A Safety Study of Intravenous Infusion of Bone Marrow Mesenchymal Stem Cell-derived Extracellular Vesicles (UNEX-42) in Preterm Neonates at High Risk for Bronchopulmonary Dysplasia
Phase: PHASE1
Conditions: Bronchopulmonary Dysplasia
Sponsor: United Therapeutics

United Therapeutics Corp. 
UNX-BP-101 Protocol Amendment 2 
 
UNEX-42 
CONFIDENTIAL AND PROPRIETARY, UNITED THERAPEUTICS CORPORATION 
All content contained herein is confidential and proprietary information of United Therapeutics 
Corporation and shall not be disclosed in whole or in part except as permitted by a signed contract with 
United Therapeutics Corporation. 
© 2020 United Therapeutics Corporation 
 
Page 1 
 
 
 
 
A Safety Study of Intravenous Infusion of Bone Marrow Mesenchymal Stem 
Cell-derived Extracellular Vesicles (UNEX-42) in Preterm Neonates at High 
Risk for Bronchopulmonary Dysplasia 
Protocol UNX-BP-101 
IND# 18,532 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
26 September 2018 
Amendment 1: 
18 December 2018 
Amendment 2: 
19 February 2020 
 
 
 
 

United Therapeutics Corp. 
UNX-BP-101 Protocol Amendment 2 
 
UNEX-42 
19 February 2020 
Confidential 
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LIST OF CONTACTS FOR STUDY 
Study Sponsor 
United Therapeutics Corporation 
55 TW Alexander Drive  
Research Triangle Park, NC 27709 
 
 
 
Senior Medical Director, Medical Monitoring  
 
 
 
 
SAE Reporting 
United Therapeutics Global Drug Safety 
 
 
 

United Therapeutics Corp. 
UNX-BP-101 Protocol Amendment 2 
 
UNEX-42 
19 February 2020 
Confidential 
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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “A Safety Study of Intravenous Infusion of Bone 
Marrow Mesenchymal Stem Cell-derived Extracellular Vesicles (UNEX-42) in Preterm 
Neonates at High Risk for Bronchopulmonary Dysplasia,” Amendment 2 dated 
19 February 2020 and agree to abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation Guideline for Good Clinical 
Practice and applicable Food and Drug Administration regulations/guidelines set forth in 21 
Code of Federal Regulations Parts 50, 54, 56, and 312 and any local regulations per country. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of United Therapeutics Corporation. 
I also have read the current Clinical Investigator’s Brochure for UNEX-42 and acknowledge that 
review of the information contained in the Clinical Investigator’s Brochure is a requirement for 
Investigators before using UNEX-42 in a clinical study. 
This protocol has been received for information only and must not be implemented before all 
necessary regulatory agency and Ethics Committee/Institutional Review Board approval 
documents have been obtained. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 

United Therapeutics Corp. 
UNX-BP-101 Protocol Amendment 2 
 
UNEX-42 
19 February 2020 
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PROTOCOL SYNOPSIS 
Title 
A Safety Study of Intravenous Infusion of Bone Marrow Mesenchymal 
Stem Cell-derived Extracellular Vesicles (UNEX-42) in Preterm 
Neonates at High Risk for Bronchopulmonary Dysplasia 
Study Phase 
Phase 1 
Indication 
Bronchopulmonary dysplasia (BPD) prevention in preterm infants 
Primary Objective 
To assess the safety and tolerability of intravenous (IV) infusion of 
UNEX-42 in infants born at <27 weeks of gestational age (GA) and 
exhibiting respiratory distress. 
Secondary Objective(s) 
To assess the effect of UNEX-42 on the following: 
 
Incidence and severity (mild, moderate, severe) of BPD or death at 
36 weeks postmenstrual age (PMA) 
 
Short-term outcomes including oxygen and ventilation exposure in 
the first 28 days after treatment. 
 
Long-term outcomes up to 1 year (corrected age). 
Study Design 
A multicenter, placebo-controlled, randomized, dose escalation, safety, 
and tolerability study of UNEX-42 in infants born at <27 weeks of GA at 
high risk for BPD 
Sample Size 
Target enrollment of 18 total subjects, with 3 cohorts of 6 subjects per 
cohort, randomly allocated 2:1 (active:placebo) 
Summary of Subject 
Eligibility Criteria 
A subject must meet the following criteria to be eligible for the study: 
 
Infant whose postnatal age is 3 to 14 days at randomization and meets 
the following criteria based on GA: 
 
23 weeks to 24 weeks 6 days: any birth weight, any oxygen 
requirement 
 
25 weeks to 26 weeks 6 days: fraction of inspired oxygen (FiO2) 
≥35% (sustained >2 hours) at any point during postnatal Days 1 
to 14 AND birth weight ≤750 g 
 
Endotracheally intubated and receiving mechanical ventilation 
 
Not expected to be extubated within the next 24 hours after 
randomization 
 
The subject has a parent/guardian who gives written informed 
consent. 
Drug Dosage  
and Formulation 
UNEX-42 is a preparation of extracellular vesicles that are secreted from 
human bone marrow-derived mesenchymal stem cells suspended in 
phosphate-buffered saline.  UNEX-42 is a clear liquid that is provided in 
appropriately sized vials and stored at -70±10°C prior to use. 
UNEX-42 will be administered via IV infusion.  Three dose cohorts will 
be evaluated: 
 
Cohort 1: 1 administration of 20 pmol phospholipid/kg body weight 
 
Cohort 2: 1 administration of 60 pmol phospholipid/kg body weight 
 
Cohort 3: 1 administration of 200 pmol phospholipid/kg body weight 
Control Group 
Placebo (phosphate-buffered saline) 
Route of  
Administration 
IV infusion (via umbilical/central/peripheral IV line) 

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Procedures 
Subjects will be assessed during Screening and Baseline (prior to 
randomization) to determine eligibility for the study.  After 
randomization, subjects will be monitored in the hospital through 
40 Weeks PMA or the time of hospital discharge (whichever comes first). 
 
The following efficacy and safety assessments will occur during the 
course of the study: 
 
Efficacy Assessments: incidence and severity of BPD, duration of 
hospitalization, duration of mechanical ventilation, duration of 
supplemental oxygen therapy, duration of postnatal steroids, tracheal 
aspirate, and Respiratory Severity Score. 
 
Safety Assessments: physical examination, vital signs, adverse events, 
predefined complications of prematurity, clinical laboratory parameters, 
and chest x-ray. 
 
Enrollment between cohorts will pause for data review by a Data 
Monitoring Committee to evaluate the data available after each of the first 
2 cohorts have been enrolled.  Dose administration for Cohort 1 will 
occur such that there is an observational period of 3 days between dosing 
the first, second, and third subject to assure the opportunity for safety 
assessments in at least 1 subject on active treatment.  This procedure will 
be followed for each cohort. 
Subjects that complete the Post-treatment Phase (including those that are 
discharged from hospital prior to 40 Weeks PMA) will continue into the 
Long-term Outcome Phase and will be assessed through 1 year of 
corrected age. 
Statistical Considerations No formal sample size calculations were performed.  Categorical 
assessments (eg, adverse events, death, incidence and severity of BPD) 
will be summarized with frequencies (number and percentage) by dose 
cohort and placebo.  Descriptive statistics (eg, mean, standard deviation, 
median, interquartile range) will be calculated to summarize continuous 
assessments (eg, vital signs, duration of hospitalization, clinical 
laboratory parameters) by dose cohort and placebo.  Kaplan-Meier curves 
will be constructed for time to event variables (eg, time to discharge from 
the hospital). 
Sponsor 
United Therapeutics Corporation 
55 TW Alexander Drive  
Research Triangle Park, NC 27709 

United Therapeutics Corp. 
UNX-BP-101 Protocol Amendment 2 
 
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19 February 2020 
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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY .....................................................................................2 
INVESTIGATOR’S AGREEMENT ......................................................................................3 
PROTOCOL SYNOPSIS ........................................................................................................4 
TABLE OF CONTENTS ........................................................................................................6 
Table of In-Text Tables ...........................................................................................................8 
Table of In-Text Figures ..........................................................................................................8 
LIST OF ABBREVIATIONS .................................................................................................9 
1 BACKGROUND AND RATIONALE ...........................................................................10 
1.1 
DEFINITION OF CLINICAL PROBLEM ..............................................................10 
1.2 
UNEX-42 BACKGROUND ........................................................................................11 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION .............................................................................................12 
1.4 
CLINICAL HYPOTHESIS ........................................................................................13 
2 OBJECTIVES ..................................................................................................................13 
2.1 
PRIMARY OBJECTIVES .........................................................................................13 
2.2 
SECONDARY OBJECTIVES ...................................................................................13 
3 EXPERIMENTAL PLAN ...............................................................................................13 
3.1 
STUDY DESIGN .........................................................................................................13 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS .............................................15 
3.3 
CLINICAL ASSESSMENTS .....................................................................................18 
3.3.1 
Efficacy ....................................................................................................................18 
3.3.1.1 
Incidence and Severity of Bronchopulmonary Dysplasia ...............................18 
3.3.1.2 
Duration of Hospitalization ...............................................................................18 
3.3.1.3 
Duration of Mechanical Ventilation..................................................................18 
3.3.1.4 
Duration of Supplemental Oxygen Therapy ....................................................18 
3.3.1.5 
Respiratory Severity Score ................................................................................19 
3.3.1.6 
Duration of Postnatal Steroids ..........................................................................19 
3.3.1.7 
Tracheal Aspirate Inflammatory Biomarkers .................................................19 
3.3.2 
Safety .......................................................................................................................19 
3.3.2.1 
Medical History, Maternal History, and Demographics .................................19 
3.3.2.2 
Physical Examination/Chest X-ray ...................................................................20 
3.3.2.3 
Vital Signs ............................................................................................................20 
3.3.2.4 
Adverse Events ....................................................................................................20 
3.3.2.5 
Predefined Complications of Prematurity ........................................................21 
3.3.2.6 
Clinical Laboratory Parameters .......................................................................21 
3.4 
NUMBER OF CENTERS ..........................................................................................22 
3.5 
NUMBER OF SUBJECTS .........................................................................................22 
3.6 
ESTIMATED STUDY DURATION .........................................................................22 
4 SUBJECT ELIGIBILITY ...............................................................................................22 

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4.1 
INCLUSION CRITERIA ...........................................................................................23 
4.2 
EXCLUSION CRITERIA ..........................................................................................23 
4.3 
PRESCRIBED THERAPY ........................................................................................24 
4.3.1 
Concomitant Medications ......................................................................................24 
5 SUBJECT ENROLLMENT ............................................................................................24 
5.1 
TREATMENT ASSIGNMENT .................................................................................24 
5.2 
RANDOMIZATION ...................................................................................................24 
5.3 
BLINDING ..................................................................................................................24 
6 TREATMENT PROCEDURES .....................................................................................24 
6.1 
UNEX-42 DOSAGE AND ADMINISTRATION .....................................................24 
6.2 
SELECTION OF DOSES FOR SUBJECT COHORTS .........................................25 
6.3 
DOSE-LIMITING TOXICITY .................................................................................26 
6.4 
ACCESS TO BLINDED TREATMENT ASSIGNMENT ......................................26 
6.5 
COMPLIANCE ...........................................................................................................27 
7 EXPERIMENTAL PROCEDURES ..............................................................................27 
7.1 
SCREENING ...............................................................................................................27 
7.2 
BASELINE ..................................................................................................................27 
7.3 
POST-TREATMENT PHASE ...................................................................................28 
7.4 
40 WEEKS PMA/HOSPITAL DISCHARGE ..........................................................28 
7.5 
LONG-TERM OUTCOME PHASE .........................................................................28 
8 STUDY TERMINATION ...............................................................................................29 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ........................................................29 
8.2 
CRITERIA FOR TERMINATING THE STUDY ...................................................29 
8.3 
CRITERIA FOR DISCONTINUING THE SITE ....................................................30 
9 ADVERSE EVENT REPORTING ................................................................................30 
9.1 
DEFINITIONS ............................................................................................................30 
9.1.1 
Adverse Event .........................................................................................................30 
9.1.2 
Serious Adverse Event ...........................................................................................31 
9.1.3 
Serious Adverse Reaction ......................................................................................32 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ......................................................32 
9.3 
FOLLOW-UP OF ADVERSE EVENTS ..................................................................32 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ........................32 
9.5 
SAFETY REPORTS ...................................................................................................33 
10 STATISTICAL CONSIDERATIONS ...........................................................................33 
10.1 DATA PROCESSING ................................................................................................33 
10.2 SAMPLE SIZE ............................................................................................................34 
10.3 ANALYSIS PLAN .......................................................................................................34 
10.3.1 
Primary Endpoints .................................................................................................35 
10.3.2 
Secondary Endpoints .............................................................................................35 
10.4 INTERIM ANALYSIS ...............................................................................................36 

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10.5 OTHER ANALYSES ..................................................................................................36 
10.6 DATA LISTINGS AND SUMMARIES ....................................................................37 
10.7 DATA MONITORING COMMITTEE ....................................................................37 
11 PACKAGING AND FORMULATION .........................................................................37 
11.1 CONTENTS OF STUDY DRUG ...............................................................................37 
11.2 LABELING ..................................................................................................................38 
11.3 STORAGE AND HANDLING OF CSM ..................................................................38 
11.4 SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL ..........................38 
11.5 DRUG ACCOUNTABILITY .....................................................................................38 
12 REGULATORY AND ETHICAL OBLIGATION.......................................................38 
12.1 UNITED STATES FDA OR APPLICABLE REGULATORY 
REQUIREMENTS ......................................................................................................38 
12.2 INFORMED CONSENT REQUIREMENTS ..........................................................39 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ........................................................................................................................39 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS .........................................39 
12.5 SUBJECT CONFIDENTIALITY..............................................................................40 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................40 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION ...........................40 
13.2 STUDY DOCUMENTATION AND STORAGE .....................................................41 
13.3 STUDY MONITORING AND DATA COLLECTION ..........................................41 
14 REFERENCES .................................................................................................................42 
15 APPENDICES ..................................................................................................................44 
15.1 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 44 
 
Table of In-Text Tables 
Table 3-1 
Schedule of Times and Events – Post-treatment Phase ...................................15 
Table 3-2 
Schedule of Times and Events – Long-term Outcome Phase ..........................17 
Table 3-3 
Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria for 
Gestational Age at Birth <32 Weeks ...............................................................18 
Table 3-4 
Maternal History Parameters ...........................................................................20 
Table 3-5 
Clinical Laboratory Parameters .......................................................................22 
 
Table of In-Text Figures 
Figure 3-1 
Schematic of Study Design for an Individual Subject .....................................14 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
BPD 
Bronchopulmonary dysplasia 
CSM 
Clinical study material 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXR 
Chest x-ray 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration  
FiO2 
Fraction of inspired oxygen  
GA 
Gestational age 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSC 
Mesenchymal stem cell 
NCI 
National Cancer Institute 
PDA 
Patent ductus arteriosus 
PMA 
Postmenstrual age 
RDS 
Respiratory distress syndrome 
RSS 
Respiratory Severity Score 
SAE 
Serious adverse event  
SAR 
Serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
 

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1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
Respiratory distress syndrome (RDS) is the failure to develop functional residual capacity and 
the propensity of affected lungs to become atelectatic.  Preterm infants born prior to 28 weeks of 
gestational age (GA), and of very low birthweight, are at an increased risk for developing RDS 
(Torchin 2016).  Surfactant production is low in these infants, and as such, lung recruitment and 
compliance are compromised.  As a result, the atelectatic alveoli are well perfused but poorly 
ventilated, resulting in hypoxia.  The clinical manifestations of RDS appear within minutes of 
birth and are recognized by respiratory distress associated with cyanosis often requiring 
respiratory support and/or resuscitation.  Symptoms of RDS include low blood oxygen, low 
blood pH, apnea/tachypnea, atelectasis, and “ground glass” appearance of the lungs on chest x-
ray (CXR).  These infants are typically treated with supplemental oxygen and continuous 
positive airway pressure to reduce or reverse the hypoxia and acidosis.  If needed, infants are 
intubated, given surfactant, and mechanical ventilation is employed.  While these interventional 
strategies improve lung compliance and increase blood oxygen level, mechanical ventilation and 
supplemental oxygen can inadvertently cause additional lung tissue damage (Jobe 2001). 
RDS in preterm infants, if unresolved, is likely to result in bronchopulmonary dysplasia (BPD).  
BPD is characterized by an inflammatory process causing abnormal lung development and 
decreased vascular and alveolar development (Collins 2017).  Improvements in neonatal care has 
led to better survival rates of premature infants, yet the cost of this improved survival is an 
increased risk of developing BPD.  While the definition has changed with improvements in 
assisted ventilation resulting in less barotrauma and oxidative injury, BPD (formerly known as 
chronic lung disease of prematurity) is currently defined as those infants requiring supplemental 
oxygen therapy for at least 28 days after birth.  Furthermore, the severity of BPD for infants born 
at less than 32 weeks of gestation is determined by the level of supplemental oxygen required to 
maintain adequate blood gas oxygen levels at 36 weeks corrected GA.  Infants requiring greater 
than 30% oxygen supplementation and/or continuous positive airway pressure are classified as 
severe, those requiring less than 30% oxygen are classified as moderate, and those not requiring 
oxygen supplementation are classified as mild (Jobe 2001). 

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BPD is associated with increased rates of mortality, pulmonary hypertension, emphysema, and 
neurodevelopmental abnormalities.  Currently employed prevention strategies include the use of 
antenatal glucocorticoids, treatment of RDS with surfactant, and supportive treatments such as 
gentler, noninvasive ventilatory modalities and fluid restriction.  Additional therapeutic 
approaches have been evaluated for preventing BPD including postnatal corticosteroids, late 
surfactant administration, inhaled nitric oxide, and anti-inflammatory agents such as 
docosahexaenoic acid.  However, many of these treatments have been shown to be either 
relatively ineffective (Collins 2017; Ballard 2014; Donohue 2011) or controversial (Watterberg 
2010).  An effective therapy to prevent the development of BPD is an unmet medical need. 
1.2 
UNEX-42 BACKGROUND 
UNEX-42 is a preparation of extracellular vesicles that are secreted from primary, 
nonimmortalized human bone marrow-derived mesenchymal stem cells (MSCs).  UNEX-42 
contains key molecular components (eg, ribonucleic acid, protein, phospholipids) that drive 
biological responses in target cells, which regulate immune modulation, angiogenesis, cellular 
salvage, and cellular metabolism.  Activity of UNEX-42 in animal models of BPD, as well as 
evidence from in vitro analyses, support the continued investigation of UNEX-42 as a potential 
therapeutic intervention for BPD in neonates. 
MSC-derived extracellular vesicles are wholly sufficient in driving improved outcomes in 
models of acute kidney injury (Bruno 2009; Gatti 2011), myocardial ischemia/reperfusion injury 
(Lai 2010), and hypoxia-induced pulmonary hypertension (Lee 2012).  In a neonatal hyperoxia 
mouse model, MSC-derived extracellular vesicles were effective in reducing lung inflammation 
and alveolar simplification, thus attenuating the development of BPD (Willis 2018).  These 
studies and others provide a strong foundation for the continued development of extracellular 
vesicle-based therapies.  Clinically, MSC-derived exosomes have been used in 1 patient to treat 
therapy-refractory graft-versus-host disease.  The patient was administered exosomes every 2 to 
3 days over a 2-week period.  All applications were tolerated well with no observed side effects 
(Kordelas 2014).  UNEX-42 specifically has not been evaluated clinically. 

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1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION 
There are currently no approved prophylactic interventions for BPD, and the preventative 
therapies employed are largely ineffective (Beam 2014).  The lack of preventative treatment 
options is in stark contrast to the poor outcomes observed in patients who develop severe BPD, 
who are at further risk for developing pulmonary hypertension, emphysema, and 
neurodevelopmental abnormalities.  These risks in the population susceptible to developing 
BPD, and the lack of effective preventative treatment options, make premature infants the 
population with the most favorable risk-potential benefit profile. 
United Therapeutics Corporation believes that safety data available from the most similar 
comparator under study in a similar population justifies the first-in-human study of UNEX-42 
being conducted in premature infants.  This comparator study used an intratracheal 
administration of human umbilical cord blood-derived MSCs to determine safety and 
inflammatory biomarkers in premature infants at risk for BPD.  The study indicated that the 
treatment was well tolerated by all subjects with no immediate cardiorespiratory compromise or 
long-term adverse effects after dosing (Chang 2014, Ahn 2017).  UNEX-42, which is acellular, 
should have an improved safety profile over the comparator cell program.  United Therapeutics 
Corporation believes that a product consisting of extracellular vesicles presents less risk of 
tumorigenesis, less risk of embolus, and less risk of immunological reaction as compared to 
whole MSCs.  As such, United Therapeutics Corporation expects a favorable safety profile. 
No adverse reactions to UNEX-42 have been observed in animal studies to date.  Toxicity 
studies conducted in neonatal rats concluded that the no-observed-adverse-effect level for 
UNEX-42 is 878 pmol phospholipid/kg.  This level was the highest feasible dose based on the 
upper limit of volume that could be administered to the rats.  Using the no-observed-adverse-
effect level as a benchmark, the starting clinical dose for this study is 20 pmol phospholipid/kg 
body weight, which takes into account a human equivalent dose conversion factor of 0.22, as 
well as a 10-fold safety margin. 

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1.4 
CLINICAL HYPOTHESIS 
The hypothesis of this study is that UNEX-42 can be administered to preterm infants at high risk 
for BPD at doses that provide a potential for therapeutic benefit in association with an acceptable 
safety profile. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
To assess the safety and tolerability of intravenous (IV) infusion of UNEX-42 in infants born at 
<27 weeks of GA and exhibiting respiratory distress. 
2.2 
SECONDARY OBJECTIVES 
To assess the effect of UNEX-42 on the following: 
1. Incidence and severity (mild, moderate, severe) of BPD or death at 36 weeks 
postmenstrual age (PMA) 
2. Short-term outcomes including oxygen utilization and ventilation exposure in the first 
28 days after treatment. 
3. Long-term outcomes up to 1 year corrected age. 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a multicenter, placebo-controlled, randomized, dose escalation, safety, and tolerability 
study of UNEX-42 in infants born at <27 weeks of GA at high risk for BPD.  UNEX-42 will be 
administered via IV infusion to 3 cohorts at 20, 60, and 200 pmol phospholipid/kg body weight.  
Within each cohort, eligible subjects will be randomly assigned to receive either UNEX-42 or 
placebo treatment (2:1 allocation ratio).  A schematic presentation of the study design is 
presented in Figure 3-1. 

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Figure 3-1 
Schematic of Study Design for an Individual Subject 
 
Study assessments will occur during the study at the following time points: Screening, Baseline, 
24 and 72 hours postdose, 7 days postdose, weekly until 35 weeks PMA, 36 weeks PMA, and 40 
weeks PMA/hospital discharge during the Post-treatment Phase.  For subjects that complete the 
Post-treatment Phase, the Long-term Outcome Phase will occur at 6 months (phone contact) and 
1 year of corrected age (site visit). 

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3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
Table 3-1 
Schedule of Times and Events – Post-treatment Phase 
Study Procedures 
Screeninga 
Baselinea 
Post-treatment Phase 
Assessment Period 
24 Hours 
Postdose 
72 Hours  
Postdose 
7 Days  
Postdose 
Weekly Until  
35 Weeks PMA 
36 Weeks 
PMAb 
40 Weeks PMA/ 
Hospital Dischargeb,c 
Study Day 
-48 Hours to 
Baseline 
1 
2 
4 
8 
15, 22, 29, 36, 43, 50, 
57, 64, 71, 78, and 85 
50 up to 88 
78 up to 116 
Visit Window 
 
 
±4 hours 
±4 hours 
±1 day 
±2 days 
±2 days 
±2 days 
Parental Informed Consent 
X 
 
 
 
 
 
 
 
Subject Eligibility 
X 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Maternal History 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
X 
X 
Length and Head Circumference 
 
X 
 
 
 
 
X 
X 
CXRd 
 
X 
 
 
 
 
X 
 
Clinical Laboratory Assessmentse 
 
X 
 
X 
 
 
X 
 
Predefined Complications of 
Prematurity 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
 
X 
 
Mean Airway Pressureg 
 
X 
X 
X 
X 
X 
X 
X 
Oxygen Saturationh 
 
X 
X 
X 
X 
X 
X 
X 
Respiratory Severity Scorei 
 
X 
X 
X 
X 
X 
X 
X 
Tracheal Aspiratej 
 
X 
 
X 
X 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsk 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
UNEX-42/Placebo Administration 
 
Xl 
 
 
 
 
 
 
Incidence and Severity of BPDm 
 
 
 
 
 
 
X 
 

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Study Procedures 
Screeninga 
Baselinea 
Post-treatment Phase 
Assessment Period 
24 Hours 
Postdose 
72 Hours  
Postdose 
7 Days  
Postdose 
Weekly Until  
35 Weeks PMA 
36 Weeks 
PMAb 
40 Weeks PMA/ 
Hospital Dischargeb,c 
Study Day 
-48 Hours to 
Baseline 
1 
2 
4 
8 
15, 22, 29, 36, 43, 50, 
57, 64, 71, 78, and 85 
50 up to 88 
78 up to 116 
Visit Window 
 
 
±4 hours 
±4 hours 
±1 day 
±2 days 
±2 days 
±2 days 
Duration of Mechanical 
Ventilation, Supplemental Oxygen 
Therapy, and Hospitalization 
 
 
 
 
 
 
 
Xn 
Abbreviations: AE, adverse event; CXR, chest x-ray; FiO2, fraction of inspired oxygen; GA, gestational age; PMA, postmenstrual age; RSS, Respiratory Severity Score 
a The Screening and Baseline assessments may be combined; however, all entry criteria must be confirmed prior to randomization.   
b The days of the 36 and 40 Weeks PMA assessments are based on each subject’s GA determined during Screening based on local standard practice. 
c Subjects that discontinue the study prematurely should have the 40 Weeks PMA/Hospital Discharge assessments performed if possible.  Subjects that complete the 40 Weeks PMA 
assessment or are discharged from hospital will continue into the Long-term Outcome Phase shown in Table 3-2. 
d The most recent CXRs prior to randomization and 36 Weeks PMA can be used. 
e Clinical laboratory assessments will consist of a complete blood count, differential count, sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, aspartate 
aminotransferase, alanine aminotransferase, and total and indirect bilirubin.  For Baseline, the clinical laboratory assessments may utilize the laboratory assessments obtained as standard 
of care treatment within the last 24 hours in lieu of drawing blood for the sole purpose of the study.  Any study-required blood tests should be obtained at the same time a blood sample 
is being collected for clinical purposes, if possible. 
f On Day 1, vital signs are to be collected just prior to dosing, at the midpoint of dosing, just after the end of dosing, and at least once every hour for the first 4 hours after dosing is 
completed.  Vital signs are to include heart rate, respiratory rate (either spontaneous rate or the sum of spontaneous rate and mechanically delivered rate), and systemic blood pressure 
(systolic and diastolic). 
g Mean airway pressure is only to be collected from subjects undergoing mechanical ventilation. 
h Oxygen saturation should be measured from a post-ductal location and should be consistently obtained post-ductally throughout the study period. 
i 
The RSS should be calculated as the mean airway pressure multiplied by FiO2.  Mean airway pressure and FiO2 will be collected at the same time, and the RSS will only be calculated 
when the subject has an obtainable mean airway pressure. 
j 
A tracheal aspirate will be collected as possible at Baseline (prior to dosing), 72 hours postdose (if still intubated), and 7 days postdose (if still intubated). 
k All AEs will be documented from the time of informed consent until the time screen failure is documented, or until the subject is either discontinued from the study or all 40 Weeks 
PMA/Hospital Discharge assessments have been completed and should be followed until either resolution (or return to normal or baseline values), until they are judged by the 
Investigator to no longer be clinically significant, or for at least 30 days if the AE extends beyond the Post-treatment Phase. 
l UNEX-42 or placebo will be administered after all other Day 1 assessments are completed, with the exception of vital signs (see footnote f). 
m This assessment to be performed at 36 Weeks PMA or at Hospital Discharge, whichever comes first (see Section 3.3.1). 
n For each parameter, the total number of days from Baseline to the 40 Weeks PMA/Hospital Discharge will be calculated. 

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Table 3-2 
Schedule of Times and Events – Long-term Outcome Phase 
Study Procedures 
Long-term Outcome Phase 
Assessment Period 
6 Months (Corrected Age) Phone Contact a 
1 Year (Corrected Age) Visit b 
Study Day 
Calculated 
Calculated 
Visit Window 
±2 weeks 
±4 weeks 
Weight, Length, and Head Circumference 
 
X 
Serious Adverse Reactions c 
X 
X 
Assessment of General Health 
X 
X 
Abbreviations: PMA, postmenstrual age 
a To be performed at 6 months corrected age for all subjects, as possible, including those discharged from the hospital prior to 40 Weeks PMA.  See Section 7.5. 
b To be performed at 1 year corrected age for all subjects, as possible, including those discharged from the hospital prior to 40 Weeks PMA.  See Section 7.5. 
c Refer to Section 9.1.3 for the definition of serious adverse reactions. 

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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
3.3.1.1 
Incidence and Severity of Bronchopulmonary Dysplasia 
A clinical diagnosis of BPD for infants born <32 weeks of GA is defined by the requirement for 
supplemental oxygen (>21%) for at least 28 days.  Furthermore, the severity of BPD is classified 
as mild, moderate, or severe based on the level of supplemental oxygen needed at 36 weeks 
PMA as shown in Table 3-3.  This assessment is performed at the 36 Weeks PMA or Hospital 
Discharge assessment, whichever comes first (Jobe 2001).  Supplemental oxygen percentage will 
be adjusted for altitude when recorded, as necessary. 
Table 3-3 
Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria for 
Gestational Age at Birth <32 Weeks 
BPD Severity 
Criteria (Treatment with oxygen >21% for at least 28 days plus) 
Mild BPD 
Breathing room air at 36 weeks PMA or hospital discharge, whichever 
comes first 
Moderate BPD 
Need for <30% oxygen at 36 weeks PMA or hospital discharge, whichever 
comes first 
Severe BPD 
Need for ≥30% oxygen and/or positive pressure (positive-pressure 
ventilation or nasal continuous positive airway pressure) at 36 weeks PMA 
or hospital discharge, whichever comes first 
Abbreviations: BPD, bronchopulmonary dysplasia; PMA, postmenstrual age 
3.3.1.2 
Duration of Hospitalization 
The total number of days between Baseline and the 40 Weeks PMA/Hospital Discharge 
assessment will determine the duration of hospitalization. 
3.3.1.3 
Duration of Mechanical Ventilation 
Duration of mechanical ventilation (invasive or noninvasive) will be determined by the total 
number of days (consecutive or nonconsecutive) that an infant receives ventilatory support 
between Baseline and the 40 Weeks PMA/Hospital Discharge assessment. 
3.3.1.4 
Duration of Supplemental Oxygen Therapy 
The number of days of supplemental oxygen therapy use (consecutive or nonconsecutive) will be 
determined between Baseline and the 40 Weeks PMA/Hospital Discharge assessment. 

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3.3.1.5 
Respiratory Severity Score 
The Respiratory Severity Score (RSS) will be calculated as the mean airway pressure multiplied 
by fraction of inspired oxygen (FiO2).  Mean airway pressure and FiO2 will be collected at the 
same time, and the RSS will only be calculated when the subject has a mean airway pressure that 
can be obtained.  The RSS will be monitored throughout the Post-treatment Phase. 
3.3.1.6 
Duration of Postnatal Steroids 
Duration of postnatal steroids for purposes of preventing and/or treating BPD (eg, 
hydrocortisone, dexamethasone, methylprednisolone) will be monitored through 40 Weeks 
PMA/Hospital Discharge.  Postnatal steroid use will be collected as part of the concomitant 
medication evaluation (see Section 4.3.1). 
3.3.1.7 
Tracheal Aspirate Inflammatory Biomarkers 
A tracheal aspirate will be collected, as possible, at Baseline (prior to dosing), 72 hours postdose 
(if still intubated), and 7 days postdose (if still intubated).  Tracheal aspirates will be evaluated at 
the local laboratory, as possible, for cell count and differential. 
3.3.2 
Safety 
During the Post-treatment Phase, treatment emergent changes in physical findings, vital signs, 
clinical laboratory parameters, and the development of adverse events (AEs) will be the primary 
assessments of safety.  During the Long-term Outcomes Phase, the development of any serious 
adverse reactions (SARs) will be monitored.  Sections 9 and 15.1 provide the guidelines and 
definitions for AE reporting. 
3.3.2.1 
Medical History, Maternal History, and Demographics 
A complete medical history, including the maternal history parameters shown in Table 3-4, and 
demographics will be obtained at Screening.  Any changes to medical history that occur between 
the Screening and Baseline assessments should be recorded.  Past or present illnesses, current 
medications, and history of medication allergies should be recorded.  Any significant changes to 
the subject’s medical condition must be documented throughout the course of the Post-treatment 
Phase. 

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Table 3-4 
Maternal History Parameters 
Maternal age/race/ethnicity 
Reason for delivery (preeclampsia, eclampsia, rupture of 
membrane, etc) 
Diagnosis of chorioamnionitis during 
pregnancy 
Mode of delivery 
Medications during pregnancy 
(corticosteroids, medications used to treat 
pre-eclampsia)/delivery 
Receipt of IV magnesium 
 
3.3.2.2 
Physical Examination/Chest X-ray 
A complete physical examination, including a CXR, will be conducted at Baseline (prior to 
randomization) and at 36 Weeks PMA.  The most recent CXR prior to randomization and 36 
Weeks PMA can be used without being retaken.  All treatment emergent clinically significant 
findings during the Post-treatment Phase will be recorded as AEs. 
3.3.2.3 
Vital Signs 
Vital signs will be collected during all study assessment timepoints from Baseline to 40 Weeks 
PMA/Hospital Discharge.  On Day 1, vital signs are to be collected 7 times:  just prior to dosing, 
at the midpoint of dosing, just after the end of dosing, and at least once every hour for the first 
4 hours after the completion of dosing. 
Vital signs measured will include systemic blood pressure (systolic and diastolic), heart rate, and 
respiratory rate (either spontaneous rate or the sum of spontaneous rate and mechanically 
delivered rate).  Except for dose administration, no other measurements or procedures should be 
performed during measurement of vital signs.  Vital signs should also be assessed in the case of 
abnormal clinical signs and symptoms. 
3.3.2.4 
Adverse Events 
All AEs will be documented from the time of informed consent until the time screen failure is 
documented, or until the subject is either discontinued from the study or all 40 Weeks 
PMA/Hospital Discharge assessments have been completed and should be followed until either 
resolution (or return to normal or baseline values), until they are judged by the Investigator to no 
longer be clinically significant, or for at least 30 days if the AE extends beyond the Post-
treatment Phase. 

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All AEs meeting the criteria for serious (ie, serious adverse events [SAEs]) should be followed 
until resolution, death, or the subject is lost to follow-up even if they are ongoing more than 30 
days after completion of the Post-treatment Phase 
Refer to Section 9.1 for detailed definitions of safety events.  All AEs/SAEs that occur during the 
study will be followed as instructed in Section 9.3. 
If, at any time, the parent/guardian withdraws their consent for the subject to remain in the study, 
any AEs/SAEs that occur from UNEX-42 treatment (including product use errors, product 
quality problems, and therapeutic failures) will be reported.  These events will not be recorded in 
the electronic Case Report Form (eCRF). 
3.3.2.5 
Predefined Complications of Prematurity 
Complications of prematurity will be assessed from Baseline to 40 Weeks PMA/Hospital 
Discharge.  The diagnosis of the following complications will be recorded: sepsis, 
pneumothorax, clinically significant patent ductus arteriosus (PDA) requiring treatment or 
ligation, necrotizing enterocolitis requiring treatment or surgery, intraventricular hemorrhage 
(including highest grade), periventricular leukomalacia, and retinopathy of prematurity 
(including stage). 
3.3.2.6 
Clinical Laboratory Parameters 
Blood samples for the clinical chemistry and hematology analyses will be collected at Baseline 
(randomization) and repeated at the 72 hours postdose and the 36 Weeks PMA assessments to 
evaluate for study treatment-emergent changes.  For Baseline, the clinical laboratory assessments 
may utilize the laboratory assessments obtained as standard of care treatment within the last 24 
hours in lieu of drawing blood for the sole purpose of the study.  Any study-required blood tests 
should be obtained at the same time a blood sample is being collected for clinical purposes, if 
possible.  Values for the following parameters will be obtained: 

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Table 3-5 
Clinical Laboratory Parameters 
Electrolyte Panel 
Chemistry Panel 
Hematology Panel 
Bicarbonate 
Alanine aminotransferase  
Hemoglobin  
Chloride 
Aspartate aminotransferase 
Hematocrit  
Potassium 
Bilirubin (total and indirect) 
Red blood cell count  
Sodium 
Creatinine 
White blood cell count  
 
Blood urea nitrogen 
Platelet count 
 
3.4 
NUMBER OF CENTERS 
This is a US-based multicenter study with approximately 6 centers participating. 
3.5 
NUMBER OF SUBJECTS 
Approximately 18 subjects will be enrolled in this study.  There will be 3 cohorts of 6 subjects 
per cohort, randomized 2:1 (active:placebo) for a total of 12 subjects receiving UNEX-42 
treatment (4 subjects each at 20, 60, and 200 pmol phospholipid/kg body weight) and 6 subjects 
receiving placebo. 
3.6 
ESTIMATED STUDY DURATION 
The expected duration for a subject to complete the study is up to 69 weeks.  Subjects are 
administered clinical study material (CSM) on Day 1 and the Post-treatment Phase will consist of 
assessments through 40 Weeks PMA (up to 17 weeks depending on subject GA at birth).  
Subjects that complete the Post-treatment Phase (including those that are discharged from 
hospital prior to 40 Weeks PMA) will continue into the Long-term Outcome Phase and will be 
assessed through 1 year of corrected age.  Analysis of data from the Post-treatment Phase will 
occur after all subjects have completed the Post-treatment Phase. 
4 
SUBJECT ELIGIBILITY 
Inclusion and exclusion criteria are to be assessed at Screening and reconfirmed at Baseline prior 
to randomization. 

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4.1 
INCLUSION CRITERIA 
A subject must meet the following criteria to be eligible for the study: 
1. Infant whose postnatal age is 3 to 14 days at randomization. 
2. Subject meets the following oxygen and birth weight criteria based on GA: 
Gestational Age at Birth 
Criteria 
23 weeks to 24 weeks 6 days 
Any birth weight, any oxygen requirement 
25 weeks to 26 weeks 6 days 
FiO2 ≥35% (sustained >2 hours) at any point during 
postnatal Days 1 to 14  
AND  
birth weight ≤750 g 
3. Endotracheally intubated and receiving mechanical ventilation at the time of Screening 
and randomization. 
4. Not expected to be extubated within the next 24 hours after randomization. 
5. The subject has a parent/guardian who gives written informed consent. 
4.2 
EXCLUSION CRITERIA 
A subject is not eligible for inclusion in this study if any of the following criteria apply: 
1. Has a congenital heart defect, except for PDA, atrial septal defect or a small/moderate, 
restrictive ventricular septal defect. 
2. Has a serious malformation of the lung, such as pulmonary hypoplasia/aplasia, congenital 
diaphragmatic hernia, or any other congenital lung anomaly. 
3. Being treated with inhaled nitric oxide. 
4. Has a known chromosomal abnormality (eg, Trisomy 18, Trisomy 13, or Trisomy 21) or 
a severe congenital malformation (eg, hydrocephalus and encephalocele, 
trachea-esophageal fistula, abdominal wall defects, and major renal anomalies). 
5. Has had a known severe congenital infectious disease (ie, herpes, toxoplasmosis rubella, 
syphilis, human immunodeficiency virus, cytomegalovirus, etc). 
6. High clinical suspicion of active systemic infection, severe sepsis, or septic shock during 
the Screening period. 
7. Underwent a surgical procedure (requiring admission to an operating room) within 
72 hours before randomization or who is anticipated to have a surgical procedure 
(requiring admission to an operating room) within 72 hours before or following 
randomization. 
8. Has had a Grade 3 or 4 intracranial hemorrhage. 
9. Has active pulmonary hemorrhage. 
10. The subject is currently participating in any other interventional clinical study. 
11. The subject is, in the opinion of the Investigator, so ill that death is inevitable, or is 
considered inappropriate for the study for any reason(s) other than those listed above. 

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4.3 
PRESCRIBED THERAPY 
Not applicable. 
4.3.1 
Concomitant Medications 
All concomitant medications taken during the Post-treatment Phase of the study, including those 
that are ongoing at Baseline or taken for AEs or other medical events, should be recorded in the 
subject’s source documents and transcribed as required to the eCRF. 
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
Within each cohort, eligible subjects will be randomly allocated to receive either UNEX-42 or 
placebo at randomization (using a 2:1 allocation ratio).  A subject number will be assigned to 
identify individual subject data.  An Interactive Response Technology (IRT) will be responsible 
for allocation of all study drug. 
5.2 
RANDOMIZATION 
The study will be randomized 2:1 UNEX-42 to placebo.  Within each dose cohort, subjects will 
be randomly allocated to receive UNEX-42 or placebo through the IRT using a centrally 
administered block randomization. 
5.3 
BLINDING 
The Investigator, study site personnel involved in preparation/administration of CSM, subject’s 
parent/guardian, and Sponsor (except for Global Drug Safety and Regulatory Affairs personnel 
involved in safety reporting) will not be aware of the treatment allocation.  All CSM will be 
provided as blinded study drug. 
6 
TREATMENT PROCEDURES 
6.1 
UNEX-42 DOSAGE AND ADMINISTRATION 
UNEX-42 will be administered to 3 cohorts at 20, 60, and 200 pmol phospholid/kg body weight, 
respectively, in a dose-escalating manner.  UNEX-42 is suspended in phosphate-buffered saline.  
UNEX-42 is a clear liquid that is provided in appropriately sized vials and stored at -70±10°C 
prior to use.  UNEX-42 will be appropriately diluted in normal saline to a achieve a final dosing 
volume of 1 mL.  

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Once all entry criteria have been met and random treatment assignment confirmed, the dose of 
CSM will be prepared by the site pharmacy staff.  The filled syringe of CSM will be delivered to 
the hospital room and administered to the subject by appropriately trained staff.  The CSM must 
be administered within 8 hours after thawing.  The CSM should be administered through an 
existing IV catheter being used for administration of crystalloids, such as an umbilical, central, 
or peripheral IV line.  If any circumstances prevent administration of CSM through an existing 
IV line, a new IV line may be started for the administration of CSM at the discretion of the 
Investigator.  If necessary, the line for infusion must first be flushed and primed with a sufficient 
volume of normal saline to clear the line at a controlled rate of 10 mL/hour by a syringe pump, 
regardless of subject weight.  The CSM syringe contents will then be administered at a controlled 
rate of 10 mL/hour by a syringe pump.  Once the CSM has been completely administered, the 
line will be flushed with a sufficient volume of normal saline to clear the CSM from the line at a 
controlled rate of 10 mL/hour.  
CSM infusions may be stopped at the discretion of the Investigator if any of the following are 
observed during the course of the infusion or the flush: 
 Acute worsening of respiratory function requiring intervention. 
 Acute hypotension requiring intervention (including but not limited to fluid bolus, 
vasopressors, or hydrocortisone). 
 Any acute change in vital signs requiring medical intervention. 
 Any other medical issue such that, in the opinion of the Investigator, continuation of 
study drug infusion represents a serious medical risk to the subject.  
Subjects that receive any amount of CSM will be followed for the duration of the study, unless 
the subject is withdrawn from the study as described in Section 8.1 of the protocol.  
6.2 
SELECTION OF DOSES FOR SUBJECT COHORTS 
The starting dose for Cohort 1 of 20 pmol phospholipid/kg body weight was selected as 
described in Section 1.3.  Dose administration for each cohort will occur such that there is an 
observational period of 3 days between dosing the first, second, and third subject.  This 
observational period will allow for the monitoring of any dose-limiting toxicities (DLTs) (see 
Section 6.3) in at least 1 subject treated with UNEX-42.  The Data Monitoring Committee 

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(DMC) will make dose escalation recommendations based on review of safety data between 
cohorts (see Section 10.7). 
6.3 
DOSE-LIMITING TOXICITY 
DLTs will be used to inform dosing decisions; however, no DLTs have been observed during 
nonclinical development of UNEX-42.  Therefore, for the purposes of this study, only an 
estimate of possible dose-limiting events can be made.  As a result, DLTs will be defined as any 
of the following toxicities assessed by the Investigator and/or Sponsor as at least possibly related 
to UNEX-42 based on the time to onset following UNEX-42 administration and judged not to be 
related to the underlying condition or any concomitant medications by the Investigator and/or 
Sponsor: 
 A treatment-emergent adverse event (TEAE) that is of potential clinical significance such 
that further dose escalation would expose subjects to unacceptable risk. 
 Increased liver enzymes (Grade 2 or higher, using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as guidance) or 
any evidence of hepatic failure. 
 Pulmonary toxicity, worsening respiratory distress, or other acute exacerbation of 
pulmonary function requiring ventilatory support or escalation of care. 
In addition, the DMC may identify as a DLT, any TEAE occurring in subjects treated with 
UNEX-42 at any time during the study.  Each DLT must be recorded in the eCRF as an AE.  In 
addition, any DLT that meets criteria for a SAE must be reported to the Sponsor in an expedited 
manner as described in Section 9.4. 
6.4 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
During the study, neither the Investigator, study site personnel involved in 
preparation/administration of CSM, subject’s parent/guardian, nor Sponsor (except for Global 
Drug Safety and Regulatory Affairs personnel involved in safety reporting) should be unblinded 
to the treatment assignment of any subject for any reason except in the event of a medical 
emergency (eg, a life-threatening event), if and when knowledge of the treatment assignment is 
considered necessary to determine the optimal medical management.  Appropriate 
communications should take place between the site staff and the Sponsor before accessing the 
IRT to allow unblinding of a subject’s treatment assignment.  In the event of a medical 

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emergency that requires immediate unblinding, the IRT may be accessed by site staff or the 
Sponsor’s Medical Monitor to determine treatment assignment. 
6.5 
COMPLIANCE 
All infusions will be administered by site staff as directed in the protocol.  Any deviations from 
planned infusion times will be documented in the subject’s source documentation.  The Principal 
Investigator or other site personnel under the direction of the Principal Investigator will be 
responsible for ensuring the appropriate dose is given to the subject and for recording all dosing 
information in source documents. 
7 
EXPERIMENTAL PROCEDURES 
Assessments during the study will be performed according to Table 3-1 and Table 3-2.  Every 
effort should be made to perform assessments as close as possible to the scheduled time points, 
within the visit window noted for each day on study as noted in Table 3-1 and Table 3-2.  Details 
of efficacy assessments and safety assessments are described in Sections 3.3.1 and 3.3.2, 
respectively.  Details of study procedures are provided in Section 7.1 for Screening, Section 7.2 
for Baseline, Section 7.3 for the Post-treatment Phase, Section 7.4 for 40 Weeks PMA/Hospital 
Discharge, and Section 7.5 for the Long-term Outcome Phase. 
7.1 
SCREENING 
Screening can begin up to 48 hours prior to Baseline.  Site personnel may conduct Pre-screening 
assessments prior to a subject’s parent/guardian signing an Informed Consent Form (ICF).  Pre-
screening assessments may include review of the hospital data to identify potential subjects that 
may be eligible for the study.  Screening assessments will be conducted in the hospital as 
inpatient assessments after informed consent has been obtained according to Table 3-1. 
7.2 
BASELINE 
Following confirmation of eligibility, Baseline assessments will be conducted according to Table 
3-1 on Day 1 prior to randomization.  Eligible subjects will be randomly allocated to receive 
either UNEX-42 or placebo as described in Section 5.2. 

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7.3 
POST-TREATMENT PHASE 
Following UNEX-42 or placebo treatment on Day 1, subjects will be assessed according to Table 
3-1.  Post-treatment study assessments will occur during the study at the following time points: 
24 and 72 hours postdose, 7 days postdose, weekly until 35 weeks PMA, 36 weeks PMA, and 40 
weeks PMA/hospital discharge.  The timing of the 36 Weeks PMA and 40 Weeks PMA/Hospital 
Discharge assessments is based upon each subject’s GA, as determined during Screening based 
on local standard practice. 
7.4 
40 WEEKS PMA/HOSPITAL DISCHARGE 
At the end of the Post-treatment Phase (40 Weeks PMA/Hospital Discharge), final assessments 
for each subject will be performed according to Table 3-1.  If a subject discontinues from the 
study prematurely, 40 Weeks PMA/Hospital Discharge assessments should occur if possible. 
7.5 
LONG-TERM OUTCOME PHASE 
Subjects that complete the 40 Weeks PMA Assessment or are discharged from the hospital prior 
to this assessment will continue into the Long-term Outcome Phase.  Assessments will occur at 6 
months (phone contact) and 1 year (site visit) of corrected age according to  
Table 3-2.  Corrected age should be calculated by the formula below: 
Actual Age (weeks) – Weeks of Prematurity (weeks)* = Corrected Age (weeks) 
*Weeks of prematurity is calculated by subtracting the subject’s GA at birth from 40 weeks.  
For example, if a subject was born at a GA of 28 weeks, they were 12 weeks premature. 
Assessment of general health will occur by phone contact at 6 months and by a study site visit at 
1 year.  The phone contact at 6 months corrected age will be made by trained site staff.  The call 
will follow a script that will facilitate the collection of relevant information.  The subject’s 
parent/guardian will be interviewed according to the script, and information relating to SARs and 
other outcome measures will be recorded.  If possible, the site staff should schedule the 1-year 
visit at the time of the phone call.  The same script used at the 6-month assessment will be used 
at the 1-year visit. 

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8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A subject’s parent/guardian may voluntarily withdraw the subject, or the subject may be 
withdrawn from the study and/or study drug by the Investigator at any time for reasons 
including, but not limited to, the following: 
 The subject’s parent/guardian wishes to withdraw the subject from further participation. 
 Any medically appropriate reason, in the opinion of the Investigator, or significant 
protocol violation likely to undermine the validity of results. 
 The Sponsor terminates the study. 
Every effort should be made to follow subjects up to their scheduled long-term follow-up visits.  
If a subject is discontinued from the study prematurely, the Investigator must provide an 
explanation in the eCRF and complete the End of Study Record for that subject.  The 
Investigator should make every effort to perform all scheduled assessments prior to hospital 
discharge.  In the event that a subject discontinues study drug infusion prematurely, the 
Investigator will still attempt to perform all planned assessments as outlined in Table 3-1 and 
Table 3-2, unless the subject is withdrawn for other reasons as stated in this section of the 
protocol.  If a subject is withdrawn due to an AE, the subject will be followed as outlined in 
Section 9.3.  The date the subject is withdrawn and the primary reason for discontinuation will be 
recorded on the eCRF. 
8.2 
CRITERIA FOR TERMINATING THE STUDY 
The study may be stopped at any time if, in the opinion of the DMC and/or Sponsor, 
continuation of the study represents a serious medical risk to the subjects.  This may include, but 
is not limited to, the presence of serious, life-threatening, or fatal AEs or AEs that are 
unacceptable in nature, severity, or frequency.  The Sponsor reserves the right to discontinue the 
study for any reason at any time. 

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8.3 
CRITERIA FOR DISCONTINUING THE SITE 
The study may also be terminated at a given center if: 
 The Principal Investigator elects to discontinue the study 
 The Sponsor elects to discontinue the study at the site 
 US Food and Drug Association (FDA) regulations are not observed 
 The protocol is violated 
 Changes in personnel or facilities adversely affect performance of the study. 
9 
ADVERSE EVENT REPORTING  
9.1 
DEFINITIONS 
9.1.1 
Adverse Event 
An AE is any untoward medical experience occurring to a subject during a clinical study whether 
or not it is related to study drug.  An AE may include an intercurrent illness, injury, or any other 
concomitant impairment of the subject’s health, as well as abnormal laboratory findings if 
deemed to have clinical significance.  AEs may also include worsening of an existing symptom 
or condition, or post-treatment events that occur as a result of protocol-mandated procedures (eg, 
exacerbation of a pre-existing illness following the start of the study or an increase in the 
frequency or intensity of a pre-existing episodic event or condition). 
Thus, no causal relationship with the study drug is implied by the use of the term “adverse 
event.” 
An AE does not include the following: 
 Medical or surgical procedures, as the condition for which the surgery is required may be 
an AE. 
 Planned surgical measures permitted by the study protocol and the condition(s) leading to 
these measures are not AEs. 
 Day-to-day fluctuations of a pre-existing disease or condition that was present or detected 
at the start of the study that do not worsen. 
Specific complications of prematurity will be assessed from Baseline to 40 Weeks PMA/Hospital 
Discharge as described in Section 3.3.2.5.  Therefore, the complications of prematurity should 
only be recorded as an AE or SAE if the event is unusual with respect to intensity, frequency, 

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duration as compared with symptoms in the subject’s medical history, or if there is a reasonable 
possibility that the event was caused by the study drug.  Congenital disorders should be recorded 
as medical history, even if diagnosed after the subject has entered the study. 
Investigators should use the NCI-CTCAE Version 5.0 as guidance to grade the severity/intensity 
of all events.  If a CTCAE criterion does not exist, the Investigator should grade the 
severity/intensity according to the following criteria: 
 Grade 1 (mild): does not interfere with the patient’s usual function 
 Grade 2 (moderate): interferes to some extent with patient’s usual function 
 Grade 3 (severe): interferes significantly with patient’s usual function 
 Grade 4 (life-threatening): results in a threat to life or in an incapacitating disability 
 Grade 5 (death): results in death 
9.1.2 
Serious Adverse Event  
A SAE is an AE occurring at any dose that results in any of the following outcomes: 
 Death 
 A life-threatening AE 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant disability/incapacity 
In addition, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and require medical/surgical intervention to prevent 1 of the 
outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug abuse. 
Life-threatening in this context 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. 

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9.1.3 
Serious Adverse Reaction 
A SAR is a SAE occurring at any dose that is assessed by the Investigator as possibly or 
probably related to the CSM.  During the Long-term Outcome Phase of the study, only SARs 
will be reported to United Therapeutics Global Drug Safety according to Section 9.4.  Other 
conditions that will be evaluated as part of the study endpoints are therefore not subject to 
expedited reporting. 
9.2 
DOCUMENTATION OF ADVERSE EVENTS 
An AE or SAE occurring during the study must be documented in the subject’s source 
documents and in the eCRF.  Information relating to the AE such as onset and cessation date, 
intensity, seriousness, relationship to study drug, and outcome is also to be documented in the 
eCRF (see Section 15.1 for definitions).  Where possible, AEs should be recorded using standard 
medical terminology.  The Investigator should attempt, if possible, to establish a diagnosis based 
on the presenting signs and symptoms.  If several signs or symptoms are clearly related to a 
medically defined diagnosis or syndrome, the diagnosis or syndrome should be recorded in the 
eCRF, not the individual signs and symptoms. 
9.3 
FOLLOW-UP OF ADVERSE EVENTS 
All AEs should be followed until either resolution (or return to normal or baseline values), until 
they are judged by the Investigator to no longer be clinically significant, or for at least 30 days if 
the AE extends beyond the Post-treatment Phase.  All SAEs that occur during the study will be 
followed until resolution, death, or the subject is lost to follow-up even if they are ongoing more 
than 30 days after completion of the final assessment.  Supplemental measurements and/or 
evaluations may be necessary to investigate fully the nature and/or causality of an AE or SAE.  
This may include additional laboratory tests, diagnostic procedures, or consultation with other 
healthcare professionals.  The eCRF should be updated with any new or additional information 
as appropriate. 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
Sites should enter initial or follow-up SAE information regardless of causality or expectedness 
into the Sponsor’s Electronic Data Capture (EDC) system (primary method) within 24 hours of 
awareness of an SAE.  The SAE will be directly transmitted from the EDC system to the Argus 

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Safety Database.  If the site is unable to enter the SAE electronically into EDC system, the 
alternative for reporting is submitting a scanned copy of the paper SAE Report Form via email to 
 within 24 hours of awareness.  If the paper 
SAE Report Form is submitted, the site staff will also be required to enter the SAE data into the 
EDC system when the EDC becomes available.  SAE source documents (eg, hospital discharge 
summary or death certificate) will be submitted by the site staff via email to 
.  The Investigator or Sponsor (if appropriate) 
must also notify their Institutional Review Board (IRB), Independent Ethics Committee (IEC), 
and/or other local equivalent body of the reported SAE, including any follow-up information.  
Copies of each report and documentation of IEC/IRB/local equivalent body notification and 
receipt will be kept in the Investigator’s study file. 
9.5 
SAFETY REPORTS 
In accordance with USA FDA regulations, the Sponsor or designee will notify the regulatory 
agency, Investigators, and/or IRBs and IECs of all relevant AEs (usually those that are 
considered to be possibly attributable to study drug and are both serious and unexpected) in 
accordance with the applicable regulations.  The Investigator must report these AEs to their 
IRB/IEC in accordance with applicable regulations and guidelines set forth by the IRB/IEC. 
10 
STATISTICAL CONSIDERATIONS 
10.1 
DATA PROCESSING 
The results of assessments will be transcribed into an eCRF for each subject who has a 
parent/guardian sign an ICF until study completion or study discontinuation for any reason.  A 
representative from the Sponsor will verify eCRF data fields against source documentation.  All 
data transmitted from the site will be reviewed and entered into a quality assured computerized 
database.  Data clarifications will be generated, and the database will be edited as appropriate.  
The eCRF screens are to be reviewed by the Investigator for completeness and accuracy.  The 
Investigator must electronically sign each subject’s eCRF to signify his/her approval of the data.  
The Investigator will be required to resign an eCRF if changes are made to a subject’s eCRF by 
the site after the Investigator initially signs the eCRF.  The database will be final when all 

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outstanding queries have been resolved and all data management quality assurance procedures 
are complete. 
10.2 
SAMPLE SIZE 
No formal sample size calculations have been performed. 
10.3 
ANALYSIS PLAN 
Analysis and unblinding of data from the Post-treatment Phase will occur after all subjects have 
completed the Post-treatment Phase.  All Long-term Outcome Phase data will be analyzed after 
the last subject completes the 1 Year Visit. 
Details of the safety and efficacy analyses are provided below.  A separate statistical analysis 
plan will document further details of the statistical methods to be employed including any 
changes to planned analyses specified within this protocol.  The analysis plan will be finalized 
prior to any unblinding of study data by the Sponsor.  Unless otherwise specified, all statistical 
tests will be 2-sided at alpha level 0.05 and for exploratory purposes only.  All statistical 
calculations will be completed using the latest version of SAS®.  Unless otherwise specified, all 
summaries will be by dose cohort and the placebo patients from all cohorts will be pooled.   
The Intent-to-Treat population will be defined as all subjects randomized into the study who 
receive any amount of study drug; efficacy analyses will be performed on this Intent-to-Treat 
population. 
The Safety population will be defined as all subjects enrolled into the study who receive any 
amount of study drug.  Safety analyses will be performed on this Safety population. 
In general, data collected prior to dosing will serve as Baseline values for the evaluation of data 
collected during the Post-treatment Phase. 

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10.3.1 
Primary Endpoints 
The primary endpoints are the following safety assessments during the Post-treatment Phase: 
 Incidence of TEAEs 
 Incidence of all-cause mortality through Week 36 PMA 
 Incidence of treatment-related AEs 
 Absolute and changes from Baseline in laboratory parameters 
 Absolute and changes from Baseline in vital signs 
All AEs as recorded by the Investigator will be assigned a Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class by the Sponsor for reporting 
purposes.  Summaries of AEs and deaths will include the number and percentage of subjects who 
experienced these events for each dose cohort and placebo.  AEs will be further summarized by 
preferred term and system organ class for each dose cohort and placebo. 
Descriptive statistics (mean, standard deviation, median, interquartile range, minimum, and 
maximum) will be computed by treatment group and overall for measured values and change 
from Baseline of clinical laboratory parameters and vital signs. 
Summaries of safety data will be descriptive with no inferential analyses planned. 
10.3.2 
Secondary Endpoints 
The number and percentage of subjects will be summarized by dose cohort and placebo for each 
of the following categorical assessments: 
 Incidence of BPD or death at 36 Weeks PMA 
 Severity of BPD (mild, moderate, severe) at 36 Weeks PMA 
 Complications of prematurity during the Post-treatment Phase (diagnosis of sepsis, 
pneumothorax, clinically significant PDA requiring treatment or ligation, necrotizing 
enterocolitis requiring treatment or surgery, intraventricular hemorrhage [including 
highest grade], periventricular leukomalacia, and retinopathy of prematurity [including 
stage]) 

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Descriptive statistics (mean, standard deviation, median, interquartile range, minimum, and 
maximum) will be computed by dose cohort and placebo for each of the following continuous 
assessments: 
 Duration (number of days) of invasive and noninvasive mechanical ventilation during the 
Post-treatment Phase 
 Duration (number of days) of supplemental oxygen during the Post-treatment Phase 
 Duration (number of days) of postnatal steroids (eg, hydrocortisone, dexamethasone, 
methylprednisolone) for the prevention and/or treatment of evolving BPD during the 
Post-treatment Phase 
 Duration (number of days) of hospitalization admission (inclusive of neonatal intensive 
care unit and step-down unit admission times) during the Post-treatment Phase 
 RSS at 36 Weeks PMA and a summary across all time points collected 
 Tracheal aspirate cell count and differential at 7 days postdose 
Kaplan-Meier curves will be constructed to assess the following time to event variables: 
 Time to discharge from the hospital 
 Time to end of mechanical ventilation 
 Time to end of supplemental oxygen 
 Time to end of postnatal steroid use 
 Time to all-cause mortality  
The appropriate statistical test may be applied to each endpoint to allow for comparison between 
the dose cohorts and placebo. 
10.4 
INTERIM ANALYSIS 
Enrollment between cohorts will pause for data review by an external DMC to evaluate the data 
available before proceeding to the next cohort.  The constitution and responsibilities of the DMC 
will be detailed in a DMC charter to be agreed with the members at the inaugural meeting.  The 
endpoints of interest for the DMC review are listed in Section 10.3.1. 
10.5 
OTHER ANALYSES 
Exploratory analyses may be conducted based on available study data. 

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10.6 
DATA LISTINGS AND SUMMARIES 
All data gathered in this study will be presented in summary tables and listings as described in 
the Statistical Analysis Plan. 
10.7 
DATA MONITORING COMMITTEE 
A DMC will be established for the study, comprised of independent members including 
physicians knowledgeable in the treatment of complications of prematurity.  A meeting will 
occur after each of the first 2 cohorts have been enrolled, as detailed in the DMC charter.  The 
DMC will make dose escalation recommendations based on review of safety data.  The criteria 
for dose escalation are based on the occurrence of AEs and/or DLTs that are unrelated to the 
underlying conditions or concomitant medications during the initial safety review period for each 
dosing cohort.  The DMC may recommend stopping dose escalation at any point based on 
available data and sufficient scientific rationale. 
All analyses will be prepared by an independent external consultant and reviewed by the DMC 
as defined in the DMC charter.  The Sponsor (with the exception of Global Drug Safety and 
Regulatory Affairs personnel involved in safety reporting) will only have access to blinded study 
data until the completion of the study.  A separate analysis plan will be prepared for these 
analyses. 
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG 
United Therapeutics will supply UNEX-42 for administration in the study.  UNEX-42 will be 
provided in 5-mL vials each containing 2 mL of sterile solution.  The phospholipid content of the 
solution will be expected to be 100 to 500 pmol/mL.  The exact concentration will be provided at 
the time of CSM manufacture and release testing.  
Placebo will be phosphate-buffered saline provided in vials matching UNEX-42 in color, size, 
and shape. 

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11.2 
LABELING 
Each vial of UNEX-42 or placebo will be labeled in accordance with all applicable regulations 
and Good Manufacturing Practice guidelines.  A description of the pharmaceutical properties and 
composition of the formulation of UNEX-42 is provided in the Investigator’s Brochure. 
11.3 
STORAGE AND HANDLING OF CSM 
UNEX-42 is stored at -70±10°C.  Once thawed, UNEX-42 cannot be refrozen for reuse. 
11.4 
SUPPLY AND RETURN OF CLINICAL STUDY MATERIAL 
Study sites will be supplied with a sufficient quantity of CSM to begin enrollment in the study.  
Appropriate arrangements will be made for resupply as needed based on enrollment rates. 
UNEX-42, including both used and unused vials, should be destroyed by the study site and 
documented according to institutional policy following consultation with the Sponsor and after 
final drug accountability by Sponsor personnel. 
11.5 
DRUG ACCOUNTABILITY 
The Investigator is responsible for CSM accountability and reconciliation.  The Investigator or 
his/her designee will be responsible for maintaining accurate records of the quantity and dates of 
all investigational product supplies received, and the amount administered to each subject.  The 
quantity of any investigational product lost, missing, destroyed, etc must also be accounted for 
and documented. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
UNITED STATES FDA OR APPLICABLE REGULATORY REQUIREMENTS 
The study will be conducted in accordance with the International Council for Harmonisation 
(ICH) and Good Clinical Practice (GCP) guidelines and all applicable national regulations.  The 
Sponsor will obtain the required approval from each national regulatory authority to conduct the 
study.  During the conduct of the study, an annual safety report will be compiled by the Sponsor 
for submission to those regulatory authorities and IRBs/IECs as required.  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. 

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12.2 
INFORMED CONSENT REQUIREMENTS 
Before a subject is enrolled in the study, the Investigator or his/her designees must explain the 
purpose and nature of the study, including potential benefits and risks and all study procedures to 
the subject's parent/guardian.  The subject's parent/guardian 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's parent/guardian and the original will be retained in the study 
site’s records. 
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
Prior to study initiation at each site, the Investigator will obtain approval for the study from an 
appropriate IRB/IEC and provide the Sponsor with a copy of the approval letter.  The IRB/IEC 
must also review and approve the study site’s ICF and any other written information provided to 
the subject's parent/guardian prior to enrollment, as well as any advertising materials used for 
subject recruitment.  Copies of the ICF and advertising materials must be forwarded to the 
Sponsor for review before submission to the IRB/IEC prior to the start of the study. 
If, during the study, it is necessary to amend either the protocol or the ICF, the Investigator is 
responsible for obtaining IRB/IEC approval of these amended documents prior to 
implementation.  Copies of the IRB/IEC correspondence and approval letters must be sent to the 
Sponsor. 
During the conduct of the study, an annual progress report will be compiled by the Sponsor for 
submission to IRBs/IECs as required. 
A written summary of the study will be provided by the Investigator to the IRB/IEC following 
study completion or termination according to the IRB or IEC standard procedures.  Additional 
updates will also be provided in accordance with the IRB/IEC’s standard procedures. 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical study, the following documents will be provided to the 
site:  Investigators’ Brochure, Protocol, ICF, Budget Agreement, and eCRF. 

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The site will be required to provide the following documents to United Therapeutics Corporation 
or designee prior to study start:  Signature page of the protocol, Form FDA 1572, Financial 
Disclosure Form, IRB/IEC composition documentation, IRB/IEC protocol and informed consent 
approval letters, and Curriculum Vitae of study staff listed on the Form FDA 1572. 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  United Therapeutics 
Corporation, the FDA or other regulatory bodies, and the IRB/IEC governing this study may 
inspect the medical records of any subject involved in this study.  The Investigator may release 
the subject’s medical records to employees or agents of the Sponsor, the IRB/IEC or the FDA or 
appropriate local regulatory agencies for purposes of checking the accuracy of the data.  A 
number will be assigned to all subjects and any report published will not identify the subject’s 
name. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially adversely affect the safety of participating subjects 
or that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, duration of therapy, assessment variables, the number of subjects treated, or 
subject selection criteria may be made only after consultation between United Therapeutics 
Corporation or its designee and the Investigator. 
All protocol amendments must be submitted to and approved by the appropriate regulatory 
authorities and IRB/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. 

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

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14 
REFERENCES 
Ahn SY, Chang YS, Kim JH, et al.  Two-year follow-up outcomes of premature infants enrolled 
in the phase I trial of mesenchymal stem cells transplantation for bronchopulmonary dysplasia.  J 
Pediatr.  2017;185:49-54. 
Ballard RA, Keller RL, Black DM, et al.  Randomized trial of late surfactant treatment in 
ventilated preterm infants receiving inhaled nitric oxide.  J Pediatr.  2016;168:23-29. 
Beam KS, Aliaga S, Ahlfeld SK, et al.  A systematic review of randomized controlled trials for 
the prevention of bronchopulmonary dysplasia in infants.  J Perinatol.  2014;34(9):705-710. 
Bruno S, Grange C, Deregibus MC, et al.  Mesenchymal stem cell-derived microvesicles protect 
against acute tubular injury.  J Am Soc Nephrol.  2009;20(5):1053-1067. 
Chang YS, Ahn SY, Yoo HS, et al.  Mesenchymal stem cells for bronchopulmonary dysplasia: 
phase 1 dose-escalation clinical trial.  J Pediatr.  2014;164(5):966-972. 
Collins CT, Makrides M, McPhee AJ, et al.  Docosahexaenoic acid and bronchopulmonary 
dysplasia in preterm infants.  N Engl J Med.  2017;376:1245-1255. 
Donohue PK, Gilmore MM, Cristofalo E, et al.  Inhaled nitric oxide in preterm infants: a 
systematic review.  Pediatrics.  2011;127:e414-e422. 
Gatti S, Bruno S, Deregibus MC, et al.  Microvesicles derived from human adult mesenchymal 
stem cells protect against ishaemia-reperfusion-induced acute and chronic kidney injury.  
Nephrol Dial Transplant.  2011;26(5):1474-1483. 
Jobe AH, Bancalari E.  Bronchopulmonary dysplasia.  Am J Respir Crit Care Med.  
2001;163:1723-1729. 
Kordelas L, Rebmann V, Ludwig AK, et al.  MSC-derived exosomes: a novel tool to treat 
therapy-refractory graft-versus-host disease.  Leukemia. 2014;28(4):970-973. 
Lai RC, Arslan F, Lee MM, et al.  Exosome secreted by MSC reduces myocardial 
ishchemia/reperfusion injury.  Stem Cell Res.  2010;4(3):214-222. 
Lee C, Mitsialis SA, Aslam M, et al.  Exosomes mediate the cytoprotective action of 
mesenchymal stromal cells on hypoxia-induced pulmonary hypertension.  Circulation.  
2012;126(22):2601-2611. 
Torchin H, Ancel P, Goffinet F, et al.  Placental complications and bronchopulmonary dysplasia: 
EPIPAGE-2 cohort study.  Pediatrics.  2016;137(3):e20152163. 
Watterberg KL.  Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia.  
Pediatrics.  2010;126:800-808. 

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Willis GR, Fernandez-Gonzalez A, Anastas J, et al.  Mesenchymal stromal cell exosomes 
ameliorate experimental bronchopulmonary dysplasia and restore lung function through 
macrophage immunomodulation.  Am J Respir Crit Care Med.  2018;197(1):104-116. 
 

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15 
APPENDICES 
15.1 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Principal Investigator or a designated member of his/her staff will probe each subject’s 
parent/guardian for any adverse events (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 is the subject doing (feeling)?” 
Based on the parent/guardian’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. 

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Definitions of Intensity, Seriousness, Causality, and Outcome 
INTENSITY 
An assessment of the relative intensity (severity) of an AE should be based on the NCI-CTCAE, 
Version 5.0.  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.  
SERIOUSNESS 
A serious adverse event (SAE) is one that represents an actual or potential significant hazard.  
This includes, but is not limited to, an event that is fatal, life-threatening, permanently or 
severely disabling, requires or prolongs inpatient hospitalizationa, is a congenital abnormality or 
is medically significant (important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent 1 of the outcomes listed in this definition). 
aHospitalizations that would not be considered SAEs include those for: 
 Routine treatment or monitoring of the study indication not associated with any 
deterioration in condition. 
 Treatment which was elective or preplanned, for a pre-existing condition not associated 
with any deterioration in condition (eg, preplanned operation which does not lead to 
further complications etc). 
 Treatment of an emergency, in an outpatient setting for an event not fulfilling any of the 
definitions of serious as given above and not resulting in hospital admission. 
CAUSALITY 
An estimate of causality between a specified AE and the study drug is made by the Investigator.  
Several factors should be considered when determining causality.  These factors include 
temporal relationship to 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: 

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 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, 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, 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. 
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 are 
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.