Clinical trial NCT02261883
Conditions: Persistent Pulmonary Hypertension of the Newborn
Keywords: PPHN
Sponsor: United Therapeutics
Start date: 2015-07-29; Completion date: 2023-05-17
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study assessed the safety and treatment effect of intravenous (IV) Remodulin as an add-on therapy in neonates with persistent pulmonary hypertension of the newborn (PPHN).

Detailed description:
This study was designed to investigate if the addition of Remodulin reduced the rate of clinical worsening (defined as the need for additional treatment targeting PPHN, need for extracorporeal mechanical oxygenation \[ECMO\], or death) in neonatal subjects with PPHN who did not show an adequate response to inhaled nitric oxide (iNO). This study was part of a pediatric investigation plan agreed upon by the EMA (EMEA 000207-PIP01-08-M08).

Arms: arm 1: The starting dose was 1 ng/kg/min (not to exceed to 2 ng/kg/min) and was titrated by up to 2 ng/kg/min every 2 hours, as tolerated and clinically indicated by the Investigator. Doses were titrated and maximized throughout the study until the desired clinical effect was observed or to each individual subject's maximally tolerated dose. There was no maximum dose. arm 2: The starting dose was 1 ng/kg/min (not to exceed to 2 ng/kg/min) and was titrated by up to 2 ng/kg/min every 2 hours, as tolerated and clinically indicated by the Investigator. Doses were titrated and maximized throughout the study until the desired clinical effect was observed or to each individual subject's maximally tolerated dose. There was no maximum dose.
Interventions: intervention 1: IV Remodulin intervention 2: Placebo
Intervention descriptions: intervention 1: Treprostinil is a chemically stable tricyclic analogue of prostacyclin. intervention 2: Sodium citrate, sodium chloride, sodium hydroxide pellets, metacresol, and citric acid (anhydrous).

Protocol documents:
Prot_000.pdf: 
 
 
RIV-PN-201 Protocol Amendment 3  
Version 15 Apr 2016 
Confidential 
Page 1 
Intravenous Remodulin (Treprostinil) as Add-on Therapy for the 
Treatment of Persistent Pulmonary Hypertension of the Newborn:  
A Randomized, Placebo-Controlled, Safety and Efficacy Study  
IND Number 67,561 
EudraCT Number: 2013-004963-30 
Protocol RIV-PN-201 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
FINAL 12 Aug 2013 
Amendment 1: 
FINAL 29 Aug 2014 
Amendment 2: 
Amendment 3: 
FINAL 30 Oct 2015 
FINAL 15 Apr 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential and Proprietary, United Therapeutics Corporation 
All content contained herein is confidential and propriety 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. 
© 2016 United Therapeutics Corporation 


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LIST OF CONTACTS FOR STUDY 
 
 
Study Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive  
Research Triangle Park, NC, USA 27709 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 


United Therapeutics Corp. 
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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “Intravenous Remodulin (treprostinil) as Add-on 
Therapy for the Treatment of Persistent Pulmonary Hypertension of the Newborn:  A 
Randomized, Placebo-Controlled, Safety and Efficacy Study,” Amendment 3 dated 
15 Apr 2016, and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation (ICH) Guideline for 
Good Clinical Practice, Declaration of Helsinki, and applicable Food and Drug 
Administration regulations/guidelines set forth in 21 Code of Federal Regulations Parts 50, 
54, 56 and 312 and any local regulations per country. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of United Therapeutics Corp.  
I have read the current Clinical Investigators’ Brochure for Treprostinil for Injection and 
acknowledge that review of the information contained in the Clinical Investigators’ Brochure 
is a requirement for Investigators before using treprostinil in this clinical trial. 
This protocol has been received for information only and must not be implemented before all 
necessary regulatory agency and ethics approval documents have been obtained. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 


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PROTOCOL SYNOPSIS 
Title  
Intravenous Remodulin (treprostinil) as Add-on Therapy for the Treatment of 
Persistent Pulmonary Hypertension of the Newborn:  A Randomized, 
Placebo-Controlled, Safety and Efficacy Study  
Study Phase 
Phase II 
Indication 
Persistent Pulmonary Hypertension of the Newborn (PPHN) 
Primary 
Objective 
To explore the safety and treatment effect of intravenous (IV) Remodulin as 
add on therapy in neonates with PPHN compared to placebo.  Efficacy will be 
assessed by a composite endpoint of clinical worsening through Day 14 as 
defined by one of the following: 
 Death 
 Initiation of extracorporeal mechanical oxygenation (ECMO) per 
institutional policies 
 Need for additional treatment (initiation of an additional targeted 
pulmonary vasodilator therapy [e.g., phosphodiesterase-5 inhibitor 
[PDE-5i], endothelin receptor antagonist [ERA], prostanoid, 
L-citrulline]) 
Secondary 
Objectives 
To assess the effect of IV Remodulin as add on therapy in neonates with 
PPHN compared to placebo in the following: 
 Change in Oxygenation Index (OI) from Baseline to Hours 12, 24, 72, 
Days 7 and 14 and/or prior to study drug discontinuation/weaning 
 Change in PaO2 /FiO2 (P/F ratio) from Baseline to Hours 12, 24, 72 
 Change in pre- and post-ductal oxygen saturation (SpO2) from 
Baseline to Hours 6, 12, 24 and 72 
 Time to discontinuation of inhaled nitric oxide (iNO)  
 Time on mechanical ventilation  
 Time to initiation of ECMO 
 Time to clinical worsening 
 Change in N-terminal pro-Brain Naturetic Peptide (NT-proBNP)   
 Safety (adverse events (AEs), clinical laboratories, and physical exam 
findings)  
To evaluate treprostinil pharmacokinetics in neonates with PPHN 
Study Design 
Randomized, double-blind, placebo-controlled, multi-center, comparative 
study 
Sample Size 
The study may enroll approximately 70 subjects to ensure at least 66 
evaluable subjects; no more than 32 evaluable subjects with a diagnosis of 
PPHN associated with congenital diaphragmatic hernia (CDH) will be 
enrolled. 


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Summary of 
Subject 
Eligibility 
Criteria 
Eligible subjects will be at least 34 weeks gestational age, 2 kg at screening 
and have a diagnosis of PPHN.  The subject must have two consecutive OIs 
of 15 or greater, separated by at least 30 minutes, after having received iNO 
for at least 3 hours prior to randomization and initiation of study drug. 
Drug Dosage  
and 
Formulation 
Study drug (Remodulin or matching placebo) will be supplied in 20mL clear 
glass vials containing 1mg/mL treprostinil or placebo.  Each vial must be 
discarded within 30 days after first opening.  A new vial should be used for 
each subject.  
Study drug must be diluted with high-pH glycine diluent (Sterile Diluent for 
Remodulin, Sterile Diluent for Flolan, or Sterile Diluent for Epoprostenol 
Sodium), Sterile Water for Injection, or 0.9% Sodium Chloride Injection, 
prior to administration as a continuous intravenous infusion via an indwelling 
central venous catheter, using an infusion pump designed for intravenous 
drug delivery.  If clinically necessary, a peripheral intravenous cannula may 
be used for short term administration of study drug.  A dedicated IV line or 
port/lumen is required for the IV administration of study drug.  
In the event dedicated central venous access cannot be established, or in the 
opinion of the Investigator the patient is too unstable to attempt to establish a 
dedicated central venous access line for IV administration of study drug, 
study drug may be initiated as a continuous subcutaneous (SC) infusion at the 
discretion of the Investigator.  Subjects initiated on IV administration of study 
drug who lose venous access may be transitioned to SC administration.  
Dilution of study drug is usually not required for continuous SC 
administration in an adult population; however, based upon the selected SC 
infusion pump flow rate capabilities, the subject’s dose weight, and dose in 
this neonate patient population, dilution will likely be required for SC 
administration (especially for smaller babies and lower doses, or during 
weaning of study drug).  If dilution is required for SC administration, Sterile 
Water for Injection or 0.9% Sodium Chloride for Injection should be used. 
The line should not be flushed to avoid an accidental over dosage. 
Initiating study drug 
Study drug will be initiated at 1ng/kg/min.  The dose of study drug should be 
increased by up to 2ng/kg/min every 2 hours as tolerated and clinically 
indicated by the physician.  As some subcutaneous infusion pumps may not 
accommodate a starting dose of exactly 1ng/kg/min, the site may proceed 
with a starting dose as close to 1ng/kg/min as possible.  The initial starting 
dose should not exceed 2ng/kg/min and should be increased by approximately 
1-2ng/kg/min every 2 hours as tolerated and clinically indicated by the 
physician. 


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Dose titration 
The dose escalation should continue in up to 2ng/kg/min increments every 2 
hours, as tolerated and clinically indicated by the physician, while the OI is 
≥15 (or the FiO2 requirement is ≥60%, if the OI is not calculated) in the 
absence of dose-limiting adverse events (e.g., due to systemic hypotension).  
When the OI is between 10-14 and the study drug dose is ≤10ng/kg/min, the 
dose should continue to be increased; if the study drug dose is >10ng/kg/min 
and the OI is between 10-14, any further dose escalation will be left to the 
discretion of the clinicians/investigator according to the clinical condition of 
the subject, and the perceived need for additional pulmonary vasodilation.     
The dosing of study drug is based upon the OI (as long as it is calculated) and 
then by the FiO2 as needed.  Suggested dose titration parameters are listed in 
the table below. 
OI 
FiO2 
(To be used 
when OI is not 
calculable) 
Dosing Strategy 
≥15 
≥60% 
Dose increase, as tolerated 
10-14 
-- 
Current Remodulin dose >10ng/kg/min  
Hold dose or dose increase if clinical condition warrants 
further pulmonary vasodilation. 
10-14 
-- 
Current Remodulin dose ≤10ng/kg/min  
Dose increase, as tolerated  
<10 
<60% 
Begin weaning. The iNO should be weaned and 
discontinued prior to initiating weaning of study drug. 
Dose maintenance 
Once the target therapeutic goal has been reached (i.e., OI <10 or FiO2 <60%) 
the current dose of study drug should continue for at least 12 hours prior to 
beginning to wean study drug.   
Dose Wean  
Down titration will begin once the subject is no longer receiving iNO and the 
OI is <10 (or the FiO2 is <60% if the OI is not calculated); iNO should be 
weaned and discontinued prior to initiating weaning of study drug. 
It is recommended the dose of study drug be decreased by no more than 
10ng/kg/min per day (in divided increments, either in the same manner as the 
dose was increased or as determined by the Investigator).  Faster weaning 
may occur if required per subject care.   


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Subjects who have residual or chronic pulmonary hypertension that does not 
fully resolve by Day 14 may continue to receive study drug for up to an 
additional 14 days (for a total of up to 28 days) per the Investigator’s 
discretion, if clinically indicated. 
Control Group Placebo  
Route of  
Administration 
Continuous intravenous infusion; administration as a continuous 
subcutaneous infusion may be used in subjects in whom dedicated central 
venous access cannot be established, who are too unstable to attempt to 
establish a dedicated central venous access line for IV administration of study 
drug, or for subjects initiated on an IV infusion of study drug who lose 
venous access. 
Procedures 
Once parental or legal guardian consent has been provided, the subject will 
undergo the appropriate screening procedures to determine eligibility.  After 
the inclusion/exclusion criteria have been confirmed, the subject will be 
enrolled and randomized via the IWRS. 
Study drug initiation and administration phase 
 First 72 hours 
o Vital signs and OI assessments will occur approximately every 
six hours (6 ± 2 hours) while on study drug.   
o BP, HR and SpO2, and doses of inotropes will also be collected 
with each study drug dose change.  
o Physical examination and NT-proBNP will be collected daily 
for the first 72 hours. 
o After 24 hours (+6 hours) on study drug, one blood sample 
will be collected for pharmacokinetic (PK) analysis.  
 Day 4 throughout duration of study drug treatment 
o Assessments will occur at least once daily including vital 
signs, FiO2, blood gasses, and OI assessment. 
o BP, HR, SpO2 and doses of inotropes will also be collected 
with each study drug dose change. 
 Day 7 and Day 14 
o In addition to the daily assessments, physical examination, 
clinical laboratory assessments, echocardiogram, and 
NT-proBNP will be performed.  
Study drug weaning and discontinuation 
 Immediately prior to weaning study drug 
o Key assessments include physical examination, vital signs, 
clinical laboratory assessments, echocardiogram, OI 
assessment, FiO2, NT-proBNP, inotrope support, and PK 
sample collection. 


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 Every 24 hours while weaning 
o Assessments will occur once each day while weaning study 
drug and include vital signs, physical examination, FiO2, and 
mean airway pressure (MAP) if still on mechanical ventilation.  
o BP, HR, SpO2, FiO2, and doses of inotropes will also be 
collected with each study drug dose change. 
Follow-up 
 Within 12 hours after last dose of study drug 
o Physical examination, vitals, FiO2, blood gasses, MAP, clinical 
laboratory assessments, and NT-proBNP 
 48 hours after the last dose of study drug 
o Vitals, clinical laboratory assessments, and echocardiogram 
 Post-treatment data will be collected until subject is withdrawn from 
the study, death, time of hospital discharge, or until 4 weeks after last 
dose of study drug, whichever comes first. 
o The following key assessments will occur at time of 
withdrawal from study, hospital discharge, or at 4 weeks after 
last dose of study drug, whichever comes first: physical exam, 
vital signs, and clinical laboratory assessments. 
o Additionally, time on mechanical ventilation, time on inhaled 
iNO, and time of initiation of EMCO (if applicable) will be 
recorded.  
o The subject’s participation in the study will conclude at the 
time of hospital discharge, death, withdrawal from the study, 
or at 4 weeks after last dose of study drug, whichever comes 
first. 
 Subjects with ongoing AEs at the time of study 
withdrawal or hospital discharge will continue to be 
followed for their AEs until either resolution (or return 
to normal or Baseline values), until judged by the 
Investigator to no longer be clinically significant, or 
until 4 weeks after last dose of study drug.  All SAEs 
will be followed until resolution, death, or the subject 
is lost to follow-up, even if they are ongoing more than 
4 weeks after the last dose of study drug. 
Statistical 
Considerations 
Based on the systematic review of use of nitric oxide for respiratory failure in 
infants by Finer and Barrington, 57.9% (194/335) subjects in the control 
group had an outcome of death or requirement for EMCO.  In this study, 
assuming 60% subjects in placebo group and 30% subjects in Remodulin 
group with an outcome of death, requirement for EMCO, or need for 
additional PAH therapy, we calculated that 66 subjects (33 subjects per 
treatment group) will have at least 80% power to show a significant 
difference in favor of Remodulin at alpha level of 0.05 (one-sided test).  


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Approximately seventy subjects are planned to be randomized (1:1) to either 
receive treatment with Remodulin or placebo on top of the standard of care.    
Sponsor 
United Therapeutics Corp. 
55 TW Alexander Dr 
PO Box 14186 
Research Triangle Park, NC, USA  27709 


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TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY .................................................................................... 2 
INVESTIGATOR’S AGREEMENT ..................................................................................... 3 
PROTOCOL SYNOPSIS ....................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 10 
Table of In-text Tables .......................................................................................................... 14 
Table of In-text Figures ........................................................................................................ 14 
LIST OF ABBREVIATIONS .............................................................................................. 15 
1 BACKGROUND AND RATIONALE .......................................................................... 17 
1.1 
DEFINITION OF CLINICAL PROBLEM ............................................................ 17 
1.2 
REMODULIN (TREPROSTINIL) BACKGROUND ........................................... 18 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN DISEASE / 
CONDITION ............................................................................................................. 19 
1.4 
CLINICAL HYPOTHESIS ...................................................................................... 19 
2 OBJECTIVES ................................................................................................................. 20 
2.1 
PRIMARY OBJECTIVE ......................................................................................... 20 
2.2 
SECONDARY OBJECTIVES ................................................................................. 20 
3 EXPERIMENTAL PLAN .............................................................................................. 21 
3.1 
STUDY DESIGN ....................................................................................................... 21 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ........................................... 23 
3.3 
CLINICAL ASSESSMENTS ................................................................................... 26 
3.3.1 Efficacy ................................................................................................................... 26 
3.3.1.1 Assessment of Clinical Worsening ............................................................... 26 
3.3.1.2 Oxygenation Index (OI) ................................................................................ 27 
3.3.1.3 Mean Airway Pressure (MAP) ..................................................................... 28 
3.3.1.4 Fraction of Inspired Oxygen (FiO2) ............................................................ 28 
3.3.1.5 Blood Gas and Lactate .................................................................................. 28 
3.3.1.6 Echocardiogram (ECHO) ............................................................................. 29 
3.3.1.7 N-Terminal pro B-Type Natriuretic Peptide (NT-proBNP) ..................... 29 
3.3.2 Safety ...................................................................................................................... 30 
3.3.2.1 Physical Examination ................................................................................... 30 
3.3.2.2 Vital Signs ...................................................................................................... 30 
3.3.2.3 Clinical Laboratory Assessments ................................................................ 30 
3.3.2.4 Adverse Events (AEs) ................................................................................... 31 
3.3.3 Pharmacokinetics .................................................................................................. 31 
3.4 
NUMBER OF CENTERS ........................................................................................ 32 
3.5 
NUMBER OF SUBJECTS ....................................................................................... 32 


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3.6 
ESTIMATED STUDY DURATION ....................................................................... 32 
4 SUBJECT ELIGIBILITY .............................................................................................. 33 
4.1 
INCLUSION CRITERIA ......................................................................................... 33 
4.2 
EXCLUSION CRITERIA ........................................................................................ 33 
4.3 
PRESCRIBED THERAPY ...................................................................................... 34 
4.3.1 Concomitant Medications ..................................................................................... 34 
4.3.1.1 Inotropic Dose Changes ................................................................................ 34 
4.3.1.2 Initiation of a Pulmonary Vasodilator Therapy ......................................... 35 
5 SUBJECT ENROLLMENT ........................................................................................... 35 
5.1 
TREATMENT ASSIGNMENT ............................................................................... 35 
5.2 
RANDOMIZATION ................................................................................................. 35 
5.3 
BLINDING ................................................................................................................ 35 
6 DRUGS AND DOSING .................................................................................................. 36 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE ................................ 36 
6.1.1 General Information ............................................................................................. 36 
6.1.2 Dose and Administration of Study Drug ............................................................. 36 
6.1.2.1 Calculating the Study Drug Dilution ........................................................... 37 
6.1.3 Dose Initiation and Titration ................................................................................ 38 
6.1.4 Dose Weaning ......................................................................................................... 40 
6.1.5 Initiation of ECMO ............................................................................................... 40 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT .................................... 40 
6.3 
COMPLIANCE ......................................................................................................... 41 
7 EXPERIMENTAL PROCEDURES ............................................................................. 41 
7.1 
SCREENING ............................................................................................................. 41 
7.2 
BASELINE ................................................................................................................ 41 
7.3 
TREATMENT PHASE ............................................................................................. 42 
7.3.1 First 72 Hours ........................................................................................................ 42 
7.3.2 Study Day 4 Throughout Duration of Study Drug Therapy ............................. 42 
7.3.2.1 Study Day 7 and Day 14 ............................................................................... 43 
7.3.3 Study Drug Discontinuation ................................................................................. 43 
7.3.3.1 Prior to Weaning or Discontinuing Study Drug ........................................ 43 
7.3.3.2 Daily While Weaning Study Drug ............................................................... 44 
7.3.3.3 Study Drug Discontinuation ......................................................................... 44 
7.3.3.4 48 Hours after Study Drug Discontinuation ............................................... 45 
7.3.4 Follow-up/End of Study ........................................................................................ 45 
8 STUDY TERMINATION ............................................................................................... 46 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ...................................................... 46 


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8.2 
CRITERIA FOR TERMINATING THE STUDY ................................................. 46 
8.3 
CRITERIA FOR DISCONTINUING A SITE ....................................................... 47 
9 ADVERSE EVENT REPORTING ................................................................................ 47 
9.1 
DEFINITIONS .......................................................................................................... 47 
9.1.1 Adverse Event (AE) ............................................................................................... 47 
9.1.2 Serious Adverse Event (SAE) ............................................................................... 47 
9.1.3 Suspected Adverse Reaction ................................................................................. 48 
9.1.4 Unexpected Adverse Event ................................................................................... 48 
9.1.5 Disease Related Events .......................................................................................... 48 
9.2 
DOCUMENTATION OF ADVERSE EVENTS .................................................... 49 
9.3 
PERIOD OF OBSERVATION ................................................................................ 50 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ...................... 50 
9.5 
SAFETY REPORTS ................................................................................................. 51 
10 STATISTICAL CONSIDERATIONS .......................................................................... 51 
10.1 
DATA PROCESSING .............................................................................................. 51 
10.2 
SAMPLE SIZE .......................................................................................................... 51 
10.3 
ANALYSIS PLAN ..................................................................................................... 52 
10.3.1 
Primary Endpoint ......................................................................................... 52 
10.3.2 
Secondary Endpoints .................................................................................... 52 
10.3.3 
Safety Analyses .............................................................................................. 52 
10.4 
INTERIM ANALYSIS ............................................................................................. 53 
10.5 
OTHER ANALYSES ................................................................................................ 53 
10.6 
DATA LISTINGS AND SUMMARIES .................................................................. 53 
10.7 
DATA SAFETY MONITORING BOARD (DSMB) ............................................. 54 
11 PACKAGING AND FORMULATION ........................................................................ 54 
11.1 
CONTENTS OF STUDY DRUG ............................................................................. 54 
11.2 
LABELING ................................................................................................................ 54 
11.3 
STORAGE AND HANDLING OF STUDY DRUG ............................................... 55 
11.4 
SUPPLY AND RETURN OF CTM ......................................................................... 56 
11.5 
DRUG ACCOUNTABILITY ................................................................................... 57 
12 REGULATORY AND ETHICAL OBLIGATION ...................................................... 57 
12.1 
U.S. FDA OR APPLICABLE REGULATORY REQUIREMENTS ................... 57 
12.2 
INFORMED CONSENT REQUIREMENTS ........................................................ 57 
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
 ..................................................................................................................................... 58 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS ....................................... 58 
12.5 
SUBJECT CONFIDENTIALITY............................................................................ 59 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 59 


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13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION ......................... 59 
13.2 
STUDY DOCUMENTATION AND STORAGE ................................................... 60 
13.3 
STUDY MONITORING AND DATA COLLECTION ........................................ 60 
14 REFERENCES ................................................................................................................ 61 
15 APPENDICES ................................................................................................................. 63 
15.1 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS63 
Definitions of Intensity, Seriousness, Causality, and Action Taken ........................... 63 
Intensity ......................................................................................................................... 63 
Difference Between “Severe” and “Serious” ............................................................. 63 
Causality ....................................................................................................................... 63 
Action Taken with Test Agent* .................................................................................. 64 
Outcome ........................................................................................................................... 64 
AE/SAE Start Date verses Serious Date ....................................................................... 64 
AE/SAE Stop Date .......................................................................................................... 65 
15.2 
PHARMACOKINETIC SAMPLE PROCESSING ............................................... 66 
Collection, Processing and Shipment of Plasma Specimens ....................................... 66 
Specimen Processing .................................................................................................... 66 
Shipping Procedures .................................................................................................... 66 
15.3 
ADMINISTRATION OF REMODULIN ............................................................... 67 
 


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Table of In-text Tables 
Table 3-1 
Schedule of Events ........................................................................................... 24 
Table 3-2 
Blood Gasses .................................................................................................... 29 
Table 3-3 
Chemistries, Hematology and Liver Function Tests ........................................ 31 
Table 6-1 
Suggested Study Drug Dose Titration Parameters ........................................... 39 
Table 9-1 
Expected Events Attributable to PPHN (System Organ Class and 
PREFERRED Term, Ver. 17.0) ....................................................................... 49 
 
Table of In-text Figures 
Figure 3-1 
Design Schematic ............................................................................................. 22 
 


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LIST OF ABBREVIATIONS 
ABG 
Arterial blood gas 
ADP 
Adenosine diphosphate 
AE 
Adverse event 
ALT 
Alanine transaminase 
ASD 
Atrial septal defect 
AST 
Aspartate transaminase 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
°C 
Degree Celsius 
cAMP 
Cyclic adenosine monophosphate 
CBG 
Capillary blood gas 
CDH 
Congenital diaphragmatic hernia 
CHD 
Congenital heart disease 
CI 
Confidence interval 
CO2 
Carbon dioxide 
CV 
Coefficient of variation  
CYP 
Cytochrome  
DSMB 
Data safety monitoring board 
ECHO 
Echocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
ERA 
Endothelin receptor antagonist 
°F 
Fahrenheit 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
HCO3 
Bicarbonate 
HR 
Heart rate 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
IND 
Investigational new drug 
iNO 
Inhaled nitric oxide 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system  
kg 
Kilogram 
LFTs 
Liver function tests 
MAP 
Mean airway pressure 
MAS 
Meconium aspiration syndrome 


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min 
Minute 
mg 
Milligram 
mmHg 
Millimeters mercury 
mL 
Milliliter 
n 
Number 
ng 
Nanogram 
NICU 
Neonatal intensive-care unit 
NO-cGMP 
Nitric oxide cyclic guanosine monophosphate 
NT-proBNP 
N-terminal pro-Brain Naturetic Peptide 
OI 
Oxygenation index 
P/F 
Ratio of arterial oxygen concentration to the fraction of inspired oxygen 
(PaO2/FiO2) 
PA 
Pulmonary artery 
PaCO2 
Partial pressure of arterial carbon dioxide 
PAH 
Pulmonary arterial hypertension 
PaO2 
Partial pressure of arterial oxygen 
PCVC 
Percutaneous central venous catheter 
PDA 
Patent ductus arteriosus 
PDE-5i 
Phosphodiesterase type-5 inhibitor 
PFO 
Patent foramen ovale 
PGI2 
Prostacyclin 
PH 
Pulmonary hypertension 
PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetic 
PPHN 
Persistent pulmonary hypertension of the newborn 
PR 
Pulmonary regurgitation 
PvCO2 
Partial pressure of venous carbon dioxide 
PvO2 
Partial pressure of venous oxygen  
RDS 
Respiratory distress syndrome 
RR 
Respiratory rate 
RV 
Right ventricle 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Standard deviation 
SpO2 
Saturation of peripheral oxygen 
SvO2 
Mixed venous oxygen saturation 
Temp 
Temperature 
TR 
Tricuspid regurgitation  
US 
United States 
UVC 
Umbilical venous catheter 
VBG 
Venous blood gas 
VSD 
Ventricular septal defect 
µL 
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1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
As part of the normal birth transition, the pulmonary vascular resistance decreases as the 
lungs expand and the ductus arteriosus closes.  Persistent pulmonary hypertension of the 
newborn (PPHN) is the failure of the pulmonary vasculature to make this transition leading to 
diminished cardiac output and obligatory right to left shunting.  The incidence of PPHN has 
been estimated at 1.9/1000 live births with reported mortality ranging from 4-33% (1).  PPHN 
can be characterized as one of three types:  abnormally constricted pulmonary vasculature due 
to lung parenchymal diseases (e.g., meconium aspiration syndrome [MAS], respiratory 
distress syndrome [RDS] or pneumonia); normal lung parenchyma with remodeled pulmonary 
vasculature (idiopathic PPHN) or hypoplastic vasculature as seen in congenital diaphragmatic 
hernia [CDH]) (2).   
Management of PPHN is aimed at optimization of cardiac and lung function and reducing 
pulmonary vascular resistance.  This may include: mechanical ventilation, sedation, 
neuromuscular blockade, inotropic support, intravenous volume replacement, pulmonary 
vasodilator therapy, inhaled nitric oxide, or therapy with phosphodiesterase-5 inhibitors 
(PDE-5i) or endothelial receptor antagonists (ERA), and in severe cases, mechanical support 
with extracorporeal membrane oxygenation (ECMO).   
Currently, inhaled nitric oxide (iNO) is the only treatment for PPHN approved by the US 
Food and Drug Administration (FDA) and European Medicines Agency (EMA).  Inhaled 
nitric oxide was studied in two double-blind, placebo-controlled trials which enrolled 
neonates with hypoxic respiratory failure.  The objectives of these studies were to determine 
whether iNO would reduce the occurrence of death and/or initiation of ECMO in neonates 
with hypoxic respiratory failure.  In these trials, hypoxic respiratory failure was caused by 
MAS, pneumonia/sepsis, idiopathic PPHN, and RDS.  Both studies demonstrated that iNO 
reduced the need for ECMO in this population; however there was no difference in mortality 
in either study.  Neither of these trials included subjects with CDH.  Across these studies, 
approximately 30-40% of neonates did not respond to iNO (defined as a change from baseline 
in partial pressure of oxygen in arterial blood (PaO2) of ≤10 mmHg) (3,4).  In clinical 


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practice, critically ill neonates unresponsive to iNO will typically receive ECMO; however, 
an alternative option could include the addition of another pulmonary vasodilator in an effort 
to reduce the pulmonary vascular resistance.    
1.2 
REMODULIN (TREPROSTINIL) BACKGROUND 
Treprostinil is a chemically stable tricyclic analogue of prostacyclin (PGI2), which is 
approved for the treatment of pulmonary arterial hypertension (PAH) in the US, EU, and 
many other countries under the brand name Remodulin.  The pharmacology of treprostinil has 
been extensively characterized for the treatment of PAH using either a subcutaneous (SC) or 
intravenous (IV) continuous infusion.  A detailed description of preclinical and clinical 
information of treprostinil for injection is provided in the Investigator’s Brochure. 
The major pharmacological actions of treprostinil are direct vasodilatation of pulmonary and 
systemic arterial vascular beds and inhibition of platelet aggregation.  In vitro, treprostinil 
induced concentration dependent relaxation of rabbit isolated precontracted mesenteric 
arteries, inhibition of adenosine diphosphate (ADP), induced aggregation in human platelet 
rich plasma, and inhibition of ADP induced platelet aggregation in rat platelet rich plasma.  In 
animals, the vasodilatory effects of treprostinil reduce right and left ventricular afterload, 
increasing cardiac output and stroke volume.  Prostacyclins lower pulmonary artery pressure, 
increase cardiac output without affecting the heart rate, improve systemic oxygen transport as 
well as possibly reversing pulmonary arterial remodeling.  There is also increasing evidence 
that the ability to block the proliferation of pulmonary artery smooth muscle cells may 
contribute, along with the capacity to produce vasodilatation and inhibition of platelet 
aggregation, to the therapeutic effects of prostacyclins in the treatment of PAH.  The 
mechanism of action is therefore likely to be multifactorial. 
The efficacy of Remodulin in adult patients with PAH has been established in both the IV and 
SC routes (5-7).  However, there is a growing body of literature to support the use of 
Remodulin in the pediatric population.  Multiple published reports of the use of chronic 
Remodulin in children as young as 20 weeks of age have been reported without unexpected 
adverse events (AEs) (8-10).  Acute dosing of SC and IV Remodulin has been used in 
children as young as 6-8 weeks, including a case report published regarding the use of IV 


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Remodulin in a neonate for the treatment of PPHN (11-13).  In this case study, the subject 
was initiated at a dose of 1ng/kg/min of IV Remodulin and was titrated to a dose of 
4ng/kg/min.  Clinical response was noted within four days of initiation and down titration 
began after 10 days on therapy (11).   
In children and adults, the most frequent AEs reported with Remodulin were related to the 
known pharmacological properties of treprostinil.  These prostacyclin-related AEs are 
typically due to systemic effects that are characteristic of the prostacyclin class of medications 
(e.g., diarrhea, headache, nausea).  To date, well over 10,000 patients, which includes over 
1,000 pediatric patients (<12 years of age) and study subjects have been exposed to 
Remodulin for more than 11 years.   
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN DISEASE / 
CONDITION 
The pathophysiology of PPHN includes disruptions in the nitric oxide cyclic guanosine 
monophosphate (NO-cGMP), prostacyclin-cyclic adenosine monophosphate (cAMP), and 
endothelin signaling pathways.  Prostacyclin appears to increase during late gestation 
suggesting its importance in the cardiopulmonary transition of newborns.  An imbalance in 
the biosynthesis of prostacyclin and synthesis of the constrictor thromboxane A2 has been 
identified to occur in pulmonary arterial hypertension, and similar imbalances in vasoactive 
and vasoconstrictive mediators has been observed in studies of fetal pulmonary hypertension 
(14,15).  Current standard of care treatment for PPHN is iNO; however, approximately 40% 
of patients do not fully respond to iNO (2,3).  Treprostinil, a prostacyclin analogue, may work 
in synergy with iNO for the treatment of PPHN to enhance smooth muscle relaxation of the 
pulmonary vasculature.  Treprostinil may also decrease the inflammatory response and 
improve pulmonary vascular remodeling in these patients.   
1.4 
CLINICAL HYPOTHESIS 
This study aims to assess the safety and treatment effect of IV Remodulin as add-on therapy 
in neonatal subjects with PPHN as compared to placebo.  This study will enroll subjects with 
PPHN who do not show an adequate response to iNO (defined as an oxygenation index [OI] 
of 15 or greater after three hours of iNO therapy) with the hypothesis that the addition of 


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Remodulin will reduce the rate of clinical worsening defined as death, the need for ECMO, or 
the need for additional pulmonary vasodilator therapy as compared to placebo.  Additionally, 
this study aims to evaluate the dosing and pharmacokinetics of Remodulin in the neonatal 
population.    
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To explore the safety and treatment effect of IV Remodulin as add on therapy in neonates 
with PPHN compared to placebo.  Efficacy will be assessed by a composite endpoint of 
clinical worsening through Day 14 as defined by one of the following: 
 Death 
 Initiation of ECMO per institutional policies 
 Need for additional treatment (initiation of an additional targeted pulmonary 
vasodilator therapy [e.g., phosphodiesterase-5 inhibitor [PDE-5i], endothelin receptor 
antagonist [ERA], prostanoid, L-citrulline]; refer to Section 3.3.1.1.1). 
2.2 
SECONDARY OBJECTIVES  
To assess the effect of IV Remodulin as add on therapy in neonates with PPHN compared to 
placebo in the following: 
 Change in OI from Baseline to Hours 12, 24, 72, Days 7 and 14 and/or prior to study 
drug discontinuation/weaning 
 Change in PaO2 /FiO2 (P/F ratio) from Baseline to Hours 12, 24, 72 
 Change in pre and post-ductal oxygen saturation (SpO2) from Baseline to Hours 6, 12, 
24 and 72 
 Time to discontinuation of iNO  
 Time on mechanical ventilation  
 Time to initiation of ECMO 
 Time to clinical worsening 
 Change in N-terminal pro-Brain Naturetic Peptide (NT-proBNP)   
 Safety (AEs, clinical laboratories, and physical examination findings)  
To evaluate treprostinil pharmacokinetics in neonates with PPHN. 


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3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multi-center, comparative study that 
will enroll neonates in the intensive care unit (ICU) with PPHN.  Eligible subjects must have 
two consecutive OIs of 15 or greater, separated by at least 30 minutes, after having received 
iNO for at least 3 hours.  Once enrolled, subjects will be randomized to receive Remodulin 
(treprostinil) or placebo.   
This study is designed to evaluate the treatment effect of Remodulin as add-on therapy 
compared to placebo during a 14-day treatment period.  However, to assess continued safety 
in this neonatal population, subjects with residual or chronic pulmonary hypertension that 
does not fully resolve within 14 days may continue to receive study drug for up to an 
additional 14 days (up to 28 days total) per the Investigator’s discretion.  Post-treatment data 
will be collected until death, time of hospital discharge, time of withdrawal from study, or for 
4 weeks after last dose of study drug, whichever comes first.  Subjects with ongoing AEs at 
the time of hospital discharge will continue to be followed for their AEs until either resolution 
(or return to normal or Baseline values), until judged by the Investigator to no longer be 
clinically significant, or until 4 weeks after last dose of study drug.  All SAEs should be 
followed until resolution, death, or the subject is lost to follow-up, even if they are ongoing 
more than 4 weeks after last dose of study drug. 


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Figure 3-1 
Design Schematic 
 


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3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
No procedures specifically for purposes of this study should be performed before a parent or legal 
guardian has provided written informed consent.  All study-related events and activities including 
specific instructions, procedures, concomitant medications, and descriptions of AEs should be 
recorded in the appropriate source documents and electronic case report forms (eCRFs).  Table 3-1 
displays the overall schedule of events. 


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Table 3-1 
Schedule of Events  
 
 
 
Study Drug Initiation and Administration 
Study Drug Discontinuation 
Follow-up/Final 
Assessments 
Procedures 
Screening Baselinea First 72 hours 
of treatment 
Day 4 throughout 
duration of study 
drug treatmentb  
Day 7 and 
Day 14b 
Dose 
Changes 
Immediately 
Prior to Study 
Drug Weaning 
or 
Discontinuationk 
Every 24 hrs 
While  
Weaning p 
Study Drug 
Discontinuation 
(within 12 
hours)q 
48 hrs after 
Study Drug 
Discontinuationq 
Hospital 
discharge (after 
Day 14) /         
4 weeks after 
Study Drug 
Discontinuationb,c 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Maternal History  
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X(daily) 
 
Xb 
 
Xk 
X 
X 
 
X 
Vital Signsd 
X 
X 
Xd,o(q6 hrs)  
Xb(daily) 
Xb 
Xd 
Xk 
X 
X 
X 
X 
OI Assessmente 
X 
X 
Xe,o(q6 hrs) 
Xb,e(daily) 
Xb,e 
 
Xe,k 
 
 
 
 
FiO2 
X 
X 
Xo(q6 hrs) 
Xb(daily) 
X 
X 
Xk 
X 
X 
 
 
Mean Airway Pressuref 
X 
X 
Xe,o(q6 hrs) 
Xb,e (daily) 
X 
 
Xe,k 
X 
Xe 
 
 
Blood Gas/Lactateg 
X 
X 
Xe,o(q6 hrs) 
Xb,e (daily) 
Xb 
 
Xe,k 
 
Xe 
 
 
Clinical Laboratoriesh 
 
X 
 
 
Xb 
 
Xk 
 
X 
X 
X 
NT-proBNP 
 
X 
X(daily) 
 
Xb 
 
Xk 
 
X 
 
 
Echocardiogrami 
X 
 
 
 
Xb 
 
Xk 
 
 
X 
 
Clinical Worseningj 
 
X--- 
---X--- 
---X(through Day 14) 
X 
 
 
 
 
 
 
Pharmacokinetic Sample 
collection 
 
 
Xl (collected 
after 24 hrs of 
treatment) 
 
 
 
Xk 
 
 
 
 
Concomitant 
Medicationsm 
X 
X--- 
---X--- 
---X--- 
 
---X--- 
---X--- 
---X--- 
---X--- 
---X 
 
Record Doses of 
Inotropes/  
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Adverse Eventsn 
X 
X--- 
---X--- 
---X--- 
 
---X--- 
---Xn--- 
---X--- 
---X--- 
---X--- 
---Xn 
aScreening assessments can be used as Baseline values if they are conducted within 3 hours of randomization.  Length and weight will only be assessed at Baseline.  All 
doses of study drug will be calculated using Baseline weight.  Study drug initiation is Hour 0 on the first day of treatment. 
b The Day 4 and the 72 hour time point assessment will fall on the same calendar day.  A separate set of assessments should be captured for the Day 4 assessment.  Day 7 and 
Day 14 assessments should be performed even if the subject has discontinued study drug.  If subjects are discharged from the hospital prior to study Day 14, Day 14 
assessments should be completed prior to hospital discharge. Subjects may receive up to 28 days of study drug.  


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cHospital discharge or 4 weeks after discontinuation of study drug (whichever comes first). 
dVital signs include BP, HR, RR, temperature, and SpO2.  SpO2 will be collected both pre- and post-ductal for the first 72 hours.  BP, HR, and SpO2 will be collected with 
each study drug dose change.  
e OI will be calculated as long as the subject is on mechanical ventilation and arterial blood gasses (ABGs) are collected.   
f Collected for as long as the subject is on mechanical ventilation. 
gABGs will be collected as long as the subject has arterial access.  Venous or capillary blood gas will be collected thereafter.  Lactate will be drawn with each blood gas. 
h Clinical labs include: chemistries, hematology, and liver function tests.  Performed by institutional laboratory.  
I If subject had historic ECHO performed within 36 hours prior to time informed consent was signed, then ECHO does not need to be repeated at Screening.  A ±2 day 
window for Day 7 and Day 14 ECHO. 
jClinical worsening is assessed from Baseline to the conclusion of Day 14 or hospital discharge, whichever comes first.  Events occurring after Day 14 will not count towards 
the primary analysis of clinical worsening. 
k“Prior to wean” assessments will be collected after the dose has been maintained for at least 12 hours and no more than 1 hour prior to beginning to wean study drug.  
Assessments should be collected for subjects randomized to placebo; PK sample not required in subjects randomized to placebo.  In the event that the subject will continue to 
receive Remodulin beyond Day 28, prior to wean assessments should take place on Day 28. 
lA single PK sample will be collected after 24+6 hours of study drug dosing.  The dose should have been maintained for at least 2 hours prior to the sample collection time. 
mConcomitant medications will be captured up to 48 hours after the subject has stopped receiving study drug. 
nDocumentation of AEs will be recorded from the time informed consent is provided until subject is withdrawn from study, time of hospital discharge, or for 4 weeks after 
last dose of study drug, whichever comes first.  All SAEs should be followed until resolution, death, or the subject is lost to follow-up, even if they are ongoing more than 4 
weeks after completion of the subject’s last dose of study drug/final visit.  If the subject receives Remodulin after hospital discharge, beyond Day 56/End of study, or 
following withdrawal from the study, AEs/SAEs will be subject to AE/SAE reporting under local government post-marketing AE/SAE reporting requirements. 
oApproximately every 6 hours (± 2 hours). 
pNot required for subjects unblinded and identified on placebo, or subjects continuing on Remodulin beyond Day 28. 
qIn the event that study drug is not discontinued (i.e., the subject continues on Remodulin beyond Day 28), the “Study Drug Discontinuation” and “48 Hour after Study Drug 
Discontinuation” assessments will not be collected.  Follow-up/End of Study assessments will be performed. 


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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
3.3.1.1 
Assessment of Clinical Worsening 
Efficacy will be assessed by a composite primary endpoint of clinical worsening assessed at Day 14 
or hospital discharge, whichever comes first, as defined by one of the following events: 
 Death 
 Initiation of ECMO per institutional policies 
 Need for additional treatment (initiation of additional targeted pulmonary vasodilator 
therapy for PPHN) 
Clinical worsening will be evaluated from Baseline (initiation of study drug) to the time of 
discontinuation of study drug, discharge from the hospital, or at the conclusion of Day 14, 
whichever comes first.  Events occurring after the first 14 days of treatment will not count towards 
the primary endpoint.   
3.3.1.1.1 
Need for Additional Treatment 
The following criteria should be met prior to initiation of additional targeted pulmonary vasodilator 
therapy for PPHN (all criteria required):  
 OI measurement >20 
 In the clinical judgment of the Investigator, subject requires addition of another 
targeted pulmonary vasodilator therapy (e.g., PDE-5i, ERA, alternate prostanoid 
[epoprostenol, iloprost], L-citrulline) due to worsening of clinical status or 
unsatisfactory clinical response 
 Subject has received study drug for at least 24 hours and reached a minimum dose of 
10ng/kg/min, or is unable to tolerate further increases (e.g., due to systemic 
hypotension); OR  
o If less than 24 hours, subject has two consecutive OI measurements >30 
separated by at least one hour OR two consecutive arterial lactate levels of 
≥4mmol/L separated by at least one hour 
If an additional pulmonary vasodilator therapy is added after Day 14, the subject will not meet the 
primary endpoint definition of clinical worsening. 


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3.3.1.1.2 
Extracorporeal Mechanical Oxygenation (ECMO) 
ECMO will be initiated per institutional policy.  Any subject who initiates on ECMO during the 
first 14 days of the study will meet the definition of clinical worsening.  The initiation of ECMO 
after Day 14 will not be considered a clinical worsening event for the purposes of the primary 
endpoint of the study. 
3.3.1.1.3 
Death 
Any subject who dies within the first 14 days of the study will meet the definition of clinical 
worsening.  Deaths that occur after Day 14 will not be considered a clinical worsening event for the 
purposes of the primary endpoint of the study. 
All deaths will be reported as a serious adverse event (SAE) (Section 9). 
3.3.1.2 
Oxygenation Index (OI) 
The OI is an assessment of how much oxygen diffuses across the membranes of the lungs and into 
the blood when a subject inhales.  Higher OIs indicate an increased risk of poor subject outcomes 
because the subject is unable to get as much oxygen out of each breath.  Typically when the OI is 
greater than 40, ECMO is considered.  The OI is calculated as follows:  
OI= [MAP(mmHg) x FiO2(%) / PaO2(mmHg)] x 100 
An OI will be calculated at Screening, Baseline, approximately every 6 hours for the first 72 hours, 
daily starting on the fourth day of study drug for as long as the subject is on study drug, and within 
1 hour prior to weaning study drug for as long as the subject has arterial access for collection of 
arterial blood gases (ABGs) and is on mechanical ventilation (Table 3-1).  An OI will be collected 
on study Day 7 and Day 14 (as long as the subject has arterial access for collection of ABGs and is 
on mechanical ventilation) regardless if the subject has already been weaned from study drug.  
The OI should be used to guide study drug dosing.  When the OI cannot be calculated (i.e., no 
arterial access for ABGs and/or subject not on mechanical ventilation), FiO2 will be used to guide 
dosing (per Section 6.1.3).   


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3.3.1.3 
Mean Airway Pressure (MAP) 
The MAP is the mean pressure applied during positive-pressure mechanical ventilation (standard or 
high frequency) and will be recorded while the subject is mechanically ventilated at Screening, 
Baseline, approximately every 6 hours for the first 72 hours, daily starting on the fourth day of 
study drug for as long as the subject is on study drug, within 1 hour prior to weaning/discontinuing 
study drug, every 24 hours while weaning, and at the time of discontinuation of study drug.  The 
MAP will be recorded on study Day 7 and Day 14 (as long as the subject is on mechanical 
ventilation) regardless if the subject has already been weaned from study drug. 
3.3.1.4 
Fraction of Inspired Oxygen (FiO2) 
The FiO2 and route of delivery will be assessed at Screening, Baseline, every 6 hours for the first 72 
hours, daily starting on the fourth day of study drug for as long as the subject is on study drug, 
within 1 hour prior to weaning/discontinuing study drug, every 24 hours while weaning, and at the 
time of discontinuation of study drug.  The FiO2 and route of delivery will be recorded on study 
Day 7 and Day 14 regardless if the subject has already been weaned from study drug. Additionally, 
FiO2 will be collected with each study drug dose change. 
When OI is no longer calculated (i.e., no arterial access for ABGs), FiO2 will be used to guide study 
drug dosing.  The dose of study drug should be increased in the absence of dose-limiting AEs (e.g., 
hypotension) if the FiO2 is ≥60%.  When the FiO2 is less than 60%, weaning of study drug can 
begin (see Section 6.1.4). 
3.3.1.5 
Blood Gas and Lactate 
Blood gas (arterial, capillary, or venous) values will be collected at Screening, Baseline, every 6 
hours for the first 72 hours, then daily starting on the fourth day of study drug for as long as the 
subject is on study drug.  Additionally, blood gases will be assessed within 1 hour prior to weaning 
and at the time of study drug discontinuation.  Blood gases will be assessed on study Day 7 and Day 
14 regardless if the subject has already been weaned from study drug. 
The ABGs should be collected from a post-ductal artery when possible.  If a post-ductal arterial 
catheter is not available, it should be noted in the eCRF that the ABG was collected from a pre-


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ductal artery.  The ABGs will include: PaO2, partial pressure of arterial carbon dioxide (PaCO2), 
bicarbonate (HCO3), oxygen saturation (SaO2), and pH. 
Capillary or venous blood gasses (CBGs or VBGs) will be collected when the subject no longer has 
arterial access.  The CBG or VBGs will include:  partial pressure of venous oxygen (PvO2), partial 
pressure of venous carbon dioxide (PvCO2), HCO3, oxygen saturation (SvO2), and pH. 
Table 3-2 
Blood Gasses 
Blood Gasses 
Arterial 
Capillary/ Venous 
PaO2 
PaCO2 
HCO3 
SaO2 
pH 
PvO2 
PvCO2 
HCO3 
SvO2 
pH 
A blood lactate level will be collected with each blood gas.     
3.3.1.6 
Echocardiogram (ECHO) 
Echocardiograms (ECHO) are used to rule out congenital heart defects and to assess the pulmonary 
artery (PA) and/or right ventricular (RV) pressures.  Specifically, the following parameters will be 
recorded: tricuspid regurgitation (TR) jet velocity (if available); pulmonary regurgitation (PR) jet 
velocity (if available); direction of shunting through patent ductus arteriosus (PDA), atrial septal 
defect (ASD), ventricle septal defect (VSD) or patent foramen ovale (PFO) (if present); evidence 
and degree of RV dilation; and interventricular septal position. 
An ECHO will be performed at Screening and repeated at Day 7 and Day 14, or prior to hospital 
discharge if that occurs prior to Day 14.  Additionally, an ECHO will be performed prior to weaning 
study drug and within 48 hours of study drug discontinuation. 
3.3.1.7 
N-Terminal pro B-Type Natriuretic Peptide (NT-proBNP) 
NT-proBNP is a cardiac biomarker associated with volume or pressure overload of the right 
ventricle.  Subjects will have samples for NT-proBNP collected at Baseline, daily during the first 72 
hours of study drug treatment, Day 7, and at Day 14, or prior to hospital discharge if that occurs 
prior to Day 14.  Additionally, subjects will have samples collected for NT-proBNP prior to 
weaning study drug and at the time of study drug discontinuation.   


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3.3.2 
Safety 
3.3.2.1 
Physical Examination 
A physical examination will be conducted at Screening, Baseline, daily during the first 72 hours of 
study drug treatment, on Day 7, and Day 14.  Additionally, subjects will have a physical 
examination prior to weaning study drug, within 24 hours of study drug discontinuation, and prior 
to hospital discharge, or at 4 weeks after discontinuing study drug, whichever comes first.  Length 
and weight will be collected at Baseline and at the final follow-up visit.  The Baseline weight will 
be used to calculate all doses of study drug.   
3.3.2.2 
Vital Signs 
Vital signs will include blood pressure (BP), heart rate (HR), respiratory rate (RR), temperature 
(temp), and oxygen saturation (SpO2).  Both pre- and post-ductal SpO2 will be collected for the first 
72 hours.  Vital signs will be collected at Screening, Baseline, and during study drug administration 
as follows: approximately every 6 hours for the first 72 hours, daily starting on the fourth day for as 
long as the subject is on study drug, prior to weaning, every 24 hours while weaning, at the time of 
study drug discontinuation, and 48 hours after study drug discontinuation.  Vital signs will also be 
collected prior to hospital discharge or at the 4 week follow-up after discontinuing study drug, 
whichever comes first.  Additionally, BP, HR, and SpO2 will be collected with each study drug dose 
change. 
3.3.2.3 
Clinical Laboratory Assessments 
3.3.2.3.1 
Chemistries, Hematology and Liver Function Tests 
A complete metabolic, hematologic, and liver function panel will be assessed at Baseline, Day 7, 
and Day 14.  Additionally, subjects will have clinical laboratory assessments prior to weaning study 
drug, within 12 hours of study drug discontinuation, 48 hours after discontinuing study drug, and 
prior to hospital discharge or at the 4 week follow-up after discontinuing study drug, whichever 
comes first.  Table 3-3 summarizes each laboratory parameter to be assessed. 


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Table 3-3 
Chemistries, Hematology and Liver Function Tests  
Chemistries 
Hematology 
Liver Function Tests (LFTs) 
Sodium 
Potassium 
Chloride 
Bicarbonate/ CO2 
Blood Urea Nitrogen (BUN) 
Creatinine 
Glucose 
Calcium 
Albumin 
Lactatea 
Red Blood Cell Count 
Hematocrit 
Hemoglobin 
Platelet Count 
White Blood Cell Count (no differential) 
Prothrombin time 
 
Alkaline Phosphatase 
Alanine Aminotransferase (ALT) 
Aspartate Aminotransferase (AST) 
Total Bilirubin 
 
aSee Section 3.3.1.5 
3.3.2.4 
Adverse Events (AEs) 
Documentation of AEs will be recorded in the eCRF from the time informed consent is provided 
until time of screen failure, time subject is withdrawn from study, time of hospital discharge, death, 
or until 4 weeks after the last dose of study drug, whichever comes first.  All AEs should be 
followed until either resolution (or return to normal or Baseline values), until judged by the 
Investigator to no longer be clinically significant or until 4 weeks after last dose of study drug.  
Subjects with ongoing AEs at the time of hospital discharge will continue to be followed for their 
AEs until either resolution (or return to normal or Baseline values), until judged by the Investigator 
to no longer be clinically significant, or until 4 weeks after last dose of study drug.  All SAEs will 
be followed until resolution, death, or the subject is lost to follow-up, even if they are ongoing more 
than 4 weeks after the last dose of study drug.  Sections 9 and 15.1 provide the definitions and 
guidelines for recording AEs.  If the subject receives Remodulin after hospital discharge, beyond 
Day 56/End of study, or following withdrawal from the study, AEs/SAEs will be subject to 
AE/SAE reporting under local government post-marketing AE/SAE reporting requirements. 
3.3.3 
Pharmacokinetics 
Blood samples will be collected from subjects on study drug for treprostinil pharmacokinetic (PK) 
analysis.  A venous or capillary blood sample, rather than arterial blood sample should be collected.  
Up to two samples will be taken from each subject: 
 
After 24 hours (+6 hours) of initiating study drug dosing (collected at least 2 hours after 
the last dose change) 
 
Immediately prior to beginning to down titrate (wean) study drug, or on Study Day 28 if 
the subject will continue on Remodulin 


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o A second sample is not required in subjects who are unblinded (after Day 14 or due 
to clinical worsening event) and identified to be on placebo  
If any early or late blood draws are performed, the time and reason should be recorded in the eCRF.  
Appendix 15.2 contains a detailed description for the pharmacokinetic blood collection, processing, 
storage, and shipment of all samples.   
3.4 
NUMBER OF CENTERS 
Approximately 40 centers are planned. 
3.5 
NUMBER OF SUBJECTS 
Approximately 70 subjects will be randomized (1:1) to either receive treatment with Remodulin or 
placebo to provide 66 evaluable neonates.  Enrollment will be closed once 66 evaluable subjects 
have been enrolled.  No more than 32 subjects with a diagnosis of PPHN associated with CDH will 
be enrolled; these subjects will be evenly enrolled (1:1) into the Remodulin and placebo groups. 
3.6 
ESTIMATED STUDY DURATION 
No subject will receive study drug for greater than 28 days (4 weeks).  Post-treatment data will be 
collected until death, time of hospital discharge, time of study withdrawal, or until 4 weeks after last 
dose of study drug, whichever comes first.  Subjects with ongoing AEs at the time of hospital 
discharge or study withdrawal will be followed for their AEs until either resolution (or return to 
normal or Baseline values), until judged by the Investigator to no longer be clinically significant, or 
for up to 4 weeks beyond the subject’s last dose of study drug.  Therefore, the maximum amount of 
time a subject randomized to study drug would be in the study is 56 days (a maximum of 28 days of 
study drug, plus 4 week follow-up (28 days) after last dose/discontinuing study drug).  Per the 
Investigator’s discretion, if Remodulin treatment is needed beyond Day 28, subjects will be 
transitioned to commercial product; Day 28 will be considered as the last day of study drug 
administration.  These subjects will continued to be followed in the study until they have reached 
Day 56 (4 weeks after last dose of study drug), have been discharged from the hospital or 
withdrawn from the study, whichever comes first. 
The study will be completed once 66 evaluable subjects have been enrolled and completed the last 
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4 
SUBJECT ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
A subject is eligible to participate if the following criteria are met: 
1. Parent(s) or legal guardian provides consent for the subject to participate, as per institutional 
policy.  
2. Weight at least 2 kg at Screening. 
3. Gestational age of at least 34 weeks and is ≤14 days old at Screening.  
4. Diagnosis of PPHN, which is either idiopathic in nature or associated with the following:  
MAS, pneumonia, RDS, sepsis, birth hypoxia, perinatal encephalopathy or unilateral CDH. 
5. Currently requiring ventilator support. 
6. Two consecutive OIs of 15 or greater separated by at least 30 minutes, after receiving iNO 
for at least 3 hours.  
7. Echocardiographic evidence of PH (e.g., ductal shunting, significant TR) with elevated RV 
pressures).  
8. Have venous access (central line or peripherally inserted central venous catheter [PICC, 
PCVC]) for the administration of study drug.  In the event central venous access cannot be 
established or in the opinion of the Investigator the patient is too unstable to attempt to 
establish a central venous access line for IV administration of study drug, subjects who are 
candidates for administration of study drug as a continuous SC infusion may be enrolled. 
4.2 
EXCLUSION CRITERIA 
A subject is ineligible for participation if any of the following criteria are met: 
1. Previous or concurrent use of a PDE-5i, ERA or prostanoid.  Previous receipt of 
prostaglandin E1 for ductal patency is allowed. 
2. Significant congenital heart disease (CHD) as detected by ECHO (excluding presence of 
minor defects such as small secundum ASD, minor valvular abnormalities, or expected 
transitional findings such as a PFO, or PDA.  Subjects with small muscular, restrictive VSD 
may be enrolled).   
3. Clinically significant, untreated active pneumothorax at Screening. 
4. Evidence of clinically significant bleeding (e.g., hemodynamic instability or requiring 
transfusion) at Screening.  Note: history of a transfusion is not necessarily an exclusion 
criterion.   
5. Necrotizing entercolitis; defined as Bells stage II or greater at Screening. 
6. Uncontrolled hypotension; defined as mean systemic pressures less than or equal to 
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7. Uncontrolled coagulopathy and/or untreated thrombocytopenia; defined as <50,000 platelets 
/µL at Screening. 
8. History of severe (Grade 3 or 4) intracranial hemorrhage at Screening.  Note: a cranial 
ultrasonography is not required during Screening. 
9. Currently receiving ECMO or has immediate plans to initiate ECMO. 
10. Expected duration on mechanical ventilation of less than 48 hours. 
11. Life expectancy is less than two months or has a lethal chromosomal anomaly. 
12. Contraindication to ECMO. 
13. Bilateral congenital diaphragmatic hernia. 
14. Active seizures at Screening. 
15. Currently participating in another clinical drug study (excluding observational registries).   
4.3 
PRESCRIBED THERAPY 
4.3.1 
Concomitant Medications 
All subjects will be concurrently receiving iNO prior to randomization.  Subjects should be 
adequately treated (as determined by the Investigator) with standard of care treatments for PPHN 
(e.g., inotropes, opioids, sedation) prior to enrollment and during the study.  Doses of medications 
should be adjusted as needed during the study.  All concomitant medications will be recorded in the 
subject’s eCRF up until 48 hours after discontinuation of study drug.  Any concomitant medications 
used in the treatment of an AE or SAE will be recorded even if it occurs more than 48 hours after 
discontinuation of study drug. 
Caution should be used with cytochrome P450 (CYP) 2C8 enzyme inducers/inhibitors, such as 
rifampin or gemfibrozil, as plasma concentrations of treprostinil may be altered.  Concomitant 
administration of Remodulin with diuretics, antihypertensive agents or other vasodilators may 
increase the risk of symptomatic hypotension.  Remodulin inhibits platelet aggregation, there may 
be an increased risk of bleeding when administered with other anticoagulants, such as warfarin, 
heparin, or NSAIDs. 
4.3.1.1 
Inotropic Dose Changes 
Doses of inotropic and vasoactive agents (e.g., dopamine, epinephrine, dobutamine, milrinone, 
vasopressin, norepinephrine) will be recorded with each dose change of study drug.   


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4.3.1.2 
Initiation of a Pulmonary Vasodilator Therapy 
If the Investigator initiates a targeted pulmonary vasodilator (after meeting the requirements 
outlined in Section 3.3.1.1.1) during the first 14 days after randomization, the subject will meet the 
definition of the primary endpoint of clinical worsening.  
Subjects randomized to study drug who meet the definition of clinical worsening may continue to 
receive study drug for a total of up to 28 days at the discretion of the Investigator.       
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
Subjects will be randomized (1:1) to receive treatment with Remodulin or placebo. 
5.2 
RANDOMIZATION 
An Interactive Web Response System (IWRS) will be utilized for the central randomization 
procedure.  Subjects will be randomized in a ratio between active and placebo of 1:1.  No more than 
32 evaluable subjects with a diagnosis of PPHN associated with CDH will be enrolled; these 
subjects will be balanced between the treatment groups. 
5.3 
BLINDING 
This will be a double-blind, placebo controlled study.  Subjects will be randomly allocated to 
Remodulin or placebo via an IWRS system.  Investigators, research staff, attending clinicians, 
NICU staff, and parents will remain blind to the treatment allocation, unless certain criteria for 
unblinding are met.  Some differences in packaging of investigational product may be observed 
during the study, but pharmacy personnel will not be made aware of the actual treatment 
assignment.  The pharmacist must not communicate with the Investigator or any members of the 
clinical team about the appearance of vials used in dose preparation.  No additional packaging or 
wrapping is required prior to dispensing the prepared syringe to the floor.  Once prepared, the 
appearance of active and placebo doses are identical. 
Access to treatment assignment is outlined in Section 6.2. 


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6 
DRUGS AND DOSING  
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE 
6.1.1 
General Information 
Study drug (Remodulin or placebo) will be supplied in multiple-dose 20mL glass vials containing 
1mg/mL treprostinil or placebo.  Vials are multi-use and may be used up to 30 days after initial 
puncture to prepare multiple doses/syringes for the assigned subject.  A new vial should be used for 
each subject.  
6.1.2 
Dose and Administration of Study Drug 
This study aims to evaluate Remodulin administered as a continuous IV infusion in a neonate 
population.  A venous access (preferred via central line (e.g., umbilical venous catheter [UVC] or 
peripherally inserted central venous catheter [PICC, PCVC]) is required for the IV administration of 
study drug.  Currently, there are no data to confirm whether Remodulin is compatible and may be 
administered in the same line/lumen with other IV administered agents; however, compatibility 
studies are planned.  Therefore, one line or lumen must be dedicated solely to study drug when 
administering as a continuous IV infusion until the Investigator is notified by United Therapeutics 
of the outcome of the compatibility studies.  Once compatibility with other IV agents has been 
confirmed, study drug may be administered in accordance with the data provided.  If clinically 
necessary, a temporary peripheral IV cannula, preferably placed in a large vein, may be used 
(Remodulin Package Insert or Summary of Product Characteristics).  However, use of a peripheral 
IV infusion may be associated with an increased risk of thrombophlebitis and administration should 
be short term (Remodulin Package Insert or Summary of Product Characteristics). 
In the event dedicated central venous access cannot be established, or in the opinion of the 
Investigator the patient is too unstable to attempt to establish a dedicated central venous access line 
for IV administration of study drug, study drug may be initiated as a continuous SC infusion at the 
discretion of the Investigator.  Subjects initiated on IV administration of study drug who lose 
venous access may be transitioned to SC administration.  Remodulin is bioequivalent between the 
SC and IV route.  Therefore, no dose adjustment in study drug is needed if the SC route is utilized 
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Study drug must be diluted with high-pH glycine diluent (Sterile Diluent for Remodulin, Sterile 
Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium), Sterile Water for Injection, or 0.9% 
Sodium Chloride Injection, prior to IV administration as a continuous infusion using an infusion 
pump designed for intravenous drug delivery. 
Diluted Remodulin has been shown to be stable at ambient temperature for up to 52 hours at 
concentrations as low as 0.00025mg/mL (250ng/mL) (e.g., infusion cassettes/syringes should be 
changed at least every 48 hours). 
If study drug will be administered as a continuous SC infusion, dilution of study drug is usually not 
required; however, based upon the selected SC infusion pump flow rate capabilities, the subject’s 
dose weight, and dose in this neonate patient population, dilution may be needed for SC 
administration (especially for smaller babies and lower doses, or during weaning of study drug).  If 
dilution is required for SC administration, Sterile Water for Injection or 0.9% Sodium Chloride for 
Injection should be used. 
Do not flush study drug line and use caution when changing the study drug infusion line to avoid an 
accidental bolus/overdosage. 
6.1.2.1 
Calculating the Study Drug Dilution 
Prior to calculating the subject dose of study drug, the following information is needed:  volume of 
infusion syringe or cassette, dose (ng/kg/min; nanogram/kilogram/minute) and weight (kg).  The 
starting dose is 1ng/kg/min.  The subject’s weight from Baseline should be used to calculate the 
dose throughout the study period.   
Study drug will be diluted to the appropriate concentration depending on the individual’s dose and 
infusion rate for intravenous, or subcutaneous (if applicable) infusion.  A separate study drug 
preparation form may be used to document preparation of dilutions. 


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Step 1: Calculate the concentration of the dilution to prepare based on subject’s Baseline 
weight, dose and infusion rate 
𝐷𝑖𝑙𝑢𝑡𝑒𝑑 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑐𝑜𝑛𝑐. (
𝑚𝑔
𝑚𝐿) =
𝑑𝑜𝑠𝑒 (𝑛𝑔/𝑘𝑔/𝑚𝑖𝑛)𝑥 𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)𝑥 0.00006∗
𝑖𝑛𝑓𝑢𝑠𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 (𝑚𝐿
ℎ𝑟)
  
* Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng 
Next, the amount of study drug from the 1mg/mL study drug vial needed to make the required 
diluted concentration for the given syringe size can be calculated using the following formula: 
Step 2: Calculate the amount of study drug need to prepare the desired concentration  
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 (𝑚𝐿) =
𝐷𝑖𝑙𝑢𝑡𝑒𝑑 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑐𝑜𝑛𝑐.(𝑚𝑔/𝑚𝐿)𝑥 𝑆𝑦𝑟𝑖𝑛𝑔𝑒 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)
1 𝑚𝑔/𝑚𝐿  𝑉𝑖𝑎𝑙 𝑆𝑡𝑟𝑒𝑛𝑔𝑡ℎ  
     
The calculated amount of study drug from the 1mg/mL vial is then added to the reservoir along with 
the sufficient volume of diluent to achieve the desired total volume in the syringe pump. 
Study drug may be continually titrated (i.e. up-titration and weaning) during the course of the trial.  
There will be multiple dose titrations occurring and the choice in concentration should be able to 
account for multiple titrations to limit the amount of times an infusion syringe or cassette must be 
prepared or changed.  
The concentration should be increased when the volume required to deliver the dose exceeds the 
ideal fluid intake.  Increasing the concentration will decrease the flow rate and volume of study drug 
administered while allowing for continued dose titrations. 
6.1.3 
Dose Initiation and Titration 
The starting dose of study drug is 1ng/kg/min, which is not anticipated to provide clinical effects.  
The dose of study drug should be increased by up to 2ng/kg/min every 2 hours, as tolerated and 
clinically indicated by the physician, based upon the OI; when the OI is no longer calculable, the 
FiO2 will be used to guide dosing.  As some subcutaneous infusion pumps may not accommodate a 
starting dose of exactly 1ng/kg/min, the site may proceed with a starting dose as close to 
1ng/kg/min as possible.  The initial starting dose should not exceed 2ng/kg/min and should be 
increased by approximately 1-2ng/kg/min every 2 hours as tolerated and clinically indicated by the 


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physician.  Subject response to study drug is individualized; not all subjects will tolerate the same 
rate of titration and clinically beneficial doses will vary.  There is no maximum dose limit.  Titration 
will be made per the subject’s response in clinical symptoms. 
If the OI is 15 or greater, the dose of study drug should be increased in the absence of dose-limiting 
adverse events (e.g., hypotension).  If the OI is between 10 -14 and the study drug dose is 
≤10ng/kg/min, the dose should continue to be increased, as tolerated.  If the study drug dose is 
>10ng/kg/min and the OI is between 10 -14, any further dose escalation will be left to the discretion 
of the clinicians/Investigators according to the clinical condition of the subject, and the perceived 
need for additional pulmonary vasodilation.  Once the OI is <10 and iNO has been discontinued, 
study drug weaning can begin (Section 6.1.4).   
If the OI cannot be calculated, dose adjustments will be based upon FiO2.  The study drug dose 
should be increased when the FiO2 is ≥60% in the absence of dose-limiting adverse events (e.g., 
hypotension).  Once the FiO2 is <60% and iNO has been discontinued, weaning of study drug can 
begin.  Table 6-1 below describes the suggested dose titration parameters.   
Table 6-1 
Suggested Study Drug Dose Titration Parameters 
Oxygenation Index 
FiO2 
(To be used when OI is 
not calculable) 
Dosing Strategy 
≥15 
≥60% 
Dose increase, as tolerated  
10-14 
(dose >10 ng/kg/min) 
-- 
Hold dose or dose increase if clinical condition 
warrants further pulmonary vasodilation. 
10-14 
(dose ≤10 ng/kg/min) 
-- 
Dose increase, as tolerated 
<10 
<60% 
Begin weaning.  The iNO should be weaned and 
discontinued prior to initiating weaning of study 
drug. 
 
Subjects may continue on study drug for up to 28 days if clinically indicated.  Per the investigator’s 
discretion, if the subject is treated with Remodulin beyond Day 28, Day 28 will be considered as the 
last day of study drug administration.  These subjects will continue to be followed in the study until 
they have reached Day 56 (4 weeks after last dose of study drug) or have been discharged from the 
hospital, whichever comes first.  


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6.1.4 
Dose Weaning 
Abrupt cessation of study drug will be avoided due to the risk of rebound pulmonary hypertension.  
Inhaled NO should be weaned and discontinued prior to initiating weaning of study drug.  When the 
subject has reached the treatment goal and is ready to start weaning, the dose of study drug will be 
held constant at the same dose for at least 12 hours prior to initiating down titration.  It is 
recommended the dose of study drug be decreased by no more than 10ng/kg/min per day either in 
the same incremental manner as the dose was increased or as determined by the Investigator.  Dose 
decreases in increments greater than 5ng/kg/min are recommended to be avoided, but faster 
weaning may occur if required per subject care.     
If withdrawal from study drug is warranted, the dose of study drug will be weaned until 
discontinued.  
6.1.5 
Initiation of ECMO 
Subjects randomized to study drug may continue to receive study drug during ECMO at the pre-
ECMO dose.  Subjects should not be unblinded upon initiation of ECMO, unless required for 
purposes of medically managing the subject.  At the conclusion of ECMO, weaning of study drug 
can begin per the Investigator’s discretion. 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
In the event of a medical emergency that requires immediate unblinding, an unblinding call may be 
made to determine treatment assignment. The identity of a subject’s treatment assignment, should it 
need to be obtained, will occur through an unblinding call to the 24 hour 
 
.  Investigators will be permitted to access the treatment assignment upon the 
subject meeting the criterion for clinical worsening or after the completion of Day 14 if required for 
purposes of medically managing the subject (e.g., another prostacyclin will be initiated).  Subjects 
randomized to placebo may be discontinued from study drug at that time.  Subjects randomized to 
Remodulin who have residual or chronic pulmonary hypertension that does not fully resolve by Day 
14 may continue to receive study drug for up to an additional 14 days (for a total of up to 28 days) 
per the Investigator’s discretion.  Subjects who have PPHN resolved by Day 14, who have already 
begun weaning by Day 14 or for whom it is anticipated that weaning of study drug will begin within 


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shortly after completing Day 14, or who are withdrawn from the study should remain blinded.  All 
attempts should be made to maintain the blind during the study. 
6.3 
COMPLIANCE 
The study will occur within the intensive care unit.  All dosing will be administered by qualified 
medical personnel.  Accurate pharmacy and clinical records will be maintained to ensure 
appropriate doses and dose adjustments are made. 
7 
EXPERIMENTAL PROCEDURES 
7.1 
SCREENING 
Screening will occur once written informed consent has been obtained from the parent(s) or legal 
guardian(s).  Some Screening and Baseline assessments may be combined if conducted within 3 
hours of randomization (noted with “*” below). 
Screening activities will include the following:  
 Informed consent 
 Confirmation of inclusion/exclusion criteria 
 Maternal and child history 
o Including birth weight, and the one and five-minute Apgar score 
 Physical examination* 
 Vital signs (BP, HR, Temp, pre and post-ductal SpO2)* 
 OI assessment* 
 Record FiO2 and MAP (including type of ventilation – high frequency vs. traditional)* 
 Arterial blood gas* 
 Echocardiogram 
 Record concomitant medications 
 Record any AEs once informed consent has been provided 
7.2 
BASELINE  
Once all Screening activities have taken place, the following Baseline activities will occur.  Once 
Baseline assessments have been completed and eligibility confirmed, subjects may be randomized 
in the IWRS.  Study drug should be initiated as soon as possible after randomization. 
 Physical examination (including length and weight)* 
 Vital signs (BP, HR, Temp, pre- and post-ductal SpO2)* 
 OI assessment* 


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 Record FiO2 and MAP (including type of ventilation – high frequency vs. traditional)* 
 Arterial blood gas* 
 Clinical laboratory assessments (See Section 3.3.2.3) 
 NT-proBNP 
 Randomization 
 Initiation of study drug  
 Assess clinical worsening  
 Record concomitant medications 
 Record any AEs 
Some Screening and Baseline assessments may be combined (i.e., not repeated) if conducted within 
3 hours of randomization (noted with “*”). 
7.3 
TREATMENT PHASE 
7.3.1 
First 72 Hours  
The following assessments will be obtained during the first 72 hours of study drug administration. 
 Physical examination (once daily) 
 Vital signs approximately every 6 hours (BP, RR, HR, Temp, pre- and post-ductal SpO2) 
 OI assessment approximately every 6 hours (as long as the subject is on mechanical 
ventilation and ABGs are obtained)  
 FiO2; approximately every 6 hours 
 MAP approximately every 6 hours (as long as the subject is on mechanical ventilation) 
 Blood gases approximately every 6 hours (ABG if possible, otherwise CBGs/VBGs) 
 NT-proBNP (once daily) 
 Record concomitant medications 
 Continue study drug, up-titrating as needed 
 BP, HR, and SpO2 will also be collected with each study drug dose change 
 Record doses of inotropes with each study drug dose change 
 Record AEs 
 Collect PK sample 24 hours after the start of study drug dosing. Sample should be collected 
at least 2 hours after the last dose change (See Section 3.3.3 and Appendix 15.2)  
 Assess clinical worsening (throughout the 14 day study period) 
7.3.2 
Study Day 4 Throughout Duration of Study Drug Therapy 
The following assessments will be obtained daily starting on the fourth day of study drug 
administration and continue throughout the duration of study drug therapy:   
 Vital signs (BP, RR, HR, Temp, SpO2) 
 OI assessment (as long as the subject is on mechanical ventilation and ABGs are obtained) 


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 FiO2 
 MAP (as long as the subject is on mechanical ventilation) 
 Blood gases (ABG if possible, otherwise CBGs/VBGs) 
 Record concomitant medications 
 Continue study drug, up-titrating as needed 
 BP, HR, and SpO2 will also be collected with each study drug dose change 
 Record doses of inotropes with each study drug dose change 
 Record AEs 
 Assess clinical worsening (throughout the 14 day period) 
Subjects who have residual or chronic pulmonary hypertension that does not fully resolve by Day 
14 may continue to receive study drug for up to an additional 14 days (for a total of up to 28 days) 
per the Investigator’s discretion. 
7.3.2.1 
Study Day 7 and Day 14 
The following assessments should be performed on study Day 7 and Day 14 regardless if the 
subject has already been weaned from study drug.  If the subject will be discharged from the 
hospital prior to Day 14, the Day 14 assessments should be completed prior to hospital discharge.   
 Physical examination 
 Vital signs (BP, RR, HR, Temp, SpO2) 
 OI assessment (as long as the subject is on mechanical ventilation and ABGs are obtained) 
 FiO2 
 MAP (as long as the subject is on mechanical ventilation) 
 Blood gases (ABG if possible, otherwise CBGs/VBGs) 
 Clinical laboratory assessments (See Section 3.3.2.3) 
 NT-proBNP  
 Echocardiogram  
 Record concomitant medications 
 Continue study drug, up-titrating as needed 
 BP, HR, and SpO2 will also be collected with each study drug dose change 
 Record doses of inotropes with each study drug dose change 
 Record AEs 
 Assess clinical worsening (throughout the 14-day period) 
7.3.3 
Study Drug Discontinuation 
7.3.3.1 
Prior to Weaning or Discontinuing Study Drug  
“Prior to wean” assessments will be collected after the dose has been maintained for at least 12 
hours and no more than 1 hour prior to beginning to wean study drug.  In the event that the subject 


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will continue on commercial Remodulin beyond Day 28, these assessments should take place on 
Day 28. 
 Physical examination 
 Vital signs (BP, RR, HR, Temp, SpO2) 
 OI assessment (as long as the subject is on mechanical ventilation and ABGs are obtained) 
 FiO2 
 MAP (as long as the subject is on mechanical ventilation) 
 Blood gases (ABG if possible, otherwise CBGs/VBGs) 
 Clinical laboratory assessments (See Section 3.3.2.3) 
 Echocardiogram 
 NT-proBNP 
 Collect PK sample (See Section 3.3.3 and Appendix 15.2) 
 Record concomitant medications 
 Record doses of inotropes 
 Record AEs 
7.3.3.2 
Daily While Weaning Study Drug 
The following will be collected every day while weaning study drug. 
 Physical examination 
 Vital signs (BP, RR, HR, Temp, SpO2) 
 BP, HR, and SpO2 will also be collected with each study drug dose change 
 FiO2  
 MAP (if the subject is on mechanical ventilation) 
 Record concomitant medications 
 Record doses of inotropes with each study drug dose change 
 Record AEs 
These assessments will not be performed in subjects who continue on commercial Remodulin 
beyond Day 28. 
7.3.3.3 
Study Drug Discontinuation 
The following will be collected immediately (within 12 hours) after study drug discontinuation.   
 Physical examination 
 Vital signs (BP, RR, HR, Temp, SpO2)  
 FiO2  
 MAP (if the subject is on mechanical ventilation) 


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 Clinical laboratory assessments (See Section 3.3.2.3) 
 NT-proBNP 
 Blood gasses (if arterial access is not available, collect CBGs/VBGs) 
 Record concomitant medications (until 48 hours after the subject has stopped receiving 
study drug) 
 Record doses of inotropes 
 Record AEs  
These assessments will not be performed in subjects who continue on commercial Remodulin 
beyond Day 28. 
7.3.3.4 
48 Hours after Study Drug Discontinuation  
The following will be collected 48 hours ± 4 hours after study drug discontinuation.   
 Vital signs 
 Clinical laboratory assessments (See Section 3.3.2.3) 
 Echocardiogram 
 Record concomitant medications (until 48 hours after the subject has stopped receiving 
study drug) 
 Record doses of inotropes 
 Record AEs  
These assessments will not be performed in subjects who continue on commercial Remodulin 
beyond Day 28. 
7.3.4 
Follow-up/End of Study 
The following assessments will be conducted during a final assessment visit at the time of 
withdrawal from the study, hospital discharge, or at 4 weeks after discontinuing study drug, 
whichever comes first, for all subjects who receive study drug.  In the event that a subject 
randomized to Remodulin will receive commercial Remodulin beyond Day 28, and the subject has 
not been discharged from the hospital or withdrawn from the study, these assessments should take 
place on Day 56. 
 Physical exam including height and weight 
 Vital signs (BP, RR, HR, Temp, SpO2) 
 Clinical laboratory assessments (See Section 3.3.2.3) 
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Subjects with ongoing AEs at the time of hospital discharge will continue to be followed for their 
AEs until either resolution (or return to normal or Baseline values), until judged by the Investigator 
to no longer be clinically significant, or until 4 weeks after last dose of study drug.   
8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A 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 or legal guardian wishes to withdraw the subject from further 
participation. 
 
A serious or life-threatening AE occurs or the Investigator considers that it is necessary to 
discontinue study drug to protect the safety of the subject. 
 
The subject did not initiate study drug.   
If a subject is discontinued from the study prematurely, the Investigator must complete all 
applicable eCRF records, including the End of Study Record for that subject.  If study drug has been 
administered, the Investigator should make every effort to perform all scheduled evaluations.  In the 
event that a subject discontinues study drug prematurely due to an AE, the subject will be followed 
until either the Investigator determines that the AE has resolved, it is no longer considered clinically 
significant, the subject is lost to further follow-up, or for 4 weeks after last dose of study drug.  
SAEs will be followed by United Therapeutics Corporation Global Drug Safety until resolution, 
death, or the subject is lost to follow-up. 
If withdrawal from study drug is warranted, the dose of study drug will be weaned until 
discontinued.  Abrupt cessation of study drug will be avoided due to the risk of rebound pulmonary 
hypertension. 
8.2 
CRITERIA FOR TERMINATING THE STUDY 
The study may be stopped at any time if, in the opinion of the Investigator and/or Sponsor, 
continuation of the study represents a serious medical risk to the subjects.  This may include, but is 
not limited to, the presence of serious, life-threatening, or fatal adverse events 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 A 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 FDA, European, or national regulations are not observed. 
 
The protocol is repeatedly violated. 
 
Changes in personnel or facilities adversely affect performance of the study. 
9 
ADVERSE EVENT REPORTING  
9.1 
DEFINITIONS 
9.1.1 
Adverse Event (AE) 
An AE is any untoward medical experience occurring to a subject whether or not it is related to the 
use of the 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. 
9.1.2 
Serious Adverse Event (SAE) 
A serious adverse event (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 
 A congenital anomaly/birth defect 
 Results in a medically important event of reaction 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the 
time of the reaction; it does not refer to a reaction that hypothetically might have caused death if 
more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered serious reactions, such as important medical events that might not be immediately life 
threatening or result in death or hospitalization, but might jeopardize the patient or might require 


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intervention to prevent one of the other outcomes listed above.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, 
or convulsions that do not result in hospitalization or development of dependency or abuse.  Any 
suspected transmission via a medicinal product of an infectious agent is also considered a serious 
adverse reaction.   
9.1.3 
Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the study 
drug caused the AE.  For the purposes of investigational new drug (IND) safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the study 
drug and the AE. 
9.1.4 
Unexpected Adverse Event 
An event is ‘unexpected’ if its specificity or severity is not consistent with the current clinical 
Investigator Brochure.  It could include an event that may be symptomatically and 
pathophysiologically related to an event listed in the labeling, but differs from the event because of 
greater severity or specificity.  Reports of death resulting from an AE are considered ‘unexpected’ 
unless the possibility of a fatal outcome from that AE is stated in the labeling. 
9.1.5 
Disease Related Events 
PPHN is often associated with signs and symptoms of perinatal distress, including but not limited 
to, those listed in Table 9-1.  These events are anticipated to occur in the study population at some 
frequency independent of drug exposure.  These events should be clearly documented in the subject 
medical record and identified as signs/symptoms of underlying disease under study. 
Events that occur during the course of the study that are listed in Table 9-1 and felt to be related to 
the underlying disease under study by the Investigator will be recorded in the eCRF as disease 
related events.  Events that are either serious or considered unusual with respect to intensity, 
frequency, or duration, or there is a reasonable possibility that it may have been caused by study 
drug as determined by the Investigator will also be recorded as an AE.  All deaths, regardless of 
underlying cause, will be reported as an SAE. 


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Table 9-1 
Expected Events Attributable to PPHN (System Organ Class and PREFERRED 
Term, Ver. 17.0) 
Hypoxia (Respiratory, thoracic & mediastinal 
disorders; HYPOXIA) 
Pallor (Vascular disorders; PALLOR) 
Cold extremities (General disorders and 
administration site conditions; PERIPHERAL 
COLDNESS) 
Cyanosis (Cardiac disorders; CYANOSIS) 
Cardiac arrhythmia (Cardiac disorders; 
ARRHYTHMIA) 
Coagulopathy (Blood and lymphatic system 
disorders, COAGULOPATHY) 
Tachypnea (Respiratory, thoracic & mediastinal 
disorders; TACHYPNOEA) 
Respiratory distress (Respiratory, thoracic and 
mediastinal disorders; RESPIRATORY 
DISTRESS) 
Polycythemia (Blood and lymphatic system 
disorders, POLYCYTHAEMIA) 
Hyperviscosity syndrome (Blood and lymphatic 
system disorders, HYPERVISCOSITY 
SYNDROME) 
Cardiovascular collapse (Vascular disorders; 
CIRCULATORY COLLAPSE) 
Asphyxia (Respiratory, thoracic and mediastinal 
disorders; ASPHYXIA) 
Postoperative hypotension (Vascular disorders, 
PROCEDURAL HYPOTENSION) 
Tachycardia (Cardiac disorders; TACHYCARDIA) 
Cor pulmonale (Cardiac disorders; COR 
PULMONALE) 
Urine output decreased (Investigations, URINE 
OUTPUT DECREASED) 
Weight loss  (Investigations; WEIGHT 
DECREASED) 
Shock (Vascular disorders; SHOCK) 
Edema (General disorders and administration site 
conditions; OEDEMA) 
Hepatomegaly (Hepatobiliary disorders; 
HEPATOMEGALY) 
Respiratory failure (Respiratory, thoracic and 
mediastinal disorders; RESPIRATORY FAILURE) 
 
 
9.2 
DOCUMENTATION OF ADVERSE EVENTS 
An AE or SAE occurring during the study must be documented in the subject’s source documents 
and on the appropriate eCRF page.  Information relating to the AE such as onset and cessation date 
and time, intensity, seriousness, relationship to study drug, and outcome is also to be documented in 
the eCRF (see Appendix 15.1 for definitions).  Serious AEs are to be reported on the SAE 
Notification Form and submitted within 24 hours to United Therapeutics Global Drug Safety 
(Section 9.4).  Where possible, AEs/SAEs should be recorded using standard medical terminology.  
If several signs or symptoms are clearly related to a medically-defined diagnosis or syndrome, the 
diagnosis or syndrome should be recorded on the eCRF page, not the individual signs and 
symptoms (e.g., pneumonia characterized by shortness of breath and wheezing). 


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9.3 
PERIOD OF OBSERVATION 
For the purposes of this study, the period of observation starts from the time the informed consent is 
signed and concludes upon meeting screen failure criteria, at the time of death, at the time of 
hospital discharge, at the time of withdrawal from the study, or at 4 weeks after last dose of study 
drug, whichever comes first.  Day 28 will be considered as the last day of study drug administration 
for subjects who continue on Remodulin.  Subjects with ongoing AEs at the time of hospital 
discharge will continue to be followed for their AEs until either resolution (or return to normal or 
Baseline values), until judged by the Investigator to no longer be clinically significant, or until 4 
weeks after last dose of study drug.  All SAEs should be followed until resolution, death, or the 
subject is lost to follow-up, even if they are ongoing more than 4 weeks after the last dose of study 
drug.   
If the subject receives commercial Remodulin after hospital discharge, beyond Day 56/End of 
study, or following withdrawal from the study, AEs/SAEs will be subject to AE/SAE reporting 
under local government post-marketing AE/SAE reporting requirements. 
Supplemental measurements and/or evaluations may be necessary to investigate fully the nature 
and/or causality of an AE or SAE.  This may include additional laboratory tests, diagnostic 
procedures, or consultation with other healthcare professionals.  The eCRF pages should be updated 
with any new or additional information as appropriate. 
If the Investigator detects an SAE in the study subject after the end of the period of observation, and 
considers the event possibly related to prior study treatment, he or she should contact the Sponsor to 
determine how the event should be documented and reported. 
9.4 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
All SAEs, regardless of expectedness or causality, must be reported to the Sponsor by fax 
 or email
 within 24 hours of awareness.  
A completed SAE Notification Form along with any relevant hospital records (e.g., discharge 
summary), death certificates and autopsy reports (if performed) should be faxed to United 
Therapeutics Global Drug Safety Department.  A follow-up SAE Notification Form must be 
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of any new/updated information or medical records.  The Investigator must also promptly notify 
their Investigational Review Board (IRB) or Ethics Committee (EC) of the SAE, including any 
follow-up information, in accordance with applicable national regulations and guidelines set forth 
by the IRB or EC.   
9.5 
SAFETY REPORTS 
In accordance with FDA, European, and national regulations, the Sponsor will notify the FDA, 
other competent authorities, and all participating Investigators of any AE that is considered to be 
possibly attributable to study drug and is both serious and unexpected.  The Investigator must report 
these AEs to their IRB or EC in accordance with applicable national regulations and guidelines set 
forth by the IRB or EC. 
10 
STATISTICAL CONSIDERATIONS 
10.1 
DATA PROCESSING 
Data collection will begin during screening (i.e., once the informed consent form has been signed).  
Subjects will be assigned a separate screening number until they are randomized, after which a 
separate subject number will be assigned for subjects enrolled into the study.   
Subject data will first be documented in the subject’s source documents, and then transferred into 
the eCRF.  All data entered into the eCRF should have a corresponding source document.  Site 
personnel will be responsible for recording all subject data into the eCRF.  The eCRF pages are to 
be reviewed by the Principal Investigator for completeness and accuracy.  The Principal 
Investigator must sign each subject’s eCRF to signify their approval of the data.  The database will 
be considered final when all outstanding queries have been resolved and all data management 
quality control procedures are complete.  
10.2 
SAMPLE SIZE 
Based on the systematic review of use of nitric oxide for respiratory failure in infants by Finer and 
Barrington, 57.9% (194/335) subjects in control group had an outcome of death or requirement for 
EMCO (18).  In this study, assuming 60% subjects in placebo group and 30% subjects in 
Remodulin group with an outcome of death, requirement for EMCO, or need for additional PAH 
therapy, we calculated that 66 subjects (33 subjects per treatment group) will have at least 80% 


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power to show a significant difference in favor of Remodulin at alpha level of 0.05 (one-sided test).  
Approximately 70 subjects are planned to be randomized (1:1) to either receive treatment with 
Remodulin or placebo on top of the standard of care. 
10.3 
ANALYSIS PLAN 
10.3.1 
Primary Endpoint 
Efficacy analyses will be performed in intention to treatment (ITT) population where ITT 
population includes all randomized subjects who have successfully initiated the study treatment. 
The primary endpoint is clinical worsening (need for additional treatment [initiation of another 
targeted pulmonary vasodilator therapy], initiation of ECMO or death) between Baseline and Day 
14 or time of discharge from the hospital, whichever comes first.  It will be analyzed as a binary 
endpoint using the percentage of subjects who meet the definition of clinical worsening within each 
treatment group.  Subjects who meet the definition of clinical worsening after Day 14 will not be 
counted towards the primary endpoint.  Chi-square test will be used to test for the treatment 
difference.  
10.3.2 
Secondary Endpoints 
Secondary endpoints (change in OI, P/F ratio, and pre- and post-ductal SpO2, time on mechanical 
ventilation, and change in NT-proBNP) will be summarized and tested using group t-test.  Kaplan-
Meier estimate will be provided for time to event variables (time to discontinuation of iNO, time to 
initiation of ECMO, and time to clinical worsening) and log-rank test will be used to test the 
treatment differences.  
Plasma samples will be analyzed for treprostinil using a validated bioanalytical plasma assay.  
Individual and mean treprostinil plasma concentration data, and treprostinil pharmacokinetic 
parameters, determined as able, will be summarized using descriptive statistics.  
10.3.3 
Safety Analyses 
Safety of study drug in neonates will be evaluated by combined assessments of AEs, clinical 
laboratory parameters, vitals, and physical examination findings.  All subjects who receive study 
drug will be included in the safety population.  Statistical summaries of safety data will be 


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descriptive and exploratory in nature, focusing on the incidence of adverse experiences.  The safety 
data collected in this study will be presented in listings and summary tables.  
Treatment-emergent changes in vital signs, incidence of treatment-emergent AEs, and treatment-
emergent changes in clinical laboratory parameters will be evaluated.   
All AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary.  The incidence of AEs within each treatment group will be presented in summary tables 
overall, and by system organ class and preferred term.  
Vital sign and clinical laboratory data collected prior to initiation of study drug will serve as 
Baseline values for evaluation of data collected during the treatment period.  Summary statistics 
will be calculated for measured values at each time point assessed, as well as change from baseline 
values within each cohort.  
No inferential statistical analyses are planned for safety data. 
10.4 
INTERIM ANALYSIS 
A safety review will be conducted by a Data Safety Monitoring Board (DSMB) after the first 10 
subjects have been randomized to receive study drug and have completed the 14-day study period.  
A second review will occur once 40 subjects have been enrolled and completed the 14-day study 
period.  Ad hoc meetings may be scheduled at additional enrollment milestones or in response to 
events related to the safety of study treatment. 
10.5 
OTHER ANALYSES 
Exploratory analyses may be conducted based on available study data, such as at additional time 
points and calculation of a Total Inotropic Dose Index with each dose change. 
10.6 
DATA LISTINGS AND SUMMARIES 
The safety population will be used for all data listings, summaries and figures.  All available data 
will be presented with no imputation for any missing data.  Subjects will contribute the data 
available up to the point of study completion, or study discontinuation for any reason. 


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In general, listings will be sorted by subject, descriptive summaries will include number of 
observations (n), mean, standard deviation (SD), median, minimum, maximum for continuous 
variables and n and percent for categorical variables.  For all continuous variable summaries, n, 
arithmetic mean, median, minimum, maximum, and SD will be provided. 
Plasma concentration data and any applicable derived pharmacokinetic parameters will be 
summarized and displayed in both tabular and graphical form.  Comparative plots of individual 
concentration data may be produced and summarized across subjects. 
10.7 
DATA SAFETY MONITORING BOARD (DSMB) 
A DSMB will be established for the study, composed of up to four independent members including 
physicians knowledgeable in the treatment of PPHN and a statistician.  The DSMB will meet to 
monitor the safety of the study as established in a DSMB charter.  
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG  
United Therapeutics will supply study drug (Remodulin or matching placebo) for administration in 
the study.  Study drug will be supplied in 20mL clear glass vials sealed with a rubber-coated stopper 
and fitted with a cap containing 20mg (1mg/mL) of treprostinil or placebo as sterile solutions in 
water for injection.   
Remodulin Composition Description: 1mg/mL treprostinil.  Each mL also contains 5.3mg sodium 
chloride, 3mg metacresol, 6.3mg sodium citrate, and water for injection.  Sodium hydroxide and 
hydrochloric acid may be added to adjust pH between 6.0 and 7.2.  
Placebo Component Description: Sodium Citrate USP/EP/JP, Sodium Chloride USP/EP/JP, Sodium 
Hydroxide Pellets, Metacresol, Citric Acid (anhydrous).  Used to adjust pH, if needed: 1M Citric 
Acid, 1N NaOH. 
11.2 
LABELING  
Each vial will be labeled in accordance with applicable national regulations, to include at least the 
following information: investigational product name, trial reference code, concentration, quantity, 
route of administration, manufacture or expiry date, lot number, Sponsor name, address and 


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telephone number, and storage conditions.  The labels may include blank fields for sites to 
document the following information, including but not limited to, Investigator name, subject 
number/initials, and date the vial was opened.   
11.3 
STORAGE AND HANDLING OF STUDY DRUG 
Study drug will be stored at a controlled temperature of 25°C (77°F) with excursions permitted to 
15-30°C (59-86°F).  Study drug vials should not be frozen or exposed to heat.  Temperature 
excursions should be reported to United Therapeutics as soon as they are identified via email 
and any affected drug should be quarantined until notified by the 
Sponsor.  Study drug should not be used after the expiry date that is stated on the vial.  The expiry 
date refers to the last day of that month.  Study drug should not be used if any damage to the vial, 
discoloration, or other signs of deterioration is noticed.  A study drug vial must be used or discarded 
within 30 days after initial puncture.   
Study drug must be diluted to the appropriate concentration based upon the subject weight, dose and 
fluid constraints (i.e. flow rate) in this neonate patient population.  Diluted study drug solution can 
be administered for up to 52 hours at 37°C when diluted to concentrations as low as 250ng/mL in 
0.9% sodium chloride; although it is recommended to change the drug solution every 48 hours.   


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Selection of Diluent  
Route 
Diluent 
Storage and Administration Limits  
IV 
Sterile Diluent for Remodulin1 
Sterile Diluent for Flolan 
Sterile Diluent for Epoprostenol Sodium
Do not use beyond 16 days from date of preparation2.  Store at 
room temperature. 
 
Syringes may be administered up to 48 hours.  
Sterile water for injection 
0.9% Sodium Chloride for Injection 
Do not use beyond 52 hours from time of preparation if maintained 
at room temperature.  Syringes may be administered up to 48 
hours3. 
 
Maybe stored up to 24 hours in the refrigerator after preparation.   
May be administered up to 48 hours once removed from the 
refrigerator3.  
SC 
None 
Do not use beyond 76 hours from time of preparation if maintained 
at room temperature.  Syringes may be administered up to 72 hours. 
 
May be stored up to 24 hours in the refrigerator after preparation.   
May be administered up to 72 hours at 37°C once removed from the 
refrigerator. 
Sterile water for injection 
0.9% Sodium Chloride for Injection 
Do not use beyond 52 hours from time of preparation if maintained 
at room temperature.  Syringes may be administered up to 48 
hours3. 
 
May be stored up to 24 hours in the refrigerator after preparation.   
May be administered up to 48 hours once removed from the 
refrigerator3.  
1Sterile Diluent for Remodulin may be provided during the trial once available. 
2Allows for multiple syringes to be prepared in advance for a subject. 
3Studies have been performed with concentrations as low as 250ng/mL in 0.9% sodium chloride administered for up to 52 hours at 
37°C; although it is recommended to change the drug solution at least every 48 hours. 
Currently, there are no data to confirm whether Remodulin is compatible and may be administered 
in the same line/lumen with other IV administered agents; however, compatibility studies are 
planned.  Therefore, until the Investigator is notified by United Therapeutics of the outcome of the 
compatibility studies, one line or lumen must be dedicated solely to study drug when administering 
as a continuous IV infusion.   
All study drug must be accounted for and the Investigator will maintain a log sheet of all vials as 
they are received and used during the study.  The pharmacist or appropriate personnel will retain all 
study drug used for each study subject.   
11.4 
SUPPLY AND RETURN OF CTM 
Study sites will be supplied with a sufficient quantity of study drug to begin enrollment in the study.  
Appropriate arrangements will be made for resupply to the site with respect to subject enrollment.  


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All used and unused study drug should be retained by the pharmacist or appropriate personnel at the 
site (including empty, partially used and unopened vials). 
11.5 
DRUG ACCOUNTABILITY 
The Investigator is responsible for study drug accountability and reconciliation overall and on a per 
subject basis.  Drug accountability records are to be maintained during the study and these records 
include: the amount of study drug received from the Sponsor, the amount dispensed to each subject, 
and the amount of unused drug.  The quantity of investigational product lost, missing, destroyed, 
etc. must also be accounted for and documented.  At the end of the study, reconciling the delivery 
records with those of usage and discarded stocks must be possible. Accounts must be given of any 
discrepancies.  Once a representative from the Sponsor is able to confirm drug accountability, study 
drug will be returned to a Sponsor-designated location for destruction. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
U.S. FDA OR APPLICABLE REGULATORY REQUIREMENTS 
The study will be conducted in accordance with ICH and GCP guidelines and all applicable national 
regulations.  The Sponsor will obtain the required approval from each national regulatory authority 
to conduct the study.  During the conduct of the study, an annual safety report will be compiled by 
the Sponsor for submission to those regulatory authorities and IRBs/ECs that require it.  Any 
additional national reporting requirements as specified by the applicable regulations, regulatory 
authorities, or IRB/EC will also be fulfilled during the conduct of the study. 
12.2 
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(s) or legal guardian(s).  The subject’s parent(s) or legal guardian(s) must sign 
and date an IRB/EC-approved informed consent/parental permission form prior to the conduct of 
any study-related activities.  A copy of the signed consent/parental permission form will be given to 
the subject’s parent(s) or legal guardian(s) and the original will be retained in the study site’s 
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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/EC and provide the Sponsor with a copy of the approval letter.  The IRB/EC must 
also review and approve the study site’s informed consent form and any other written information 
provided to the subject prior to enrollment, as well as any advertising materials used for subject 
recruitment.  Copies of the informed consent form and advertising materials must be forwarded to 
the Sponsor for review before submission to the IRB/EC prior to the start of the study. 
If, during the study, it is necessary to amend either the protocol or the informed consent form, the 
Investigator is responsible for obtaining IRB/EC approval of these amended documents prior to 
implementation.  Copies of the IRB/EC correspondence and approval letters must be provided to the 
Sponsor. 
During the conduct of the study, an annual progress report will be compiled by the Sponsor for 
submission to those IRBs/ECs that require it. 
A written summary of the study will be provided by the Investigator to the IRB/EC following study 
completion or termination according to their standard procedures.  Additional updates will also be 
provided in accordance with the IRB/EC’s standard procedures. 
12.4 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before the commencement of the clinical trial, the following documents will be provided to the site:  
Investigator’s Brochure, protocol, model informed consent form, budget, and clinical trial 
agreement. 
The site will be required to provide the following documents to United Therapeutics Corporation or 
designee prior to study start: Investigator signature page of the protocol, Form FDA 1572, IRB/EC 
Composition and Roster, IRB/EC protocol and informed consent approval letters, Curriculum Vitae, 
financial disclosure forms of study staff listed on the Form FDA 1572, and an authorized clinical 
trial agreement. 


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12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  United Therapeutics 
Corporation and the agents of the Sponsor, the FDA or other regulatory bodies, and the IRB/EC 
governing this study may inspect the medical records of any subject involved in this study.  The 
Investigator may release the subject’s medical records to employees or agents of the Sponsor, the 
IRB/EC or the FDA or appropriate local regulatory agencies for purposes of checking the accuracy 
of the data.  A number will be assigned to all subjects and any report published will not identify the 
subject’s name. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
It is understood that the term “Investigator” as used in this protocol and on case report forms refers 
to the Principal Investigator or a member of the staff that the Principal Investigator designates to 
perform a certain duty (as documented on the Delegation of Authority Log).  The Principal 
Investigator is ultimately responsible for the conduct of all aspects of the study in accordance with 
the protocol, even those tasks delegated to others, and ensuring written informed consent is obtained 
from the parent(s) or legal guardian for each individual participating in this study. 
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/EC prior to implementation. 
A report documenting study termination must also be submitted to and acknowledged by the 
appropriate IRB/EC for each study site, in accordance with IRB/EC policies. 
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.  Where required by other applicable regulatory requirements, the 
Investigator shall retain the documents for a longer period.  
The Investigator must notify United Therapeutics Corporation in writing 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 site and conduct on-site visits.  
During these visits, the monitor will at a minimum:  confirm ethical treatment of subjects, assess 
study progress, review data collected, conduct source document verification, verify drug 
accountability periodically, and identify any issues requiring resolution.   
The Investigator agrees to allow the monitor direct access to all relevant documents and to allocate 
his/her time and his/her staff to the monitor to discuss any findings or any relevant issues. 


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14 
REFERENCES 
1. Roofthooft MTR, Elma A, Bergman KA and Berger RMF.  Patient Characteristics in 
Persistent Pulmonary Hypertension of the Newborn. Pulm Medicine, 2011; vol 2011, Article 
ID 858154, 8 pages. 
2. RH, Steinhorn. Nitric Oxide and beyond: new insights and therapies for pulmonary 
hypertension. J Perinatol. 2008; 28(Suppl 3): S67–S71. 
3. Neonatal Inhaled Nitric Oxide Study Group.  Inhaled Nitric Oxide in Full-Term and Nearly 
Full-Term Infants with Hypoxic Respiratory Failure. N England J Med. 1997; 336: 597-604. 
4. Clark RH, Kuesser RJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent 
pulmonary hypertension of the newborn. N Engl J Med. 2000: 342: 469-474. 
5. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a 
prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, 
randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002; 165(6): 800-804. 
6. Rubenfire M, McLaughlin VV, Allen RP, et al. Transition from intravenous epoprostenol to 
subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial. Chest. 2007; 
132 (3): 757-63. 
7. Hiremath J, Thanikachalam S, Parikh K, et al. Exercise improvement and plasma biomarker 
changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a 
placebo-controlled trial. J Heart Lung Transplant. 2010; 29(2): 137-149. 
8. Levy M, Celermajer D, Bourges-Petit E, et al. Add-on Therapy with Subcutaneous 
Treprostinil for Refractory Pediatric Pulmonary Hypertension. J Pediatr. 2011; 158 (4): 
584-588.  
9. Ivy DD, Claussen L, and Doran A. Transition of stable pediatric patients with pulmonary 
arterial hypertension from intravenous epoprostenol to intravenous treprostinil. Am J 
Cardiol. 2007; 99(5): 696-698.  
10. Ferdman D, Rosenzweig EB, Zuckerman WA, et al. Subcutaneous Treprostinil for 
Pulmonary Artery Hypertension Associated with Chronic Lung Disease of Infancy. 
Pediatrics. 2014; 134:e274-e278. . 
11. Porta NFM, Beier J, Gotteiner N, et al. Use of subcutaneous treprostinil in critically ill 
infants with pulmonary hypertension. Presented at the Conference on Neonatal and 
Childhood Pulmonary Vascular Disease, March 2011. 
12. Sochet AA, Perez VM, Wadhawan R, et al. Intravenous Treprostinil Therapy of the Acute 
Management of Persistent Pulmonary Hypertension of the Newborn. Presented at the 
American Thoracic Society Conference, May 2012.   


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13. Olson, E, Lusk, L, Fineman J, et al. Short-Term Treprostinil Use in Infants with Congenital 
Diaphragmatic Hernia following Repair. J Pediatr. 2015; 167(3):762-764. 
14. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of 
thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med.  1992; 
327 (2): 70-75. 
15. Storme L, Aubry E, Razka T, et al. Pathophysiology of persistent pulmonary hypertension of 
the newborn: Impact of the perinatal environment. Arch Cardiovasc Dis.  2013; 106:169-
177. 
16. Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state 
bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and 
subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004 Aug;44(2):209-
214. 
17. Wade M, Baker FJ, Roscigno R, DellaMaestra W, Hunt TL, Lai AA. Absolute 
bioavailability and pharmacokinetics of treprostinil sodium administered by acute 
subcutaneous infusion. J Clin Pharmacol. 2004;44:83-88.  
18. Finer N and Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term 
(review). Cochrane Database of Systematic Reviews. 2006; Issue 4. Art. No.: CD000399. 
DOI: 10.1002/14651858.CD000399.pub2. 


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15 
APPENDICES 
15.1 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
For each adverse event, the Investigator will:  (1) rate the intensity and seriousness of the AE, (2) 
estimate the causality of the AE to study drug, and (3) note actions taken to counteract the AE. 
Definitions of Intensity, Seriousness, Causality, and Action Taken 
Intensity 
An assessment of the relative intensity (severity) of an AE is based on the investigator’s clinical 
judgment.  The maximum intensity encountered during the evaluation period should be checked.  
The assessment of intensity should be independent of the assessment of the seriousness of the AE. 
• 
Mild:      No limitation of usual activities. 
• 
Moderate:   Some limitation of usual activities.  
• 
Severe:    Inability to carry out usual activities. 
Difference Between “Severe” and “Serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself; however, may be of relatively minor 
medical significance (such as severe headache).  This is not the same as “serious”, which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning.  Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
Causality 
An estimate of causality between a specified AE and the study drug is made by the Investigator.  
Definitions of the categories follow: 
 POSSIBLE - the AE MAY have been caused by study drug.  There is a reasonable causal 
relationship between the study drug and the SAE.  The event responds to dechallenge. 
Rechallenge is not required. 
 PROBABLE - it is LIKELY that the AE was caused by study drug.  There is a reasonable 
causal relationship between the study drug and the SAE.  Dechallenge information is lacking 
or unclear. 
 NOT RELATED - it is UNLIKELY that the AE was caused by study drug.  There is not a 
temporal relationship to study drug administration (too early, or late, or study drug not 


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taken), or there is a reasonable causal relationship between another drug, or concurrent 
disease and the SAE. 
Action Taken with Test Agent* 
The action taken with test agent as a direct result of the AE: 
 DOSE NOT CHANGED - there was no alteration in either the dose or regimen of the test 
agent 
 DOSE INCREASED – dose was increased 
 DOSE DECREASED – dose was decreased 
 DRUG INTERRUPTED - the dose or regimen of the test agent was altered or administration 
of the test agent was stopped temporarily 
 DRUG WITHDRAWN- administration of the test agent was stopped permanently and not 
restarted. This does not apply if the subject was on drug at the time of death. For this 
scenario “Dose not changed” would be marked. 
 Not Applicable- (i.e., AE occurred prior to administration of test agent) 
* Only the last action should be recorded on the CRF.   
Outcome 
 Fatal – The study subject died 
 Not Recovered/Not Resolved – The AE was ongoing at the end of the study/AE observation 
period 
 Recovered/Resolved – The AE resolved 
 Recovered/Resolved with Sequelae – The AE is considered resolved; however, there is a 
residual sequelae 
 Recovering/Resolving – The AE is improving but is not yet completely recovered/resolved 
at the end of study/AE observation period 
 Unknown – The outcome of the AE cannot be determined 
AE/SAE Start Date verses Serious Date 
The AE start date is classified as the first day the subject experiences sign and symptoms of an 
event and should be entered on the eCRF and SAE Notification Form section “Onset date of 
symptoms.”  The date the event became serious is the first day the event meet one of the serious 
criterion (see section 9.1.2).  The start date and date event became serious could be the same date 
(e.g., clavicle fracture from a fall). 
Note: The start date (onset) should never be a date prior to the subject signing the informed consent. 


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AE/SAE Stop Date 
For AEs and SAEs the dates listed on the eCRF and SAE Notification Form will always be the 
same.  For non-fatal events, this is the date the last sign and/or symptom resolved.  For fatal events 
this is the date of Death.  If the event Recovered/Resolved with Sequelae enter the date the subject’s 
medical condition resolved or stabilized.  
For SAEs follow-up must continue until resolution, death, end of study, or subject is lost to follow-
up. 


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15.2 
PHARMACOKINETIC SAMPLE PROCESSING 
Collection, Processing and Shipment of Plasma Specimens 
Up to 2 blood specimens (approximately 0.5-1mL of blood per sample) for pharmacokinetic 
analysis will be collected during the study from each subject who receives study drug the following 
times relative to study drug administration: 
 
24 hours (+6 hours) following initiation of study drug dosing (collected at least 2 hours 
after the last dose change) 
 
Immediately prior (within 1 hour) to beginning to down titrate (wean) study drug, or on 
Study Day 28 if the subject continued on IV Remodulin 
o A second sample will not be required in subjects who are unblinded and identified to 
be on placebo 
Time and date of blood draws will be recorded.  If any early or late blood draws are performed, the 
time and reason should be recorded in the eCRF.     
Specimen Processing 
 
Collect approximately 0.5- 1mL blood specimen in a collection tube containing 
K3-EDTA or K2-EDTA as an anticoagulant and immediately place the specimen on ice. 
 
Within 1 hour of collection, centrifuge the specimen at 4ºC for 10-15 minutes at 3000g. 
 
Label the shipping tube with the subject number, and specimen collection time and date. 
 
Pipette approximately 250µL plasma into a cryogenic storage tube.  Pipette the 
remainder of the plasma into a second, identically labeled cryogenic storage tube for use 
as a backup specimen for storage at the clinical site. 
 
Freeze samples immediately at -70-80ºC (-20 to -25ºC permitted) until instructed to ship 
by Sponsor.  
Shipping Procedures 
 
The sample will be transported on dry ice to the Sponsor-designated laboratory.  The 
backup sample will be retained at the site and transported later in the event of an 
emergency or if deemed necessary by the Sponsor. 
 
All shipments must be accompanied by a packing list.  Please note on the packing list 
any specimens that are hemolyzed. 
 
Package the shipping tubes to prevent breakage and contamination in Styrofoam boxes 
containing a generous supply of dry ice that will allow for 3 days in transit. 
 
Prior to the shipment of specimens, contact the Sponsor and the bioanalytical laboratory 
by phone and fax or email.  An electronic copy of the packing list (manifest) should be 
provided to the laboratory in advance of the shipment. 
 
The bioanalytical lab shipping address and contact person will be provided prior to 
shipping of samples. 


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15.3 
ADMINISTRATION OF REMODULIN 
The preferred method of administration of Remodulin is by central venous access via an umbilical 
venous catheter (UVC) or peripherally inserted central catheter (PICC).  Currently, there are no data 
to confirm whether Remodulin is compatible and may be administered in the same line/lumen with 
other IV administered agents; however, compatibility studies are planned.  Therefore, one line or 
lumen must be dedicated solely to study drug when administering as a continuous IV infusion until 
the Investigator is notified by United Therapeutics of the outcome of the compatibility studies.  
Once compatibility with other IV agents has been confirmed, study drug may be administered in 
accordance with the data provided.  It is recommended that an infusion set with a 0.22 or 0.2 micron 
pore size in-line filter should be used for IV administration, unless institutional policies and 
practices restrict use of in-line filters in this patient population. 
If clinically necessary, a temporary peripheral IV cannula, preferably placed in a large vein, may be 
used for short term administration of study drug (Remodulin Package Insert).  However, use of a 
peripheral IV infusion for more than a few hours may be associated with an increased risk of 
thrombophlebitis (Remodulin Package Insert).   
Due to the inherent risks associated with central venous catheter placement, IV Remodulin was 
infused peripherally to healthy volunteers in two Phase I, open-label studies (16, 17).  In the first 
study, Remodulin was diluted with 5% dextrose and administered to 15 subjects at a rate of 
15ng/kg/minute for 150 minutes (17).  No phlebitis was reported during the 150-minute peripheral 
IV infusion.  The most common adverse events were headache (53%), dizziness (27%), and nausea 
(20%).  In the second study, Remodulin was diluted with normal saline and administered to 53 
subjects at 10ng/kg/minute for 3 days (16).  This longer infusion was more problematic.  Although 
no adverse events were judged to be serious, the most common adverse events involved the infusion 
site and included infusion site pain (57%), infusion site erythema (55%), infusion site edema (43%), 
and infusion site tenderness (13%).  Other adverse events were mostly typical of prostacyclin 
administration, including:  headache (53%), jaw pain (26%), and nausea (23%).  Further analyses of 
these data to determine the optimal maximum duration of a peripheral infusion of Remodulin have 
not been conducted.   


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With any type of line, caution should be taken to ensure that: 
1. No other drug or solution is co-administered through the line dedicated solely to study drug 
until notified by United Therapeutics of the outcome of the compatibility studies.  Once 
compatibility with other IV agents has been confirmed, study drug may be administered in 
accordance with the data provided.   
2. No blood specimens are drawn from the dedicated study drug line; this may lead to a 
temporary interruption in the study drug infusion.  
3. The dedicated study drug line is not flushed as is standard nursing practice for most 
peripheral lines as flushing may lead to the delivery of a bolus dose. 
Precautions should be taken to ensure that the study drug infusion continues uninterrupted.  
Suggested precautions may include labeling the study drug lumen with warnings such as: “Do Not 
Stop,” “Call MD Before Stopping,” “Dedicated to study drug,” “Do Not Flush,” and/or “Do Not 
Draw Bloods.”  
In the event dedicated central venous access cannot be established, or in the opinion of the 
Investigator the patient is too unstable to attempt to establish a dedicated central venous access line 
for IV administration of study drug, study drug may be initiated as a continuous SC infusion at the 
discretion of the Investigator.  Subjects initiated on IV administration of study drug who lose 
venous access may be transitioned to SC administration.  Remodulin is bioequivalent between the 
SC and IV route, therefore no dose adjustment is needed if the SC route is utilized. 

SAP_001.pdf: 
United Therapeutics Corp. 
RIV-PN-201 Statistical Analysis Plan 
 
Remodulin® (treprostinil) 
 
Page 1 
Document Type: 
Statistical Analysis Plan 
Protocol/Study No.: 
RIV-PN-201 
 
Finalization Date: 
 
04 JUN 2019 
Total Number of Pages 
including Appendices: 
26 
Classification: 
Confidential 
Version:  
1.0 
 
Title: 
Intravenous Remodulin (Treprostinil) as Add-on Therapy for the Treatment of Persistent Pulmonary 
Hypertension of the Newborn:  A Randomized, Placebo-Controlled, Safety and Efficacy Study 
 
 
 
 
 
 
Author:  
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY, UNITED THERAPEUTICS CORPORATION 
All content contained herein is confidential and proprietary information of United Therapeutics 
Corporation and shall not be disclosed in whole or in part except as permitted by a signed contract with 
United Therapeutics Corporation. © 2019 United Therapeutics Corporation 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
Table of In-Text Tables .................................................................................................................3 
ABBREVIATIONS AND DEFINITIONS ...................................................................................4 
1 PREFACE .................................................................................................................................5 
2 STUDY OBJECTIVES AND ENDPOINTS ..........................................................................5 
2.1 
PRIMARY ENDPOINT .....................................................................................................5 
2.2 
SECONDARY ENDPOINTS .............................................................................................5 
2.3 
SAFETY ENDPOINTS .......................................................................................................6 
3 STUDY DESIGN ......................................................................................................................6 
4 SEQUENCE OF PLANNED ANALYSES ............................................................................7 
5 SAMPLE SIZE CONSIDERATIONS ...................................................................................7 
6 ANALYSIS POPULATIONS .................................................................................................8 
7 INTERIM ANALYSES ...........................................................................................................8 
8 GENERAL CONSIDERATIONS FOR DATA ANALYSES ..............................................9 
8.1 
COVARIATES ....................................................................................................................9 
8.2 
EXAMINATION OF SUBGROUPS ...............................................................................10 
8.3 
PREMATURE DISCONTINUATION AND MISSING DATA ...................................10 
8.3.1 
Missing Data Handling for Primary Efficacy Endpoint ...........................................10 
8.3.2 
Missing Data Handling for Secondary Efficacy Endpoints ......................................10 
8.4 
MULTIPLE COMPARISONS AND MULTIPLICITY ...............................................10 
8.5 
DERIVED AND TRANSFORMED DATA ....................................................................10 
8.5.1 
Baseline Values .............................................................................................................10 
8.5.2 
Change from Baseline Values ......................................................................................10 
8.5.3 
Time to Event and Censor Status ...............................................................................10 
8.6 
ASSESSMENT WINDOWS .............................................................................................11 
9 STUDY POPULATION ........................................................................................................12 
9.1 
SUBJECT ACCOUNTABILITY .....................................................................................13 
9.2 
PROTOCOL DEVIATIONS ...........................................................................................13 
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATION ..............................................14 
9.3.1 
Demographics ...............................................................................................................14 
9.3.2 
Medical History and PPHN and Neonatal History ...................................................14 
9.3.3 
Concomitant Medications ............................................................................................14 
10 EFFICACY ANALYSES.......................................................................................................15 
10.1 PRIMARY EFFICACY MEASURES ............................................................................15 
10.1.1 
Primary Efficacy Analyses ..........................................................................................15 
10.1.1.1 
Hypothesis .................................................................................................................15 
10.1.1.2 
Primary Efficacy Analysis .......................................................................................15 
10.1.1.3 
Sensitivity and Subgroup Analyses .........................................................................15 
10.2 SECONDARY EFFICACY MEASURES.......................................................................16 


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10.2.1 
Change in OI .................................................................................................................16 
10.2.2 
Change in PaO2/FiO2 ...................................................................................................17 
10.2.3 
Change in SpO2 .............................................................................................................17 
10.2.4 
Change in NT-proBNP .................................................................................................17 
10.2.5 
Time to Clinical Worsening .........................................................................................17 
10.2.6 
Time to Initiation of ECMO ........................................................................................18 
10.2.7 
Time to Discontinuation of iNO ..................................................................................18 
10.2.8 
Time on Mechanical Ventilation .................................................................................18 
11 HEALTH OUTCOMES ........................................................................................................18 
12 SAFETY ANALYSES ...........................................................................................................18 
12.1 EXTENT OF EXPOSURE ...............................................................................................18 
12.2 ADVERSE EVENTS .........................................................................................................19 
12.3 CLINICAL LABORATORY EVALUATIONS .............................................................20 
12.3.1 
Clinical Chemistry ........................................................................................................20 
12.3.2 
Hematology ...................................................................................................................21 
12.4 OTHER SAFETY MEASURES ......................................................................................21 
12.4.1 
Echocardiograms ..........................................................................................................21 
12.4.2 
Vital Signs .....................................................................................................................22 
12.4.3 
PPHN Disease-related Events .....................................................................................22 
13 PHARMACOKINETICS ......................................................................................................22 
14 REFERENCES .......................................................................................................................22 
15 LIST OF TABLES, LISTINGS, AND FIGURES ...............................................................23 
15.1 LIST OF TABLES ............................................................................................................23 
15.2 LIST OF LISTINGS .........................................................................................................25 
15.3 LIST OF FIGURES ..........................................................................................................26 
 
Table of In-Text Tables 
Table 8-1 
Time to Event and Censor Status Rules .................................................................11 
Table 8-2 
Assessment Windows for Scheduled Assessments................................................11 
 


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ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse event 
APGAR 
Appearance, Pulse, Grimace, Activity, Respiration 
CDH 
Congenital diaphragmatic hernia 
CSR 
Clinical Study Report 
DSMB 
Data Safety Monitoring Board 
ECMO 
Extracorporeal mechanical oxygenation 
eCRF 
Electronic Case Report Form 
ERA 
Endothelin receptor antagonist 
FiO2 
Fraction of inspired oxygen 
ICF 
Informed Consent Form 
ICU 
Intensive care unit 
iNO 
Inhaled nitric oxide 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-proBNP 
N-Terminal pro-brain natriuretic peptide 
OI 
Oxygenation index 
PaO2 
Partial pressure of oxygen saturation 
PDE-5I 
Phosphodiesterase type 5 inhibitor 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic(s) 
PPHN 
Persistent pulmonary hypertension of the newborn 
PT 
Preferred term 
P/F 
Partial pressure of oxygen saturation/fraction of inspired oxygen ratio 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
SpO2 
Saturation of peripheral capillary oxygenation 
TEAE 
Treatment-emergent adverse event 
WHO-DD 
World Health Organization Drug Dictionary 
 


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1 
PREFACE 
This plan provides further details of the planned analyses for the RIV-PN-201 study as presented 
in the study protocol.  This plan, based on the original RIV-PN-201 study protocol dated 12 Aug 
2013 and the subsequent study protocol amendments (latest version study protocol amendment 3 
dated 15 Apr 2016), provides further details of the planned analyses stated in the study protocol 
and any additional planned analyses.  Additional post-hoc or unplanned analyses that are not 
defined in this Statistical Analysis Plan (SAP) may be performed.  Such analyses will be 
documented in the Clinical Study Report (CSR). 
2 
STUDY OBJECTIVES AND ENDPOINTS 
The primary study objective is to explore the safety and treatment effect of intravenous (IV) 
Remodulin as add-on therapy in neonates with persistent pulmonary hypertension of the newborn 
(PPHN) compared to placebo.  A secondary objective is to evaluate treprostinil pharmacokinetics 
(PK) in neonates with PPHN. 
2.1 
PRIMARY ENDPOINT 
The primary endpoint is the composite endpoint of clinical worsening through Day 14 as defined 
by one of the following: 
• Death 
• Initiation of extracorporeal mechanical oxygenation (ECMO) per institutional policies 
• Need for additional treatment (initiation of an additional targeted pulmonary 
• vasodilator therapy [eg, phosphodiesterase type 5 inhibitor {PDE-5I}, endothelin receptor 
antagonist {ERA}, prostanoid, L-citrulline]) 
2.2 
SECONDARY ENDPOINTS 
The secondary endpoints are as follows: 
• Change in oxygenation index (OI) from Baseline to Hours 12, 24, and 72, and Days 7 and 
14 and/or prior to study drug discontinuation/weaning 
• Change in partial pressure of oxygen saturation (PaO2)/fraction of inspired oxygen (FiO2) 
(P/F ratio) from Baseline to Hours 12, 24, and 72 
• Change in pre- and post-ductal saturation of peripheral capillary oxygenation (SpO2) 
from Baseline to Hours 6, 12, 24, and 72 
• Time to discontinuation of inhaled nitric oxide (iNO) 
• Time on mechanical ventilation 


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• Time to initiation of ECMO 
• Time to clinical worsening 
• Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) 
2.3 
SAFETY ENDPOINTS 
Safety endpoints are as follows: 
• Adverse events (AEs) 
• Clinical laboratory parameters 
• Physical examinations 
3 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multi-center, comparative study that will 
enroll neonates in the intensive care unit (ICU) with PPHN.  Eligible subjects must have 2 
consecutive OIs of 15 or greater, separated by at least 30 minutes, after having received iNO for 
at least 3 hours.  Once enrolled, subjects will be randomized to receive Remodulin (treprostinil) 
or placebo. 
This study is designed to evaluate the treatment effect of Remodulin as add-on therapy compared 
to placebo during a 14-day treatment period.  However, to assess continued safety in this 
neonatal population, subjects with residual or chronic pulmonary hypertension (PH) that does not 
fully resolve within 14 days may continue to receive study drug for up to an additional 14 days 
(up to 28 days total) per the Investigator’s discretion.  Post-treatment data will be collected until 
death, time of hospital discharge, time of withdrawal from study, or for 4 weeks after last dose of 
study drug, whichever comes first.  Subjects with ongoing AEs at the time of hospital discharge 
will continue to be followed for their AEs until either resolution (or return to normal or Baseline 
values), until judged by the Investigator to no longer be clinically significant, or until 4 weeks 
after last dose of study drug.  All serious adverse events (SAEs) should be followed until 
resolution, death, or the subject is lost to follow-up, even if they are ongoing for more than 4 
weeks after last dose of study drug. 


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4 
SEQUENCE OF PLANNED ANALYSES 
Interim Safety Analyses 
A safety review will be conducted by a Data Safety Monitoring Board (DSMB) after the first 10 
subjects have been randomized to receive study drug and have completed the 14-day treatment 
period.  A second review will occur once 40 subjects have been enrolled and completed the 14-
day treatment period.  Ad hoc meetings may be scheduled at additional enrollment milestones or 
in response to events related to the safety of study treatment. 
Interim Efficacy and Futility Analyses 
Efficacy and futility will be assessed at the second formal data review.  Details of the planned 
analyses and stopping rules are specified in the DSMB SAP.  If the DSMB votes to stop the 
study at the second review, all analyses will be conducted as specified in this SAP on the 
40 available subjects.  Otherwise, these analyses will not be conducted until the study is 
completely enrolled. 
Final Analysis after Database Lock and Study Unblinding 
After the database has been quality assured and locked, the treatment assignments will be 
provided to the Sponsor’s project statistician by the central randomization service and all 
planned analyses described in this document will be performed.  By intent, no changes will be 
made to the clinical database after unblinding.  However, any changes that are deemed 
necessary, after unblinding, will be clearly documented in the CSR. 
5 
SAMPLE SIZE CONSIDERATIONS 
Based on the systematic review of use of nitric oxide for respiratory failure in infants by Finer 
and Barrington (2006), 57.9% (194/335) subjects in the control group had an outcome of death 
or requirement for ECMO (Finer 2006).  In this study, assuming 60% of subjects in the placebo 
group and 30% of subjects in the Remodulin group with an outcome of death, requirement for 
ECMO, or need for additional PH therapy, we calculated that 66 subjects (33 subjects per 
treatment group) will have at least 80% power to show a significant difference in favor of 
Remodulin at alpha level 0.05 (1-sided test).  Approximately 70 subjects are planned to be 


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randomized (1:1) to either receive treatment with Remodulin or placebo in addition to the 
standard of care. 
6 
ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) population is defined as all subjects randomized into the study who 
received at least 1 dose of study drug.  All ITT subjects will be counted in the group to which 
they were randomized, regardless of the study drug they were given.  All efficacy analyses will 
be performed on this ITT population, unless otherwise specified. 
The Safety population is defined as all subjects enrolled into the study who received at least 
1 dose of study drug.  All Safety population subjects will be counted in the group corresponding 
to the study drug received, regardless of randomized assignment.  All safety analyses will be 
performed on this Safety population, unless otherwise specified. 
The Per-protocol population will include all subjects in the ITT population, excluding subjects 
with major protocol deviations that may have an impact on the primary efficacy analyses.  The 
major protocol deviations and the subject’s exclusion from the Per-protocol population will be 
reviewed at a blinded data review meeting and documented prior to the database lock and the 
study unblinding. 
The PK population will include all subjects in the ITT population with evaluable PK data.  All 
PK analyses will be performed on this PK population, unless otherwise specified. 
7 
INTERIM ANALYSES 
A DSMB will be established for the study including physicians knowledgeable in the treatment 
of PPHN and a statistician.  Throughout the course of the study the DSMB will meet on a regular 
basis to monitor the safety of the study.  Meetings will occur as outlined in the DSMB Charter.  
All analyses will be prepared by an independent external consultant and reviewed only by the 
DSMB as defined in the DSMB Charter.  The Sponsor will only have access to blinded study 
data during this process.  The details regarding the interim efficacy and safety analysis are 
included in a separate SAP. 


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8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All the data collected in the electronic Case Report Form (eCRF) will be listed.  In general, 
listings will be sorted by treatment group, subject number, and scheduled assessment (if 
applicable).  Listings will include assessment date, assessment time (if available), study day, and 
all relevant data collected in the eCRFs.  For data collected on a fixed schedule, the assessment 
identifier or the nominal time point will also be included on the listing.  Repeat or redundant 
observations within an assessment window and observations that do not fall within any 
predefined assessment window (and will, therefore, be excluded from summaries) will be 
flagged in these listings.  Subjects who are not to be included in the analysis population (eg, 
Safety population, Per Protocol population) will be flagged. 
In general, the data will be summarized by scheduled assessment (if applicable) within each 
treatment group.  For continuous variables, summary statistics will include the mean, standard 
deviation, median, minimum, and maximum.  For summaries of non-normal data, interquartile 
range (lower quartile, upper quartile) may also be included.  Minimums and maximums will be 
expressed using the level of precision in which the variable was collected.  All other statistics 
will be rounded, using an additional decimal place than was collected.  For discrete variables, 
summaries will include the frequency and percentage in each category.  Percentages will be 
rounded to 1 decimal place.  For all inferential analyses and descriptive comparisons, p-values 
will be rounded to 4 decimal places.  Values less than 0.0001 will be denoted as <0.0001, and 
values greater than 0.9999 will be denoted as >0.9999 whenever practical. Categories of discrete 
variables will be ordered and labelled as they appear in the eCRF, and all categories represented 
on the eCRF will be included in summaries, even when they do not apply to any subjects in the 
study. 
Unless otherwise specified, all statistical tests will be 2-sided at alpha level 0.05.  All statistical 
calculations will be completed using the SAS® Version 9.4 or above. 
8.1 
COVARIATES 
There are no planned covariates. 


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8.2 
EXAMINATION OF SUBGROUPS 
If the data permit, analyses may be stratified by presence/absence of congenital diaphragmatic 
hernia (CDH). 
8.3 
PREMATURE DISCONTINUATION AND MISSING DATA 
8.3.1 
Missing Data Handling for Primary Efficacy Endpoint 
Any subject with a missing value for clinical worsening will be assigned a value of “Yes.” 
8.3.2 
Missing Data Handling for Secondary Efficacy Endpoints 
For any continuous secondary endpoint, missing values will be imputed using last observation 
carried forward (LOCF).  If an assessment is missing at Baseline, change from Baseline will not 
be calculated and the subject will not be included in the analyses of this assessment. 
Time to event will be derived as detailed in Section 8.5.3. 
8.4 
MULTIPLE COMPARISONS AND MULTIPLICITY 
The primary efficacy endpoint of clinical worsening through Day 14 will be tested at alpha level 
0.05.  If the primary efficacy endpoint is statistically significant at alpha level 0.05, the statistical 
tests for secondary efficacy endpoints will be performed.  As these comparisons are exploratory, 
no adjustments for multiplicity are planned. 
8.5 
DERIVED AND TRANSFORMED DATA 
8.5.1 
Baseline Values 
In general, Baseline is defined as the last value for an assessment prior to randomization.  This 
value may be obtained at either the Screening or the Baseline visit, depending upon the visit 
schedule. 
8.5.2 
Change from Baseline Values 
Change from Baseline for an assessment is defined as the difference between the observed value 
and its associated Baseline value. 
8.5.3 
Time to Event and Censor Status 
Time to event and censor status will be calculated based on the rules in Table 8-1 for time to 
clinical worsening, time to initiation of ECMO, and time to discontinuation of iNO. 


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Table 8-1 
Time to Event and Censor Status Rules 
Parameter 
Scenario 
Formula 
Censor 
Status 
Time to Clinical 
Worsening 
(days) 
Subject with clinical 
worsening or subject died 
between Baseline and 
Day 14 
= minimum of (Worsening date, death 
date) - Randomization date 
0 (event) 
Subject without clinical 
worsening between 
Baseline and Day 14 
= minimum of (Last assessment date - 
Randomization date, 14) 
1 
(censored) 
Time to 
initiation of 
ECMO (days) 
Subject initiated ECMO 
between Baseline and 
Day 14 
= Initiation date - Randomization date 
0 (event) 
Subject did not initiate 
ECMO between Baseline 
and Day 14 
= minimum of (Last assessment date - 
Randomization date, 14) 
1 
(censored) 
Time to 
discontinuation 
of iNO (days) 
Subject discontinued iNO 
between Baseline and 
Day 14 
= iNO discontinuation date - 
Randomization date 
0 (event) 
Subject did not discontinue 
iNO between Baseline and 
Day 14 
= minimum of (Last assessment date - 
Randomization date, 14) 
1 
(censored) 
ECMO, extracorporeal mechanical oxygenation; iNO, inhaled nitric oxide 
8.6 
ASSESSMENT WINDOWS 
For some assessments, target study day and time have been specified in the protocol.  These 
scheduled assessments, as recorded on the eCRFs, and the corresponding target days and times 
and study days and time intervals are specified in Table 8-2. 
Table 8-2 
Assessment Windows for Scheduled Assessments 
Visit 
Target  
Study Day/Time 
Study Day/Time Interval 
Echocardiograms: 
Day 7 
Day 7 
2  Study Day  9 
Day 14 
Day 14 
10  Study Day 
Vital signs, OI, FiO2, Blood Gas/Lactate: 
Hour 6 
Day 1/6 hours 
1  Study Day 1, Hour 6  9 
Hour 12 
Day 1/12 hours 
10  Study Day 1, Hour 12  15 
Hour 18 
Day 1/18 hours 
16  Study Day 1, Hour 18  21 
Hour 24 
Day 1/24 hours 
22  Study Day 1, Hour 24  27 
Hour 30 
Day 2/6 hours 
28  Study Day 2, Hour 6  33 


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Visit 
Target  
Study Day/Time 
Study Day/Time Interval 
Hour 36 
Day 2/12 hours 
34  Study Day 2, Hour 12  39 
Hour 42 
Day 2/18 hours 
40  Study Day 2, Hour 18  45 
Hour 48 
Day 2/24 hours 
46  Study Day 2, Hour 24  51 
Hour 54 
Day 3/6 hours 
52  Study Day 3, Hour 6  57 
Hour 60 
Day 3/12 hours 
58  Study Day 3, Hour 12  63 
Hour 66 
Day 3/18 hours 
64  Study Day 3, Hour 18  69 
Hour 72 
Day 3/24 hours 
70  Study Day 3, Hour 24 
PK Assessments 
After 24 hours of study drug 
dosing 
Day 1 
24 hours ± 12 hours 
Abbreviations: FiO2, fraction of inspired oxygen; OI, oxygenation index; PK, pharmacokinetic(s) 
Note: Study Day = (Assessment Date) - (First Dosing Date) +1 
For assessments that are not listed in Table 8-2, the nominal assessment name recorded in the 
eCRF will be used. 
Multiple Evaluations Within the Same Analysis Window 
After all the observations have been slotted based on the specifications above, if there are 
multiple valid observations for an assessment within an assigned analysis visit window, only 1 of 
these observations will be used for summary statistics and analyses.  The observation to be used 
is determined using the following hierarchy (in decreasing order): 
• The observation closest to the target study day and time 
• The later observation if 2 observations are equally close to the target study day and time 
For missing values where the LOCF algorithm is applied, it is always the last valid observation 
on treatment carried forward, even though this might not be the observation obtained by the 
above hierarchy and used in the summaries by visit window. 
9 
STUDY POPULATION 
Unless otherwise specified, all efficacy analyses will be performed on the ITT population, all 
safety analyses will be based on the Safety population, and all PK analyses will be carried out 
based on the PK population.  In the ITT population, the treatment assignment is based on the 
assignment upon randomization.  In the Safety population, the treatment assignment is based on 


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the actual treatment the subject received.  The PK population will be comprised of those subjects 
with PK data. 
The comparability between the 2 treatment groups will be checked for demographic and baseline 
characteristics.  The p-values from Fisher’s exact test (for discrete variables) or Group t-test or 
Wilcoxon rank sum test (for continuous variables) will be included on summaries but are not 
intended to be used to test formal hypotheses.  For these comparisons, missing or unknown 
values will be excluded from the calculations. 
9.1 
SUBJECT ACCOUNTABILITY 
All subjects’ disposition information will be listed, including the study population the subjects 
belong to, premature study drug discontinuation status, reason for premature study drug 
discontinuation, premature study discontinuation status, and primary reason for premature study 
discontinuation. 
The listing of subject accountability will include dates of informed consent, randomization, first 
study drug dose, each study drug dose change, last study drug dose, and last assessment.  Each of 
these assessments will be summarized by treatment group and overall. 
Information regarding whether each subject is included in each analysis population will be listed.  
If a subject is not included in an analysis population, the reason for exclusion will be noted on 
the listing.  Also noted on the listing will be the randomized treatment assignment and the actual 
treatment received.  The summary will include the frequency and percentage of all subjects in 
each analysis population as well as summaries for reason for exclusion. 
Status of the treatment blind and, if broken, date/time of blind broken and reason will be listed. 
9.2 
PROTOCOL DEVIATIONS 
The status of the entry criteria will be listed for all subjects.  The listing will include the date of 
the initial screening assessment and a list of any specific entry criteria not met.  This listing will 
also include the protocol version that the subject was enrolled under.  Entry criteria violations 
will be summarized by treatment group and overall. 


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Additional protocol deviations will be documented throughout the study.  Protocol deviations 
will be listed, including the date of the deviation, the type of deviation, and the severity of the 
deviation.  The protocol deviations will also be summarized by treatment group and overall. 
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATION 
9.3.1 
Demographics 
All demographic data will be listed for all subjects, including assessment date, date of birth, 
country, age (in days), sex, ethnicity, race, length, and weight.  Age (in days), sex, ethnicity, 
race, length, and weight will be summarized.  The summary will include p-values (2-sided) from 
Fisher’s exact test (for sex, ethnicity, and race) and Group t-test or Wilcoxon rank sum test (for 
age, length, and weight) comparing treatment groups. 
9.3.2 
Medical History and PPHN and Neonatal History 
All significant past or ongoing medical conditions will be listed for all subjects.  The listing will 
include the Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) 
and preferred term (PT) for each condition listed, and if the condition is ongoing at Baseline.  
These medical conditions will be summarized by PT within each SOC by treatment group and 
overall. 
PPHN and neonatal history will be listed for all subjects.  The listing will include current PPHN 
diagnosis; gestational age; birth weight; Appearance, Pulse, Grimace, Activity, Respiration 
(APGAR) scores at 1 and 5 minutes; and prior surfactant and prostaglandin therapy.  Each of 
these assessments will also be summarized by treatment group and overall with appropriate 
summary statistics. 
9.3.3 
Concomitant Medications 
All concomitant medications specified on the eCRF will be mapped to a standard name using the 
World Health Organization Drug Dictionary (WHO-DD). 
The standard name and verbatim term of all concomitant medications will be listed for all 
subjects.  This listing will include the date started (or indication that drug was ongoing at 
randomization), date discontinued (or indication that drug was ongoing at end of study), and the 
condition(s) treated/indication(s).  If a subject received no medications, this will be indicated on 


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the listing.  A summary of concomitant medications present at Baseline and a summary of 
concomitant medications added during the study will include the frequency and percentage of 
subjects in each treatment group receiving each drug (by coded standard name). 
10 
EFFICACY ANALYSES 
Except where otherwise noted, all efficacy analyses will only be performed on the ITT 
population. 
10.1 
PRIMARY EFFICACY MEASURES 
10.1.1 
Primary Efficacy Analyses 
10.1.1.1 
Hypothesis 
The primary efficacy endpoint of clinical worsening assesses if treprostinil reduces the incidence 
of clinical worsening through Day 14 over placebo in subjects with PPHN.  The null and 
alternative hypotheses are: 
𝐻଴: 𝑝ଵ= 𝑝ଶ 
𝐻௔: 𝑝ଵ≠𝑝ଶ, 
where p1 and p2 are the proportion of subjects who experience clinical worsening in the 
treprostinil and placebo treatment groups, respectively. 
10.1.1.2 
Primary Efficacy Analysis 
The frequency and percentage of subjects who experience clinical worsening through Day 14 
will be calculated for each treatment group.  A chi-square test will be conducted to compare the 
incidence of clinical worsening between the treprostinil and placebo treatment groups. 
The SAS Procedure FREQ will be used.  The pseudo SAS statements are listed below: 
proc freq; 
     tables Treatment* Worsening / chisq; 
run; 
10.1.1.3 
Sensitivity and Subgroup Analyses 
To further support the robustness and assess the sensitivity of the primary efficacy analysis of 
clinical worsening through Day 14 (provided that the primary analysis yields significant results), 


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the above summary and chi-square test will be repeated using each of the following 
modifications (if data permit): 
• The Per Protocol population will be used instead of the ITT population 
• PPHN diagnosis (associated with unilateral CDH versus not associated with unilateral 
CDH) 
10.2 
SECONDARY EFFICACY MEASURES 
The secondary endpoints are as follows: 
• Change in OI from Baseline to Hours 12, 24, and 72, and Days 7 and 14 and/or prior to 
study drug discontinuation/weaning 
• Change in PaO2/FiO2 (P/F ratio) from Baseline to Hours 12, 24, and 72 
• Change in pre- and post-ductal SpO2 from Baseline to Hours 6, 12, 24, and 72 
• Time to discontinuation of iNO 
• Time on mechanical ventilation 
• Time to initiation of ECMO 
• Time to clinical worsening 
• Change in NT-proBNP 
10.2.1 
Change in OI 
The secondary efficacy endpoint of change in OI assesses if treprostinil decreases the level of OI 
over placebo in subjects with PPHN.  The null and alternative hypotheses are: 
𝐻଴: 𝜇ଵ= 𝜇ଶ 
𝐻௔: 𝜇ଵ≠𝜇ଶ, 
where µ1 and µ2 are the median change from Baseline in OI of the treprostinil and placebo 
treatment groups, respectively. 
The OI values will be listed for all subjects, including the nominal time point and collection 
date/time.  The values and their respective changes from Baseline will be summarized for all 
scheduled timepoints.  The difference between treatment groups for the change from Baseline at 
Day 14 will be tested via a Group t-test at the following timepoints:  Hour 12, Hour 24, Hour 72, 
Day 7, Day 14, and prior to study drug discontinuation/weaning. 


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If normality assumptions for the parametric test are violated, the nonparametric Wilcoxon rank 
sum test will be used.  For subjects who do not have OI measurements at a timepoint, the LOCF 
imputation will be used.  The analyses will also be performed for the data without imputation for 
the missing measures. 
10.2.2 
Change in PaO2/FiO2 
PaO2/FiO2 and change from Baseline in PaO2/FiO2 will be analyzed in a similar manner as 
described in Section 10.2.1 at 12 hours, 24 hours, and 72 hours. 
10.2.3 
Change in SpO2 
Pre- and post-ductal SpO2 and change from Baseline in pre- and post-ductal SpO2 will each be 
analyzed in a similar manner as described in Section 10.2.1.  Additionally, change from Baseline 
in pre- and post-ductal SpO2 will be summarized by treatment group at 6 hours, 12 hours, 24 
hours, and 72 hours. 
10.2.4 
Change in NT-proBNP 
NT-proBNP and change from Baseline in NT-proBNP at Day 14 will be analyzed as described in 
Section 10.2.1 at Day 7 and Day 14.  The listing will include normal range and high/low flags as 
well as all collected assessments of NT-proBNP. 
10.2.5 
Time to Clinical Worsening 
Data on the clinical worsening assessment page of the eCRF will be used to determine clinical 
worsening status.  Clinical worsening events including the date (study day) of the event and 
details of the clinical worsening event will be listed.  The time to clinical worsening will be 
calculated according to the rules specified in Table 8-1. 
Time to clinical worsening will be summarized by treatment group using product-limit estimates 
calculated by the Kaplan-Meier method, and displayed graphically as Kaplan-Meier curves.  A 
tabular summary of this analysis will include the number of subjects at risk (sample size), 
estimated median duration, and a 95% confidence interval for the median duration for each 
treatment group.  The log-rank test will be used to calculate the p-value for treatment differences. 


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The SAS Procedure LIFETEST will be used.  The pseudo SAS statements are listed below: 
proc lifetest; 
     time TimeToWorsening*Censor_Status(1); 
     strata Treatment; 
run; 
In addition, the Cox proportional hazards model will be fit to obtain the hazard ratio.  The model 
will include treatment as an explanatory variable.  The SAS procedure PHREG will be used.  
The pseudo SAS statements are listed below: 
proc phreg; 
  Model TimeToWorsening*Censor_Status(1) = treatment           
        / risklimits alpha=0.05 ties=efron; 
run; 
10.2.6 
Time to Initiation of ECMO 
Time to initiation of ECMO will be analyzed as described in Section 10.2.5. 
10.2.7 
Time to Discontinuation of iNO 
Time to discontinuation of iNO will be analyzed as described in Section 10.2.5. 
10.2.8 
Time on Mechanical Ventilation 
A listing that includes start date and time, stop date and time, and total time on mechanical 
ventilation will be prepared.  Time on mechanical ventilation will be summarized by treatment 
group, as appropriate.  A Wilcoxon rank sum test will be conducted to assess differences 
between treatment groups. 
11 
HEALTH OUTCOMES 
No health outcome assessments will be collected in this study. 
12 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety population. 
12.1 
EXTENT OF EXPOSURE 
A listing of study drug dosing will include route of administration (IV or subcutaneous); initial 
dose and date and time of initial dose; and dose, date, and time of each dose change.  Overall 


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duration of exposure will be included as well as the final dose and the maximum study drug dose 
reached for each subject.  Summaries of initial dose, final dose, and maximum dose will be 
provided by treatment group.  If the data warrant, these summaries will also be produced by 
route of administration. 
12.2 
ADVERSE EVENTS 
All AEs will be coded to PT and SOC using the latest version of the MedDRA coding dictionary.  
Treatment-emergent adverse events (TEAEs) are those AEs with onset date equal to or after the 
start date of the study drug.  TEAEs will appear in listings and summaries.  Non–treatment-
emergent AEs (the AEs occurring after signing the Informed Consent Form (ICF), but before 
receiving study drug) will be listed, but will not be included in summary tables. 
The AE listings will include the AE verbatim term and its corresponding PT and SOC, all eCRF 
details, and a treatment-emergent indicator flag.  The following AE listings will be provided: 
• All AEs 
• Deaths 
• SAEs 
• AEs leading to permanent discontinuation of study drug 
All AE summaries will be sorted by overall frequency and/or SOC and will include the number 
and percentage of subjects experiencing each type of AE, the total number of each type of AE, 
and the AE rate of each type of AE.  AE rate will be calculated as the total number of AEs 
divided by the total patient days of exposure to study drug per treatment group. 
The following AE summaries will be provided: 
• AEs by SOC and PT 
• AEs by PT 
• Deaths 
• SAEs by SOC and PT 
• Non-serious AEs by SOC and PT 
• AEs probably or possibly related to study drug by SOC and PT 
• AEs leading to permanent discontinuation by PT 
• AEs by SOC, PT, and severity (mild, moderate, severe) 


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12.3 
CLINICAL LABORATORY EVALUATIONS 
Blood samples will be taken at Baseline, Day 7, Day 14, immediately prior to study drug 
weaning or discontinuation, within 12 hours of study drug discontinuation, 48 hours after study 
drug discontinuation, and upon hospital discharge or 4 weeks after study drug discontinuation.  
All samples will be sent to the institutional laboratory for evaluation of clinical chemistry and 
hematology. 
12.3.1 
Clinical Chemistry 
The following clinical chemistry parameters will be evaluated by the central laboratory: 
Parameter 
Units 
Sodium 
mmol/L 
Potassium 
mmol/L 
Bicarbonate 
mmol/L 
Chloride 
mmol/L 
Total bilirubin 
umol/dL 
Alkaline phosphatase 
U/L 
Alanine aminotrasferase  
U/L 
Aspartate aminotransferase 
U/L 
Urea nitrogen 
mmol/dL 
Creatinine 
umol/L 
Glucose 
mmol/L 
Calcium 
mmol/L 
Albumin 
g/L 
Lactate 
mg/dL 
pH 
 
 
Values that are “high” or “low” with respect to the reference range provided by the central 
laboratory will be flagged with an “H” or an “L,” respectively.  All parameters will be listed for 
all subjects and assessments, along with their respective “high/low” flags. 
Values of these parameters at each scheduled timepoint and their corresponding changes from 
Baseline will be descriptively summarized. 
For each parameter, the frequency and percentage of subjects within each treatment group who 
had “low,” “normal,” or “high” Baseline values, then subsequently had “low,” “normal,” or 


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“high” follow-up values at each scheduled timepoint will be presented in a shift summary at each 
scheduled timepoint. 
12.3.2 
Hematology 
The following hematology parameters will be evaluated by the central laboratory: 
Parameter 
Units 
Hemoglobin 
g/dL 
Hematocrit 
% 
Red blood cell count 
106/uL 
White blood cell count 
103/uL 
Platelet count 
103/uL 
Prothrombin time 
sec 
 
Values that are “high” or “low” with respect to the reference range provided by the central 
laboratory will be flagged with an “H” or an “L,” respectively.  All parameters will be listed for 
all subjects and assessments, along with their respective “high/low” flags. 
Numeric values of these parameters at each scheduled timepoint and their corresponding changes 
from Baseline will be summarized. 
For each parameter, the frequency and percentage of subjects within each treatment group who 
have “low,” “normal,” or “high” Baseline values, then subsequently have “low,” “normal,” or 
“high” follow-up values at each scheduled timepoint will be presented in a shift summary. 
12.4 
OTHER SAFETY MEASURES 
12.4.1 
Echocardiograms 
Echocardiograms will be collected at Screening, Day 7, Day 14, immediately prior to study drug 
weaning or discontinuation, and 48 hours after study drug discontinuation.  All echocardiogram 
assessments will be listed for all subjects.  This listing will include the date and time of 
assessment, tricuspid regurgitant jet velocity, pulmonary regurgitant jet velocity, shunting details 
(through patent ductus arteriosus, through atrial septal defect or patent foramen ovale, and 
through ventricular septal defect), right ventricle dilation, and interventricular septal position.  


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The echocardiogram results will be descriptively summarized by treatment group at each planned 
assessment time. 
12.4.2 
Vital Signs 
All vital sign assessments will be listed for all subjects.  This listing will include weight, length, 
heart rate, systolic and diastolic blood pressures, respiration rate, temperature, and SpO2.  The 
vital sign results at each scheduled timepoint and the associated change from Baseline will be 
descriptively summarized by treatment group. 
12.4.3 
PPHN Disease-related Events 
The number and percentage of subjects who experienced any PPHN disease-related event will be 
summarized by treatment group.  Each category of disease-related event will also be summarized 
by treatment group.  A listing of PPHN disease-related events will also be provided. 
13 
PHARMACOKINETICS 
A listing that includes treprostinil plasma concentration, sample collection date and time, and 
nominal timepoint will be created.  A separate listing will include the calculated PK parameters 
(if possible) for each subject. 
Treprostinil plasma concentrations and PK parameters will be summarized by treatment group 
and nominal timepoint.  The summary will include geometric mean and standard deviation in 
addition to arithmetic mean, standard deviation, minimum, and maximum. 
Full details for the analysis of the PK data will be provided in a separate analysis plan. 
14 
REFERENCES 
Finer N and Barrington KJ.  Nitric oxide for respiratory failure in infants born at or near term 
(review). Cochrane Database of Systematic Reviews. 2006; Issue 4. Art. No.: CD000399. DOI: 
10.1002/14651858.CD000399.pub2. 
SAS Institute Inc., SAS OnlineDoc 9.4, Cary, NC: SAS Institute Inc. 


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15 
LIST OF TABLES, LISTINGS, AND FIGURES 
15.1 
LIST OF TABLES 
Table Number 
Table Title 
14.1.1 
Summary of Subject Accountability 
14.1.2 
Summary of Analysis Population Information 
14.1.3 
Summary of Demographic Data 
14.1.4 
Summary of Baseline Characteristics 
14.1.5 
Summary of PPHN History 
14.1.6 
Summary of Neonatal History 
14.1.7.1 
Summary of Entry Criteria Violations 
14.1.7.2 
Summary of Protocol Deviations 
14.1.8 
Summary of Medical History  
14.1.9 
Summary of Concomitant Medications Ongoing at Baseline 
14.1.10 
Summary of Concomitant Medications Added During the Study  
14.1.11 
Summary of Study Drug Dosing and Exposure 
14.2.1.1 
Summary and Analysis of Clinical Worsening through Day 14 – Primary 
Efficacy Endpoint – ITT Population 
14.2.1.2 
Summary and Analysis of Clinical Worsening through Day 14 – Primary 
Efficacy Endpoint – Per Protocol Population 
14.2.2.1 
Summary and Analysis of Oxygenation Index – Secondary Efficacy Endpoint 
14.2.2.2 
Summary and Analysis of PaO2/FiO2 – Secondary Efficacy Endpoint 
14.2.2.3 
Summary and Analysis of Pre-ductal SpO2 – Secondary Efficacy Endpoint 
14.2.2.4 
Summary and Analysis of Post-ductal SpO2 – Secondary Efficacy Endpoint 
14.2.2.5 
Summary and Analysis of NT-proBNP (pg/mL) – Secondary Efficacy 
Endpoint 
14.2.2.6 
Summary and Analysis of Time to Clinical Worsening – Secondary Efficacy 
Endpoint 
14.2.2.7 
Summary and Analysis of Time to Initiation of ECMO – Secondary Efficacy 
Endpoint 
14.2.2.8 
Summary and Analysis of Time to Discontinuation of iNO – Secondary 
Efficacy Endpoint 
14.2.2.9 
Summary and Analysis of Time on Mechanical Ventilation – Secondary 
Efficacy Endpoint 
14.3.1.1 
Overall Summary of Adverse Events 
14.3.1.2 
Summary of Adverse Events by System Organ Class and Preferred Term 
14.3.1.3 
Summary of Adverse Events by Preferred Term 
14.3.1.4 
Summary of Deaths 
14.3.1.5 
Summary of Serious Adverse Events by System Organ Class and Preferred 
Term 
14.3.1.6 
Summary of Non-serious Adverse Events by System Organ Class and 
Preferred Term 


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Table Number 
Table Title 
14.3.1.7 
Summary of Adverse Events Probably or Possibly Related to Study Drug by 
System Organ Class and Preferred Term 
14.3.1.8 
Summary of Adverse Events Leading to Permanent Discontinuation of Study 
Drug by Preferred Term 
14.3.1.9 
Summary of Adverse Events by System Organ Class, Preferred Term, and 
Severity 
14.3.2.1 
Listing of Deaths 
14.3.2.2 
Listing of Serious Adverse Events 
14.3.3 
Summary of PPHN Disease Related Events 
14.3.4.1 
Summary of Laboratory Data – Clinical Chemistry 
14.3.4.2 
Summary of Clinical Chemistry Shift from Baseline 
14.3.4.3 
Summary of Laboratory Data - Hematology 
14.3.4.4 
Summary of Hematology Shift from Baseline 
14.3.5 
Summary of Vital Signs 
14.3.6 
Summary of Echocardiogram Parameters 
14.3.7.1 
Summary of FiO2 
14.3.7.2 
Summary of Blood Gas 
14.3.7.3 
Summary of Lactate 
14.4.1 
Summary of Plasma Treprostinil Concentrations 
14.4.2 
Summary of Pharmacokinetic Parameters 
 


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15.2 
LIST OF LISTINGS 
Listing Number 
Listing Title 
16.2.1.1 
Subject Disposition 
16.2.1.2 
Subject Accountability 
16.2.2 
Protocol Deviations 
16.2.3.1 
Subject Randomization 
16.2.3.2 
Analysis Population Information 
16.2.3.3 
Entry Criteria 
16.2.4.1 
Demographics 
16.2.4.2 
PPHN 
16.2.4.3 
Neonatal History 
16.2.4.4 
Medical History 
16.2.4.5 
Concomitant Medications 
16.2.5 
Study Drug Dosing 
16.2.6.1 
Clinical Worsening Events 
16.2.6.2 
FiO2/O2 Assessment 
16.2.6.3 
Blood Gas/Lactate 
16.2.6.4 
Plasma NT-proBNP (pg/mL) 
16.2.6.5 
Mechanical Ventilation 
16.2.6.6 
Nitric Oxide 
16.2.7.1 
Death Records 
16.2.7.2 
Adverse Events 
16.2.7.3 
Adverse Events Leading to Permanent Discontinuation of Study Drug 
16.2.8.1 
Laboratory Results – Clinical Chemistry 
16.2.8.2 
Laboratory Results – Hematology 
16.2.8.3 
Vital Signs 
16.2.8.4 
Echocardiogram Results 
16.2.8.5 
PPHN Disease-related Events 
 


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15.3 
LIST OF FIGURES 
Figure Number 
Figure Title 
14.2.1 
Kaplan-Meier Plot of Time to Clinical Worsening 
14.2.2 
Kaplan-Meier Plot of Time to Discontinuation of iNO 
14.2.3 
Kaplan-Meier Plot of Time to Initiation of ECMO 
14.2.4 
Line Plot of Mean Change in OI over Time 
14.2.5 
Line Plot of Mean Change in PaO2/FiO2 over Time 
14.2.6 
Line Plot of Mean Change in Pre-ductal SpO2 over Time 
14.2.7 
Line Plot of Mean Change in Post-ductal SpO2 over Time 
14.2.8 
Line Plot of Mean Change in NT-proBNP over Time