assessment during the visit.  Assessment of 
proper use and data capture should be performed by the study site staff at all scheduled visits. 
q Subjects will use their Sponsor-provided smart device from Study RIN-PH-304 for at-home capture of PGA data up to Quarterly Visit 4 (Year 1) or the Discontinuation Visit (whichever 
occurs first).  Subjects will be asked to perform the PGA at the same time as their at-home spirometry assessment.  Subjects are encouraged to complete the activity ahead of their 
scheduled visit.  If the PGA is not completed prior to a visit, the subject should complete the PGA during the visit.  Assessment of proper use and data capture should be performed by 
the study site staff at all applicable visits. 
r Applicable only if an onsite study visit. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 16 
3.3 
CLINICAL ASSESSMENTS 
Safety and efficacy assessments will be performed at all study visits.  All attempts should be 
made to have onsite clinic visits in order to perform these assessments.  If the conduct of an 
onsite visit poses a safety risk due to the COVID-19 pandemic, subjects may have telemedicine 
visits in lieu of onsite visits, as described in Section 7.5. 
3.3.1 
Demographics and Medical History 
Demographic and medical history information from Study RIN-PH-304 will be used for 
RIN-PH-305 and should not be re-entered into the electronic Case Report Form (eCRF).  Any 
significant changes in a subject’s medical condition throughout the course of the study must also 
be documented in the subject’s source documents and in the eCRF. 
3.3.2 
Safety 
The safety of inhaled treprostinil will be evaluated on the following: AEs, physical examinations 
(PEs), vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory assessments, 
pulmonary function tests (PFTs), at-home spirometry, and oxygenation.  Safety assessments 
collected as part of the final visit for Study RIN-PH-304 will be used as the Enrollment Visit 
safety assessments for RIN-PH-305 and do not need to be repeated. 
3.3.2.1 
Physical Examination 
A complete PE will be conducted by appropriate study personnel (as documented on the 
Delegation of Authority Log) at all study visits.  Any clinically significant changes from the 
Enrollment Visit should be reported as AEs. 
In the event of Sponsor-approved telemedicine visits, PE assessments will not be performed. 
3.3.2.2 
Vital Signs 
Vital signs will be collected at all study visits after at least 5 minutes of seated rest.  No other 
measurement or procedure should be performed during the rest period.  When possible, vital 
signs should be collected prior to the 6-Minute Walk Test (6MWT).  Vital signs to be collected 
include weight, respiratory rate (RR), heart rate (HR), and systolic and diastolic blood pressure 
(BP).  Any clinically significant changes from the Enrollment Visit should be reported as AEs. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 17 
In the event of Sponsor-approved telemedicine visits, vital sign assessments will not be 
performed. 
3.3.2.3 
12-Lead Electrocardiogram 
A 12-lead ECG will be recorded at all study visits after at least 5 minutes of seated rest.  No 
other measurement or procedure should be performed during the rest period.  When possible, the 
ECG should be collected prior to the 6MWT.  Recordings should include Lead II as a rhythm 
strip, at least 5 QRS complexes, rhythm, HR, PR interval, QT interval, QRS duration, and any 
abnormalities.  Any clinically significant changes from the Enrollment Visit should be reported 
as AEs. 
In the event of Sponsor-approved telemedicine visits, 12-lead ECG assessments will not be 
performed. 
3.3.2.4 
Clinical Laboratory Assessments 
Clinical laboratory assessments will be performed at all study visits.  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 results should 
be reported as AEs and treated and/or followed-up until the symptoms or values return to normal 
or acceptable levels, as judged by the Investigator.  Where appropriate, medical tests and 
examinations will be performed to assess and document resolution. 
In the event of Sponsor-approved telemedicine visits, clinical laboratory assessments will not be 
performed. 
3.3.2.4.1 
Chemistry and Hematology Testing 
Blood will be collected to assess treatment-emergent changes in the clinical chemistry and 
hematology tests listed below in Table 3-2. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 18 
Table 3-2 
Clinical Chemistry and Hematology 
Electrolyte Panel 
Chemistry Panel 
Hematology Panel 
Sodium 
Total bilirubin 
Hemoglobin 
Potassium 
Alkaline phosphatase 
Hematocrit 
Bicarbonate 
Alanine aminotransferase 
Red blood cell count 
Chloride 
Aspartate aminotransferase 
Red blood cell morphology 
 
Urea nitrogen 
White blood cell count 
 
Creatinine 
Platelet count 
 
Calcium 
 
 
Albumin 
 
 
3.3.2.4.2 
Pregnancy Testing 
Females of childbearing potential will undergo a urine pregnancy test at the Enrollment Visit, 
prior to study drug administration, and a serum pregnancy test at every visit thereafter.  A 
positive pregnancy test will result in a subject’s withdrawal from the study. 
In the event of Sponsor-approved telemedicine visits, pregnancy tests will not be performed, but 
subjects will be asked to verbally confirm they are not pregnant.  Verbal confirmation of 
pregnancy will also result in a subject’s withdrawal from the study.  
Refer to Section 9.4.2 for information related to the reporting and following of pregnancy. 
3.3.2.5 
Pulmonary Function Tests 
Pulmonary function testing should be conducted either before the 6MWT or after recovery from 
the 6MWT at all study visits.  If PFTs are done both pre- and post-bronchodilator administration, 
only the post-bronchodilator values will be recorded.  The following will be recorded (absolute 
values and % predicted): FEV1, FVC, total lung capacity (TLC), and diffusion capacity for 
carbon monoxide (DLCO; uncorrected for hemoglobin and lung volume); TLC and DLCO will 
be assessed only when clinically feasible. 
In the event of Sponsor-approved telemedicine visits, PFTs will not be performed. 
3.3.2.6 
At-home Spirometry 
Subjects will use their Sponsor-provided spirometry device from Study RIN-PH-304 for at-home 
capture of FEV1 and FVC data.   

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 19 
Subjects will be asked to perform the spirometry assessment at home during the allowable 
window for each study visit up to Quarterly Visit 4 (Year 1) or the Discontinuation Visit 
(whichever occurs first).  Subjects are encouraged to complete the activity ahead of their 
scheduled visit.  If spirometry is not performed prior to a visit, the subject should perform the 
spirometry assessment during the visit.  Assessment of proper use and data capture should be 
performed by the study site staff at all scheduled visits. 
3.3.2.7 
Oxygenation - Pulse Oximetry 
Oxygenation via pulse oximetry will be assessed continuously prior to, during, and immediately 
following each 6MWT.  Pulse oximetry will include the measurement of saturation peripheral 
capillary oxygenation (SpO2) and HR.  The SpO2 and HR obtained immediately prior to and 
immediately following each 6MWT will be recorded in the subject’s source documents and the 
eCRF.  In addition, the lowest recorded SpO2 and associated HR obtained during each 6MWT 
will be recorded in the subject’s source documents and eCRF. 
Study sites must use the same pulse oximeter model from Study RIN-PH-304 to maintain 
consistency and facilitate documentation of oxygen saturation. 
In the event of Sponsor-approved telemedicine visits, oxygenation assessments will not be 
performed. 
3.3.2.8 
Adverse Events 
Adverse events that are ongoing at the final visit for Study RIN-PH-304 should be recorded in 
the eCRF as continuing in this study and followed as instructed below. 
Subjects should be assessed for AEs from the time they sign the Informed Consent Form (ICF) 
until study discontinuation or completion.  Subjects should be questioned for AEs at all study 
visits, including telephone contacts and telemedicine visits, and instructed to report all AEs upon 
occurrence. 
All AEs should be followed until resolution (or return to normal/baseline), until they are judged 
by the Investigator to no longer be clinically significant, or for at least 30 days if the AE is 
ongoing at the final study visit.  

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 20 
All serious adverse events (SAEs) should be followed until resolution, death, or the subject is 
lost to follow-up, even if the SAE is ongoing more than 30 days after the final study visit. 
Section 9 and Appendix 15.3 provide guidelines and definitions for the reporting and recording 
of AEs, respectively. 
3.3.2.9 
Concomitant Medications 
All concomitant medications taken during the conduct of the study, including those taken for 
AEs or historical medical conditions, should be recorded in the subject’s source documents and 
eCRF. 
3.3.2.9.1 
Supplemental Oxygen Use at Rest 
The amount of supplemental oxygen (L/min) required at rest will be assessed at all study visits.  
Any changes in the amount of supplemental oxygen required at rest should be recorded in the 
subject’s source documents and on the concomitant medication eCRF page.  Supplemental 
oxygen should not be introduced after enrollment, unless there is a medical need in the clinical 
judgement of the Investigator; however, if supplemental oxygen is started after enrollment, the 
flow should be consistent for all subsequent tests where oxygen is required at rest. 
3.3.3 
Efficacy 
The efficacy of inhaled treprostinil will be evaluated on the following: N-terminal pro-brain 
natriuretic peptide (NT-proBNP), 6-Minute Walk Distance, Borg dyspnea score, patient global 
assessment (PGA), and physical activity (actigraphy).  Efficacy assessments collected as part of 
the final visit for Study RIN PH-304 will be used as the Enrollment Visit efficacy assessments 
for RIN-PH-305 and do not need to be repeated. 
3.3.3.1 
N-Terminal Pro-brain Natriuretic Peptide 
N-terminal pro-brain natriuretic peptide is a biomarker associated with changes in right heart 
morphology and function (Fijalkowska 2006).  Samples for NT-proBNP will be collected at all 
study visits and must be drawn prior to the 6MWT and study drug administration.  
In the event of Sponsor-approved telemedicine visits, NT-proBNP assessments will not be 
performed. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 21 
3.3.3.2 
6-Minute Walk Test 
The 6MWT is a validated and reliable measure of exercise ability in patients with chronic 
respiratory diseases (Holland 2014).  This study will utilize an unencouraged 6MWT.  The 
6MWT is to be performed at all study visits.  All 6MWTs performed after enrollment must be 
conducted following at least 10 minutes of seated rest and between 10 to 60 minutes after study 
drug administration.  The 6MWT will be conducted by qualified, trained staff in a designated 
6MWT area that meets the requirements described in Appendix 15.1. 
Pulse oximetry is to be measured continuously prior to, during, and immediately following each 
6MWT, as outlined in Section 3.3.2.7. 
If a study site or subject has implemented protective measures against COVID-19 (eg, use of an 
alternative 6MWT testing area or use of personal protective equipment [mask, face shield]), all 
subsequent 6MWTs should be carried out in a generally consistent manner. 
In the event of Sponsor-approved telemedicine visits, 6MWT assessments will not be performed, 
but the subject should continue to wear an actigraph and maintain normal activity. 
3.3.3.2.1 
Supplemental Oxygen Use During the 6-Minute Walk Test 
Subjects receiving supplemental oxygen during any 6MWT should continue to receive the same 
flow rate for all subsequent 6MWTs.  The amount of supplemental oxygen (L/min) required 
during any 6MWT should be recorded on the concomitant medication eCRF page.  Supplemental 
oxygen should not be introduced after enrollment, unless there is a medical need in the clinical 
judgement of the Investigator; however, if supplemental oxygen is started after enrollment, the 
flow should be consistent for all 6MWTs. 
3.3.3.3 
Borg Dyspnea Score 
The Borg dyspnea score is a 0 to 10 scale rating the level of dyspnea experienced during the 
6MWT and should be assessed immediately following each 6MWT.  Subjects will be asked to 
rate their shortness of breath on a scale from 0 (no shortness of breath) to 10 (maximal shortness 
of breath).  The Borg dyspnea scale and instructions for rating the level of dyspnea are provided 
in Appendix 15.2. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 22 
In the event of Sponsor-approved telemedicine visits, Borg dyspnea assessments will not be 
performed. 
3.3.3.4 
Patient Global Assessment 
The PGA is used to rate subject fatigue and shortness of breath.  Subjects will use their Sponsor-
provided smart device from Study RIN-PH-304 for at-home capture of PGA data up to Quarterly 
Visit 4 (Year 1) or the Discontinuation Visit (whichever occurs first).  Subjects will be asked to 
perform the PGA at the same time as their at-home spirometry assessment.  Subjects are 
encouraged to complete the activity ahead of their scheduled visit.  If the PGA is not completed 
prior to a visit, the subject should complete the PGA during the visit.  Assessment of proper use 
and data capture should be performed by the study site staff at all applicable visits.  An example 
of the PGA can be found in Appendix 15.4. 
3.3.3.5 
Actigraphy 
Daily physical activity, including overall, non-sedentary, and moderate to vigorous physical 
activity will be measured via a wrist-worn medical grade physical activity monitor (actigraph).  
Subjects will receive a new Sponsor-provided actigraph at the Enrollment Visit for capture of 
activity data up to Quarterly Visit 4 (Year 1) or the Discontinuation Visit (whichever occurs 
first).  Subjects will be asked to wear the device continuously with the exception of certain 
activities of daily living (eg, bathing) or when the device is being charged.  Assessment of proper 
use and data capture should be performed by the study site staff at all scheduled visits. 
3.3.4 
Exploratory 
 
 
3.3.4.1 
 
 
 
 
 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 23 
 
 
 
 
 
 
 
3.3.5 
Telephone Contact 
Telephone contact will occur weekly during the dose titration period and monthly thereafter for 
the remainder of the study, as described in Section 7.4.  Subjects will also be directed to call the 
study site or Investigator at any time to discuss study-related issues of concern (AEs, symptoms, 
tolerability, device issues, etc).  Face-to-face interaction may replace telephone contact for the 
weeks/months where onsite study visits occur and the information can be obtained during the 
visit.  All telephone contact (ie, dosing instructions, reported AEs, and/or medication changes) 
must be documented on telephone contact sheets and kept in the subject’s source documents. 
3.4 
NUMBER OF SITES 
The same study sites that were identified to recruit subjects for Study RIN-PH-304 will be used 
for RIN-PH-305.  Active subjects from Study RIN-PH-304 who meet eligibility criteria will be 
permitted to enroll in RIN-PH-305. 
3.5 
NUMBER OF SUBJECTS 
The total sample size will be approximately 136 subjects from Study RIN-PH-304 in the 
Original Crossover Design or approximately 314 subjects if the Contingent Parallel Design is 
applied. 
3.6 
ESTIMATED STUDY DURATION 
Subjects will remain in the study from the date their ICF is signed until they withdraw 
participation, die, are lost to follow-up, or the study ends.  It is estimated that the study will last 
3 years, but the actual duration may be shorter or longer. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 24 
The study is expected to continue until inhaled treprostinil becomes commercially available for 
PH-COPD or the Sponsor discontinues development for the indication of PH-COPD, whichever 
occurs first.  The Sponsor may discontinue the study for any reason, at any time.  The study may 
also be discontinued if the Investigators and/or Sponsor determine that continuing the study 
represents a serious medical risk to study subjects. 
4 
SUBJECT ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
Subjects who meet the following criteria may be included in the study: 
1. Voluntarily gives informed consent to participate in the study.  
2. Completed Study RIN-PH-304. 
3. Females of childbearing potential (defined as less than 1 year postmenopausal and not 
surgically sterile) must agree to practice abstinence or use 2 highly effective methods of 
contraception (defined as a method of birth control that results in a less than 1% per year 
failure rate, such as an approved hormonal contraceptive, barrier method [condom or 
diaphragm] with a spermicide, or an intrauterine device) for the duration of study 
treatment and for 48 hours after discontinuing study drug.  
4. Males with a partner of childbearing potential must agree to use a barrier method 
(condom) with a spermicide for the duration of treatment and for at least 48 hours after 
discontinuing study drug. 
4.2 
EXCLUSION CRITERIA 
Subjects who meet the following criteria are excluded from the study: 
1. Pregnant or lactating. 
2. Prematurely discontinued Study RIN-PH-304. 
3. Intolerant to inhaled prostanoid therapy. 
4. Unwilling or unable to use Sponsor-provided devices (actigraph, spirometer, or smart 
device). 
5. Scheduled to receive another investigational drug, device, or therapy during the course of 
this study. 
6. Any other clinically significant illness or abnormal laboratory value that, in the opinion 
of the Investigator, might adversely affect the interpretation of the study data or subject 
safety. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 25 
4.3 
PRESCRIBED THERAPY 
There are no restrictions on concomitant medications with the exception of chronic dosing of any 
other prostanoid therapy.  Subjects who require 29 days or more of such therapy must 
discontinue from this study. 
All concomitant medications taken during the conduct of the study, including those taken for 
AEs or historical medical conditions, should be recorded in the subject’s source documents and 
eCRF.  The amount of supplemental oxygen (L/min) required at rest and/or during any 6MWT 
should be recorded in the subject’s source documents and on the concomitant medication eCRF 
page. 
5 
SUBJECT ENROLLMENT 
Subjects will retain the same subject number they were assigned in Study RIN-PH-304. 
5.1 
TREATMENT ASSIGNMENT 
This is an open-label study and all subjects will receive treatment with the study drug, inhaled 
treprostinil.  This study is not randomized or blinded. 
6 
DRUGS AND DOSING (OR TREATMENT PROCEDURES) 
6.1 
DRUG DOSAGE, ADMINISTRATION, AND SCHEDULE 
Treprostinil for inhalation solution (0.6 mg/mL) is delivered via the Tyvaso Inhalation System, 
which emits a dose of approximately 6 mcg per breath.  Subjects will be provided a Tyvaso 
Inhalation System by the Sponsor. 
All subjects who meet eligibility for RIN-PH-305 will transition from Study RIN-PH-304 and 
initiate inhaled treprostinil at a dose of 3 breaths (18 mcg) QID during waking hours.  Study drug 
doses should be titrated to a target dosing regimen of 15 breaths (90 mcg) QID or the maximum 
tolerated dose.  Dose titrations can occur as rapidly as possible (as directed by the Investigator).  
Subjects should be instructed to call the study site if they experience any AEs during the dose 
titration period. 
A sample dose escalation schedule in provided in Table 6-1. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 26 
Table 6-1 
Sample Inhaled Treprostinil Dose Escalation 
Study Daya 
Single Dose 
Total Daily Dose 
Titrating to maximum dose of 15 breaths QID 
1 to 3 
3 breaths QID (18 mcg) 
72 mcg 
4 to 6 
4 breaths QID (24 mcg) 
96 mcg 
7 to 9 
5 breaths QID (30 mcg) 
120 mcg 
10 to 12 
6 breaths QID (36 mcg) 
144 mcg 
13 to 15 
7 breaths QID (42 mcg) 
168 mcg 
16 to 18 
8 breaths QID (48 mcg) 
192 mcg 
19 to 21 
9 breaths QID (54 mcg) 
216 mcg 
22 to 24 
10 breaths QID (60 mcg) 
240 mcg 
25 to 27 
11 breaths QID (66 mcg) 
264 mcg 
28 to 30  
12 breaths QID (72 mcg) 
288 mcg 
31 (and beyond) 
15 breaths QID (90 mcg) 
360 mcg 
QID, 4 times daily 
a  Study day refers to the days on study drug with Day 1 referring to the first dose of study drug. 
The above dosing schedule is only a guide.  The Investigator may accelerate or decelerate the 
dosing titration schedule on an individual basis, considering subject safety, tolerability, and 
functional improvement. 
Dose adjustments should be carried out under appropriate medical supervision and in 
consultation with the appropriate study site staff.  Telephone contact between study site staff and 
subjects should occur prior to each dose adjustment or at least weekly during dose titration (until 
15 breaths QID or the maximum tolerated dose is achieved) and monthly thereafter for the 
remainder of the study, as described in Section 7.4.  All telephone contact (ie, dosing 
instructions, reported AEs, and/or medication changes) must be documented on telephone 
contact sheets and kept in the subject’s source documents.   
If subjects are prescribed bronchodilators, study drug should be administered post-bronchodilator 
use. 
6.2 
COMPLIANCE 
Study drug (used and unused) must be returned to the study site at each visit and will be 
dispensed/resupplied, as needed.  Study site staff must document the number of used and unused 
ampoules and assess treatment compliance at each visit.   

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 27 
Subjects will be asked throughout the study whether they have been compliant with study drug 
dosing instructions.  If it is determined that a subject is noncompliant, the study site staff must 
re-educate the subject on proper dosing compliance and its importance.  Continued 
noncompliance may lead to withdrawal of the subject from the study, after consultation between 
the Investigator and the Sponsor’s Medical Monitor or other Sponsor representative. 
Subjects will be asked throughout the study whether they have been compliant with actigraphy, 
spirometry, and smart device use.  Assessment of proper use and data capture should be 
performed by the study site staff at all applicable visits.  If it is determined that a subject is 
noncompliant, the study site staff must re-educate the subject on compliance and its importance. 
7 
EXPERIMENTAL PROCEDURES 
All attempts should be made to have onsite clinic visits.  With Sponsor approval, subjects may 
have telemedicine visits in lieu of onsite visits, as described in Section 7.5. 
Refer to Table 3-1 for the schedule of times and events and Table 6-1 for a suggested dose 
titration schedule. 
7.1 
ENROLLMENT VISIT 
Subjects must sign an approved ICF and meet study-specific inclusion and exclusion criteria 
before any study-related procedures are performed.  The following final visit assessments for 
Study RIN-PH-304 will serve as the Enrollment Visit assessments for RIN-PH-305: 
demographics, medical history, PE, vital signs, 12-lead ECG, clinical laboratory assessments, 
NT-proBNP, PFTs, 6MWT, pulse oximetry (oxygenation), and Borg dyspnea score.  As such, 
these assessments and the corresponding eCRF data entry do not need to be repeated. 
The following assessments are required prior to study drug administration: 
• Urine pregnancy test (females of childbearing potential) 
• 
 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 28 
The following assessments are required prior to completion of the Enrollment Visit: 
• Re-educate subject on the use of inhaled treprostinil with the Tyvaso Inhalation System, 
and the actigraphy, spirometry, and smart devices, if needed 
• Dispense device accessories, as applicable 
• Dispense study drug 
• Assess for AEs (from the time of informed consent for RIN-PH-305) 
• Assess for changes in concomitant medications (from the time of informed consent for 
RIN-PH-305) 
Subjects will be called mid-week following initiation of study drug and routinely thereafter, as 
described in Section 7.4. 
7.2 
WEEK 6 VISIT 
Subjects are to return to the study site at Week 6 (±3 days).  The following sequence of 
assessments is recommended: 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest; no other 
measurement or procedure should be performed during the rest period) 
• 12-lead ECG (following at least 5 minutes of seated rest; no other measurement or 
procedure should be performed during the rest period) 
• PE 
• Serum pregnancy test (females of childbearing potential) 
• Blood draws for clinical laboratory assessments and NT-proBNP (NT-proBNP must be 
drawn prior to the 6MWT and study drug administration) 
• PFTs (performed before the 6MWT or after recovery from the 6MWT) 
• Study drug administration 
• Pulse oximetry (measured continuously prior to, during, and following the 6MWT) 
• 6MWT (following at least 10 minutes of seated rest and between 10 to 60 minutes after 
study drug administration) with documentation of supplemental oxygen requirement, if 
applicable 
• Borg dyspnea score (immediately following the 6MWT) 
• Confirm proper use and capture of actigraphy, spirometry, and PGA data 
• Assess for AEs  
• Assess for changes in concomitant medications 
• Dispense study drug/device accessories and assess drug accountability/compliance 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 29 
In the event of Sponsor-approved telemedicine visits, only the actigraphy, spirometry, PGA, AE, 
concomitant medication, and drug/device assessments will be performed. 
7.3 
QUARTERLY VISITS 
Subjects are to return to the study site quarterly (±14 days).  The following sequence of 
assessments is recommended: 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest; no other 
measurement or procedure should be performed during the rest period) 
• 12-lead ECG (following at least 5 minutes of seated rest; no other measurement or 
procedure should be performed during the rest period) 
• PE 
• Serum pregnancy test (females of childbearing potential) 
• Blood draws for clinical laboratory assessments and NT-proBNP (NT-proBNP must be 
drawn prior to the 6MWT and study drug administration) 
• 
 
 
• PFTs (performed before the 6MWT or after recovery from the 6MWT) 
• Study drug administration 
• Pulse oximetry (measured continuously prior to, during, and following the 6MWT) 
• 6MWT (following at least 10 minutes of seated rest and between 10 to 60 minutes after 
study drug administration) with documentation of supplemental oxygen requirement, if 
applicable 
• Borg dyspnea score (immediately following the 6MWT) 
• Confirm proper use and capture of actigraphy, spirometry, and PGA data (up to Quarterly 
Visit 4 [Year 1] or the Discontinuation Visit [whichever occurs first]) 
• Assess for AEs 
• Assess for changes in concomitant medications 
• Dispense study drug/device accessories and assess drug accountability/compliance 
In the event of Sponsor-approved telemedicine visits, only the actigraphy, spirometry, PGA, AE, 
concomitant medication, and drug/device assessments will be performed. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 30 
7.4 
TELEPHONE CONTACTS 
Subjects will be called mid-week following initiation of study drug to perform dose titration and 
discuss study drug tolerability and any study-related issues. 
At least weekly telephone contact is required throughout the dose titration period (until 
15 breaths QID or the maximum tolerated dose is achieved) to assess study drug tolerability, 
AEs, concomitant medications, drug/device compliance, and any other study-related issues.  
Face-to-face interaction may replace telephone contact for the weeks where onsite study visits 
occur and the information can be obtained during the visit. 
At least monthly telephone contact is required after the dose titration period is complete 
(15 breaths QID or the maximum tolerated dose is achieved) for the remainder of the study to 
assess study drug tolerability, AEs, concomitant medications, drug/device compliance, and any 
other study-related issues.  Face-to-face interaction may replace telephone contact for the months 
where onsite study visits occur and the information can be obtained during the visit. 
Subjects will also be directed to call the study site or Investigator at any time to discuss any 
issues of concern (AEs, symptoms, tolerability, device issues, etc).  All telephone contact 
(ie, dosing instructions, reported AEs, and/or medication changes) must be documented on 
telephone contact sheets and kept in the subject’s source documents. 
7.5 
TELEMEDICINE VISITS 
All attempts should be made to have onsite clinic visits.  With Sponsor approval, subjects may 
have telemedicine visits in lieu of onsite visits, if the conduct of an onsite clinic visit poses a 
safety risk due to the COVID-19 pandemic.  The following assessments will be performed 
during telemedicine visits:  
• Confirm proper use and capture of actigraphy, spirometry, and PGA data (up to Quarterly 
Visit 4 [Year 1] or the Discontinuation Visit [whichever occurs first]) 
• Assess for AEs 
• Assess for changes in concomitant medications 
• Assess study drug accountability/compliance 
• Confirm receipt of study drug/device accessories 
• Confirm the subject is not pregnant (females of childbearing potential) 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 31 
If the Enrollment Visit is done via telemedicine, study drug and a new actigraph will be shipped 
from the study site directly to subjects and subjects should begin study drug and actigraphy 
assessments as soon as they arrive. 
7.6 
UNSCHEDULED VISIT 
An Unscheduled Visit may occur at any time and may involve any study-related procedures 
deemed appropriate by the Investigator. 
7.7 
DISCONTINUATION VISIT 
This visit is required if the subject cannot be seen during a regularly scheduled study visit 
(ie, Week 6 or Quarterly Visit) to undergo discontinuation procedures.  If possible, the subject 
should remain on study drug until completion of the discontinuation procedures.  The following 
sequence of assessments is recommended: 
• Vital signs: weight, RR, HR, and BP (following at least 5 minutes of seated rest; no other 
measurement or procedure should be performed during the rest period) 
• 12-lead ECG (following at least 5 minutes of seated rest; no other measurement or 
procedure should be performed during the rest period) 
• PE 
• Serum pregnancy test (females of childbearing potential) 
• Blood draws for clinical laboratory assessments and NT-proBNP (NT-proBNP must be 
drawn prior to the 6MWT and the last study drug administration, if possible) 
• 
 
 
 
• PFTs (performed before the 6MWT or after recovery from the 6MWT) 
• Study drug administration 
• Pulse oximetry (measured continuously prior to, during, and following the 6MWT) 
• 6MWT (following at least 10 minutes of seated rest and between 10 to 60 minutes after 
the last study drug administration, if possible) with documentation of supplemental 
oxygen requirement, if applicable 
• Borg dyspnea score (immediately following the 6MWT) 
• Confirm capture of actigraphy, spirometry, and PGA data 
• Assess for AEs 
• Assess for changes in concomitant medications 
• Collect study drug and perform final drug accountability 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 32 
• Collect the Tyvaso Inhalation System, actigraph, spirometry, and smart devices 
• Complete the Discontinuation Form 
The study site should complete a Discontinuation Form at the end of the subject’s participation 
in the study, regardless of the visit type. 
8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
Subjects may voluntarily withdraw from the study at any time, for any reason after completing a 
formal and written withdrawal of consent.  Subject withdrawal of consent would preclude data 
collection after the date the withdrawal of consent was documented. 
The Investigator should make every effort to perform all scheduled evaluations prior to study 
discontinuation. 
A positive pregnancy test or verbal confirmation of pregnancy will result in a subject’s 
withdrawal from the study.  Refer to Section 9.4.2 for information related to the reporting and 
following of pregnancy. 
In the event a subject discontinues study drug prematurely due to an AE, the subject will be 
followed, as instructed in Section 9.3.  The study site should complete a Discontinuation Form at 
the end of the subject’s participation in the study, regardless of the visit type.   
8.2 
CRITERIA FOR STUDY TERMINATION 
The study may be stopped at any time if, in the opinion of the Sponsor, continuation of the study 
represents a serious medical risk to the subjects.  This may include, but is not limited to, the 
presence of serious, life-threatening, or fatal AEs, or AEs that are unacceptable in nature, 
severity, or frequency.  The Sponsor reserves the right to discontinue the study for any reason at 
any time. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 33 
8.3 
CRITERIA FOR SITE DISCONTINUATION 
The study may also be terminated at a given study site if any of the following occur: 
• Principal Investigator elects to discontinue the study 
• Sponsor elects to discontinue the study at the study site 
• Applicable regulations are not observed 
• Protocol is repeatedly violated or critical violations are documented 
• Changes in staff or facilities adversely affect performance of the study 
9 
ADVERSE EVENT REPORTING  
All AEs that occur while a subject is participating in this study will be documented, as outlined 
in Section 9.2. 
9.1 
DEFINITIONS 
9.1.1 
Adverse Event  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment.  An AE can be any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
9.1.2 
Serious Adverse Event  
An SAE is an AE that results in any of the following outcomes: 
• Death 
• Life-threatening event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
In addition, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and require medical/surgical intervention to prevent any of the 
outcomes listed above.   

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 34 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or abuse. 
Life-threatening means that the subject was, 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 
All AEs will be documented from the time of informed consent until study completion or early 
termination.  Any AE occurring during the study must be documented in the subject’s source 
documents and on the appropriate eCRF page.  Information relating to the AE such as onset and 
cessation date and times, intensity, seriousness, relationship to study drug, and outcome is also to 
be documented in the eCRF.  Refer to Appendix 15.3 for guidelines and definitions for recording 
AEs.  Where possible, AEs should be recorded using standard medical terminology.  If several 
signs or symptoms are clearly related to a medically defined diagnosis or syndrome, the 
diagnosis or syndrome should be recorded on the eCRF page, not the individual signs and 
symptoms. 
9.3 
FOLLOW-UP OF ADVERSE EVENTS 
Supplemental measurements and/or evaluations may be necessary to fully investigate the nature 
and/or causality of an AE.  This may include additional laboratory tests, diagnostic procedures, 
or consultation with other healthcare professionals.  Applicable eCRF pages should be updated 
with new or additional information, as appropriate. 
All AEs should be followed until resolution (or return to normal/baseline), until they are judged 
by the Investigator to no longer be clinically significant, or for at least 30 days if the AE is 
ongoing at the final study visit. 
All SAEs should be followed until resolution, death, or the subject is lost to follow-up, even if 
the SAE is ongoing more than 30 days after completion of the final study visit. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 35 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
9.4.1 
Serious Adverse Event Reporting 
Study sites should enter all available initial and follow-up SAE information in the eCRF 
(primary method) within 24 hours of awareness, regardless of causality or expectedness.  The 
SAE information will be directly transmitted from the eCRF into the safety database (Argus) for 
review by Drug Safety.  If the study site is unable to enter the SAE information into the eCRF 
within 24 hours of awareness, the alternative is to email a paper SAE Report Form to 
 or fax it to 
. 
Any information submitted on a paper SAE Report Form must also be entered in the eCRF by 
the study site as soon as possible thereafter.  Any subject source documents related to the SAE 
(eg, hospital discharge summary, treatment records, death certificate, diagnostic test results) 
should be emailed to 
.  All subject identifiers (eg, name, medical record 
number, birth date) must be redacted by the study site before sending to the Sponsor.  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, as per local requirements.  Copies of each notification and 
subsequent documentation of the IEC/IRB/local equivalent body receipt will be kept in the 
Investigator study file. 
9.4.2 
Pregnancy Reporting 
Both female and male subjects must be instructed to contact the Investigator immediately if they 
suspect they or their partner became pregnant while participating in this study.  Any pregnancy 
that occurs during the study must be reported to the Sponsor within 24 hours of awareness via 
email 
 or fax 
 using the Pregnancy Notification and 
Outcome Form.  All pregnancies, including those of a male subject’s female partner, must be 
followed until outcome.  Pregnancy is not an AE.  If there is an abnormal pregnancy outcome, a 
spontaneous abortion, an elective termination for medical reasons, or a congenital anomaly in the 
offspring, the pregnancy outcome becomes an AE. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 36 
9.5 
SAFETY REPORTS 
In accordance with national regulations, the Sponsor will notify the appropriate regulatory 
authority(ies) and all participating Investigators of any AE that is considered possibly 
attributable to study drug and is both serious and unexpected.  The Investigator must report these 
AEs to their IRB or EC in accordance with applicable national regulations and guidelines set 
forth by the IRB or EC. 
10 
STATISTICAL CONSIDERATIONS 
This section briefly describes the planned statistical analyses.  A complete description of the 
methodology will be specified in the Statistical Analysis Plan (SAP), which will be finalized 
prior to clinical database lock. 
Any changes in the statistical methods described in this protocol that occur prior to clinical 
database lock will be documented in the SAP and will not require a protocol amendment. 
10.1 
DATA PROCESSING 
The eCRF is the primary data collection instrument for the study.  All data requested in the eCRF 
must be recorded following the eCRF completion guidelines provided to the study site.  Data will 
be entered in the eCRF for all subjects who sign an ICF up until study completion or 
discontinuation.  Data recorded in the eCRF should be consistent with source documents.  A 
representative from the Sponsor will verify eCRF data fields against source documents per the 
established monitoring plan.  Data transmitted from the study site will be reviewed by the 
Sponsor and data clarification requests may be generated in the eCRF, as appropriate.  The eCRF 
screens are to be reviewed by the Investigator for completeness and accuracy.  The Investigator 
must electronically sign each subject eCRF to signify their approval of the data.  The Investigator 
will be required to re-sign an eCRF if changes are made by the study site after the Investigator 
initially signs the eCRF.  The clinical database will be final when all outstanding queries are 
resolved and all data management quality assurance procedures are complete. 
Additional data resulting from actigraphy, spirometry, and PGA will be transmitted to the 
Sponsor from the respective vendors during the study and at study completion.   

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 37 
These data will be reviewed by the Sponsor accordingly, but will not be recorded in the eCRF.  
These data will be merged into the clinical database after completion of the study. 
10.2 
SAMPLE SIZE 
No formal sample size calculation has been conducted.  Eligible subjects from Study 
RIN-PH-304 may enter this study. 
10.3 
ANALYSIS PLAN 
All safety and efficacy data will be summarized in tables and listings and analyzed for trends 
over time.  No formal hypothesis testing is planned.  The SAP will detail the specific analyses 
and methods. 
10.3.1 
Safety Analyses 
The Safety Population will be defined as all subjects in the study that receive inhaled treprostinil 
at any time during the course of the study.  Safety analyses will be performed on the Safety 
Population.  Treatment-emergent AEs and changes in PEs, vital signs, ECGs, clinical laboratory 
assessments, PFTs, at-home spirometry, and oxygenation will be the primary assessments of 
safety.  All reported AEs will be assigned Preferred Terms per the Medical Dictionary for 
Regulatory Activities. 
10.3.2 
Efficacy Analyses 
The effect of inhaled treprostinil will be evaluated on changes from baseline in NT-proBNP, 6-
Minute Walk Distance, Borg dyspnea score, PGA, and physical activity (actigraphy). 
10.3.3 
Exploratory Analyses 
 
 
10.4 
INTERIM ANALYSIS 
Interim analyses for safety data will be performed as needed by the Sponsor for regulatory 
submissions and other purposes.  Given the open-label nature of the study, the Sponsor may 
tabulate study data and present or publish such data during the course of the study. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 38 
10.5 
OTHER ANALYSES 
Other analyses may be conducted based on available study data.  Details of any other planned 
statistical analyses will be specified in the SAP. 
10.6 
DATA LISTINGS AND SUMMARIES 
All scientifically relevant data gathered in this study will be presented in summary tables and 
listings in the clinical study report. 
11 
PACKAGING AND FORMULATION 
11.1 
STUDY SUPPLIES 
11.1.1 
Actigraphy, Spirometry, and Smart Devices 
Subjects will receive a new actigraph at enrollment and continue to use their Sponsor-provided 
spirometry and smart devices from Study RIN-PH-304. 
If a device is defective or suspected to be defective and the issue cannot be resolved via 
troubleshooting, the study site should complete a THREAD Help Desk Ticket.  A replacement 
device will be issued to the subject.  Replacement devices will be provided using standard 
packaging labeled with the study number and accompanied by the Instructions for Use. 
11.2 
CONTENTS 
11.2.1 
Study Drug 
The Sponsor will supply study drug (treprostinil inhalation solution, 0.6 mg/mL) as clear liquid 
packaged in 2.9-mL ampoules.  Each ampoule will provide for a single day of treatment across 
the QID dosing.  The ampoules will be packaged in groups of 4 and sealed in aluminum foil 
pouches that are placed inside a carton (containing 12 pouches per carton).  Subjects will be 
supplied enough cartons to cover the QID dosing between study visits.   
If study drug is believed to be suspect by study site staff or a subject, the study site should 
complete a Product Complaint Form (provided in the Study Procedures Manual), submit it to the 
Sponsor within 24 hours of awareness, and follow any additional instructions provided by the 
Sponsor. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 39 
11.2.2 
Study Inhalation Device 
Treprostinil for inhalation solution (0.6 mg/mL) is delivered via the Tyvaso Inhalation System.  
Subjects will be provided a Tyvaso Inhalation System by the Sponsor. 
If a device is defective or suspected to be defective and the issue cannot be resolved via 
troubleshooting, the study site should complete a Product Complaint Form (provided in the 
Study Procedures Manual), submit it to the Sponsor within 24 hours of awareness, and follow 
any additional instructions provided by the Sponsor.  Damaged devices will be replaced as 
needed during the study. 
11.3 
LABELING 
11.3.1 
Study Drug 
The aluminum foil pouches (containing the ampoules) and the outer carton will be labeled with 
the same information.  At a minimum, the outer packaging (pouch and carton) will be labeled to 
clearly disclose the product name, study number, kit identification number, expiration date, 
Sponsor’s name and address, Instructions for Use, and storage information (subject to regulatory 
requirements in each study region or country).   
11.3.2 
Study Inhalation Device 
The Tyvaso Inhalation System and device accessories will be supplied using standard packaging 
and labeled with the study number. 
11.4 
STORAGE AND HANDLING OF STUDY DRUG 
All study drug must be stored at room temperature 77°F (~25°C) with excursions permitted to 
59°F to 86°F (15°C to 30°C).  Study drug should not be frozen, refrigerated, or exposed to heat.  
The ampoules must be kept in the foil pouch to protect from light.  Subjects should be instructed 
that once a foil pouch is opened, the study drug ampoules inside should be used within 7 days.  
Refer to the study drug label for information on use and storage of the product. 
Study drug must be stored in a securely locked cabinet or enclosure with appropriate temperature 
monitoring.  Access should be strictly limited to the Investigators and their designees.  
Investigators and designees may not provide study drug to any individual not participating in this 
study. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 40 
11.5 
SUPPLY AND RETURN OF STUDY DRUG AND DEVICES 
Study sites will be supplied with a sufficient quantity of study drug to begin enrollment in the 
study.  At each study visit, all study drug previously dispensed to a subject should be returned to 
the study site, including all used and unused ampoules. 
To accommodate Sponsor-approved telemedicine visits, study drug and device accessories may 
be shipped directly to the subject. 
Subjects should return all Sponsor-provided devices and any remaining study drug to the study 
site at the end of their study participation (withdrawal, discontinuation, termination, or 
completion). 
In the event of Sponsor-approved telemedicine visits, the Sponsor-provided devices and study 
drug may be returned to the study site via mail. 
11.6 
DRUG AND DEVICE ACCOUNTABILITY 
The Investigator is responsible for study drug and device accountability and reconciliation 
overall and on a per subject basis.  Accountability records are to be maintained throughout the 
study and these records include, but are not limited to, the amount of study drug and devices 
received from the Sponsor, the amount dispensed to each subject, and the amount returned to the 
study site from the subject. 
At each study visit, study site staff will: 
• Collect and document all used/unused study drug and any devices/device accessories 
dispensed and returned. 
• Assess study drug compliance per the dosing instructions given at the previous study 
visit. 
• Re-educate the subject about the importance of compliance with the prescribed dosing 
regimen and device-related assessments (if compliance is low). 
In the event of Sponsor-approved telemedicine visits, the subject may return the 
Sponsor-provided devices and study drug to the study site via mail. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 41 
Once the Sponsor confirms drug accountability for a completed subject, the study site may 
destroy the used/unused study drug locally (with a destruction certification placed in the 
subject’s file) or ship it to a Sponsor-designated location for destruction.  Refer to the Study 
Procedures Manual regarding the return of Sponsor-provided devices for a completed subject. 
12 
REGULATORY AND ETHICAL OBLIGATIONS 
12.1 
US FDA OR APPLICABLE REGULATORY REQUIREMENTS 
The study will be conducted in accordance with ICH and GCP guidelines and all applicable 
national regulations.  The Sponsor will obtain the required approval from each national 
regulatory authority to conduct the study.  During the conduct of the study, an annual safety 
report will be compiled by the Sponsor for submission to regulatory authorities and any IRB/IEC 
that requires it.  Any additional national reporting requirements as specified by the applicable 
regulations, regulatory authorities, or IRB/IEC will also be fulfilled during the conduct of the 
study. 
12.2 
INFORMED CONSENT REQUIREMENTS 
Before a subject is enrolled in the study, the Investigator or their designee(s) must explain the 
purpose and nature of the study, including potential benefits and risks, and all study procedures 
to the subject.  The subject must sign and date an IRB/IEC-approved ICF prior to the conduct of 
any study-related activities.  A copy of the signed consent form will be given to the subject and 
the original will be retained in the study site’s records. 
The subject should also be informed that if they wish to withdraw from the study any time, a 
written withdrawal of consent will be required. 
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
Prior to study initiation at each study 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 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 or 
designee for review before submission to the IRB/IEC prior to the start of the study. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 42 
If, during the study, it is necessary to amend either the protocol or the ICF, the Investigator is 
responsible for obtaining IRB/IEC approval of these amended documents prior to 
implementation.  Copies of the IRB/IEC correspondence and approval letters must be sent to the 
Sponsor or designee.   
During the conduct of the study, an annual progress report will be compiled by the Sponsor for 
submission to those IRBs/IECs that require it. 
A written summary of the study will be provided by the Investigator to the IRB/IEC following 
study completion or termination according to the IRB/IEC standard procedures.  Additional 
updates will be provided in accordance with the IRB/IEC’s standard procedures. 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the study, the following documents will be provided to the study 
site: Investigator’s Brochure, protocol, ICF, budget agreement, and eCRF. 
Study sites will be required to provide the following documents to United Therapeutics 
Corporation’s designee (Lung Biotechnology PBC): signature page of the protocol, Form FDA 
1572, Financial Disclosure Form, IRB/IEC composition and roster, IRB/IEC protocol and ICF 
approval letters, and Curriculum Vitae of the study staff listed on Form FDA 1572. 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep subject medical information confidential.  United Therapeutics 
Corporation, Lung Biotechnology PBC, the FDA, other regulatory bodies, and the IRB/IEC 
governing this study may inspect the medical records of any subject involved in this study.  The 
Investigator may release subject medical records to employees or agents of the Sponsor, the 
IRB/IEC, the FDA, or appropriate local regulatory agencies for purposes of checking the 
accuracy of the data.  A number will be assigned to all subjects, but no published information 
will identify any subject’s name or any other personal information, such as medical record 
number, national identification number, etc. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 43 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially adversely affect the safety of participating subjects 
or that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, duration of therapy, assessment variables, the number of subjects treated, or 
subject selection criteria may be made only after consultation between United Therapeutics 
Corporation’s designee, Lung Biotechnology PBC, and the Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory 
authorities and IRB/IEC prior to implementation. 
A report documenting study termination must also be submitted to and acknowledged by the 
appropriate IRB/IEC for each study site. 
At the end of the study, where applicable, a final report will be provided to the local regulatory 
agencies. 
13.2 
STUDY DOCUMENTATION AND STORAGE 
In accordance with federal/national regulations, the ICH, and GCP guidelines, the Investigator 
must retain study records for at least 2 years after the last approval of a marketing application in 
an ICH region, and until there are no pending or contemplated marketing applications in an ICH 
region, or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. 
The Investigator must notify United Therapeutics Corporation or its designee, Lung 
Biotechnology PBC, before any disposal or change in location of study records. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
In accordance with federal/national regulations, the ICH, and GCP guidelines, Monitors for 
United Therapeutics Corporation or its designee, Lung Biotechnology PBC, will periodically 
contact the study site and conduct onsite or remote monitoring visits.   

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 44 
During these visits, the Monitor will, at a minimum, confirm ethical treatment of subjects, assess 
study progress, review data collected, conduct source document verification, periodically verify 
drug accountability, and identify any issues requiring resolution. 
The Investigator agrees to allow the Monitor direct access to all relevant documents and to 
allocate their time and their staff to the Monitor to discuss any findings or relevant issues. 
13.4 
QUALITY ASSURANCE 
The Sponsor is responsible for ensuring that the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, GCP guidelines, and applicable 
regulatory requirements.   
The Sponsor or a contracted representative of the Sponsor may conduct a quality assurance audit 
of this study.  If such an audit occurs, the Investigator agrees to allow the Auditor direct access to 
all relevant study documents and source data and to allocate time to discuss findings and any 
relevant issues.  In addition, this study is subject to an audit by the relevant Regulatory 
Authorities.  If such a regulatory inspection occurs, the Investigator agrees to allow the Inspector 
direct access to all relevant study documents and source data. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 45 
14 
REFERENCES 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories.  ATS 
statement: Guidelines for the Six-Minute Walk Test.  Am J Respir Crit Care Med.  
2002;166(1):111-117. 
Fijalkowska A, Kurzyna M, Torbicki A, et al.  Serum N-terminal brain natriuretic peptide as a 
prognostic parameter in patients with pulmonary hypertension.  Chest.  2006;129(5):1313-1321. 
Holland AE, Spruit MA, Troosters T, et al.  An official European Respiratory Society/American 
Thoracic Society technical standard: field walking tests in chronic respiratory disease.  Eur 
Respir J.  2014;44(6):1428-1446. 
Klinger JR.  Group III Pulmonary Hypertension: pulmonary hypertension associated with lung 
disease: epidemiology, pathophysiology and treatments.  Cardiol Clin.  2016;34(3):413-433. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 46 
15 
APPENDICES 
15.1 
PROCEDURE FOR 6-MINUTE WALK TEST 
General Procedures 
The 6MWT should be administered consistently at each study site throughout the study.  The 
administration of the test and specifications of the testing area should be generally consistent 
with the American Thoracic Society guidelines and the usual practice of the study site.  Subjects 
receiving supplemental oxygen during their baseline 6MWT must continue to receive the same 
flow rate at all subsequent 6MWT assessments.  Similarly, if the baseline assessment was 
conducted without oxygen therapy, then subsequent assessments should also be conducted 
without oxygen therapy.  Before each 6MWT, the subject should rest (seated) for at least 10 
minutes. 
The area used for the 6MWT should be premeasured at approximately 30 meters in length (but 
no shorter than 15 meters [16 yards or 50 feet] in length) and at least 2 to 3 meters in width.  
There must be no turns or significant curves to the 6MWT area.  The length should be marked 
with gradations to ensure the accurate measurement of the distance walked.  The area should be 
well ventilated.  The tester may be at the starting end of the corridor or at the midpoint of the 
corridor with a stopwatch.  Intermittent rest periods are allowed if the subject can no longer 
continue.  If the subject needs to rest briefly, they may stand or sit and then begin again when 
they are sufficiently rested, but the clock will continue to run.  At the end of 6 minutes, the tester 
will call out, “stop where you are” while simultaneously stopping the watch, and then measuring 
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.   

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 47 
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 at the end (eg, chair), 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 again.  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 let you know when the 6 minutes are up.  When I say STOP, please stand 
right where you are.” 
After these instructions are given to the subject, the person administering the test will then 
ask: 
“Do you have any questions about the test?” 
The person administering the test will then start the test by saying the following to the 
subject: 
“Are you ready?” 
“Start when I say “GO.” 
The person administering the test will tell the subject the time at each minute by saying: 
“You have 5 minutes to go.” 
“You have 4 minutes to go.” 
“You have 3 minutes to go.” 
“You have 2 minutes to go.” 
“You have 1 minute to go.” 
At 6 minutes, the person administering the test will tell the subject: “Stop where you are.” 
No other instruction or encouragement will be given during the test.  Eye contact with the subject 
should be avoided during the test. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 48 
15.2 
MODIFIED BORG DYSPNEA SCALE 
Immediately following the 6MWT, the person administering the test will obtain a rating of 
dyspnea using the Borg dyspnea scale.   
The person will use the following dialogue:  
“I would like to use the following scale to indicate the maximal shortness of breath you had 
during the walk test (indicate the Borg dyspnea scale).  If there was no shortness of breath at all 
you would point to 0; if the shortness of breath was not very great you would choose from 0.5 to 
2; if you were somewhat more short of breath you would select 3; and if the breathing was 
getting very difficult, you would choose 4 to 9, depending on just how hard it was; 10 represents 
the greatest shortness of breath you have ever experienced in your life.  If one of the numbers 
does not exactly represent how short of breath you are, then you can choose a fraction between.  
For example, if you had shortness of breath somewhere between 4 and 5, you could choose 4.5.”  
Perceived Breathlessness (Borg Dyspnea Scale)  
0 NOTHING AT ALL  
0.5 VERY VERY SLIGHT (just noticeable)  
1 VERY SLIGHT  
2 SLIGHT  
3 MODERATE  
4 SOMEWHAT SEVERE  
5 SEVERE  
6  
7 VERY SEVERE  
8  
9 VERY VERY SEVERE (almost maximum)  
10 MAXIMUM 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 49 
15.3 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Investigator or a designated member of their staff will probe each subject for any AEs that 
may have occurred.  The Investigator should always ask the same question when conducting the 
verbal probe in order to ensure uniformity between subjects.   
The Investigator should ask: 
 
“How are you doing (feeling)?” 
Based on the subject’s response to this question, the Investigator should ask additional questions 
relevant to the specific complaint such as: 
 
“How severe is/was the symptom?” 
 
“How often did the symptom occur?” 
 
“How long did the symptom last?” 
It is the Investigator’s responsibility to review the results of all diagnostic and laboratory tests as 
they become available and ascertain if there is a clinically significant change from baseline.  If 
the results are determined to be a clinically significant change from baseline, this should be 
reported as an AE.  The Investigator may repeat the diagnostic procedure or laboratory test or 
request additional tests to verify the results of the original tests.  When possible, a diagnosis 
associated with the abnormality should be used as the reported AE. 
Using provided definitions, the Investigator will then: 
1. Rate the intensity and seriousness of the AE 
2. Estimate the causality of the AE to study drug 
3. Note actions taken to counteract the AE 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 50 
Definitions of Intensity, Seriousness, Causality, Action Taken, and Outcome 
INTENSITY 
An assessment of the relative intensity (severity) of an AE is based on the Investigator’s clinical 
judgment.  The maximum intensity encountered during the evaluation period should be checked.  
The assessment of intensity should be independent of the assessment of the seriousness of the 
AE. 
• Mild: Discomfort noticed, but no disruption to daily activity 
• Moderate: Discomfort sufficient to disrupt normal daily activity 
• Severe: Inability to work or perform normal daily activity 
SERIOUSNESS 
An SAE is an AE that results in any of the following outcomes:  
• Death 
• Life-threatening event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
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, 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 and not associated with any 
deterioration in condition (eg, hospitalization for a routine right heart catheterization). 
• Treatment that was elective or pre-planned for a pre-existing condition and not associated 
with any deterioration in condition (eg, pre-planned operation that does not lead to further 
complications). 
• 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. 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 51 
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: 
• 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 - 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 on reintroduction of study drug 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 52 
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 study drug was stopped temporarily 
• Drug Withdrawn: Administration of study drug was stopped permanently 
• Unknown: Changes to the administration of the study drug cannot be determined 
• Not Applicable: Only used if the AE started and resolved prior to study drug dosing, or 
for an AE that started after permanent discontinuation of study treatment 
NOTE: Only the last study drug action should be recorded in the eCRF.  For example, if the 
study drug is withdrawn and then the decision is made to restart, the dose modification of “Drug 
Interrupted” should be reported on the SAE form. 
OUTCOME 
• Fatal: The study subject died 
• Not Recovered/Not Resolved: The AE was ongoing at the time of death or at the time the 
subject was lost to follow up 
• Recovered/Resolved: The AE resolved 
• Recovered/Resolved with Sequelae: The AE is considered resolved however there is 
residual sequelae.  Some events do not return to baseline, such as metastasis or 
progression of disease; however, once these events are determined by the Investigator to 
be stable or chronic, the Investigator may consider the event to be resolved or resolved 
with sequelae. 
• Recovering/Resolving: The AE is improving but is not yet completely recovered/resolved 
• Unknown: The outcome of the AE cannot be determined 

United Therapeutics Corp.  
RIN-PH-305 Protocol Amendment 2 
Lung Biotechnology PBC 
Inhaled Treprostinil 
Version Date 29 January 2021 
CONFIDENTIAL 
Page 53 
15.4 
PATIENT GLOBAL ASSESSMENT (EXAMPLE) 
Question 1: “Over the past week, on average, how many times has fatigue limited your physical 
ability to do what you wanted?” 
• Always 
• Often 
• Sometimes 
• Rarely 
• Never 
Question 2: “Over the past week, on average, how many times has shortness of breath limited 
your physical ability to do what you wanted?” 
• Always 
• Often 
• Sometimes 
• Rarely 
• Never 

Signature Page for RIN-PH-305 Protocol Amendment 2 v1.0
Approver Task
28-Jan-2021 16:28:49 GMT+0000
Approver Task
28-Jan-2021 17:05:43 GMT+0000
Approver Task
29-Jan-2021 19:28:02 GMT+0000
Approver Task
29-Jan-2021 20:10:10 GMT+0000
Approver Task
30-Jan-2021 02:53:19 GMT+0000