Clinical trial NCT01560637
Conditions: Pulmonary Arterial Hypertension
Keywords: PAH PH FREEDOM 6 minute walk test treprostinil open label
Sponsor: United Therapeutics
Start date: 2013-09-11; Completion date: 2021-08-12
Enrollment: 471 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is an international, multi-center, open-label study designed to provide oral treprostinil (UT-15C) to eligible subjects with pulmonary arterial hypertension who have completed the TDE-PH-310 study. The purpose of this study is to assess the long-term safety of UT-15C and to assess the effects of long-term treatment with UT-15C on exercise capacity.

Detailed description:

Arms: arm 1: Open label access
Interventions: intervention 1: UT-15C (treprostinil diolamine)
Intervention descriptions: intervention 1: UT-15C extended release oral tablet three times daily

Protocol documents:
ICF_002.pdf: 
United Therapeutics Corporation 
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INFORMED CONSENT FORM 
Title of Research Study: 
An Open-Label Extension Study of UT-15C in Subjects with 
Pulmonary Arterial Hypertension - A Long-Term Follow-Up to 
Protocol TDE-PH-310 
Protocol Number: 
Principal Investigator: 
TDE-PH-311 
 
Phone: 
 
 
Sub-Investigator: 
 
 
 
 
Sponsor: 
United Therapeutics Corporation 
 
 
Research Site/Hospital: 
 
 
 
 
Before agreeing to participate in this research study, it is important that you read the following 
information describing the purpose, procedures, benefits, risks, discomforts, and precautions of 
the study.  Please take time to read the following information carefully and discuss it with friends 
and family if you wish. 
This consent form may contain words that you do not understand.  You will need to ask your 
doctor or the study staff to explain any words or information that you do not clearly understand. 
Your doctor should answer your questions before you sign this consent form.  Once you sign this 
form you will be given a copy. 
INTRODUCTION 
You are being asked to be in this research study because you recently completed the TDE-PH-
310 study.  If you did not participate, participated and did not complete the TDE-PH-310 study, 
you cannot participate in this study. 
You are being asked to be in a research study because your doctors have informed you that you 
have pulmonary arterial hypertension (PAH).  This means that your blood vessels going from the 
right side of the heart to the lungs (pulmonary arteries) have higher than normal pressure.  This 
puts strain on your heart.  This strain causes the heart to pump less blood into the lungs.  This 
will result in symptoms like shortness of breath, tiredness, and swelling in the feet and stomach.  
Over time, these symptoms can get worse because the heart cannot pump enough blood into the 
lungs. 
This research study is under the direction of <name>, who is the “principal investigator,” also 
known as the “study doctor.”  As the study doctor, <name> will make sure that this study is done 
properly and that your rights and safety as a participant in this study are protected.  <Name> will 
carry out the day-to-day activities of the research study using his/her <his/her> best medical 
judgment. 


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United Therapeutics Corporation, a drug company, is the “sponsor” of this research study and is 
responsible for the development and broad oversight of the study. 
PURPOSE 
The purpose of this research study is to assess how an investigational drug works to treat PAH.  
An investigational drug is one that has not yet been approved for use by the Food and Drug 
Administration (FDA) or has not yet been approved for treatment of PAH.  The drug in this 
research study is called UT-15C (treprostinil diethanolamine also known as treprostinil 
diolamine).  UT-15C (brand name Orenitram) was approved by the United States Food and Drug 
Administration (FDA) in December 2013 for the treatment of PAH.  UT-15C will be provided in 
different strength tablets that are taken by mouth three times in a day.  UT-15C is a sustained 
release tablet.  This means study drug is released slowly over an extended period of time.  This 
study will evaluate the long-term safety of UT-15C and the effects of continued therapy on your 
ability to exercise. 
Before this study, UT-15C has been given to over 1800 subjects.  In this study, up to 
850 subjects may participate. 
PROCEDURES 
Once you complete the TDE-PH-310 study, you and your doctor will be told whether you were 
receiving UT-15C (active drug) or placebo (sugar pill).  If you were receiving UT-15C, you will 
continue receiving UT-15C while participating in this open-label study.  If you were receiving 
placebo, you will stop taking placebo and start taking UT-15C during this open-label study. 
TREATMENT PHASE 
If you choose to participate in this study, your doctor will use the procedures done at the last visit 
in the TDE-PH-310 study to determine if you can enter in this open-label study.  The final visit 
in TDE-PH-310 (Study Termination Visit) will also be the Baseline Visit for this open-label 
study.  If you meet all study entry conditions for the open-label study, the dose of study drug you 
receive from your doctor will depend on whether you were on placebo or UT-15C in TDE-PH-
310 study. 
If you were on placebo in the TDE-PH-310 study, you will be given the first dose of UT-15C in 
the hospital or clinic.  The first dose will be 0.125 mg.  You will be asked to take the study drug 
with food.  If you were on UT-15C in the TDE-PH-310 study, you will start with the same dose 
that you were taking at the Study Termination Visit in the TDE-PH-310 study.  You will be 
given a supply of study drug before leaving the clinic.  Study drug should be taken three times a 
day.  The study drug should always be taken approximately every 6-8 hours during the day about 
10 minutes after consuming food and should not be split, crushed, or chewed. 
After the Baseline visit you will be required to visit the hospital, or clinic, on at least two 
separate occasions over the first 12 week period.  After the first 12 weeks, you will be required to 
visit the hospital, or clinic, once every 12 weeks until you discontinue from the study or the 
study ends.  


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Throughout this study, you will be asked to report any difficulties or side effects you experience, 
and whether or not you feel they are related to or caused by the study drug.  It is very important 
for you to discuss any illnesses, difficulties or side effects you may have during the study with 
your doctor.  If your condition worsens, your doctor will then decide if you should come in to the 
hospital or clinic to change your dose of study drug or to change your treatment.  Any changes in 
your dose of study drug will be made by the doctor responsible for this study and it is important 
to contact the site staff prior to making any change to your dose of study drug. Your doctor may 
remove you from the study to consider other treatments. 
Optional Whole Genome Sequencing: You are being asked to participate in an optional portion 
of this study which involves additional blood samples for pharmacogenomic research. 
Pharmacogenomic research is an important way to try to understand the role of genetics in 
human disease and how genes impact the effectiveness of drugs.  There are many differences, or 
variations, in genes from one person to another that may affect a person’s chances of suffering 
from a particular disease.  These differences in genes can also change the way a person responds 
to a particular drug.  We would like to learn more about PAH and the response to treatment by 
measuring different types of genetic material (ie, deoxyribonucleic acid [DNA]) found in your 
blood that is associated with PAH and/or your response to treatment.  The aim is to find out if 
there are genetic markers which may help predict how well treatment with oral treprostinil 
works. Better understanding of these differences today can help doctors in the future more 
accurately determine which treatments are best for their patients and which treatments are least 
likely to cause side effects. 
Blood samples will be analysed by a method called genetic sequencing.  Genetic sequencing is a 
type of testing that enables researchers to analyze a person’s genetic code, also known as the 
genome.  Genetic sequencing will be performed by a company hired by the Sponsor. 
If you choose to participate, you will be asked to give 1 additional blood sample (about 
2 teaspoons [10 mL]) for the genetic sequencing.  Blood will be drawn from a vein using a 
needle.  Your blood sample, together with certain information about you obtained from your 
participation in the study, will be provided to a company hired by the Sponsor to conduct genetic 
sequencing and additional research.  Neither you nor your physician will receive any genetic 
sequence information from your participation in this research.  The information resulting from 
the analysis will be used anonymously, meaning that your identity will not be revealed.  The 
research done with your blood sample may be used by the Sponsor to develop new therapies or 
diagnostic tests in the future.  If the sponsor or any of its affiliates make a profitable product 
from the development of new therapies or diagnostic tests, there is no plan to share any of the 
profits with you. 
You do not have to agree to this optional testing in order to be in this study.  It is important that 
before you make a decision to participate, you read the rest of this form.  You should ask as 
many questions as you need to understand what will happen to you if you decide to participate.  
You will have an opportunity to note your decision to participate in the whole genome 
sequencing separately at the end of this form. 


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REGULAR TELEPHONE CONTACT 
You will be contacted each week by one of the study staff members by telephone weekly during 
the first 12 weeks of the study.  After the first 12 weeks, you will be contacted by one of the 
study staff members by telephone at least once a month.  During the telephone calls, you will be 
asked if you took the study drug as directed, if your symptoms of PAH are improved, the same, 
or worse, and if you have experienced any illness or side effects.  You will be asked to provide 
information about the medications you are currently taking, including over the counter and 
herbal medications.  Based on your answers, your doctor will determine if the dose of your study 
drug should be changed. 
Additional procedures will be done during your scheduled clinic visits.  They include: 
Weeks 6 and 12 Visits 
 Vital signs (blood pressure, heart rate, breathing rate, and weight) will be recorded 
 Ranking of the severity of your PAH on a scale (WHO functional class) 
 Review of any illnesses or side effects that you may have experienced 
 Six-minute walk test (to measure the distance you can walk in 6 minutes).  After the six-
minute walk test, you will be asked to rate your shortness of breath (by using the Borg 
dyspnea score to rate your shortness of breath during the six-minute walk test ranging 
from 0-nothing at all to 10-very, very heavy shortness of breath) 
 If you are a woman capable of giving birth, you will also have a urine pregnancy test 
 Blood (about 3-4 teaspoons, or 15-20 milliliters) will be collected for routine laboratory 
tests (Only done at the Week 12 Visit) 
 If necessary, your study drug dose will be adjusted 
 You will be asked to return all study drug, including empty bottles, to the clinic so the 
site staff can determine if you have been taking the study drug as directed.  You will be 
given a new supply of study drug 
 Review of all the medications that you are taking 
Follow-Up Visits after Week 12 (Once every 12 weeks) 
 Vital signs (blood pressure, heart rate, breathing rate, and weight) will be recorded  
 Ranking of the severity of your PAH on a scale (WHO functional class) 
 Review of any illnesses or side effects that you may have experienced 
 Six-minute walk test (to measure the distance you can walk in 6 minutes).  After the six-
minute walk test, you will be asked to rate your shortness of breath (by using the Borg 
dyspnea score to rate your shortness of breath during the six-minute walk test ranging 
from 0-nothing at all to 10-very, very heavy shortness of breath) 
 If you are a woman capable of giving birth, you will also have a urine pregnancy test 
 Blood (about 3-4 teaspoons, or 15-20 milliliters) will be collected for routine laboratory 
tests. This will be done at the first follow up visit and at every other visit afterwards  
 At the third follow up visit, additional blood test will be done to see how your heart is 
working by measuring the level of a PAH blood marker (NT-proBNP)  


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 If necessary, your study drug dose will be adjusted 
 At each of these visits, you will be asked to return all study drug, including empty bottles, 
to the clinic so the site staff can determine if you have been taking the study drug as 
directed.  You will be given a new supply of study drug 
 Review of all the medications that you are taking 
 Collection of a single blood sample (about 2 teaspoons [10 mL]) for evaluation of 
pharmacogenomics (optional)* 
* Sample to be collected at a Follow-up Visit when routine clinical laboratory samples are 
collected. 
Study Termination Visit 
 Vital signs (blood pressure, heart rate, breathing rate, and weight) will be recorded 
 Physical examination 
 Ranking of the severity of your PAH on a scale (WHO functional class) 
 Review of any illnesses or side effects that you may have experienced 
 Six-minute walk test (to measure the distance you can walk in 6 minutes).  After the 
six-minute walk test, you will be asked to rate your shortness of breath (by using the 
Borg dyspnea score to rate your shortness of breath during the six-minute walk test 
ranging from 0-nothing at all to 10-very, very heavy shortness of breath) 
 If you are a woman capable of giving birth, you will also have a urine pregnancy test 
 Blood (about 3-4 teaspoons, or 15-20 milliliters) and urine will be collected for routine 
laboratory tests 
 Used and unused study drug will be counted  
 Review of all the medications that you are taking 
 Collection of blood sample (about 2 teaspoons [10 mL]) for evaluation of 
pharmacogenomics (optional) * 
* If you discontinue prior to your next Follow-up Visit, the pharmacogenomic sample will be 
collected at the Study Termination Visit. 
Once you complete the study, the study staff will contact you approximately 30 days after the 
study termination visit to evaluate your overall health status. 
WOMEN OF CHILDBEARING POTENTIAL 
Women who can have children and who want to enter this study must have a negative pregnancy 
test before beginning the study and must use two acceptable methods of birth control during the 
study.  Being a part of this study while pregnant or breastfeeding may expose the unborn or 
nursing infant to known and unknown risks.  Therefore, pregnant and nursing women cannot 
enroll in the study.  The effects of UT-15C on a fetus are not fully known.  It is very important 
that you do not become pregnant during this study. 


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In an animal study, some undesirable effects were seen in the development of rabbit fetuses after 
the pregnant animals received high doses of study drug. 
If you are a woman who can have children, you must agree to either avoid sexual intercourse 
(abstinence) when it is in line with your preferred and usual lifestyle or use two different forms 
of effective contraception from the time you sign informed consent until 30 days after the last 
dose of study drug.  Medically acceptable, effective, birth control methods include: (1) approved 
hormonal contraceptives, such as birth control pills (2) barrier methods (such as a condom or 
diaphragm) used with a spermicide, (3) an intrauterine device (IUD), (4) partner(s) with a 
vasectomy.  If you have previously undergone surgical sterilization such as tubal ligation or 
hysterectomy, then you will not need to practice these methods of contraception.  If you are a 
woman of childbearing potential, a urine pregnancy test will be conducted at each study visit. 
You should not take part in this study if you plan to become pregnant from the time you sign this 
consent form until 30 days after the last dose of study drug. 
If you do become pregnant while participating in this study, you must notify your study doctor.  
Your doctor will slowly decrease your dose until you are no longer taking study drug.  You will 
have to withdraw from active participation in the study.  The site staff will continue to contact 
you until the outcome of the pregnancy is known.  Possible outcomes include normal birth, 
miscarriage, or elective abortion. 
MEN 
The effects of UT-15C on a fetus are not fully known.  You should not take part in this study if 
your partner plans to become pregnant during your participation in the study.  You will need to 
use a condom during the entire length of the study, and for 2 days after taking the last dose of 
UT-15C.  Even if your partner is pregnant at the beginning of the study, you must still use a 
condom.  This is because some UT-15C could be in your semen and may reach the fetus. 
In an animal study, some undesirable effects were seen in the development of rabbit fetuses after 
the pregnant animals received high doses of study drug. 
RISKS AND DISCOMFORTS 
Risks of UT-15C 
There may be serious risks involved with being in this study.  The risks may be with the UT-15C 
itself, the combination of UT-15C with the other drug(s) you take for PAH, and/or the scheduled 
procedures.  These may include serious side effects of UT-15C, not all of which are known.  The 
side effects that have been observed in patients most often so far include, but are not limited to, 
headache, nausea, diarrhea, facial flushing, vomiting, jaw pain, pain in extremity, dizziness and 
hypokalemia .  If these side effects develop, the dose of the drug may need to be reduced until 
the side effects go away.  Do not take UT-15C with alcohol as release of treprostinil from the 
tablet may occur at a faster rate than intended which could cause undesirable effects. 
 
Bleeding is a rare side effect that could occur because of the way that the study drug 
(treprostinil) acts in the body. Bleeding has been reported in patients taking the study drug 


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especially when taken with other medications that can also cause bleeding.  When it happens, 
bleeding is usually minor such as a nose bleed or bleeding from the skin after an injury or blood 
draw.  However, there is a risk of bleeding being more severe, with some patients experiencing 
bleeding in the stomach and intestines. 
 
Studies were conducted to determine whether diethanolamine (a part of UT-15C) by itself 
(without treprostinil or any other drug) causes cancer.  Two years of topical administration 
(applying the medication on the skin) of diethanolamine to mice produced an increased incidence 
(compared to mice that did not receive diethanolamine) of malignant liver tumors in male and 
females, as well as an increased incidence of malignant kidney tumors in males.  However, in 
rats, topical administration of diethanolamine for 2 years was not associated with the 
development of any cancers.  The relevance of the mouse tumor findings to humans is not clear. 
 
An additional study was conducted to find out whether UT-15C causes cancer.  Six months of 
oral administration of treprostinil diethanolamine (UT-15C) to mice did not increase rates of 
death or occurrence of tumors or cancer in mice. 
 
Care should be taken to avoid missing doses of study drug.  If you miss two or more doses of 
your study drug in a row, you should contact your study doctor immediately to get information 
about how to restart your medication.  You may need to restart at a lower dose.  Also, stopping 
the study drug suddenly may cause worsening of your PAH symptoms, such as shortness of 
breath, dizziness, or chest pain, which could also be life threatening.  You must swallow the 
tablets whole and never split, crush, or chew them.  Splitting, crushing, or chewing them may 
cause an unexpected rapid release of drug into your body.  This may result in undesirable effects 
such as flushing, nausea or fainting.  There is also the remote possibility that an individual tablet 
may release drug more rapidly than it normally should.  This may bring about undesired effects 
as described above.  The tablet shell does not dissolve. In subjects with diverticulosis or other 
blind-end pouches in the gut, tablets can lodge in these pouches.  
 
Other risks of study procedures include the following: 
Risks of the Six-Minute Walk Test 
The risks associated with the six-minute walk test may include the possibility of fatigue, fainting, 
muscle soreness, strain or injury. 
Risks of Blood Draws 
You may experience slight bruising or pain on your arm where blood samples are taken.  There 
is also the slight risk of infection, light-headedness, and/or fainting. 
Risks of Genetic Sequencing 
There are known and possible risks of whole genome sequencing which may include the loss of 
privacy and confidentiality and the risk of discrimination.  There also may be other privacy risks 
that we have not foreseen. 
Loss of Privacy and Confidentiality:  Even without your name or other identifiers being 
associated with your genome sequence data, there is a potential risk that someone will 


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identify you from your genetic information or learn something about you by looking at 
your genetic information.  This risk may increase in the future as technologies advance 
and as more researchers study your genetic information.  These risks may also affect 
members of your family because, although your genetic information is unique to you, you 
do share some genetic information with your children, parents, brothers, sisters, and other 
blood relatives.  Consequently, it may be possible that genetic information from them 
could be used to help identify you.  Similarly, it may be possible that genetic information 
from you could be used to help identify them. 
 
Discrimination Risks: Since some genetic variations can help to predict the future health 
problems of you and your relatives, this information might be of interest to health 
providers, life insurance companies, and others.  A federal law, called the Genetic 
Information Nondiscrimination Act (GINA), generally makes it illegal for health 
insurance companies, group health plans, and most employers (those with over 
15 employees) to discriminate against you based on your genetic information.  GINA 
does not, however, protect you against genetic discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance.  GINA also does not protect 
you against discrimination based on an already-diagnosed genetic condition or disease. 
Additional Risks 
You will be informed as additional information is discovered about how the study drug may 
affect the risk and/or your willingness to continue to participate in this study.  Your study doctor 
will inform you of all known risks; however, there may be physical, mental or genetic adverse 
effects that are not yet known. 
You understand that your study doctor, sponsor (or its designee), the FDA, institutional review 
boards, or other regulatory agencies have the right to withdraw you from this research study or 
stop the research study based on any information, not just medical information, at any time and 
without your agreement.  If you are removed from this research study or if the study is 
discontinued, the study drug will no longer be provided to you and the study doctor will advise 
you of other available treatments that may be of benefit. 
BENEFITS 
There is no guarantee that you will receive any benefit from this study.  There is the possibility 
that being in this open-label study may temporarily improve your symptoms of PAH.  Another 
benefit may be the satisfaction you receive knowing that by participating in this open-label 
study, other patients with PAH may benefit from the overall results. 
ALTERNATIVE THERAPY 
Currently, the only medicine(s) approved for the treatment of PAH in the United States are the 
following: 
 Phosphodiesterase-5 inhibitors (PDE-5 inhibitors) (i.e., sildenafil and tadalafil) 
 Endothelin receptor antagonists (ERA) (i.e., bosentan, ambrisentan, and macitentan) 
 Prostacyclins and Prostacyclin Analogues: 


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o Epoprostenol sodium  
o Subcutaneous (SC), intravenous (IV) treprostinil sodium  
o Inhaled treprostinil sodium  
o Inhaled iloprost   
o Selexipag  
 Soluble guanylate cyclase stimulator (i.e., riociguat) 
 
Oral vasodilators (medications used to dilate blood vessels), oxygen, blood thinner medications, 
diuretics or “water pills,” and digoxin (medication to help your heart pump) may also be used to 
treat your PAH.  Lung transplantation and atrial septostomy may also be a possibility.  You 
should discuss these alternatives with your doctor when deciding whether to participate in this 
study. Your doctor should tell you the risks and benefits of the alternative treatments.  
Also, your study doctor will inform you if there are other studies of new medications that may be 
a good fit for you.  You should discuss these with your study doctor before deciding whether to 
participate in this study. 
CONFIDENTIALITY 
Every reasonable effort will be made to keep your medical and study related records 
confidential.  This Informed Consent and another document called an “Authorization to Use and 
Disclose Protected Health Information” will determine how your health information is used and 
disclosed.  The study sponsor and its employees or agents may use or release information from 
this study.  Information may be given to the United States Food and Drug Administration (FDA) 
or regulatory agencies in other countries where the study drug may be considered for approval.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This web site will not include information that can identify you.  At most, the web 
site will include a summary of the results.  You can search this web site at any time. 
Once you meet all study entry conditions, your records will be identified with your initials and 
the subject number you were previously assigned during participation in the TDE-PH-310 study.  
The information gathered from your participation in this study will not be shared with anyone 
not listed in this informed consent or as permitted by the “Authorization to Use and Disclose 
Protected Health Information” that you signed, unless required by law.  Medical records 
including electronic medical records that identify you and the Informed Consent Form that you 
sign will be looked at and/or copied for research or regulatory purposes by the study sponsor, its 
employees or agents.  Your medical records and Informed Consent Form may be looked at 
and/or copied for research or regulatory purposes by the US FDA, the US Department of Health 
and Human Services agencies, or regulatory agencies in other countries and <name of IRB/EC>. 
Although you may be identified on study specific tests (e.g., pulmonary function tests, six minute 
walk test, physical examination, ECGs, echocardiograms, right heart catheterization reports, and 
laboratory results) that may be sent away for review outside of your study doctor's office or 
hospital, the sponsor, its employees or agents will take reasonable actions to protect the health 
information that identifies you.  Also, health information obtained in this study that identifies 
you will be securely retained for a period of up to 25 years after this study ends. 


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The scientific results from this study may be presented at meetings or published in an article.  
You will not be identified in any presentation or published report. 
In order to participate in this study, you will need to sign both this Informed Consent Form and 
the “Authorization to Use and Disclose Protected Health Information.”  You do not have to sign 
these documents if you do not agree with the uses and disclosures of your records and data 
described above.  By signing this Informed Consent Form, you agree to participate in this study 
and give permission to the sponsor, its employees or agents to make, receive, save and/or send 
out information about your health. By signing this consent form, you are not giving up any legal 
rights. 
BIOLOGICAL SAMPLES  
Biological samples including blood and urine will be collected from you during this study.  
These samples will be identified using your initials, gender, and clinical study subject number 
and will not have any of your identifying information (i.e., name, date of birth, etc.). Only the 
sponsor and its employees or agents will have access to these samples and to your identifying 
information. The recipient of the samples will not be able to link the samples to you. 
Your blood and urine samples will be collected and analyzed for the following:  
 Routine laboratory tests 
 To assess how your heart is working by measuring the level of a PAH blood marker 
(NT-proBNP) 
 Pregnancy test 
 Optional pharmacogenomic sequencing 
 
Any blood and urine samples obtained for this purpose become the exclusive property of the 
study sponsor.  The sponsor may retain, preserve or dispose of these samples and may use these 
samples for research that may result in commercial applications.  The study sponsor will own the 
results of research conducted using your samples collected as part of this study.   
<All deviations from the text in the previous paragraph must be approved by the UT legal 
department>. 
RIGHT TO WITHDRAW 
Participation in this study is voluntary.  You do not have to participate in this research—it is your 
decision.  You are free to withdraw your consent at any time.  Your withdrawal, or refusal to 
participate, will not affect your current or future medical care in any way.  If you wish to stop 
taking part in this study, it is important that you inform your study doctor who will explain to 
you the best way for you to end your participation.  If you withdraw from the study, you must 
return all study medication and supplies to your study doctor. 
During the course of the study, you will be told of any significant new findings that may affect 
your willingness to continue participating in the study. 


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Your participation in this study may be stopped with or without your consent at any time for any 
reason, including:  
 You did not follow the instructions provided by your study doctor 
 You become pregnant 
 You experience a severe side-effect 
 Your study doctor feels it is best to withdraw you from the study 
 United Therapeutics Corporation decides to stop the study 
COSTS/COMPENSATION 
If you choose to participate in this study, the investigational drug will be provided at no charge to 
you.  UT-15C will be provided free of charge only during the course of the study.  The study 
sponsor will pay for procedures that are performed specifically for the study.  Medical expenses 
for tests and medical procedures that would normally be performed to treat patients with PAH 
will be billed as normally done by the clinic or hospital (e.g., billed to your insurance company). 
There is no direct payment for participating in this study.  Some payment may be provided for 
travel related expenses required for study participation (e.g., parking fees). 
Participating in research may result in an injury, as explained above.  If you suffer an injury 
directly related to your participation in this research study, this institution will provide any 
necessary emergency care and will help you obtain medical treatment for the specific injury.  
The institution will also provide referrals to other health care facilities, as appropriate. 
In the event that you suffer a research-related injury, your medical expenses will be your 
responsibility or that of your third-party payer, although you are not prevented from seeking to 
collect payment for injury related to malpractice, fault, or blame on the part of those involved in 
the research. 
< Please note that the previous paragraph is a verbatim example from an FDA guidance 
document on appropriate language in informed consent documents.  Some institutions may have 
their own statement on injury compensation that they would prefer to use.  All deviations from 
the standard text in the previous paragraph must be approved by the UT legal department.>  
CONTACTS FOR QUESTIONS OR PROBLEMS 
All of my questions have been answered to my satisfaction.  I understand that the <Institutional 
Review Board/Ethics Committee> has reviewed and approved this research study.  The IRB / EC  
consists of a group of people established to make sure that the rights of human subjects that 
participate in medical research are protected. 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7, Master Version 8.0, 13 July 2018, US Version 8.0, 13 July 2018     Page 12 of 13 
If I have further questions about: 
 This research study, I should contact: 
Investigator name 
Telephone number 
E-mail address: <email address> 
 Research subjects' rights, I should contact: 
Name of IRB/EC representative 
Institutional Review Board/Ethics Committee 
Address 
Telephone number 
E-mail address: <email address> 
 A study-related injury, I should contact the following person for information on 
compensation/treatment of a study-related injury: 
Name of Investigator 
Telephone number 
E-mail address: <email address> 
 
In addition to the required study procedures, I have decided the following in regard to the 
optional study procedure. 
Optional Whole Genome Sequencing  
I agree to participate in the optional whole genome sequencing in addition to the required 
study procedures.  I agree that the blood sample collected as a part of this optional testing can 
be used for the purposes provided for in this Informed Consent Form.  I give up any property 
rights I may have to the sample collected for this optional research, and any genomic 
sequencing information or other data derived research using the sample.  I understand that I 
do not have to participate in this optional blood collection in order to participate in this study. 
_____ (initials) Yes, I will participate in the OPTIONAL whole genome sequencing.  
_____ (initials) No, I will not participate in the OPTIONAL whole genome sequencing. 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7, Master Version 8.0, 13 July 2018, US Version 8.0, 13 July 2018     Page 13 of 13 
I have carefully read or have had read to me this consent form.  I understand the purpose 
and nature of this research study, the potential risks involved and alternative treatments.   
All of my concerns and questions about this research study have been answered to my 
satisfaction.  I have been given a copy of this consent form. 
By voluntarily signing this document, I am saying that I understand the information in the 
form, assume any potential risks associated with this study, and confirm that I voluntarily 
agree to take part in this study.  I understand that this consent document is not an 
agreement between myself and the study sponsor. 
By consenting to participate in this research, I give up any property rights I may have to 
bodily fluids collected during this research. 
 
 
 
 
 
 
Print Name of Subject 
 
Signature of Subject 
 
Date 
 
 
 
 
 
Print Name of Investigator  
(or designee obtaining consent) 
 
Signature of Investigator  
(or designee obtaining consent) 
 
Date 
 
 
 
 
 
Print Name of Witness  
(If applicable) 
 
Signature of Witness 
(If applicable) 
 
Date 
 
An impartial witness is required to be present during the entire informed consent process if a 
subject is unable to read, or if a legally acceptable representative is unable to read.  The person 
administering the consent cannot sign as a witness.  By signing the consent form, the witness 
attests that the information in the consent form and any other written information was accurately 
explained to and appropriately understood by the subject or the subject's legally acceptable 
representative, and that informed consent was freely given by the subject or the subject's legally 
acceptable representative.


United Therapeutics Corporation 
TDE-PH-311 Amendment 7, Master Version 8.0, 13 July 2018, US Version 8.0, 13 July 2018      Page 1 of 2 
AUTHORIZATION TO USE AND DISCLOSE PROTECTED 
HEALTH INFORMATION FOR RESEARCH 
I agree to permit <name of hospital/clinical site>, my doctors and my other health care 
providers (together “Providers”) to use and disclose (release) health information about me as 
described below. 
1. The health information that may be used and disclosed includes: 
 All information collected for purposes of carrying out the TDE-PH-311 as 
described in the Informed Consent Form; and 
 Health information in my medical records that is relevant to the Study. 
2. The Providers may: 
 Use and share my health information among themselves and with the study 
sponsor (and its agents and contractors) to carry out research activities under the 
Study; and 
 Disclose my health information to representatives of government agencies, review 
boards, and other persons who watch over the safety, effectiveness and conduct of 
research. 
3. Sponsor (and its agents and contractors) may use and share my health information as 
permitted by the Informed Consent Form. 
4. Once my health information has been disclosed, federal privacy laws may no longer 
protect it from further disclosure. 
5. Please note that you do not have to sign this Authorization, but if you do not, you may 
not participate in the Study.  
6. You may change your mind and revoke (take back) this Authorization at any time and 
for any reason.  To revoke this Authorization, you must write to <site specific contact 
information>.  However, if you revoke this Authorization, you will not be allowed to 
continue taking part in the Study.  Also, even if you revoke this Authorization, your 
Providers and sponsor (and its agents and contractors) may continue to use and 
disclose the information they have already collected to protect the integrity of the 
research or as permitted by the Informed Consent Form. 
7. This Authorization does not have an expiration (ending) date. 
8. You will be given a copy of this Authorization after you have signed it. 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7, Master Version 8.0, 13 July 2018, US Version 8.0, 13 July 2018      Page 2 of 2 
__________________________________ 
Signature of participant or participant’s 
legal guardian 
____________________________________ 
Date 
__________________________________ 
Printed name of participant 
_____________________________________ 
Printed name of legal representative (if 
applicable) 
 
Representative’s Relationship to 
participant: 
 
_____________________________________ 
 

Prot_000.pdf: 
TDE-PH-311 Amendment 7 
Oral Treprostinil 
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. © 2018 United Therapeutics 
Corporation 
 
Page 1 
An Open-Label Extension Study of UT-15C in Subjects with 
Pulmonary Arterial Hypertension - A Long-Term Follow-up to 
Protocol TDE-PH-310 
IND Number 71, 537 
EudraCT Number 2012-000098-21 
Protocol TDE-PH-311 
CONFIDENTIAL 
UNITED THERAPEUTICS CORPORATION 
Original Protocol Date: 
Amendment 01 
Amendment 02 
Amendment 03 
Amendment 04 
Amendment 05 
Amendment 06 
Amendment 07 
03 February 2012 
14 March 2012 
13 June 2012 
05 December 2012 
10 March 2014 
09 January 2015 
29 September 2016 
13 July 2018 
 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
Confidential 
Page 2 
LIST OF CONTACTS FOR STUDY 
Contract Research 
Organization: 
PRA International 
4130 Parklake Avenue 
Suite 400 
Raleigh, NC 27614 
USA 
Ileana Guerschman 
Project Director 
Telephone:  +54 1152784612  
Facsimile:  +54 1152784601  
GuerschmanIleana@prahs.com 
Study Sponsor 
United Therapeutics Corp. 
55 TW Alexander Drive  
Research Triangle Park, NC 
27709 USA 
Aliou Ousmanou, PharmD, MBA 
Director, Clinical Operations  
Telephone:  +1 919 425-5796 
Facsimile: + 1 919 485-8352 
aousmanou@unither.com 
 
United Therapeutics Europe 
Ltd. 
Unither House, Curfew Bell 
Road 
Chertsey, Surrey KT16 9FG 
United Kingdom 
Leigh Peterson, PhD 
Vice President, Product 
Development  
Telephone: +1 919 425-8165 
Facsimile:  +1 919 485-8352  
lpeterson@unither.com 
Jeff Sigman 
Vice President, Clinical Operations 
Telephone:  +1 919 425-8173 
Facsimile:  +1 919 485-8352 
jsigman@unither.com 
Medical Monitor 
Rob Grover, FRCA 
Vice President, Medical Development  
Telephone:  +44 (0)1932 573805 
Facsimile:  +44 (0)1932 573806 
Email:  310and311medicalmonitoring@unither.com 
SAE Reporting 
UT Global Drug Safety 
Telephone: 
 
Worldwide:  +1 484-533-2849 
 
Toll-free:  +1 855-735-7312 (US / Canada only) 
Facsimile: 
 
Americas/Japan : +1 919 313-1297 
 
Europe/ROW: +44 1932 573 888 
Email:  drugsafety@unither.com 
Central Clinical Laboratory 
Covance Central Laboratories 
 
 
Indianapolis 
8211 SciCor Drive 
Indianapolis, IN  46214-2985 
USA   
Telephone:  
+1 317 271-1200 
 
+1 888 268-2653 
Singapore 
1, International Business Park 
#05-12A/B The Synergy 
Singapore 609917 
Telephone: + 65-6560-8793 
 
Genève 
7, rue Moïse-Marcinhes 
1217 Meyrin 
Genève 
Switzerland 
Telephone:  +41 58 822 7000 
Shanghai 
1st Floor, No. 6 Building 
151 Li Bing Rd 
Zhangjiang Hi-Tech Park 
Shanghai 201203 
China 
Telephone: +86 21 5137 1111 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
Confidential 
Page 3 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “An Open-Label Extension Study of UT-15C in 
Subjects with Pulmonary Arterial Hypertension - A Long-Term Follow-up to Protocol 
TDE-PH-310” Amendment 7 dated 13 July 2018 and agree to abide by all provisions set forth 
therein. 
I agree to comply with the International Council for Harmonisation (ICH) Guideline for Good 
Clinical Practice (GCP) and applicable Food and Drug Administration (FDA) 
regulations/guidelines set forth in 21 Code of Federal Regulations Parts 50, 54, 56, and 312 
and local regulations per country. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of United Therapeutics Corp. 
I also have read the current Investigator’s Brochure for UT-15C (treprostinil diethanolamine) 
and acknowledge that review of the information contained in the Investigator’s Brochure is a 
requirement for Investigators before using UT-15C (treprostinil diethanolamine) in a clinical 
study. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
Confidential 
Page 4 
LIST OF ABBREVIATIONS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BID 
Twice daily 
Cmax 
Maximum Plasma Concentration 
CTD 
Connective Tissue Disease 
CVD 
Cardiovascular Disease 
CYP 
Cytochrome P450 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
ERA 
Endothelin Receptor Antagonist 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GLP 
Good Laboratory Practice 
HIV 
Human Immunodeficiency Virus 
H-L 
Hodges-Lehmann 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional/Independent Review Board 
IV 
Intravenous(ly) 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
NTP 
National Toxicology Program 
NT-proBNP 
N-Terminal Pro-Brain Natriuretic Peptide 
PAH 
Pulmonary Arterial Hypertension 
PDE5-I 
Phosphodiesterase-5 Inhibitor 
PGI2 
Prostacyclin 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard Deviation 
sGC 
Soluble Guanylate Cyclase Stimulator 
TID 
3 Times Daily 
UT-15C 
Treprostinil Diethanolamine 
WHO 
World Health Organization 
WOCBP 
Woman of Childbearing Potential 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
Confidential 
Page 5 
PROTOCOL SYNOPSIS 
Title  
Open-Label Extension Study of UT-15C in Subjects with 
Pulmonary Arterial Hypertension - A Long-Term Follow-up 
to Protocol TDE-PH-310 
Study Phase 
III 
Indication 
Pulmonary Arterial Hypertension (PAH) 
Primary Objective 
 To provide UT-15C for eligible subjects who 
participated in Study Protocol TDE-PH-310 
Secondary Objective(s) 
 To assess the long-term safety of oral UT-15C 
 To assess the effect of continued long-term therapy 
with UT-15C on exercise capacity (6-Minute Walk 
Distance [6MWD]/Borg dyspnea score), World Health 
Organization (WHO) Functional Class, and 
N-terminal pro-brain natriuretic peptide (NT-proBNP) 
(at Week 48 only) 
Exploratory Objective 
 Optional evaluation of pharmacogenomics 
Study Design 
Multi-center, open-label study for eligible patients who 
participated in TDE-PH-310 
Sample Size 
Up to 850 subjects from Protocol TDE-PH-310 will be 
enrolled. 
Summary of Subject 
Eligibility Criteria 
Participation and completion of required visits from 
TDE-PH-310.  Discontinued due to clinical worsening in 
TDE-PH-310.  All ongoing subjects at the time the number of 
adjudicated clinical worsening (morbidity or mortality) events 
specified in Protocol TDE-PH-310 has occurred will be 
eligible to participate in this open-label study. 
Drug Dosage  
and Formulation 
All subjects will receive oral treprostinil diethanolamine 
(UT-15C) sustained release tablets.  Study drug will be 
provided in 0.125, 0.25, 0.5, 1.0, and 2.5 mg sustained-release 
(SR) tablets to be administered 3 times daily (TID) 
immediately after (~10 minutes) consuming food. 
For subjects who were randomly allocated to UT-15C in 
TDE-PH-310, the initial dose of UT-15C in the open-label 
study will be based upon their final dose in TDE-PH-310.  
Dose escalation of UT-15C may occur in either 0.125 or 
0.25 mg increments no more than every 24 hours based on 
adverse effects and signs and symptoms of PAH. 
For subjects who were randomly allocated to placebo in 
Protocol TDE-PH-310, dosing of UT-15C will be initiated at 
0.125 mg TID.  Dose escalations can occur no more than 
every 24 hours (3 consecutive doses) in 0.125 mg increments 
TID during the first 4 weeks of the study.  Following 4 weeks 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
Confidential 
Page 6 
of treatment, dose escalation may occur no more than every 
24 hours in either 0.125 mg or 0.25 mg increments TID every 
24 hours.  There is no maximum dose specified for this study. 
Note that sudden dose escalations or reductions may lead to 
intolerable adverse effects or worsening PAH and gradual 
dose titrations are recommended to reduce the risk to subjects. 
Control Group 
None 
Route of  
Administration 
Oral 
Procedures 
Study visits will occur at Baseline, Weeks 6, 12, and every 
12 weeks thereafter.  Study visits will continue until either 
UT-15C becomes commercially available within the 
respective territories, or the study is discontinued by the 
Sponsor.  Study assessments will include: 
 6-Minute Walk Test (6MWT)/Borg dyspnea score 
 WHO Functional Class 
 NT-proBNP (Week 48 only) 
 Safety (vital signs, adverse events [AEs], clinical 
laboratory parameters, concomitant medications) 
 Optional assessment of pharmacogenomics. 
Statistical Considerations All data will be summarized in tables and listings. 
Sponsor 
United Therapeutics Corp. 
55 T. W. Alexander Drive 
Research Triangle Park, NC  27709 
USA 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
Confidential 
Page 7 
TABLE OF CONTENTS 
LIST OF CONTACTS FOR STUDY .................................................................................... 2 
INVESTIGATOR’S AGREEMENT ..................................................................................... 3 
LIST OF ABBREVIATIONS ................................................................................................ 4 
PROTOCOL SYNOPSIS ....................................................................................................... 5 
TABLE OF CONTENTS ........................................................................................................ 7 
Table of In-Text Figures ......................................................................................................... 9 
1 BACKGROUND AND RATIONALE .......................................................................... 10 
1.1 
DEFINITION OF CLINICAL PROBLEM ............................................................. 10 
1.2 
TREPROSTINIL DIETHANOLAMINE BACKGROUND .................................. 11 
1.2.1 
General Pharmacology .......................................................................................... 11 
1.2.2 
General Toxicology ................................................................................................ 12 
1.2.3 
Clinical Pharmacology .......................................................................................... 15 
1.2.4 
Efficacy and Safety Data ....................................................................................... 18 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION ............................................................................................ 23 
1.4 
CLINICAL HYPOTHESIS ....................................................................................... 24 
2 OBJECTIVES ................................................................................................................. 24 
2.1 
PRIMARY OBJECTIVE .......................................................................................... 24 
2.2 
SECONDARY OBJECTIVES .................................................................................. 24 
2.3 
EXPLORATORY OBJECTIVE ............................................................................... 24 
3 EXPERIMENTAL PLAN .............................................................................................. 24 
3.1 
STUDY DESIGN ........................................................................................................ 24 
3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS ............................................ 25 
3.3 
CLINICAL ASSESSMENTS .................................................................................... 26 
3.3.1 
Efficacy ................................................................................................................... 26 
3.3.1.1 
Six-Minute Walk Test ........................................................................................ 26 
3.3.1.2 
Borg Dyspnea Score ........................................................................................... 26 
3.3.1.3 
WHO Functional Class ...................................................................................... 26 
3.3.1.4 
N-terminal proBNP ............................................................................................ 26 
3.3.1.5 
Optional Pharmacogenomics ............................................................................ 26 
3.3.2 
Safety ...................................................................................................................... 27 
3.3.2.1 
Vital Signs ........................................................................................................... 27 
3.3.2.2 
Physical Examination ........................................................................................ 27 
3.3.2.3 
Clinical Laboratory Assessments ..................................................................... 27 
3.3.2.4 
Adverse Event Assessments .............................................................................. 27 
3.3.2.5 
Concomitant Medications ................................................................................. 28 
3.4 
NUMBER OF CENTERS .......................................................................................... 28 
3.5 
NUMBER OF SUBJECTS ........................................................................................ 28 
3.6 
ESTIMATED STUDY DURATION ......................................................................... 28 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
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Page 8 
4 SUBJECT ELIGIBILITY .............................................................................................. 29 
4.1 
INCLUSION CRITERIA .......................................................................................... 29 
4.2 
EXCLUSION CRITERIA ......................................................................................... 29 
4.3 
PRESCRIBED THERAPY ........................................................................................ 30 
4.3.1 
Concomitant Medications ..................................................................................... 30 
5 SUBJECT ENROLLMENT ........................................................................................... 30 
5.1 
TREATMENT ASSIGNMENT ................................................................................ 30 
5.2 
RANDOMIZATION .................................................................................................. 30 
5.3 
BLINDING .................................................................................................................. 30 
6 DRUGS AND DOSING (OR TREATMENT PROCEDURES) ................................. 30 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE ................................. 30 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT ..................................... 31 
6.3 
COMPLIANCE .......................................................................................................... 32 
7 EXPERIMENTAL PROCEDURES ............................................................................. 32 
7.1 
TREATMENT PHASE .............................................................................................. 32 
7.1.1 
Baseline/Study Entry ............................................................................................. 32 
7.1.2 
Week 6 Visit ........................................................................................................... 34 
7.1.3 
Week 12 Visit ......................................................................................................... 34 
7.1.4 
Follow-up Visits (every 12 weeks) ........................................................................ 35 
7.1.5 
Study Termination Visit ........................................................................................ 35 
8 STUDY TERMINATION ............................................................................................... 36 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL ....................................................... 36 
8.2 
CRITERIA FOR TERMINATING THE STUDY .................................................. 36 
8.3 
CRITERIA FOR DISCONTINUING THE SITE ................................................... 37 
9 ADVERSE EVENT REPORTING ................................................................................ 37 
9.1 
DEFINITIONS ........................................................................................................... 37 
9.1.1 
Adverse Event ........................................................................................................ 37 
9.1.2 
Serious Adverse Event .......................................................................................... 37 
9.1.3 
Adverse events associated with progression of PAH .......................................... 38 
9.2 
DOCUMENTATION OF ADVERSE EVENTS ..................................................... 38 
9.3 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR ....................... 39 
9.4 
PREGNANCY ............................................................................................................ 39 
9.5 
SAFETY REPORTS .................................................................................................. 40 
10 STATISTICAL CONSIDERATIONS .......................................................................... 40 
10.1 DATA PROCESSING ................................................................................................ 40 
10.2 SAMPLE SIZE ........................................................................................................... 40 
10.3 ANALYSIS PLAN ...................................................................................................... 41 
10.4 OTHER ANALYSES ................................................................................................. 41 
11 PACKAGING AND FORMULATION ........................................................................ 41 
11.1 CONTENTS OF STUDY DRUG .............................................................................. 41 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
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Page 9 
11.2 LABELING ................................................................................................................. 41 
11.3 STORAGE AND HANDLING OF CLINICAL TRIAL MATERIAL ................. 42 
11.4 SUPPLY AND RETURN OF CLINICAL TRIAL MATERIAL ........................... 42 
11.5 DRUG ACCOUNTABILITY .................................................................................... 42 
12 REGULATORY AND ETHICAL OBLIGATION ...................................................... 43 
12.1 ICH GCP OR APPLICABLE REGULATORY REQUIREMENTS .................... 43 
12.2 INFORMED CONSENT REQUIREMENTS ......................................................... 43 
12.3 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW 
BOARD ....................................................................................................................... 43 
12.4 PRESTUDY DOCUMENTATION REQUIREMENTS ......................................... 44 
12.5 SUBJECT CONFIDENTIALITY ............................................................................. 44 
13 ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 44 
13.1 PROTOCOL AMENDMENTS AND STUDY TERMINATION .......................... 44 
13.2 STUDY DOCUMENTATION AND STORAGE .................................................... 45 
13.3 STUDY MONITORING AND DATA COLLECTION .......................................... 45 
14 REFERENCES ................................................................................................................ 46 
15 APPENDICES ................................................................................................................. 47 
15.1 PROCEDURE FOR SIX MINUTE WALK EXERCISE TEST AND BORG 
DYSPNEA SCORE .................................................................................................... 47 
15.2 WHO FUNCTIONAL CLASS FOR PAH ............................................................... 49 
15.3 CLINICAL LABORATORY PARAMETERS ....................................................... 50 
15.4 GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE 
EVENTS ...................................................................................................................... 51 
15.5 EXPECTED EVENTS ATTRIBUTABLE TO THE PROGRESSION OF 
PULMONARY ARTERIAL HYPERTENSION (SYSTEM ORGAN CLASS 
AND PREFERRED TERM, VER. 16.0) .................................................................. 53 
 
Table of In-Text Figures 
Figure 1 
Mean Plasma Treprostinil Concentration vs Time Curve Following the 
First Single 0.5 mg Dose of UT-15C on Day 1 and Following the Last 
Dose of 0.5 mg on Day 8 at Steady State ........................................................ 17 
Figure 2 
Mean Steady-State Plasma Treprostinil Concentration vs Time Curve 
Following Administration of 0.5 mg TID of UT-15C .................................... 18 
 


United Therapeutics Corporation 
TDE-PH-311 Amendment 7 
 
Oral Treprostinil 
Version date: 13 July 2018 
Confidential 
Page 10 
1 
BACKGROUND AND RATIONALE 
1.1 
DEFINITION OF CLINICAL PROBLEM 
Pulmonary arterial hypertension (PAH), defined as an elevation in pulmonary arterial pressure 
and pulmonary vascular resistance, is a severe hemodynamic abnormality common to a 
variety of diseases and syndromes.  Elevation in pulmonary arterial pressure causes an 
increase in right ventricular afterload, impairing right ventricular function and ultimately 
leading to heart failure and death. 
The typical etiologies of PAH include idiopathic, heritable or associated with collagen 
vascular/connective tissue disease (CTD), portal hypertension, infection with the human 
immunodeficiency virus (HIV), a history of cocaine inhalation, or exposure to appetite 
suppressant drugs.  An estimated annual incidence of approximately 2 cases per million has 
been reported for idiopathic PAH (Rich, 1987, Rubin 1997). 
There are 3 major factors thought to contribute to the increased pulmonary vascular resistance 
seen in this disease: vasoconstriction, remodeling of the vessel wall, and thrombosis.  There 
are a number of metabolic pathways which contribute to these changes that involve vasoactive 
mediators such as the vasodilators nitric oxide and prostacyclin, and the vasoconstrictor 
endothelin-1.  These substances affect both vascular tone and remodeling leading to their use 
as pharmacologic targets (Farber, 2004). 
Approved pharmacotherapies for PAH include: (1) intravenous prostacyclin (epoprostenol 
sodium or Flolan®, Veletri®); (2) the prostacyclin (PGI2) analogues, subcutaneous (SC), 
intravenous (IV), and inhaled treprostinil (Remodulin®, Tyvaso®), oral treprostinil 
diethanolamine (Orenitram®), oral selexipag (Uptravi®), and inhaled iloprost (Ventavis®); 
(3) the phosphodiesterase-5 inhibitors (PDE5-I), tadalafil (Adcirca®) and sildenafil 
(Revatio®); (4) the oral endothelin receptor antagonists (ERAs), bosentan (Tracleer®), 
ambrisentan (Letairis®, Volibris®), and macitentan (Opsumit®), and (5) a soluble guanylate 
cyclase stimulator (sGC), riociguat (Adempas®). 


United Therapeutics Corporation 
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Oral Treprostinil 
Version date: 13 July 2018 
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Page 11 
1.2 
TREPROSTINIL DIETHANOLAMINE BACKGROUND 
1.2.1 
General Pharmacology 
Treprostinil, [[(1R,2R,3aS,9aS) 2,3,3a,4,9,9a hexahydro 2 hydroxy 1 [(3S) 3 hydroxyoctyl] 
1H benz [f]inden 5 yl]oxy] acetic acid, is a chemically stable tricyclic analogue of PGI2. 
The pharmacology of treprostinil has been extensively characterized in well-established 
models all confirming the suitability of the drug for the treatment of PAH following either the 
SC, IV, inhaled (as treprostinil sodium), or oral (as treprostinil diethanolamine) routes of 
administration. 
The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and 
systemic arterial vascular beds and inhibition of platelet aggregation.  In vitro, treprostinil 
induced concentration dependent relaxation of rabbit isolated precontracted mesenteric 
arteries, and inhibition of adenosine diphosphate induced platelet aggregation in human and 
rat platelet rich plasma.  In animals, the vasodilatory effects of treprostinil reduce right and 
left ventricular afterload, thereby increasing cardiac output and stroke volume.  Prostacyclins 
lower pulmonary artery pressure, increase cardiac output without affecting the heart rate, 
improve systemic oxygen transport as well as possibly reversing pulmonary artery 
remodeling.  There is also increasing evidence that the ability to block the proliferation of 
pulmonary artery smooth muscle cells may contribute, along with vasodilation, to the 
therapeutic effects of prostacyclins in the treatment of PAH.  The mechanism of action is 
therefore likely to be multifactorial. 
Treprostinil diethanolamine (UT-15C) was selected from a series of treprostinil salts based on 
critical physicochemical characteristics (eg, solubility, hygroscopicity, melting point) with a 
goal of delivering treprostinil by the oral route as a sustained-release (SR) dosage form.  In 
solution, both treprostinil sodium and treprostinil diethanolamine are disassociated from their 
respective salt counter-ions and exist as the freely ionized form of treprostinil.  As a result, the 
bioactive form present in the bloodstream is identical irrespective of the selection of the 
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A rat blood pressure model study confirmed that the diethanolamine salt of treprostinil 
exhibits dose dependent pharmacological activity with a cardiovascular profile comparable to 
that of treprostinil.  Overall, no highly active metabolite has been identified, as all the 
metabolites evaluated had greatly reduced activity compared to UT-15C.  Thus, it would 
appear that the observed pharmacological profile of UT-15C reflects the activity of the parent 
molecule, treprostinil, and that the contribution to that profile of any known metabolite that 
would be formed in vivo would be minimal. 
1.2.2 
General Toxicology 
UT-15C is a novel salt form of Remodulin (treprostinil) Injection and Tyvaso (treprostinil) 
Inhalation Solution, which are approved in the United States and other countries for the 
treatment of patients with PAH.  The active pharmaceutical ingredient, treprostinil, exists as 
the sodium salt in the drug product of Remodulin and Tyvaso.  Given that the only change to 
the drug substance synthesis route for UT-15C is the diethanolamine addition step, and 
treprostinil is not altered, the bioactive form of treprostinil diethanolamine and treprostinil 
sodium is predicted to be identical.  Therefore, in addition to the nonclinical studies 
conducted with UT-15C, an extensive amount of pharmacology, pharmacokinetic, and 
toxicology information on treprostinil sodium is available from Remodulin and Tyvaso 
development. 
During the development of Remodulin, treprostinil sodium was administered SC and/or IV in 
acute toxicity studies, repeat-dose toxicity studies, reproductive toxicity studies, and 
genotoxicity studies, and has a well-defined clinical safety profile.  Treprostinil sodium was 
administered via continuous infusion to both rats and dogs in toxicity studies for up to 
6 months, which supported the chronic administration of Remodulin to patients. 
In addition to the extensive toxicology data with treprostinil sodium, the toxicity and 
toxicokinetic profiles of UT-15C have been evaluated in acute and repeat-dose oral toxicity 
studies of up to 13 weeks in duration in rodents and up to 9 months duration in dogs.  UT-15C 
has also been evaluated in reproductive-developmental toxicity studies in pregnant rats and 
rabbits and in an in vivo rat micronucleus assay. 


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Nonclinical findings from 13 week toxicology studies with UT-15C have included dose 
dependent, yet transient decreases in mean body weight gain and food consumption in both 
rats and dogs and soft/mucoid stools, diarrhea, and vomitus in dogs.  Many of these findings 
have been seen previously during development of Remodulin and are consistent with 
prostacyclin induced effects.  In addition, post-mortem findings in rats administered UT-15C 
included changes in organ weight data and histological findings related to the adrenal gland, 
heart, spleen, thymus and bone marrow; some of which were not seen with Remodulin.  The 
majority of these findings were reversible following a 4-week recovery period.  Data from a 
9-month dog study provides additional toxicology information following chronic dosing.  
UT-15C was reasonably well-tolerated following daily oral administration at dose levels up to 
35 mg/dog/day for 9 months.  The primary adverse effect was judged to be gastrointestinal 
disturbance, evidenced by increased incidence of soft stools, mucoid stools and diarrhea.  By 
the end of the study, all dogs were in good condition.  No systemic adverse effects were 
detected as judged by ophthalmology, ECG, clinical pathology and histopathological 
examination. 
In vitro genotoxicity studies with UT-15C have not been conducted; however, data are 
available for such studies using high doses of Remodulin (treprostinil sodium).  Remodulin 
(treprostinil sodium) was non-mutagenic in bacterial reverse mutation assays (Ames assay) at 
concentrations up to 5,000 mcg/plate with and without S9 metabolic activation, and in the 
mouse lymphoma assay at concentrations up to 400 mcg/mL without S9 metabolic activation 
and up to 300 mcg/mL in the presence of S9. 
UT-15C was tested in vivo in the rat micronucleus assay, which aimed to evaluate the 
potential of UT-15C to increase the incidence of micronucleated polychromatic erythrocytes 
in bone marrow of rats.  The results of the assay indicated that oral administration of UT-15C 
at total doses up to and including a dose of 50 mg treprostinil (equivalent to 63.4 mg 
UT-15C/kg) did not induce a significant increase in the incidence of micronucleated 
polychromatic erythrocytes in either male or female Sprague Dawley rats.  Mortality observed 
at the high dose indicates systemic exposure of animals to the test article.  Based upon these 


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findings, treprostinil diethanolamine (UT-15C) was concluded to be negative in the rat 
micronucleus assay. 
Segment I (rat) and Segment II (rat and rabbit) reproductive and developmental toxicology 
studies have also been conducted.  No adverse effects for fetal viability/growth and fetal 
development (teratogenicity) were seen in rats at or below 20 mg/kg/day or rabbits at or 
below 0.5 mg/kg/day.  At high doses, there were teratogenic effects of UT-15C observed 
when administered to rabbits.  Findings included increased fetal incidence of external, soft 
tissue, and skeletal malformations.  Additionally, a Segment III reproductive and 
developmental toxicology study has been conducted in female rats.  F0 female rats receiving 
10 mg/kg/day had decreased food consumption and body weights during gestation, increased 
duration of gestation, had slight decreases in the viability and number of pups per litter, and 
pups with decreased mean neonatal body weights.  F1 pups of females that received 
20 mg/kg/day had abnormalities in physical development (developmental landmarks), reflex 
development, exploratory behavior, learning and memory, and sexual maturation. 
A 6 month carcinogenicity study in hemizygous Tg.rasH2 mice administered UT-15C at daily 
oral doses of 3, 7.5, 15 mg/kg and 5, 10, 20 mg/kg in females and males, respectively, for 26-
weeks did not increase the incidence of neoplastic lesions.  A 2 year rat carcinogenicity study 
is ongoing.  Studies have been conducted by the United States National Toxicology Program 
(NTP) to determine whether diethanolamine by itself (without treprostinil or any other drug) 
causes cancer.  Two years of topical administration of diethanolamine to mice produced an 
increased incidence (compared to a control group) of malignant liver tumors in males and 
females, as well as an increased incidence of malignant kidney tumors in males.  Doses used 
in this study were approximately 720 to 2900 times higher (based on mg/m2 dosing) than the 
proposed starting doses for the UT-15C clinical studies.  However, in transgenic mice and 
rats, topical administration of diethanolamine for 20 weeks and 2 years, respectively, was not 
associated with the development of any cancers.  The relevance of the mouse tumor findings 
to humans is currently unknown.  Diethanolamine is listed on the FDA database of inactive 
ingredients for a number of approved drug products with no apparent safety concerns. 


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A good laboratory practices (GLP) cardiovascular safety pharmacology study 
(Study 1259DU16.003) to evaluate diethanolamine effects, independent of treprostinil, on 
cardiovascular function in telemetered beagle dogs was also conducted.  Since there are 0.269 
grams of diethanolamine per each gram of treprostinil in UT-15C, for this study doses of 
diethanolamine were selected that were similar or higher than the amount of diethanolamine 
contained in the doses of UT-15C assessed in the UT-15C cardiovascular safety 
pharmacology study (Study 1259DU16.002).  Doses of 0, 2, 3 and 4 mg/kg/day of 
diethanolamine (equivalent to the amount of diethanolamine administered with 7, 11, and 
15 mg/kg/day of treprostinil, the free acid of UT-15C), were selected to be administered to 
each of 1 group of 4 telemetered male dogs.  Preliminary data support that oral administration 
of diethanolamine at doses up to 2 mg/kg/dose twice daily (BID) (4 mg/kg/day) to male dogs 
was not associated with any definitive changes in arterial pressure, heart rate or 
electrocardiogram parameters.  In addition, no abnormal clinical signs were noted in the 
animals dosed with the vehicle or with any of the doses of diethanolamine. 
1.2.3 
Clinical Pharmacology 
In solution, both treprostinil sodium and treprostinil diethanolamine are disassociated from 
their respective salt counter-ions and exist as the freely ionized form of treprostinil.  As a 
result, the bioactive form present in the bloodstream is identical irrespective of the selection 
of the counter-ion.  Given this premise, the development of this new diethanolamine salt of 
treprostinil is expected to retain the bioactivity and safety profile of treprostinil sodium. 
The most frequent adverse events (AEs) associated with Remodulin in clinical trials of 
patients with PAH were related to the pharmacological properties of Remodulin and were 
generally not serious.  These prostacyclin-related AEs included diarrhea, headache, and 
nausea.  Remodulin has not been associated with any significant changes in laboratory 
parameters or end-organ toxicity.  The safety profile noted in the open-label extension study, 
with much longer durations of exposure and a larger, more diverse patient population, was 
consistent with the profile noted in the controlled trials.  To date, over 17,000 subjects and 
patients have been exposed to Remodulin.  This number includes patients who have received 
single administration, to patients receiving continuous infusion for greater than 10 years. 


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UT-15C has been administered to approximately 1800 subjects in Phase 1–3 clinical trials.  
UT-15C doses of up to 3 mg BID have been administered to healthy volunteers and patients 
with PAH have received up to 27.5 mg 3 times daily dosing (TID) in the ongoing Phase 1–3 
development program.  The average exposure is approximately 2 years; the longest exposure 
is almost 7 years. 
The absolute bioavailability of the UT-15C 1 mg tablet is 17% compared with IV Remodulin.  
Following administration, treprostinil diethanolamine is widely distributed.  Treprostinil is 
approximately 96% protein bound with no effect on warfarin or digoxin displacement.  
Pharmacokinetic data (area under the curve) indicate that Day 1 pharmacokinetic data are 
predictive of Day 13, and linearity was observed in plasma exposure comparing 1 mg and 
2 mg doses in healthy volunteers.  Food, particularly a high calorie meal, has been observed to 
increase absorption and prolong the systemic exposure to treprostinil, contributing to the 
desired pharmacokinetic profile.  Consistent with in vitro studies, clinical studies assessing 
the impact of induction and inhibition of the cytochrome P450 (CYP) 2C8 and CYP 2C9 
metabolic pathways on treprostinil diethanolamine indicate that CYP 2C8 appears to be of 
major importance and CYP 2C9 of minor importance to in vivo metabolism of UT-15C in 
humans. 
To date, the majority of UT-15C studies have been conducted with BID dosing.  In an attempt 
to understand the pharmacokinetics of TID a study was conducted in healthy volunteers.  In 
this open-label, single-center study 19 healthy subjects received 0.5 mg TID for 7 days.  On 
the morning of Day 1 subjects received a single 0.5 mg dose, on Day 2 to Day 7 the subjects 
received TID dosing of 0.5 mg (approximately 8AM, 2PM, and 8PM) with a meal.  On the 
morning of Day 8, the subjects received a final dose of 0.5 mg. 
Intensive 24 hour pharmacokinetic sampling occurred following the 8AM doses on Days 1, 7, 
and 8.  Trough samples were collected prior to the morning (8AM) and evening (8PM) doses 
on Days 4, 5, and 6. 
Nineteen subjects (9 Females:10 Males) with a mean age of 35.2 years (range: 20 to 54 years) 
were enrolled.  On Day 1 the mean (±standard deviation [SD]) maximum plasma 


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concentration (Cmax) of treprostinil was 0.574±0.22 ng/mL, occurring at a median time of 
4 hours (range: 2 to 6 hours).  In comparison, the Day 8 mean (±SD) Cmax was 0.615±0.32 
ng/mL, occurring at a median time of 4 hours (range: 1 to 6 hours) (See Figure 1). 
Figure 1 
Mean Plasma Treprostinil Concentration vs Time Curve Following the 
First Single 0.5 mg Dose of UT-15C on Day 1 and Following the Last Dose 
of 0.5 mg on Day 8 at Steady State  
 
On Day 7, the mean Cmax (±SD) was 0.810±0.491 ng/mL, occurring at a median time of 
14 hours (range: 6 to 20 hours) following the morning dose (Figure 2).  This indicates that 
maximum plasma concentration during a daily interval at steady state occurs after the evening 
(or third) dose of the day. 


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Figure 2 
Mean Steady-State Plasma Treprostinil Concentration vs Time Curve 
Following Administration of 0.5 mg TID of UT-15C 
 
Mean trough plasma concentrations prior to the morning dose on Days 5, 6, 7, and 8 were 
0.049, 0.049, 0.050, and 0.053 ng/mL, respectively.  Mean trough concentrations prior to the 
evening dose on Days 4, 5, 6, and 7 were 0.487, 0.396, 0.437, and 0.353 ng/mL, respectively. 
Fifteen AEs occurred in 7 subjects and primarily included known prostacyclin class-effect 
related AEs (eg, headache, diarrhea, and jaw pain). 
A comprehensive description of UT-15C (treprostinil diethanolamine), including the 
pharmacology, toxicology, and clinical studies completed to date may be found in the most 
recent Investigator’s Brochure. 
1.2.4 
Efficacy and Safety Data 
UT-15C has previously been evaluated in 3 randomized, placebo-controlled Phase 3 studies 
(TDE-PH-301, TDE-PH-302, and TDE-PH-308).  Additionally, subjects completing these 
studies have been provided long-term access to UT-15C in an open-label extension study 
(TDE-PH-304).  To date, over 1,000 PAH patients have been exposed to study drug (UT-15C 
or placebo) in the TDE-PH-301, TDE-PH-302, and TDE-PH-308 studies and over 
800 patients have received UT-15C in the open-label extension study. 


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TDE-PH-301 was a 16-week, randomized, double-blind, placebo-controlled, international 
Phase 3 efficacy and safety study of treprostinil diethanolamine (UT-15C), in patients with 
PAH.  Patients received UT-15C or placebo BID in combination with an ERA, a PDE5-I, or 
both.  The primary endpoint was placebo-corrected change in 6MWD from Baseline to 
Week 16.  Secondary endpoints included Borg dyspnea score, dyspnea-fatigue index, WHO 
Functional Class, and time to clinical worsening.  Study drug dose was titrated up to a 
maximum of 16 mg BID based on clinical response and study drug tolerability. 
A total of 354 subjects were enrolled with 30% receiving an ERA alone, 25% a PDE5-I alone, 
and 45% both agents.  The population was 81% female, predominantly WHO Functional 
Class 3 (76%), and had a mean Baseline 6MWD of 346 m.  PAH etiology included idiopathic 
or heritable PAH (66%), or PAH associated with CTD (26%), repaired congenital systemic-
to-pulmonary shunt (7%), or HIV infection (1%).  There were no remarkable demographic 
differences between treatment groups. 
Twenty-two percent of subjects discontinued UT-15C therapy compared to 14% in the 
placebo group.  The primary reason for discontinuation was AEs: 14% in the UT-15C group 
compared to 5% in placebo.  There were 3 deaths in each of the treatment groups. 
The Hodges-Lehmann (H-L) estimate of 6MWD median change from Baseline at Week 16 
was +11 m (p=0.072).  The change in 6MWD was significant at Week 12 (+13 m, p=0.015).  
The lack of significance at Week 16 may be attributable to the number of subjects who did not 
provide an efficacy measure at Week 16 due to discontinuing from the study prematurely. 
Secondary endpoints of the combined 6MWD and Borg dyspnea score and the 
dyspnea-fatigue index demonstrated statistically significant changes at Week 16 for UT-15C 
compared to Baseline (p=0.013 and 0.01, respectively). 
TDE-PH-301 was initiated with subjects administered a 1 mg starting dose with dose 
increases in 1 mg increments.  Additional tablet strengths of 0.25 mg and 0.5 mg were made 
available to subjects at sequentially later times in the study.  A post-hoc analysis demonstrated 
that during the course of the study those subjects with access to 0.25 mg tablets at 


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randomization had a lower discontinuation rate due to AEs (0%, n=23) as well as a higher 
H-L estimate of 6MWD treatment effect (+28.5 m) at Week 16.  Presumably titrating up the 
dose of study drug slowly with smaller increments may allow subjects to tolerate and thereby 
maintain therapy on UT-15C and achieve optimal dosing.  In addition, those subjects that 
were able to titrate to doses between 1.25 and 3.25 mg BID and doses greater than or equal to 
3.5 mg BID also demonstrated a more robust treatment effect of +18 and +34 m, respectively.  
Thus, premature discontinuations and inability to achieve doses greater than 1 mg BID during 
TDE-PH-301 appear to have muted the overall treatment effect detected by the study. 
TDE-PH-302 was a 12-week, randomized (2:1 UT-15C to placebo), double-blind, 
placebo-controlled, international Phase 3 efficacy and safety study of UT-15C in patients with 
PAH not currently receiving approved background therapy.  The primary endpoint was 
placebo corrected change in 6MWD from Baseline to Week 12.  Secondary endpoints 
included Borg dyspnea score, dyspnea-fatigue index, WHO Functional Class and time to 
clinical worsening.  Study drug dose was titrated up to a maximum of 12 mg BID based on 
clinical response and study drug tolerability. 
The study enrolled 349 subjects who were not receiving any approved PAH medication, with 
the population for primary analysis consisting of 228 subjects who had access to the 0.25 mg 
tablet strength at randomization.  These subjects were administered UT-15C or placebo BID, 
with the doses titrated to effect over the course of the 12-week study.  The majority of 
subjects were in WHO Functional Class 2 (33%) and Class 3 (66%) of varied etiologies, 
including idiopathic or heritable PAH (75%), cardiovascular disease (CVD) associated PAH 
(19%), and PAH associated with HIV or other associated conditions (6%).  The subjects’ 
mean Baseline 6MWD was approximately 330 m. 
The primary efficacy analysis comparing change in 6MWD from Baseline to Week 12 
between treatment groups in the primary analysis population (n=228) was +23 m (p=0.0125, 
H-L estimate).  The UT-15C group improved by a median of +25 m compared to -5 m change 
in the placebo group. 


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The combined 6MWD and Borg dyspnea score was also significantly improved (p=0.0497) at 
Week 12.  Preliminary analysis of other secondary efficacy measures, including change in 
trough 6MWD at Week 11, change in dyspnea fatigue index, change in Borg dyspnea score, 
change in WHO Functional Class, time to clinical worsening (as defined by death, 
transplantation, atrial septostomy, hospitalization due to PAH or at least a 20% decrease in 
6MWD and initiation of another approved PAH therapy), and PAH signs and symptoms at 
Week 12 did not differ significantly between the UT-15C and placebo groups (p>0.05). 
An analysis of all 349 subjects enrolled in the study demonstrated that those subjects 
receiving UT-15C improved their median 6MWD by approximately +25.5 m (H-L estimate, 
p=0.0001) as compared to subjects receiving placebo. 
Adverse Events during the study included headache, nausea, diarrhea, and flushing, which 
were expected in subjects receiving prostanoid therapy.  A low discontinuation rate due to 
AEs in the primary analysis population and the type of AEs resulting in discontinuation 
(mostly prostacyclin related, which are not life threatening) indicate that use of UT-15C may 
provide a significant improvement in the safety profile of treprostinil and result in a reduction 
in the occurrence of life-threatening AEs compared with parenteral treprostinil therapy (eg, 
central venous catheter-related blood stream infection). 
TDE-PH-308 was a 16-week, randomized, double-blind, placebo-controlled, international 
Phase 3 efficacy and safety study of UT-15C in patients with PAH.  Patients received UT-15C 
or placebo BID in combination with either an ERA, a PDE5-I, or both.  The primary endpoint 
was placebo-corrected change in 6MWD from Baseline to Week 16.  Secondary endpoints 
included Borg dyspnea score, dyspnea-fatigue index, WHO Functional Class and time to 
clinical worsening.  Study drug dose was titrated up to a maximum of 16 mg BID based on 
clinical response and study drug tolerability. 
A total of 310 subjects (157 UT-15C and 153 placebo) were randomized, received a dose of 
study drug, and contributed to the analysis population for the study.  The study population had 
a mean age of 51 years of age (range 18 to 76 years), was 78% female and had a diagnosis of 
idiopathic or heritable PAH (65%), PAH related to CVD (31%), PAH related to HIV infection 


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(2%), or PAH related to repaired systemic-to-pulmonary shunts (1%).  The population was 
predominantly WHO Functional Class 3 (73%) with a mean Baseline 6MWD of 333 m.  As 
for PAH-approved background therapy, 53 (17%) subjects were receiving ERA therapy alone, 
132 (43%) subjects were receiving a PDE5-I alone, and 125 (40%) subjects were receiving 
the combination of an ERA and a PDE5-I at Baseline.  The UT-15C and placebo groups were 
well balanced across all Baseline indices. 
The primary efficacy analysis comparing change in 6MWD from Baseline to Week 16 
between treatment groups was +10 m (H-L estimate; p=0.089).  The UT-15C group improved 
by a median of +15 m compared to a +11 m median change in the placebo group.  
Placebo-corrected changes from Baseline in 6MWD at Week 16 by PAH-approved 
background therapy were as follows: ERA only (H-L estimate of treatment effect = +7.7 m; 
p=0.739), PDE5-I only (H-L estimate = +15.0 m; p=0.054), and combination ERA and 
PDE5-I (H-L estimate = +4.0 m; p=0.674).  The mean ± SD maximum dose of UT-15C was 
3.1±1.9 mg BID in the UT-15C group as compared to 6.1±3.6 mg BID in the placebo group.  
Secondary endpoints including change in 6MWD at Weeks 4, 8, and 12, combined 6MWD 
and Borg dyspnea score, dyspnea-fatigue index, clinical worsening, serum N-terminal 
proBNP (NT-proBNP), WHO Functional Class, quality of life, and symptoms of PAH at 
Week 16 were not found to be statistically significant. 
TDE-PH-304 is a long-term, open-label, international, Phase 3 studies designed to provide 
access to UT-15C for subjects previously enrolled in studies TDE-PH-301, TDE-PH-302, 
TDE-PH-308, or other specified studies conducted during the UT-15C development program.  
Secondary objectives of the study are to assess the long-term safety of UT-15C in PAH 
patients and to assess the effect of continued therapy on exercise capacity via 6MWD 
following one year of treatment with UT-15C.  As of 01 September 2015, over 896 subjects 
were enrolled, representing 2377.7 patient-years of exposure.  The mean and maximum 
duration of exposure was 138.8 and 444.9 weeks (2.66 and 8.53 years), respectively.  The 
mean dose of oral treprostinil achieved was 3.9, 4.5, 4.8, 5.0, 5.5, 5.9, and 5.9 mg BID at 
1 year (N=605), 2 years (N=472), 3 years (N=337), 4 years (N=230), 5 years (N=119), 6 years 
(N=77), and 7 years (N=37), respectively.  Adverse Events were typical of prostacyclin 


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therapy; laboratory findings were unremarkable and did not suggest any specific safety 
concerns related to long-term treatment with UT-15C.  Following 12 months of oral 
treprostinil treatment, the mean 6MWD increased by +25 meters as compared with Baseline.  
Kaplan-Meier analysis of subject survival demonstrated 1-, 2-, and 3-year survival estimates 
of approximately 93.6%, 87.9%, and 82.2%, respectively. 
1.3 
RATIONALE FOR DEVELOPMENT OF STUDY DRUG IN 
DISEASE/CONDITION 
Prostacyclin is a potent endogenous vasodilator and inhibitor of platelet aggregation.  A 
synthetic salt of prostacyclin (ie, Flolan) has been previously shown to prolong survival in 
patients with PAH (Barst 1996).  However, due to its very short half-life and chemical 
instability, Flolan has to be continuously infused by IV delivery.  Treprostinil sodium is a 
chemically stable, longer acting analogue that has shown clinical effectiveness when 
administered by SC, IV (Remodulin, Remodulin Package Insert 2014], or inhaled routes 
(Tyvaso, Tyvaso Package Insert 2017). 
Parenteral prostacyclins are considered by many providers as the “gold standard” for 
treatment of PAH; however, they are typically used later in the course of the disease due to 
the risks and difficulties associated with administration.  Consequently, physicians managing 
patients with PAH commonly initiate treatment with an approved oral monotherapy to allow 
patients to benefit from the simplicity of an oral dosage form. 
An innovative salt form, treprostinil diethanolamine, has been developed to deliver 
prostacyclin therapy via the oral route in a solid dosage form.  Because the bioactive species 
is the same, treprostinil diethanolamine is expected to retain a similar safety and efficacy 
profile as parenteral treprostinil sodium in the convenience of an oral dosage form.  It has 
been suggested that combination therapy, particularly with a prostacyclin, may prevent or 
delay the progression of the disease and thereby prolong the time to clinical worsening. 


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1.4 
CLINICAL HYPOTHESIS 
This open-label study will evaluate the safety of continued therapy with UT-15C in subjects 
who have completed TDE-PH-310.  This study will provide long-term, open-label data 
regarding the safety and efficacy of UT-15C for the treatment of PAH. 
The hypothesis for the frequency of dosing change from BID to TID is that delivering more 
sustained concentrations of treprostinil may allow for systemic exposure to drug that more 
closely resembles the approved parenteral product, Remodulin, and reduces the occurrence of 
prostacyclin AEs previously seen with the BID regimen.  Both of these improvements may 
allow study subjects to titrate to a more effective UT-15C dose and thus study drug may show 
a clinically and statistically significant difference compared to placebo in delaying time to 
first clinical worsening and improving exercise capacity at Week 24. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to provide UT-15C SR tablets for eligible subjects who 
participated in TDE-PH-310. 
2.2 
SECONDARY OBJECTIVES 
Secondary objectives of this study are: 
 To assess the long-term safety of UT-15C 
 To assess the effect of continued long-term therapy with UT-15C on exercise capacity 
(6MWD/Borg dyspnea score), WHO Functional Class, and plasma concentrations of 
NT-proBNP (Week 48 only) 
2.3 
EXPLORATORY OBJECTIVE 
Optional evaluation of pharmacogenomics 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is an open-label study.  Subject visits will occur at Baseline, Weeks 6 and 12, and every 
12 weeks thereafter.  The study will continue until either oral UT-15C becomes available 
within the respective territories or the study is discontinued by the Sponsor. 


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3.2 
OVERALL SCHEDULE OF TIMES AND EVENTS 
Study Timeline 
Baselineb 
(Study Entry) 
Week 6c 
Week 12c 
Follow-up Visits 
(every 12 weeks)c 
Study 
Termination 
Visitk 
Informed consent 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
Vital signs a 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
X 
6MWT / 
Borg dyspnea scored 
X 
X 
X 
X 
X 
WHO Functional Class 
X 
X 
X 
X 
X 
Clinical laboratory 
assessments  
X 
 
X 
Xe 
X 
Urine pregnancy test f 
X 
X 
X 
X 
X 
Dose titration 
X 
X 
X 
X 
 
NT-proBNP 
X 
 
 
Xg 
 
Drug accountability/ 
Compliance 
X 
X 
X 
X 
X 
AEs 
Xh 
X 
X 
X 
Xi 
Concomitant 
medications 
X 
X 
X 
X 
X 
Phone calls j 
X 
X 
X 
X 
X 
Pharmacogenomic 
Sample (Optional) 
 
 
 
Xl 
Xl 
Abbreviations: 6MWT, 6-Minute Walk Test; AE, adverse event; NT-proBNP, N-Terminal pro-brain natriuretic 
peptide; WHO, World Health Organization 
a  Vital signs should be conducted following at least 5 minutes of rest and prior to or at least 30 minutes following the 
corresponding 6MWT. 
b  Baseline/study entry assessments (6MWT/Borg dyspnea score, WHO Functional Class, clinical laboratory 
parameters, NT-proBNP, vitals, and physical examination) for this study are those collected at the Study 
Termination Visit from Study TDE-PH-310 and prior to initiation of open-label study drug.  Informed consent and 
inclusion/exclusion criteria are exclusive to this Protocol. 
c  Visit windows are ±14 days. 
d  6MWT must be conducted 3 to6 hours after the last dose of UT-15C.  Subject should rest for 5 minutes prior to 
each 6MWT. 
e  During the follow-up visits, clinical laboratory samples should be collected at the first Follow-up Visit and every 
other Follow-up Visit thereafter. 
f  If applicable, for women of child-bearing potential (WOCBP). 
g  NT-proBNP should only be collected at the Follow-up Visit # 3 (Week 48). 
h Any AEs that are ongoing at the Study Termination Visit from Study TDE-PH-310 should be recorded as 
continuing AEs in this open-label study. 
i 
Any AEs that are ongoing at the Study Termination Visit from Study TDE-PH-311 should be followed for up to 
30 days after completion of the Study Termination Visit. 
j  Phone calls to the subject should occur at least weekly for the first 12 weeks, and at least monthly thereafter 
k After the Study Termination Visit is completed, subjects should down titrate the study drug over an appropriate 
period of time in accordance with their clinical condition.  Once the study drug has been discontinued, any 
remaining supplies should be returned to the clinic for drug accountability. 
l  For subjects consenting to the optional pharmacogenomic sample.  The sample should be collected at the next 
scheduled Follow-up Visit when clinical labs are also collected.  If the subject discontinues prior to the next 
Follow-up Visit, pharmacogenomic samples should be collected at the Study Termination Visit. 


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3.3 
CLINICAL ASSESSMENTS 
3.3.1 
Efficacy 
3.3.1.1 
Six-Minute Walk Test 
A 6MWT (described in Appendix 15.1) will be conducted at Baseline as part of Study 
Termination assessments from Protocol TDE-PH-310, Week 6 and Week 12, every 12 weeks 
thereafter, and at the Study Termination Visit.  Before each 6MWT, the subject should rest 
(seated) for at least 5 minutes.  The 6MWTs will be conducted by qualified, trained personnel 
in a designated 6MWT area which meets the requirements outlined in Section 15.1.  The 
6MWT should be conducted approximately 3 to 6 hours after the last dose of UT-15C. 
3.3.1.2 
Borg Dyspnea Score 
The Borg dyspnea score will be assessed following each 6MWT.  The Borg dyspnea score is a 
10-point scale rating the maximum level of dyspnea experienced during the 6MWT 
(Appendix 15.1).  Scores range from 0 (for the best condition) to 10 (for the worst condition). 
3.3.1.3 
WHO Functional Class 
The WHO Functional Class for PAH (Appendix 15.2) will be assessed at Baseline as part of 
Study Termination assessments from Protocol TDE-PH-310, Week 6, Week 12, every 
12 weeks thereafter, and at the Study Termination Visit. 
3.3.1.4 
N-terminal proBNP 
Plasma NT-proBNP concentration is a useful biomarker for PAH as it is associated with 
changes in right heart morphology and function (Fijalkowska 2006).  The NT-proBNP sample 
collection will occur at Baseline as part of Study Termination assessments from Protocol 
TDE-PH-310 and at Follow-up Visit #3 (Week 48) only. 
3.3.1.5 
Optional Pharmacogenomics 
For subjects consenting to pharmacogenomic analysis, blood samples will be collected at the 
first possible Follow-up Visit when clinical labs are also collected.  If the subject discontinues 
prior to their next Follow--up Visit, pharmacogenomic samples will be collected at the Study 
Termination Visit.  Pharmacogenomic samples will be shipped to the central laboratory for 
processing and storage prior to analysis.  Genetic variants will be analyzed to evaluate their 


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association with observed clinical response during the blinded Study TDE-PH-310 and 
tolerability to prostacyclin therapy.  Subjects who do not wish to participate in the optional 
pharmacogenomic research may still participate in the clinical study. 
3.3.2 
Safety 
3.3.2.1 
Vital Signs 
Vital signs will be assessed at Baseline as part of Study Termination assessments from 
Protocol TDE-PH-310 and at all subsequent protocol-required visits.  All vital signs will be 
collected prior to or at least 30 minutes following the corresponding 6MWT.  Vital signs 
include blood pressure, peripheral (radial/brachial artery) heart rate, respiration rate, and 
weight.  Vital signs must be collected following at least 5 minutes of rest to ensure accurate 
measurement. 
3.3.2.2 
Physical Examination 
A physical examination will be assessed at Baseline as part of Study Termination assessments 
from Protocol TDE-PH-310 and at the Study Termination Visit. 
3.3.2.3 
Clinical Laboratory Assessments 
Clinical laboratory parameters will be assessed at Baseline/Study Entry as part of Study 
Termination assessments from Protocol TDE-PH-310.  Clinical laboratory assessments will 
also be assessed at Week 12, at every other Follow-up Visits thereafter, and at the Study 
Termination Visit.  Clinical laboratory parameters to be assessed at the study visits are listed 
in Appendix 15.4.  A urine pregnancy test will be collected at every visit for women of 
childbearing potential (WOCBP). 
3.3.2.4 
Adverse Event Assessments 
Any AEs that are ongoing at the Study Termination Visit from Study TDE-PH-310 should be 
recorded as continuing AEs in this open-label study.  Section 9 and Appendix 15.4 provide 
the guidelines and definitions for recording AEs. 
All AEs will be captured from the time the informed consent form (ICF) is signed.  All AEs 
should be followed until resolution (or return to normal or Baseline values), until they are 
judged by the Investigator to no longer be clinically significant, or for up to 30 days if the AE 


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extends beyond the final visit.  All serious adverse events (SAEs) should be followed until 
resolution, death, or the subject is lost to follow-up even if they are ongoing more than 
30 days after completion of the final visit.  Sections 9 and Appendix 15.4 provide the 
guidelines and definitions for recording AEs. 
Symptoms of PAH (disease-related events) should only be recorded as an AE if the event is 
either serious, new, or unusual with respect to intensity, frequency, duration as compared to 
symptoms in the subject’s medical history, or there is a reasonable possibility that the event 
was caused by the study drug. 
3.3.2.5 
Concomitant Medications 
Concomitant medication may be adjusted as deemed clinically necessary by the Investigator 
during the study.  However, additional prostanoid therapies should not be permanently added.  
Concomitant medications used during the study will be reviewed at each protocol-required 
visit and recorded as they are prescribed in the Electronic Case Report Form (eCRF).  
Concomitant medications that were ongoing at the end of the TDE-PH-310 Study will be 
recorded in the eCRF for the open-label study. 
3.4 
NUMBER OF CENTERS 
The centers who participate in Study TDE-PH-310 (approximately 150) will take part in the 
study. 
3.5 
NUMBER OF SUBJECTS 
Up to 850 subjects from TDE-PH-310 may be eligible to participate in the study. 
3.6 
ESTIMATED STUDY DURATION 
The study will continue for approximately 6 years.  The study may be discontinued at any 
time if, in the opinion of the Investigators and/or Sponsor, continuation of the study represents 
a serious medical risk to the subjects.  This may include, but is not limited to, the presence of 
serious, life-threatening, or fatal AEs, or AEs that are unacceptable in nature severity, or 
frequency.  The Sponsor reserves the right to discontinue the study for any reason at any time.  
Subjects that discontinue the study will be contacted approximately 30 days (±5 days) after 
study drug discontinuation to confirm their survival status.  Subjects may also continue to be 


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contacted after the final study visit to assess AEs/SAEs (see Section 9.2 for additional 
details). 
4 
SUBJECT ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
A subject is eligible to participate in this study if all of the following criteria apply: 
1. The subject voluntarily provides informed consent to participate in the study.  
2. The subject participated in Study TDE-PH-310 and met the definition of clinical 
worsening (as specified in Protocol TDE-PH-310), remained on study drug, was 
compliant with study procedures and assessments during the TDE-PH-310 Study or 
was currently enrolled in that study at the time the study was discontinued by the 
Sponsor. 
3. All WOCBP must practice true abstinence from intercourse when it is in line with 
their preferred and usual lifestyle, or use 2 different forms of highly effective 
contraception for the duration of the study, and for at least 30 days after discontinuing 
study medication.  Medically acceptable forms of effective contraception include: (1) 
approved hormonal contraceptives (such as birth control pills), (2) barrier methods 
(such as a condom or diaphragm) used with a spermicide, (3) an intrauterine device, or 
(4) partner vasectomy.  For women of childbearing potential, a negative urine 
pregnancy test is required at Baseline (study entry) prior to initiating study medication.  
WOCBP includes any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea for at least 
12 consecutive months).   
4. Males participating in the study must use a condom during the length of the study, and 
for at least 48 hours after their last dose of study medication. 
4.2 
EXCLUSION CRITERIA 
A subject is not eligible to participate in this study if any of the following criteria apply: 
1. The subject is pregnant or lactating. 
2. The subject has received infused or inhaled prostacyclin therapy for 29 days or more. 
3. The subject was prematurely discontinued from Study TDE-PH-310 for reasons other 
than a clinical worsening event. 
4. The subject developed a concurrent illness or condition during the conduct of 
TDE-PH-310 which, in the opinion of the Investigator, would represent a risk to 
overall health if they enrolled in this study. 


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4.3 
PRESCRIBED THERAPY 
4.3.1 
Concomitant Medications 
In this open-label study, there are no restrictions on concomitant medications, including the 
approved PAH therapies, with the exception of the permanent addition (29 days or more) of 
prostacyclin or prostacyclin analogue therapy.  Subjects who receive permanent prostacyclin 
or prostacyclin analogue therapy must discontinue this open-label study. 
5 
SUBJECT ENROLLMENT 
5.1 
TREATMENT ASSIGNMENT 
All subjects will receive UT-15C SR tablets during this open-label study.  Subjects will retain 
the same subject number as assigned for the TDE-PH-310 study. 
5.2 
RANDOMIZATION 
This study is not randomized. 
5.3 
BLINDING 
This study is not blinded. 
6 
DRUGS AND DOSING (OR TREATMENT PROCEDURES) 
6.1 
DRUG DOSAGE, ADMINISTRATION AND SCHEDULE 
The UT-15C tablets are sustained release osmotic tablets.  UT-15C tablets are provided as 
0.125, 0.25, 0.5, 1.0, and 2.5 mg tablet strengths.  The 0.125, 0.25, 0.5, 1.0, and 2.5 mg tablets 
are colored blue, green, white, yellow, and pink, respectively.  The formulation contains 
pharmaceutically acceptable excipients used in other approved drug products. 
For subjects who were randomly allocated to receive placebo in TDE-PH-310, dosing of 
UT-15C will be initiated and optimized as in the previous protocol, including all safety 
monitoring and periodic telephone contacts.  That is, the first dose of UT-15C (0.125 mg) 
should be taken by the subject at the site immediately after (approximately 10 minutes) 
consuming food.  Oral dosing of study drug will be continued at 0.125 mg TID (every 6 to 8 
hours) immediately after (approximately 10 minutes) consuming food.  Subjects must be 
instructed to take the appropriate amount of UT-15C tablets based upon their prescribed dose.  
For the first 4 weeks, each dose of study drug should be adjusted in 0.125 mg increments no 


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more than every 24 hours as clinically indicated.  Following 4 weeks of treatment, each dose 
of study drug may be adjusted in 0.125 or 0.25 mg increments every 24 hours as clinically 
indicated.  Doses of UT-15C should continue to be increased in the absence of dose-limiting 
drug-related adverse effects, to ensure the subject receives the optimal clinical dose 
throughout the study.  There is no maximum dose of UT-15C in this open-label study. 
Subjects who were randomly allocated to receive UT-15C in TDE-PH-310 will begin the 
open-label study at the same dose they were receiving at the Study Termination Visit in 
TDE-PH-310, and subsequent adjustments will be made based on symptoms of PAH and 
adverse effects. 
All subjects must be instructed to take the appropriate amount of 0.125, 0.25, 0.5, 1.0 and/or 
2.5 mg tablets based upon their prescribed dose.  All dose changes should be conducted under 
appropriate medical supervision in consultation with the study site.  At least weekly telephone 
calls between site personnel and the subject should be made during the first 12 weeks of the 
study to monitor AEs and make decisions about dose titration.  After Week 12, at least 
monthly telephone calls should be made to continue to monitor AEs and make decisions 
regarding appropriate dose titrations.  If dose titration is considered appropriate, site personnel 
will instruct the subject to modify their dose and the dose change will be recorded in source 
documentation.  If it becomes necessary for a subject to modify their dose of UT-15C (eg, due 
to an AE) without prior instructions from site personnel, the subject should be instructed to 
contact the site as soon as possible and report any dose changes to site personnel for updating 
in source documentation. 
In the event of continued intolerable AEs, dose reductions may occur.  The exact dose 
reduction and frequency of dose reduction should be based on the clinical condition of the 
subject and the severity/seriousness of the event.  In general, dose reductions may occur in 
0.125 or 0.25 mg increments every 12 to 24 hours.  Larger dose reductions may be necessary 
in the event of an emergency situation. 
6.2 
ACCESS TO BLINDED TREATMENT ASSIGNMENT 
This study is not blinded. 


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6.3 
COMPLIANCE 
The Principal Investigator or other site personnel under the direction of the Principal 
Investigator will be responsible for dose titration of UT-15C and recording all dosing 
information in source documents.  During telephone calls, site personnel will record the 
current dosing regimen of UT-15C and determine if the subject is taking UT-15C as 
prescribed. 
At scheduled study visits, subjects should be instructed to bring all study drug (including 
empty and unused bottles) to the investigational site.  Upon return of study drug at each 
required protocol visits (eg, Weeks 6, 12, 24, etc), the study coordinator or pharmacist must 
document the number of returned tablets of each strength and determine if the appropriate 
amount of study drug remains based upon the dose of study drug prescribed.  Each subject 
will also be asked at each visit whether he or she has been compliant with dosing instructions.  
Subject compliance with the prescribed dosage regimen will be monitored throughout the 
study.  If it is determined that a subject is not compliant with study drug, then site personnel 
must re-educate the subject on proper dosing compliance and its importance.  Continued 
noncompliance may lead to withdrawal of the subject from the study, after consultation 
between the Investigator and the Sponsor. 
Upon return of study drug at all protocol-required on-site study visits (eg, Weeks 6, 12, 24, 
etc), all bottles of study drug will be collected.  Study drug returned will not be re-dispensed 
to the subject.  Site personnel will dispense a new supply of study drug at each protocol-
required visit for the subsequent interval.  If necessary, additional study drug may be 
dispensed in between protocol-required visits at unscheduled visits. 
7 
EXPERIMENTAL PROCEDURES 
7.1 
TREATMENT PHASE 
7.1.1 
Baseline/Study Entry 
All data collected at the subject’s Study Termination Visit during TDE-PH-310 and prior to 
initiating open-label study drug will serve as Baseline/Study Entry assessments for this study.  
Following completion of the Study Termination assessments for a subject and entry of 
required data into the interactive voice or web response system (IVRS/IWRS), the site 


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personnel will be unblinded to that subject’s treatment assignment.  Subjects must sign an ICF 
and meet inclusion/exclusion criteria specific to this protocol.  The recommended sequence of 
events for Baseline/Study Entry is displayed below: 
 Informed consent (prior to any study assessments) 
 Inclusion/exclusion criteria 
 Vital signs (following at least 5 minutes of rest)* 
 Physical examination* 
 WHO Functional Class* 
 AE assessment* 
 6MWT/Borg dyspnea score (for subjects randomized to UT-15C in TDE-PH-310, the 
6MWT to be initiated 3 to 6 hours after the last dose of UT-15C; 6MWT to be 
conducted following at least 5 minutes of rest; Borg dyspnea score to be conducted 
immediately following 6MWT)* 
 Urine pregnancy test (for WOCBP)* 
 Clinical laboratory assessments* 
 Plasma NT-proBNP* 
 Study drug dosing (for subjects randomized to placebo in TDE-PH-310, the initial 
dose of UT-15C in TDE-PH-311 should be taken at the study site) 
 Drug accountability 
 Concomitant medications* 
 Weekly telephone calls are highly recommended especially after any dose changes 
*assessments conducted during the Study Termination Visit for the TDE-PH-310 study 
will not need to be repeated 
The AEs that were ongoing at the end of the TDE-PH-310 study will be recorded as ongoing 
events for this open-label study.  Concomitant medications that were ongoing at the 
TDE-PH-310 Study Termination Visit will be recorded in the eCRF for the open-label study.  
Once the subject signs the ICF for this study, all ongoing AEs must be recorded and 
documented on the eCRF.  All AEs and concomitant medications will be reported 
continuously for the duration of the study.  Phone calls to the subject must begin within 
1 week of the subject receiving the first dose of study drug and continue to be made weekly 
for the first 12 weeks of the study.  After the first 12 weeks, phone calls must be made at least 
monthly.  Dose titration should occur as needed in accordance with Section 6.1. 


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7.1.2 
Week 6 Visit 
Subjects are to return to the study site at Week 6.  This visit should be conducted within 
14 days of the scheduled visit (as determined by the Baseline/Study Entry Visit) and the 
following assessments are to occur in the order recommended below: 
 Vital signs (following at least 5 minutes of rest) 
 WHO Functional Class 
 AE assessment 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after the last dose of 
UT-15C; Borg dyspnea score to be conducted immediately following 6MWT) 
 Urine pregnancy test (for WOCBP) 
 UT-15C dose titration 
 Drug accountability/compliance 
 Concomitant medications 
 Weekly telephone calls are highly recommended, especially after any dose changes 
7.1.3 
Week 12 Visit 
Subjects are to return to the study site at Week 12.  This visit should be conducted within 
14 days of the scheduled visit (as determined by the Baseline/Study Entry Visit) and the 
following assessments are to occur in the order recommended below: 
 Vital signs (following at least 5 minutes of rest) 
 WHO Functional Class 
 AE assessment 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after the last dose of 
UT-15C; Borg dyspnea score to be conducted immediately following 6MWT) 
 Urine pregnancy test (for WOCBP) 
 Clinical laboratory assessments 
 UT-15C dose titration 
 Drug accountability/compliance 
 Concomitant medications 
 Monthly telephone calls are highly recommended 


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7.1.4 
Follow-up Visits (every 12 weeks) 
Subjects should return to the study site every 12 weeks after the Week 12 visit.  These visits 
should be conducted within 14 days of the scheduled visit (as determined by the 
Baseline/Study Entry Visit).  Assessment of AEs, concomitant medications, and dose titration 
should occur continuously between and during study visits.  The recommended sequence of 
events for Follow-up Visits is displayed below: 
 Vital signs (following at least 5 minutes of rest) 
 WHO Functional Class 
 AE assessment 
 6MWT/Borg dyspnea score (6MWT to be initiated 3 to 6 hours after the last dose of 
UT-15C; Borg dyspnea score to be conducted immediately following 6MWT) 
 Urine pregnancy test (for WOCBP) 
 Clinical laboratory assessments* 
 Plasma NT-proBNP** 
 UT-15C dose titration 
 Drug accountability/compliance 
 Concomitant medications 
 Monthly telephone calls are highly recommended 
 Collection of blood sample for evaluation of pharmacogenomics (optional) *** 
*to be assessed at the first Follow-up Visit and every other visit thereafter 
**to be assessed at the third Follow-up Visit only (Week 48) 
*** The sample should be collected at the next scheduled Follow-up Visit when clinical 
labs are also collected.  Subjects must sign an informed consent prior to sample 
collection. 
7.1.5 
Study Termination Visit 
When subjects discontinue the study, they will complete a Study Termination Visit. If 
possible, each subject should remain on study drug until they have completed the Study 
Termination visit. After the Study Termination Visit is completed, subjects should down 
titrate the study drug over an appropriate period of time in accordance with their clinical 
condition. Once the study drug has been discontinued, any remaining study drug should be 
returned to the clinic for drug accountability. The following assessments will take place at the 
Study Termination visit: 


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 Vital signs (following at least 5 minutes of rest) 
 Physical examination 
 WHO Functional Class 
 AE assessment (for AEs ongoing at the Study Termination Visit, assessments to 
continue for up to 30 days beyond the Study Termination Visit) 
 6MWT/Borg dyspnea score (if possible, the 6MWT is to be initiated 3 to 6 hours after 
the last dose of UT-15C; Borg dyspnea score to be conducted immediately following 
6MWT) 
 Urine pregnancy test (for WOCBP) 
 Clinical laboratory assessments 
 Drug accountability/compliance 
 Concomitant medications 
 Collection of blood sample for evaluation of pharmacogenomics (optional) * 
* If a subject discontinues prior to their next Follow-up Visit, pharmacogenomic samples 
will be collected at the Study Termination Visit.   
8 
STUDY TERMINATION 
8.1 
CRITERIA FOR SUBJECT WITHDRAWAL 
A subject may voluntarily withdraw or will 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 wishes to withdraw 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 deviated from the protocol 
 The subject’s behavior is likely to undermine the validity of his/her results 
 The subject becomes pregnant 
When a subject is discontinued from the study, the Investigator will complete the Study 
Termination record and provide an explanation, if needed.  If UT-15C has been administered, 
the Investigator should make every effort to perform all Study Termination evaluations 
following termination of UT-15C treatment but prior to discharge from the study. 
8.2 
CRITERIA FOR TERMINATING THE STUDY 
The study may be stopped at any time if, in the opinion of the Investigator and/or Sponsor, 
continuation of the study represents a serious medical risk to the subjects.  This may include, 


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but is not limited to, the presence of serious, life-threatening, or fatal AEs, or AEs that are 
unacceptable in nature, severity, or frequency.  The Sponsor reserves the right to discontinue 
the study for any reason at any time. 
8.3 
CRITERIA FOR DISCONTINUING THE SITE 
The study may also be terminated at a given center if: 
 The Principal Investigator elects to discontinue the study 
 The Sponsor elects to discontinue the study at the site 
 International Council for Harmonisation (ICH) Good Clinical Practice (GCP) or 
applicable regulations are not observed 
 The protocol is repeatedly violated or critical violations are documented 
 Changes in personnel or facilities adversely affect performance of the study 
9 
ADVERSE EVENT REPORTING  
9.1 
DEFINITIONS 
9.1.1 
Adverse Event  
An AE is any untoward medical experience occurring to a subject during a clinical study 
whether or not it is related to 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 pre/post-treatment events that occur as a result of 
protocol-mandated procedures. 
9.1.2 
Serious Adverse Event  
An 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 
In addition, important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 


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judgment, they may jeopardize the subject and require medical/surgical intervention to 
prevent one of the outcomes listed above.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse. 
Life threatening means that the subject was, in the view of the Investigator, at immediate risk 
of death from the event as it occurred.  It does not mean that the event, had it occurred in a 
more severe form, might have caused death. 
9.1.3 
Adverse events associated with progression of PAH 
Expected AEs that may be related to the progression of a subject’s PAH are defined in 
Appendix 15.5.  All events that occur during the course of the study that are included on this 
list and felt to be related to the progression of the disease by the Investigator should not be 
recorded as AEs in the eCRF as these PAH symptoms will be evaluated and recorded as an 
efficacy endpoint and/or will be captured as disease-related events. 
However, each event must be recorded as an AE/SAE in the eCRF, if it meets 1 or more of 
the following criteria: 
 There is a reasonable possibility that it may have been caused by study drug. 
 It is serious. 
 It has occurred at greater than expected severity (intensity, frequency, or duration). 
9.2 
DOCUMENTATION OF ADVERSE EVENTS 
All AEs will be captured from the time the ICF is signed.  Any AEs that are ongoing at the 
Study Termination Visit from Study TDE-PH-310 should be recorded as continuing AEs in 
this open-label study.  An AE or SAE occurring during the study must be documented in the 
subject’s source documents and on the appropriate eCRF page.  Information relating to the 
AE such as onset and cessation date and times, intensity, seriousness, relationship to study 
drug, and outcome is also to be documented in the eCRF (see Appendix 15.4 for definitions).  
Where possible, AEs should be recorded using standard medical terminology.  If several signs 


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or symptoms are clearly related to a medically defined diagnosis or syndrome, the diagnosis 
or syndrome should be recorded on the eCRF page, not the individual signs and symptoms. 
All AEs should be followed until either resolution (or return to normal or baseline values), 
until they are judged by the Investigator to no longer be clinically significant, or for up to 
30 days, if the AE extends beyond the final visit.  All SAEs that occur during the study will be 
followed until resolution, death, or the subject is lost to follow-up even if they are ongoing 
more than 30 days after completion of the final visit.  Supplemental measurements and/or 
evaluations may be necessary to investigate fully the nature and/or causality of an AE or SAE.  
This may include additional laboratory tests, diagnostic procedures, or consultation with other 
healthcare professionals.  The eCRF pages should be updated with any new or additional 
information as appropriate. 
9.3 
REPORTING RESPONSIBILITIES OF THE INVESTIGATOR 
All SAEs, regardless of expectedness or causality, must be reported to the Sponsor within 
24 hours of awareness by fax (+ 1 919-313-1297 [U.S./Japan] or + 44 1932 573 888 
[Europe/ROW]) or email (drugsafety@unither.com).  A completed SAE report form along 
with any relevant hospital records and autopsy reports should be provided to Global Drug 
Safety at United Therapeutics Corp.  A follow-up SAE report form must be forwarded to 
Global Drug Safety at United Therapeutics Corp. within 48 hours of the receipt of any 
new/updated information.  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. 
9.4 
PREGNANCY 
If a study subject becomes pregnant during participation in this clinical study, site staff must 
notify the Sponsor within 24 hours of learning of the pregnancy by completing the Pregnancy 
Notification Form and either faxing or emailing this form to Global Drug Safety at United 
Therapeutics Corp. (+ 1 919-313-1297 [U.S./Japan] or + 44 1932 573 888 [Europe/ROW]) or 
drugsafety@unither.com).  Subjects who become pregnant during the study will be withdrawn 


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from active participation in the study and will discontinue study drug after an appropriate 
period of down-titration.   
United Therapeutics Global Drug Safety Department will follow up with the Investigator to 
ensure appropriate data are provided regarding the outcome of the pregnancy, and to request 
that the Investigator complete a Pregnancy Outcome Report Form.  Pregnancy only becomes 
an AE/SAE if there is an abnormal outcome, a spontaneous abortion, a termination for 
medical reasons other than PAH, or a congenital anomaly in the offspring. 
9.5 
SAFETY REPORTS 
In accordance with national regulations, the Sponsor or designee, will notify the regulatory 
agencies, Investigators, IRBs, and/or ECs of all relevant AEs (usually those that are 
considered to be possibly attributable to study drug and are both serious and unexpected) in 
accordance with the applicable national regulations.  The Investigator must report these SAEs 
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 
Subject data will first be documented in the subject’s source documents, and then transferred 
into the eCRF.  Site personnel will be responsible for recording all subject’s data into the 
eCRF.  Data for any subject who signs an informed consent form will be captured in the 
eCRF.  The eCRF screens 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 final when final query resolution has been 
completed and all data management quality control procedures are complete. 
10.2 
SAMPLE SIZE 
No formal sample size calculation has been conducted.  All eligible subjects from 
TDE-PH-310 may enter this study. 


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10.3 
ANALYSIS PLAN 
All safety and efficacy data will be summarized in tables and listings and analyzed for trends 
over time.  No formal hypothesis testing is planned. 
The safety population will be defined as all subjects in the study that received UT-15C at any 
time during the course of the study.  Safety analyses will be performed on the safety 
population.  All AEs as recorded by the Investigators will be assigned MedDRA preferred 
terms by the Sponsor for reporting purposes. 
10.4 
OTHER ANALYSES 
Pharmacogenomic samples will be evaluated for genetic variants.  Other exploratory analyses 
may be conducted based on available study data. 
11 
PACKAGING AND FORMULATION 
11.1 
CONTENTS OF STUDY DRUG  
United Therapeutics Corp. will supply UT-15C for administration during the study.  UT-15C 
tablets will be provided as 0.125, 0.25, 0.5, 1, and 2.5 mg strengths for the study.  The UT-
15C tablets are sustained release osmotic tablets. Active treatment will be UT-15C tablets 
provided as 0.125, 0.25, 0.5, 1, and 2.5 mg strengths for the study.  Each tablet contains either 
0.125 mg treprostinil (equivalent to 0.15875 mg treprostinil diethanolamine), 0.25 mg 
treprostinil (equivalent to 0.3175 mg treprostinil diethanolamine), 0.5 mg treprostinil 
(equivalent to 0.635 mg treprostinil diethanolamine), 1 mg of treprostinil (equivalent to 
1.27 mg treprostinil diethanolamine), 2.5 mg of treprostinil (equivalent to 3.17 mg treprostinil 
diethanolamine).  The 0.125, 0.25, 0.5, 1, and 2.5 mg tablets are colored blue, green, white, 
yellow, and pink, respectively.  UT-15C tablets will be provided in child resistant bottles each 
containing 100 tablets, or in other appropriate packaging configurations as may be required. 
11.2 
LABELING  
Each bottle will be labeled in accordance with applicable national regulations, to include at 
least the following information: study drug, study reference code, strength, quantity, route of 
administration, manufacture or expiry date, lot number, Sponsor name, address and telephone 
number, and storage conditions.  The labels on the bottles may include blank fields for sites to 


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document the following information specific to each bottle, including but not limited to, 
Investigator name, subject number / initials, and date dispensed. 
11.3 
STORAGE AND HANDLING OF CLINICAL TRIAL MATERIAL 
All study drug will be stored at room temperature (up to 25°C with brief excursions to 30°C 
permitted).  Study drug should not be frozen, refrigerated, or exposed to heat.  Site personnel 
should refer to investigational medicinal product labeling or regulatory submissions for 
specific requirements by country or region in accordance with local regulations or guidance. 
Study drug at the investigational site will be stored in a securely locked cabinet or enclosure 
with appropriate temperature monitoring.  Access should be strictly limited to the 
Investigators and their designees.  Neither the Investigators nor any designees may provide 
study drug to any person not participating in this study. 
The pharmacist or appropriate personnel at the investigational site will deliver and retrieve 
each bottle assigned to the subject at each study visit during the course of the study.  Subjects 
should be instructed to return all study drug, including empty bottles, to the appropriate study 
personnel at every protocol-required visit. 
11.4 
SUPPLY AND RETURN OF CLINICAL TRIAL MATERIAL 
Study sites will be supplied with a sufficient quantity of UT-15C to begin enrollment in the 
study.  An IVRS/IWRS will be utilized to manage resupply with respect to each subject’s visit 
schedule.  If required, additional study drug may be dispensed to a subject between protocol-
required visits.  At each protocol required visit, all study drug dispensed to the subject should 
be returned to the study site (including empty and unopened bottles).  A new supply of study 
drug will be dispensed at each protocol-required visit. 
11.5 
DRUG ACCOUNTABILITY 
The Investigator is responsible for study drug accountability and reconciliation overall and on 
a per subject basis.  Drug accountability records will be maintained during the study and these 
records will include: the amount of study drug received from the Sponsor, the amount 
dispensed to each subject, and the amount of unused drug.  At each visit, site personnel should 
assess drug dispensed, drug returned, and dosing information to confirm drug accountability 


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and compliance.  Once a representative from the Sponsor is able to confirm drug 
accountability for that subject, study drug will be returned to a Sponsor designated location 
for destruction.  Study drug will not be destroyed on-site by the study staff or in the 
pharmacy. 
12 
REGULATORY AND ETHICAL OBLIGATION 
12.1 
ICH GCP OR APPLICABLE REGULATORY REQUIREMENTS 
The study will be conducted in accordance with ICH 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 
development safety update 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 authorized designees must 
explain the purpose and nature of the study, including potential benefits and risks and all 
study procedures to the subject.  The subject must sign and date an IRB/EC-approved ICF 
prior to the conduct of any study-related activities.  A copy of the signed ICF will be given to 
the subject and the original will be retained in the study site’s records. 
12.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
Prior to study initiation at each site, the Investigator will obtain approval for the study from an 
appropriate IRB/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 ICF 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 ICF, the Investigator is 
responsible for obtaining IRB/EC approval of these amended documents prior to 


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implementation.  Copies of the IRB/EC correspondence and approval letters must be sent to 
the Sponsor. 
During the conduct of the study, an annual progress report will be compiled by the Sponsor 
for submission to those IRBs/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 the IRB or EC 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 study, the following documents (at minimum) will 
be provided to the site: Investigator’s Brochure, Protocol, ICF, Budget Agreement, and access 
to an eCRF. 
The site will be required to provide the following documents (at minimum) to United 
Therapeutics Corp. or designee prior to study start: Signature page of the protocol, Form FDA 
1572, IRB/EC Composition and Roster, IRB/EC protocol and informed consent approval 
letters, Curriculum Vitae of study staff listed on the Form FDA 1572, and authorized clinical 
study agreement (as required). 
12.5 
SUBJECT CONFIDENTIALITY 
Every effort will be made to keep medical information confidential.  United Therapeutics 
Corp., 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 appropriate local 
regulatory agencies for purposes of checking the accuracy of the data.  A unique number will 
be assigned to all subjects and any report published will not identify the subjects by name. 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Protocol amendments that could potentially adversely affect the safety of participating 
subjects or that alter the scope of the investigation, the scientific quality of the study, the 


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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 Corp. 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. 
At the end of the study, where applicable, a final report will be provided to the local 
regulatory agencies. 
13.2 
STUDY DOCUMENTATION AND STORAGE 
In accordance with federal/national regulations, ICH 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.  For Investigators in the European Economic 
Area, the study records should be maintained for at least 15 years after study discontinuation.  
The Investigator must notify United Therapeutics Corp. before any disposal or change in 
location of study records. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
In accordance with federal/national regulations, ICH GCP guidelines, monitors for United 
Therapeutics Corp. 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 must agree 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.  In addition, auditors for United Therapeutics Corp. or its designee may periodically 
contact the site and conduct on-site visits. 


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14 
REFERENCES 
ATS Statement:  Guidelines for the Six-Minute Walk Test.  Am J Respir Crit Care Med.  
2002;166:111-117. 
Barst RJ, Rubin LJ, Long WA, et al.  A comparison of continuous intravenous epoprostenol 
with conventional therapy for primary pulmonary hypertension.  The Primary Pulmonary 
Hypertension Study Group.  N Engl J Med.  1996;334:296–302. 
Barst RJ, Gibbs SR, Ghofrani HA, et al.  Updated Evidence-Based Treatment Algorithm in 
Pulmonary Arterial Hypertension.  J of Amer College of Cardiology.  2009;54(1)S78–S84. 
Farber HW & Loscalzo J.  Mechanisms of Disease: Pulmonary Arterial Hypertension.  
N Engl J Med.  2004;3511(16):1655–1665. 
Fijalkowska A, Kurzyna M, Torbicki A, et al.  Serum N-Terminal Brain Natriuretic Peptide as 
a Prognostic Parameter in Patients With Pulmonary Hypertension.  Chest.  2006;129:1313–
1321. 
Remodulin® (treprostinil) Injection, for subcutaneous or intravenous use [package insert].  
Research Triangle Park, NC: United Therapeutics Corporation, 2014. 
Rich S, Dantzker DR, Ayres SM, et al.  Primary Pulmonary Hypertension: A National 
Prospective Study.  Ann Intern Med.  1987;107:216–223. 
Rubin LJ.  Primary Pulmonary Hypertension.  N Engl J Med.  1997;336:111–117. 
Tyvaso® (treprostinil) inhalation solution, for oral inhalation only [package insert].  Research 
Triangle Park, NC: United Therapeutics Corporation, 2017. 


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15 
APPENDICES 
15.1 
PROCEDURE FOR SIX MINUTE WALK EXERCISE TEST AND BORG 
DYSPNEA SCORE 
General Procedures 
The 6-Minute Walk exercise test should be administered by the same tester and on the same 
course at each study site throughout the study for a given subject.  The administration of 
the test and specifications of the testing area should be generally consistent with the 
American Thoracic Society guidelines and the usual practice of the investigative site 
[ATS guidelines; 2002]. 
The area used for the 6-Minute Walk Test should be pre-measured at approximately 30 meters 
in length (but no shorter than 15 meters [16 yards or 50 feet] in length at minimum) and at 
least 2 to 3 meters in width.  There should be no turns or curves to the 6-Minute Walk area.  
The length should be marked with gradations at least every 3 meters to ensure the accurate 
measurement of the distance walked.  The area should be well ventilated.  The tester may be 
at the starting end of the corridor or at the midpoint of the corridor with a stop-watch.  
Intermittent rest periods are allowed if the subject can no longer continue.  If the subject needs 
to rest briefly, he/she may stand or sit and then begin again when he/she is sufficiently rested 
but the clock will continue to run.  At the end of 6 minutes, the tester will call “stop” while 
simultaneously stopping the watch and then measure the distance walked.  The Borg dyspnea 
rating will be administered immediately following completion of the 6MWT. 
Instructions to the Subject  
Subjects will be instructed that the preceding meal should be light.  Subjects should be told to 
wear comfortable clothing and sneakers or comfortable walking shoes.  The person 
administering the test will use the following exact dialogue with the subject: 
“The purpose of this test is to find out how far you can walk in 6 minutes.  You will start 
from this point and follow the hallway to the marker (eg, chair) at the end, turn around and 
walk back.  When you arrive back at the starting point you will go back and forth again.  
You will go back and forth as many times as you can in the 6-minute period.  You may 
stop and rest if you need to.  Just remain where you are until you can go on again.  
However, the most important thing about the test is that you cover as much ground as you 


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possibly can during the 6 minutes.  I will tell you the time, and I will let you know when 
the 6 minutes are up.  When I say STOP, please stand right where you are.” 
After these instructions are given to the subject, the person administering the test will then 
ask: 
“Do you have any questions about the test?” 
“Please explain to me what you are going to do.” 
The person administering the test will then start the test by saying the following to the subject: 
“Are you ready?” 
“Start when I say ‘GO.’” 
The person administering the test will tell the subject the time at 2 and 4 minutes by saying: 
“You have completed 2 minutes.” 
And then by saying: 
“You have completed 4 minutes.” 
No other instruction or encouragement will be given during the test.  Eye contact with the 
subject should be avoided during the test. 
Following the walk, the person administering the test will obtain a rating of dyspnea using the 
Borg Scale.  The person will use the following dialogue: 
“I would like to use the following scale to indicate the maximal shortness of breath you 
had during the walk test (indicate the Borg Scale).  If there was no shortness of breath at 
all you would point to 0; if the shortness of breath was not very great you would choose 
from 0.5 to 2; if you were somewhat more short of breath you would select 3; and if the 
breathing was getting very difficult, you would choose 4 to 9, depending on just how hard 
it was; 10 represents the greatest shortness of breath you have ever experienced in your 
life, and if you feel more short of breath than you have ever been in your life before, 
choose a number greater than 10 that represents how short of breath you feel.  If one of the 
numbers does not exactly represent how short of breath you are, then you can choose a 
fraction between.  For example, if you had shortness of breath somewhere between 4 and 
5, you could choose 4 ½. 


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15.2 
WHO FUNCTIONAL CLASS FOR PAH 
Class I:   Patients with pulmonary hypertension but without resulting limitation of physical 
activity.  Ordinary physical activity does not cause undue dyspnea or fatigue, chest 
pain, or near syncope. 
Class II:   Patients with pulmonary hypertension resulting in slight limitation of physical 
activity. These subjects are comfortable at rest, but ordinary physical activity 
causes undue dyspnea or fatigue, chest pain or near syncope. 
Class III:   Patients with pulmonary hypertension resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Ordinary activity causes undue dyspnea or 
fatigue, chest pain, or near syncope. 
Class IV:  Patients with pulmonary hypertension with inability to carry out any physical 
activity without symptoms.  These subjects manifest signs of right heart failure. 
Dyspnea and/or fatigue may be present even at rest.  Discomfort is increased by 
any physical activity. 


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15.3 
CLINICAL LABORATORY PARAMETERS 
Blood Chemistries 
Hematology 
Other 
Sodium 
Red Blood Cell Count 
NT-proBNP (plasma)* 
Potassium 
Hemoglobin 
Urine dipstick analysis** 
Chloride 
Hematocrit 
Urine pregnancy test*** 
Bicarbonate/CO2 
Platelet Count 
 
Albumin 
White Blood Cell Count (no differential) 
 
Blood Urea Nitrogen/Urea 
 
 
Total Bilirubin 
 
 
Indirect Bilirubin 
 
 
Direct Bilirubin 
 
 
Alkaline Phosphatase 
 
 
Alanine Aminotransferase (ALT) 
 
 
Aspartate Aminotransferase (AST) 
 
 
Gamma-glutamyl transferase 
(GGT) 
 
 
Creatinine 
 
 
 
Visit Test Schedule 
Visit 
Labs Collected 
Baseline/Study Entry**** 
Chemistries, Hematology, NT-proBNP, urine dipstick, urine 
pregnancy*** 
Week 6 Visit 
Urine pregnancy*** 
Week 12 Visit 
Chemistries, Hematology, urine pregnancy*** 
Follow-up Visits***** 
Chemistries, Hematology, NT-proBNP*, urine pregnancy*** 
Study Termination Visit 
Chemistries, Hematology, urine dipstick, urine pregnancy*** 
* NT-proBNP collected at Baseline/Study Entry and Follow-up Visit (Week 48) only 
** pH, specific gravity, presence of protein or blood 
*** For women of childbearing potential (WOCBP) 
**** Baseline/Study Entry clinical laboratory assessments for this study are those collected at the last visit (Study 
Termination) from study TDE-PH-310 and prior to initiation of open-label UT-15C. 
***** During Follow-up Visits, clinical laboratory samples should be collected at the first Follow-up Visit and every 
other Follow-up Visit thereafter. 


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15.4 
GUIDELINES AND DEFINITIONS FOR RECORDING ADVERSE EVENTS 
The Principal Investigator or a designated member of his/her staff will probe each subject for 
any AEs that may have occurred.  The Investigator should always ask the same question when 
conducting the verbal probe in order to ensure uniformity between subjects.  The Investigator 
should ask: 
 
“How are you doing (feeling)?” 
Based on the subject’s response to this question, the Investigator should ask additional 
questions relevant to the specific complaint such as: 
 
“How severe is/was the symptom?” 
 
“How often did the symptom occur?” 
 
“How long did the symptom last?” 
Using provided definitions, the Investigator will then: 
(1) rate the intensity and seriousness of the AE, (2) estimate the causality of the AE to study 
drug, and (3) note actions taken to counteract the AE.  
Definitions of Intensity, Seriousness, Causality, Action Taken, and Outcome 
INTENSITY 
An assessment of the relative intensity (severity) of an AE is based on the Investigator’s 
clinical judgment.  The maximum intensity encountered during the evaluation period should 
be checked.  The assessment of intensity should be independent of the assessment of the 
seriousness of the AE.  
SERIOUSNESS 
A SAE is one that represents an actual or potential significant hazard.  This includes, but is 
not limited to, an event that is fatal, life-threatening, permanently or severely disabling, 
requires or prolongs inpatient hospitalization, is a congenital abnormality (offspring of 
subject) or is medically significant (important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a SAE when, based upon 


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appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition). 
CAUSALITY 
An estimate of causality between a specified AE and the study drug is made by the 
Investigator.  Definitions of the categories follow: 
 NOT RELATED - there is not a temporal relationship to study drug administration 
(too early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, or concurrent disease and the SAE 
 POSSIBLE - there is a reasonable causal relationship between the study drug and the 
SAE.  Dechallenge information is lacking or unclear 
 PROBABLE - there is a reasonable causal relationship between the study drug and the 
SAE.  The event responds to dechallenge.  Rechallenge is not required 
ACTION TAKEN 
 TEST AGENT DOSE MODIFICATION* 
 Dose Increased - the dose or regimen of the test agent was increased 
 Dose Not Changed - the dose or regimen of the test agent was not changed 
 Dose Reduced - the dose or regimen of the test agent was decreased 
 Drug Interrupted - administration of the test agent was stopped temporarily 
 Drug Withdrawn - administration of the test agent was stopped permanently and not 
restarted 
 Unknown - changes to the administration of the test agent cannot be determined 
*NOTE:  Only the last test agent action should be recorded in the eCRF. 
OUTCOME 
 Fatal – The study subject died 
 Not Recovered / Not Resolved – The AE was ongoing 
 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 
 Unknown – The outcome of the AE cannot be determined 


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15.5 
EXPECTED EVENTS ATTRIBUTABLE TO THE PROGRESSION OF 
PULMONARY ARTERIAL HYPERTENSION (SYSTEM ORGAN CLASS 
AND PREFERRED TERM, VER. 16.0) 
Abdominal pain (Gastrointestinal disorders; 
ABDOMINAL PAIN) 
Hemoptysis (Respiratory, thoracic & mediastinal 
disorders; HAEMOPTYSIS) 
Anorexia (Metabolism and nutrition 
disorders; ANOREXIA) 
Hypoxia (Respiratory, thoracic & mediastinal 
disorders; HYPOXIA) 
Ascites (Gastrointestinal disorders; 
ASCITES) 
Loss of consciousness  
(Nervous system disorders; LOSS OF 
CONSCIOUSNESS) 
Cardiac arrhythmia (Cardiac disorders; 
ARRHYTHMIA) 
Nausea (Gastrointestinal disorders; NAUSEA) 
Cardiac arrest (Cardiac disorders; CARDIAC 
ARREST) 
Edema (General disorders and administration site 
conditions; OEDEMA) 
Heart failure (including exacerbation of) 
(Cardiac disorders; CARDIAC FAILURE) 
Orthopnea (Cardiac disorders; ORTHOPNOEA) 
Chest pain (General disorders and 
administration site conditions; CHEST PAIN) 
Pallor (Vascular disorders; PALLOR) 
Cardiovascular collapse (Vascular disorders; 
CIRCULATORY COLLAPSE) 
Palpitations (Cardiac disorders; PALPITATIONS) 
Cor pulmonale (Cardiac disorders;  
COR PULMONALE) 
Cool extremities  
(General disorders and administration site 
conditions; PERIPHERAL COLDNESS) 
Cough (Respiratory, thoracic & mediastinal 
disorders; COUGH) 
Pulmonary arterial hypertension, exacerbation of 
(Vascular disorders; PULMONARY ARTERIAL 
HYPERTENSION) 
Cyanosis (Cardiac disorders; CYANOSIS) 
Sudden death (Cardiac disorders; SUDDEN 
DEATH) 
Dizziness (Cardiac disorders; DIZZINESS) 
Syncope (Cardiac disorders; SYNCOPE) 
Dyspnea at rest (Respiratory, thoracic & 
mediastinal disorders; DYSPNOEA) 
Vasovagal reaction (Nervous system disorders; 
SYNCOPE VASOVAGAL) 
Dyspnea on exertion  
(Respiratory, thoracic & mediastinal 
disorders; DYSPNOEA EXERTIONAL) 
Tachycardia (Cardiac disorders; 
TACHYCARDIA) 
Paroxysmal nocturnal dyspnea  
(Cardiac disorders; DYSPNOEA 
PAROXYSMAL NOCTURNAL) 
Vomiting (Gastrointestinal disorders; VOMITING) 
Exercise intolerance (General disorders and 
administration site conditions; EXERCISE 
TOLERANCE DECREASED) 
Weight loss (Investigations; WEIGHT 
DECREASED) 
Fatigue (General disorders and administration 
site conditions; FATIGUE) 
Weight gain (Investigations; WEIGHT 
INCREASED) 
 

SAP_001.pdf: 
United Therapeutics Corp. 
 
TDE-PH-311 Statistical Analysis Plan 
Oral Treprostinil 
Version 15 Jan 2019 
Confidential 
Page 1 
Document Type: Statistical Analysis Plan 
Protocol / Study No.: 
TDE-PH-311 
Draft Date: 
 
15-Jan-2019 
Total Number of Pages 
including Appendices: 
 
15 
Classification: 
Confidential 
 
 
 
Title: 
An Open-Label Extension Study of UT-15C in Subjects with Pulmonary Arterial 
Hypertension – A Long-Term Follow-up to Protocol TDE-PH-310 
 
 
Author: CQ Deng, MB, MPH, PhD 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
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 
ABBREVIATIONS AND DEFINITIONS ............................................................................ 3 
1 
PREFACE ....................................................................................................................... 4 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 4 
2.1 OBJECTIVES ................................................................................................................ 4 
2.2 ENDPOINTS .................................................................................................................. 4 
3 
STUDY DESIGN ............................................................................................................ 5 
4 
RANDOMIZATION ...................................................................................................... 5 
5 
SEQUENCE OF PLANNED ANALYSES .................................................................. 5 
6 
SAMPLE SIZE CONSIDERATIONS ......................................................................... 5 
7 
ANALYSIS POPULATIONS ........................................................................................ 5 
8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES .................................... 6 
8.1 EXAMINATION OF SUBGROUPS ............................................................................ 6 
8.2 PREMATURE DISCONTINUATION AND MISSING DATA ................................ 6 
8.3 MULTIPLE COMPARISONS AND MULTIPLICITY ............................................ 7 
8.4 ASSESSMENT WINDOWS .......................................................................................... 7 
9 
STUDY POPULATION ................................................................................................ 7 
9.1 SUBJECT ACCOUNTABILITY .................................................................................. 7 
9.2 ELIGIBILITY CRITERIA ........................................................................................... 8 
9.3 OTHER DESCRIPTIONS OF STUDY POPULATION ........................................... 8 
9.3.1 Demographics ................................................................................................................. 8 
9.3.2 Baseline Characteristics................................................................................................. 8 
9.3.3 PAH History ................................................................................................................... 9 
9.3.4 Concomitant Medications .............................................................................................. 9 
9.3.5 UT-15C Dosing ............................................................................................................... 9 
10 
EFFICACY ANALYSES ............................................................................................. 10 
10.1 6-MINUTE WALK TEST ........................................................................................... 10 
10.2 BORG DYSPNEA SCORE ......................................................................................... 10 
10.3 WHO FUNCTIONAL CLASS .................................................................................... 11 
11 
SAFETY ANALYSES .................................................................................................. 11 
11.1 ADVERSE EVENTS .................................................................................................... 11 
11.2 DISEASE-RELATED EVENTS ................................................................................. 12 
11.3 DEATHS ....................................................................................................................... 12 
11.4 CLINICAL LABORATORY TESTS ......................................................................... 13 
11.5 VITAL SIGNS .............................................................................................................. 13 
12 
APPENDICES .............................................................................................................. 14 
12.1 LIST OF TABLES ....................................................................................................... 14 
12.2 LIST OF LISTINGS .................................................................................................... 15 
12.3 LIST OF FIGURES ..................................................................................................... 15 
 


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ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
BMI 
Body Mass Index 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
ERA 
Endothelin receptor antagonist 
K-M 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-proBNP 
N-Terminal pro-brain natriuretic peptide 
PAH 
Pulmonary arterial hypertension 
PDE-5I 
Phosphodiesterase type 5 inhibitor 
PT 
Preferred Term 
SAP 
Statistical analysis plan 
sGC 
Soluble guanylate cyclase 
SOC 
System Organ Class 
SR 
Sustained release 
TID 
3 times daily 
UT-15C 
Treprostinil diethanolamine 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 


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1 
PREFACE 
This document describes the planned analyses for the TDE-PH-311 study.  This plan is based 
on the original TDE-PH-311 protocol dated 03 Feb 2012 and subsequent protocol 
amendments (latest version protocol amendment 6 dated 29 Sep 2016), and provides further 
details of the analyses presented in the protocol as well as 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 
2.1 
OBJECTIVES 
The objectives of this study are to: 
 Provide treprostinil diethanolamine (UT-15C) sustained-release (SR) tablets for 
eligible subjects who participated in study protocol TDE-PH-310 
 Assess the long-term safety of oral UT-15C 
 Assess the effect of continued long-term therapy with UT-15C on exercise capacity 
(6-Minute Walk Distance [6MWD]/Borg dyspnea score), World Health Organization 
(WHO) Functional Class, and plasma concentrations of N-terminal pro-brain 
natriuretic peptide (NT-proBNP) (at Week 48 only). 
2.2 
ENDPOINTS 
The safety endpoints are as follows: 
 Adverse events (AEs) 
 Clinical laboratory parameters 
 Vital signs 
Concomitant medications, including PAH concomitant medications, also will be documented. 
Efficacy will be assessed by: 
 6-Minute Walk Test (6MWT)  
 Borg dyspnea score  
 WHO Functional Class  
 NT-proBNP 


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3 
STUDY DESIGN 
This is an open-label study.  Subject visits will occur at Baseline, Weeks 6 and 12, and every 
12 weeks thereafter.  The study will continue until either oral UT-15C becomes available 
within the respective territories or the study is discontinued by the Sponsor.  The Baseline 
Visit corresponds to the Study Termination Visit from the parent study (TDE-PH-310) and 
occurs prior to initiation of the open-label study.  
4 
RANDOMIZATION 
This study is not randomized.  All subjects will receive UT-15C during the open-label study if 
the subjects were randomized to UT-15C or placebo in the parent study.  However, some 
analyses are based on the treatment assignment in the parent study.  
5 
SEQUENCE OF PLANNED ANALYSES 
Along with the safety information from the parent study (TDE-PH-310), safety information 
from the TDE-PH-311 study will be provided to the Data Monitoring Committee (DMC) 
periodically for safety review. 
At the time of study completion and unblinding for the parent study (TDE-PH-310), a data cut 
for the TDE-PH-311 study will be performed to facilitate the analysis for the TDE-PH-311 
study.  Analyses based on additional data cuts and the final analyses at the time of study 
closing will be performed separately.  
6 
SAMPLE SIZE CONSIDERATIONS 
No formal sample size calculation has been conducted.  All eligible subjects from the parent 
study (TDE-PH-310) may be enrolled into this open-label extension study.   
7 
ANALYSIS POPULATIONS 
All available data from all subjects will be used as detailed in this analysis plan. 
The safety population will include any subject who received UT-15C at any time during the 
course of the TDE-PH-311 study.  All analyses are based on the safety population.  


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8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All data included in each data cut will be listed.  In general, listings will be sorted by subject 
number and scheduled assessment (if applicable) or the visit date.  Listings will include 
assessment date, assessment time (if available), and study day.  The study day is calculated as 
the assessment date minus the date of the first UT-15C dose in the TDE-PH-311 study.  For 
data collected on a fixed schedule, the assessment identifier will also be included on the 
listing.   
In general, the data will be summarized by visit window.  The visit window is calculated 
based on the time from the first dosing date of UT-15C in the TDE-PH-311 study.  For all 
presentations of the summary tables, the data will be presented by subjects in the UT-15C and 
placebo groups from the parent study (TDE-PH-310) and overall.  
For continuous variables, the summary statistics will include the mean, standard deviation, 
median, minimum, and maximum.  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 point.  For discrete variables, summaries will include the 
frequency and percent in each category.  Percentages will be rounded to 1 decimal point.  
Whenever practical, categories of discrete variables will be ordered and labeled as they appear 
in the electronic case report form (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. 
8.1 
EXAMINATION OF SUBGROUPS 
Exploratory subgroup analyses will be performed as data permit.   
8.2 
PREMATURE DISCONTINUATION AND MISSING DATA 
A subject may voluntarily withdraw or be withdrawn from the study by the Investigator at any 
time for reasons including, but not limited to, the following: 
 The subject wishes to withdraw from further participation. 
 A serious or life-threatening AE occurs or the Investigator considers that it is 
necessary to discontinue study drug to protect the safety of the subject. 
 The subject deviated from the protocol. 
 The subject’s behavior is likely to undermine the validity of his/her results. 


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 The subject becomes pregnant 
All available data from all subjects in the safety population, as defined in Section 7, will be 
used as detailed in this analysis plan.  
Missing data will not be imputed. 
8.3 
MULTIPLE COMPARISONS AND MULTIPLICITY 
No multiple comparison adjustments are planned for analysis of this study. 
8.4 
ASSESSMENT WINDOWS 
For efficacy and safety assessments, Baseline is defined as the measurements prior to the first 
dose of UT-15C in the TDE-PH-311 study.   
Summary analyses will be based on the scheduled (norminal) visits with no visit windows 
applied. 
9 
STUDY POPULATION 
9.1 
SUBJECT ACCOUNTABILITY 
A listing of subject disposition and UT-15C exposure will include subject number, treatment 
group in the parent study, first and last UT-15C dose date/time in the TDE-PH-311 study, date 
completed/discontinued the study, cut off date, study drug exposure (weeks), reason for 
discontinuation, and any other details regarding reason for discontinuation.  The summary of 
subject accountability will include the number (percent) of subjects by treatment group who 
completed the study without early termination, the number of subjects who completed 
UT-15C treatment by each visit acheived, number of subjects who discontinued UT-15C 
treatment, and the reason for discontinuation.  This summary will be provided by treatment 
group in the parent study and overall. 
UT-15C exposure and the total subject-years of UT-15C exposure will be summarized by the 
treatment group in the parent study and overall.   
In addition, for subjects who were in UT-15C group in the parent study (TDE-PH-310), their 
exposure to UT-15C in the parent study will be combined into the TDE-PH-311 study.  The 


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overall exposure to UT-15C across both the parent study and the TDE-PH-311 study will be 
summarized.  
9.2 
ELIGIBILITY CRITERIA 
The listing of entry criteria for all subjects will include whether the subject rolled over from 
the previous study, each subject’s treatment group in the parent study, status regarding 
meeting all eligibility criteria (yes/no), and will include an explanation if not all eligibility 
criteria are met.  The summary of entry criteria will include the number and percent of 
subjects who did meet and the number and percent of subjects who did not meet all eligibility 
criteria by treatment group in the parent study and overall.  
In addition, a listing will be provided for protocol deviations.  The listing will include the 
subject number, deviation date, deviation type, deviation severity, and deviation description 
by treatment group in the parent study.   
9.3 
OTHER DESCRIPTIONS OF STUDY POPULATION 
9.3.1 Demographics  
The listing of subject demographics will be organized by treatment group in the parent study, 
and will include subject number, country, assessment date, date of birth, subject age (years), 
sex, ethnicity, race, height, weight, and body mass index (BMI).  The age will be calculated 
based on the first UT-15C dose date in the TDE-PH-311 study.  The summary of 
demographics will include descriptive statistics for age (years) at first dose of UT-15C and 
categorical summaries for age (<65 and ≥65 years), sex, ethnicity, race, height, weight, and 
BMI, where weight is the measure before the first dose of UT-15C for the TDE-PH-311 study 
and height is obtained from the parent study.   
9.3.2 Baseline Characteristics 
Baseline characteristics include 6MWD, 6MWD category (≤380 m versus >380 m), Borg 
dyspnea score, and WHO Functional Class, and will be summarized by treatment group in the 
parent study and overall.  Baseline measures are defined as the last measurement prior to the 
first UT-15C dose in the TDE-PH-311 study. 


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9.3.3 PAH History 
The listing of PAH history will be organized by treatment group in the parent study, and will 
include the subject number, the date of initial PAH diagnosis, number of years since PAH 
diagnosis, etiology, WHO Functional Class at Baseline, 6MWD at Baseline, Borg dyspnea 
score at Baseline, background PAH therapy (endothelin receptor antagonist [ERA] alone, 
phosphodiesterase type 5 inhibitor [PDE-5I] alone, or soluble guanylate cyclase [sGC] 
stimulator alone), and background PAH medication name.  The number of years since PAH 
diagnosis will be calculated based on the first UT-15C dose date in the TDE-PH-311 study.  
The summary of PAH history will include descriptive statistics for years since PAH diagnosis 
and categorical summaries for etiology and background PAH therapy at randomization in the 
parent study. 
9.3.4 Concomitant Medications 
The listing of concomitant medications will be organized by treatment group in the parent 
study, and will include subject number, whether the subject has had any concomitant 
medications, and all concomitant medications (including PAH medications) that were 
reported on or after the date of the first UT-15C dosing in the TDE-PH-311 study.  The 
concomitant medications will be listed by verbatim term, WHO Drug Dictionary (WHO-DD) 
standard name, start and stop dates, condition treated/indication, whether the concomitant 
medication is ongoing from parent study, and whether or not the concomitant medication is 
ongoing at the end of the study.  Summaries will be provided for medications ongoing from 
the parent study and for those added in the TDE-PH-311 study.  Each summary will be 
provided by treatment group in the parent study and overall, and will include the number 
(percent) of subjects reporting each medication (based on the WHO-DD medication name) 
and the number of records for each medication.   
9.3.5 UT-15C Dosing  
In the TDE-PH-311 study, UT-15C dosing information will be collected on a monthly basis.  
A listing and a summary will be provided for UT-15C dosing.  The listing will be organized 
by treatment group in the parent study, and will include the subject number, dose recording 
date, and the actual dose (in milligrams) for morning, mid-day, and evening.  


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The UT-15C dose will be summarized by analysis visit.  The summary will also include the 
number and percent of subjects in each dose category by treatment group in parent study and 
overall.  The same summary table will be repeated by each background PAH therapy.  The 
dose categories include UT-15C drug dose (3 times daily [TID]) <1 mg, 1 to <2 mg, 2 to 
<4 mg, 4 to <6 mg, 6 to <8 mg, 8 to <10 mg, 10 to <12 mg, and ≥12 mg. 
10 EFFICACY ANALYSES 
10.1 6-MINUTE WALK TEST 
The listing of the 6MWT will be organized by treatment group in the parent study, and will 
include subject number, analysis visit, assessment date/time (day), last UT-15C dose 
date/time (day), the last UT-15C dose (in milligrams), hours from last UT-15C dose to 
6MWT, 6MWD results, Borg dyspnea scores, use of supplemental oxygen, and any 
circumstances affecting the 6MWT.  The summaries of 6MWD will be provided by treatment 
assignment in the parent study (UT-15C or placebo) by visit, PAH etiology (idiopathic, 
heritable, associated with connective tissue disease, and other), Baseline WHO Functional 
Class, and quartiles of the last UT-15C dose.  The summaries will include descriptive 
statistics for 6MWD measure at each analysis visit and the change from Baseline.  Baseline is 
defined as the last 6MWD measured prior to the first dose of UT-15C in the TDE-PH-311 
study.  
Achievement of a walk distance of at least 440 m by each analysis visit will be summarized 
by treatment group in the parent study and overall.  Achievers and non-achievers will then be 
summarized based on their Baseline walk (<=440 m vs >440 m) by treatment group in the 
parent study and overall. 
10.2 BORG DYSPNEA SCORE 
Borg dyspnea score information will be listed as part of the 6MWD.  The summary of the 
Borg dyspnea score will be provided by treatment group in the parent study.  The summaries 
will include descriptive statistics for measurements at each analysis visit and the change from 
Baseline values.  Baseline is defined as the last Borg dyspnea score measured prior to the first 
dose of UT-15C in the TDE-PH-311 study.  


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10.3 WHO FUNCTIONAL CLASS 
WHO Functional Class information will be listed by treatment group in the parent study, and 
will include subject number, analysis visit, assessment date (day), and WHO Functional 
Class.  The summaries of the WHO Functional Class will be provided by treatment group in 
the parent study.  The summaries will include descriptive statistics for measurements at each 
analysis visit and the change from Baseline values.  Baseline is defined as the last WHO 
Functional Class assessed prior to the first dose of UT-15C in the TDE-PH-311 study.  
11 SAFETY ANALYSES 
11.1 ADVERSE EVENTS 
AEs are captured from the time the Informed Consent Form is signed.  Any AEs that are 
ongoing at the Study Termination Visit from study TDE-PH-310 are recorded as continuing 
AEs in TDE-PH-311 study.  All AEs with an onset date on or after the first dose of UT-15C 
in the TDE-PH-311 study or AEs ongoing from the parent study will be included in data 
listing and summaries.  
The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and all summaries will utilize the Preferred Term (PT) and/or System Organ Class (SOC).  
All AEs and serious AEs will be organized by treatment group in the parent study, and listed 
by subject, including onset date (day), cessation date (day), verbatim term, corresponding PT 
and SOC, seriousness, date AE became serious, severity, frequency, relationship to study 
drug, action taken with study drug, and outcome.   
The overall summary of AEs includes the number of subjects with any AE, the number of 
subjects with any study drug-related AEs, the number of subjects with AEs leading to study 
drug withdrawal, the number of subjects with any serious AEs, the number of subjects with 
any severe AEs, and the number of subjects with any study drug-related severe AEs.  
The summaries of AEs by SOC and PT will be provided by treatment group in the parent 
study and overall.  The summaries of AEs, serious AEs, severe AEs, AEs probably or 
possibly related to UT-15C, serious AEs probably or possibly related to UT-15C, and AEs 


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leading to permanent discontinuation of UT-15C will include the number of subjects (percent 
of subjects) and number of events for each reported PT.   
The summary of AEs adjusted for UT-15C exposure will include the number of subjects 
(percent of subjects) and number of events for each reported PT, as well as the number of 
events per patient-year of exposure. 
11.2 DISEASE-RELATED EVENTS 
Disease-related events will be listed by the subject number, treatment group in parent study, 
and events (yes/no).  The summary will include the number (percent) of subjects who reported 
each symptom by treatment group in the parent study and overall.  Disease-related events 
include abdominal pain, anorexia, ascites, chest pain, cool extremities, cor pulmonale, cough, 
cyanosis, dizziness, dyspnea, general edema, hemoptysis, fatigue, hypoxia, loss of 
consciousness, nausea, orthopnea, pallor, palpitations/cardiac arrhythmia, paroxysmal 
nocturnal dyspnea, pulmonary hypertension exacerbation, syncope, tachycardia, weight 
loss/gain, vasovagal reaction, and vomiting.  
11.3 DEATHS 
All deaths will be listed (including those occurring within 30 days of the last UT-15C dose) 
by subject, and will include the subject number, treatment group in the parent study, date of 
assessment (day), whether subject died, date of death (day), and cause of death (including 
other, specify text [if applicable]).  An additional listing of deaths will include the subject 
number, first UT-15C dose in TDE-PH-311 study, last UT-15C dose (day) in TDE-PH-311 
study, date of death (day), and cause of death.  The summary of deaths will be presented by 
the parent study and overall and will include the number (percent) of subjects who died 
(including those within 30 days of study participation) and their causes of death. 
Time to death will be calculated as:  
(the death date – the date of the first UT-15C dosing in TDE-PH-311 study) 
The Kaplan-Meier (K-M) estimator will be provided for the time to death, and K-M plots will 
be provided by treatment group in the parent study. 


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11.4 CLINICAL LABORATORY TESTS 
Laboratory results will be mapped into the analysis visit based on the assessment date.  The 
laboratory data will be listed by subject and treatment group in the parent study, including all 
hematology and clinical chemistry parameters by analysis visit.  The listings will include the 
collection date/times (day), laboratory test, and results.  The normal laboratory reference 
ranges will be included in the listings.  A designation for low (L) or high (H) will be included 
for those laboratory values that are outside the relevant normal range.  The listing of 
urinalysis will also be presented by subject and the treatment group in the parent study, and 
will include each scheduled and unscheduled urinalysis assessment.  The laboratory sample 
collection date/time (day), laboratory test, normal range, designation for high or low, and 
analysis visit will be provided for each assessment, as well as the result of the test. 
For hematology and clinical chemistry parameters, the original values and their changes from 
Baseline (defined as the last measurement prior to the first dose of UT-15C in the 
TDE-PH-311 study) will be summarized for each analysis visit by the treatment group in the 
parent study and overall.  Shift tables will also be provided.  For urinalysis results, the number 
and percent of subjects within each category will be summarized for all analysis visits by 
treatment group in the parent study and overall.  
Pregnancy test results for the female subjects will be organized by treatment group in the 
parent study, and listed by subject number, analysis visit, and did the subject become pregnant 
during the study (yes/no).   
11.5 VITAL SIGNS 
Vital sign results will be mapped into the analysis visit based on the assessment date.  The 
vital sign data will be listed by subject and treatment group in the parent study for each 
analysis visit by assessment date/time (day), weight, heart rate, blood pressure, and respiration 
rate.  The original measures and their changes from Baseline (defined as the last measurement 
prior to the first UT-15C dosing in the TDE-PH-311 study), and descriptive statistics, will be 
summarized for all analysis visits by the treatment group in the parent study and overall.  


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12 APPENDICES 
12.1 LIST OF TABLES 
Table titles suggested here may be altered or edited as appropriate by the clinical data 
programmers while maintaining the original intent of the summary. 
Table Number 
Table Title 
14.1.1 
Summary of Subject Accountability 
14.1.2 
Summary of UT-15C Exposure 
14.1.3 
Summary of UTC Exposure in TDE-PH-310 and TDE-PH-311 Studies  
14.1.4 
Summary of Demographics 
14.1.5 
Summary of Baseline Characteristics 
14.1.6 
Summary of PAH History 
14.1.7 
Summary of Study Entry Criteria 
14.1.7.1 
Summary of UT-15C Dosing 
14.1.7.2 
Summary of UT-15C Dosing by Background PAH Therapy 
14.1.8.1 
Summary of Concomitant Medications Ongoing from the Previous Study 
14.1.8.2 
Summary of Concomitant Medications Added in TDE-PH-311 Study 
14.2.1.1 
Summary of 6MWD (meter) by Visit  
14.2.1.2 
Summary of Borg Dyspnea Score by Visit 
14.2.1.3 
Summary of 6MWD (meter) by PAH Etiology 
14.2.1.4 
Summary of 6MWD (meter) by Baseline WHO Functional Class 
14.2.1.5 
Summary of 6MWD (meter) by Quartiles of the Last UT-15C Dose 
14.2.1.6 
Summary of 6MWD Achieving > 440 Meters by Visit 
14.2.1.7 
Summary of 6MWD Achieving >440  Meters by Baseline 6MWD 
Category 
14.2.1.8 
Summary of WHO Functional Class by Visit 
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 Serious Adverse Events by Preferred Term 
14.3.1.4 
Summary of Severe Adverse Events by Preferred Term 
14.3.1.5 
Summary of Serious Adverse Events Probably or Possibly Related to 
UT-15C by Preferred Term 
14.3.1.6 
Summary of Adverse Events Probably or Possibly Related to UT-15C by 
Preferred Term 
14.3.1.7 
Summary of Adverse Events Leading to Permanent Discontinuation of 
UT-15C 
14.3.1.8 
Summary of Disease-Related Events 
14.3.1.9 
Summary of Adverse Events Adjusted for Length of UT-15C Exposure 
14.3.2.1 
Listing of Deaths 
14.3.2.2 
Summary of Deaths 
14.3.2.3 
Listing of Serious Adverse Events 


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Table Number 
Table Title 
14.3.4.1 
Summary of Hematology Data 
14.3.4.2 
Summary of Hematology Shifts from Baseline 
14.3.4.3 
Summary of Clinical Chemistry Data 
14.3.4.4 
Summary of Clinical Chemistry Shifts from Baseline 
14.3.4.5 
Summary of Urinalysis Data 
14.3.4.6  
Summary of Vital Signs 
12.2 LIST OF LISTINGS 
Listing titles suggested here may be altered or edited as appropriate by the clinical data 
programmers while maintaining the original intent of the listing. 
Appendix Number 
Listing Title 
16.2.1 
Subject Disposition and Study Drug Exposure 
16.2.2.1 
Entry Criteria 
16.2.2.2 
Protocol Deviations 
16.2.4.1 
Demographics 
16.2.4.2 
PAH History  
16.2.4.3 
Concomitant Medications  
16.2.5 
UT-15C Dose 
16.2.6.1 
6-Minute Walk Test and Borg Dyspnea Score Data 
16.2.6.2 
WHO Functional Class for PAH 
16.2.6.3 
Death Records 
16.2.6.4 
Disease-Related Events 
16.2.7 
Adverse Events 
16.2.8.1 
Laboratory Results – Clinical Chemistry 
16.2.8.2 
Laboratory Results – Hematology 
16.2.8.3 
Laboratory Results – Urinalysis 
16.2.8.4 
Pregnancy Test Results (Female Subjects Only) 
16.2.8.5 
Vital Signs 
12.3 LIST OF FIGURES 
Figure titles suggested here may be altered or edited as appropriate by the clinical data 
programmers while maintaining the original intent of the figure. 
Figure Number 
Figure Title 
14.2.1 
Kaplan-Meier Plot of Time to Death by Treatment Group in Parent Study