Conditions: Respiratory Distress Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 221
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the safety and efficacy of lucinactant for inhalation administered as an aerosolized dose in two doses to preterm neonates 26 - 32 weeks gestational age who are receiving nasal continuous positive airway pressure (nCPAP) for Respiratory Distress Syndrome (RDS) compared to neonates receiving nCPAP alone.

Detailed description:
The purpose of this study is to investigate the safety and efficacy of lucinactant for inhalation in preterm neonates 26 to 32 completed weeks post-menstrual age (PMA). Efficacy and safety are based on clinical evaluations. The endpoints specified are similar to those in Protocols 03-CL-1201 and 03-CL-1401 to allow for potential comparison and pooling of results.

The objective of this study is to evaluate the safety and efficacy of lucinactant for inhalation in conjunction with nCPAP, compared to nCPAP alone, in preterm neonates with RDS, as assessed by the time to and incidence of respiratory failure and/or death due to RDS over the first 72 hours of life, the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks PMA, and change in physiologic parameters (FiO2 and PCO2) over the first 72 hours of life.

Arms:
arm 1: Lucinactant for inhalation with nCPAP; up to 2 repeat doses will be allowed if repeat dosing criteria are met. arm 2: Lucinactant for inhalation with nCPAP; up to 2 repeat doses will be allowed if repeat dosing criteria are met. arm 3: nCPAP alone

Interventions: intervention 1: Lucinactant delivered via investigational delivery device intervention 2: nCPAP
Intervention descriptions: intervention 1: Lucinactant for inhalation refers to the active investigational agent lucinactant in combination with the investigational delivery device (drug-device combination product) intervention 2: Nasal CPAP

Protocol document:
ICF_002.pdf: 
Discovery Laboratories, Inc., Protocol Number 03-CL-1202, Amendment 1,  
Informed Consent Form 
Master_ICF_Final v1.2_25Feb2016 
Page 1 of 16 
WPD-SIA-01br00 
Effective Date: 13 January 2015 
 
 
 
INFORMATION for PARENTS/GUARDIANS of PARTICIPANTS 
 
NAME OF STUDY: 
A Multinational, Multicenter, Masked, Randomized, 
Controlled Study to Assess the Safety and Efficacy of 
Lucinactant for Inhalation in Preterm Neonates 26 to 32 
Weeks Gestational Age with Respiratory Distress 
Syndrome 
STUDY NUMBER: 
03-CL-1202 
STUDY SPONSOR: 
Discovery Laboratories, Inc. 
2600 Kelly Road, Suite 100 
Warrington, PA 18976 
STUDY DOCTOR (INVESTIGATOR): 
[Investigator Name] 
[Site Address] 
[Office Hours Tel] 
[Out of Hours Tel] 
[ETHICS COMMITTEE (EC) or 
INVESTIGATIONAL REVIEW BOARD (IRB):] 
[EC/IRB Name] 
[EC/IRB Address] 
[Office Hours Tel] 
[Out of Hours Tel] 
 
 
Why are you receiving this information? 
Your baby is eligible to participate in a research study. You, as a parent or legal guardian, have the right to know 
all the details about this research. When you understand these details, including all of the possible risks, hazards, 
or benefits involved, you may then decide whether or not your baby should participate in this study. This consent 
form will help you understand this study. It will also help you decide whether to give or withhold your consent 
to allow your baby’s participation in this research study. This informed consent does not replace any other 
informed consents you may have signed. 
 
You are being asked to consider whether you would like your baby to participate in a clinical research study. 
The following information describes the study and your baby’s role as a possible participant.  Please read this 
information carefully and do not hesitate to ask the study doctor any questions to ensure that you are able to 
make an informed decision as to whether you would like your baby to participate. 
 
You have been asked to take part because your baby was born approximately 8 to 14 weeks before your baby’s 
due date. Also, your baby is at a gestational age between 26 and 32 weeks and is receiving supplemental oxygen 
and breathing support by nasal continuous positive airway pressure (nCPAP). This is because your baby has 
suspected respiratory distress syndrome (RDS) and surfactant deficiency. 
 
 
 
What is the purpose of this clinical research study? 
Babies born before 36 weeks gestational age often develop breathing problems. One of the reasons for this is 
that their lungs are not fully able to make a substance called surfactant, which is a liquid that coats the surface of 
our lungs. Surfactants are natural chemicals in our lungs. Our bodies normally make surfactant in our lungs to 
help them work properly. Babies who are born early and who have too little surfactant may develop a lung 


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problem called respiratory distress syndrome, or RDS. Babies with RDS often need to be treated with oxygen 
and/or a breathing machine. If a baby needs a lot of support to help the baby breathe, the baby’s doctor may 
place a tube into the baby’s windpipe. This tube can be connected to a breathing machine. This tube can also be 
used to treat the baby with surfactant by delivering the surfactant as a liquid to the lungs. 
 
If a baby is breathing but needs a little support, then he or she may receive supplemental oxygen and continuous 
positive airway pressure (CPAP) through a pair of short tubes called nasal prongs. The nasal prongs fit into the 
baby’s nostrils. This type of support is called nasal continuous positive airway pressure (nCPAP). Babies who do 
not have a tube placed in their windpipe and instead receive nCPAP support do not get surfactant unless they 
develop more severe breathing problems. 
 
Babies with RDS who need supplemental oxygen and nCPAP for breathing support are at risk for developing 
more severe breathing problems and may require placing a tube in the baby’s windpipe and connecting that tube 
to a breathing machine. If this happens, the baby may also receive surfactant directly into the lungs through the 
tube in the windpipe. In some babies, the amount of supplemental oxygen decreases through the first day after 
birth. In other babies, the amount of supplemental oxygen needed may stay the same, or the baby may need 
increasing amounts of supplemental oxygen. The more supplemental oxygen the baby needs, the higher the risk 
that the baby will need a tube placed in the windpipe and be connected to a breathing machine. 
 
Aerosolized lucinactant is a synthetic (man-made) surfactant that is made by Discovery Laboratories, Inc. They 
have also designed a new device known as an Aerosurf Delivery System (ADS). This device heats the surfactant 
as it passes through a small tube called a capillary. As the liquid passes through the capillary, it becomes a fine 
mist, or aerosol. The ADS is an investigational device and is currently not approved for use to aerosolize 
medications. Aerosolized lucinactant delivered as a mist, or aerosol, using the ADS is an investigational drug-
device combination that is not approved for general use and can be used only in this research study. This 
investigational drug-device combination is being developed in order to be able to give surfactant to babies with 
RDS who need supplemental oxygen and nCPAP for breathing support without having to place a tube in the 
baby’s windpipe. 
 
The purpose of this study, which involves research of an investigational drug-device combination, is to evaluate 
the safety and tolerability of two different doses of an aerosolized surfactant (lucinactant mist, or aerosol) 
delivered using the investigational ADS device in babies with RDS who are being treated with supplemental 
oxygen and nCPAP. 
 
Lucinactant, in the form of a liquid, has been approved by the United States Food and Drug Administration 
(FDA). Lucinactant is delivered through a tube in the baby’s windpipe for the prevention of RDS in premature 
babies at severe risk for RDS. The Sponsor no longer makes the liquid form of lucinactant.  The experimental 
portion of this study is the use of lucinactant as a mist or aerosol in combination with the aerosol delivery 
system, in babies being supported with supplemental oxygen and nCPAP. 
 
It is expected that approximately 240 babies will be enrolled in this study. 
 
What makes this different from the usual treatment? 
Usually when babies require surfactant to help them breathe, the doctor places either a breathing tube or other 
small tube into the windpipe and puts the surfactant directly into the lungs through the tube. In this study, the 
baby will receive lucinactant, a surfactant, as a mist, or aerosol, through the nasal prongs. The amount of 
surfactant delivered to the baby will be less than what is typically delivered as a liquid through a tube in the 
windpipe. 


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Aerosolized lucinactant delivered as a mist, or aerosol, and the ADS are currently being used together in two 
other studies in babies of a different gestational age who also have RDS. 
 
How long will your baby be in the trial? 
The duration of the study intervention will be approximately 2-3 days. Your baby will continue to have their 
health information collected while he or she is in the hospital, until he or she reaches approximately 36 weeks 
gestational age.  After that,  the study doctor or a member of the site research team will contact you around your 
baby’s 6 month corrected-age to ask you about how your baby is doing. Also around your baby’s 1 year 
corrected-age, the site research team will request that you visit the study site again so the study doctor can 
perform a brief physical and a developmental exam. The 6 month and 1 year corrected-age  means 
approximately6 months and 1 year after the baby was due to be born, not when they were born 
 
What procedures are involved? 
If your baby requires more than a small amount of supplemental oxygen and is receiving nCPAP, your baby will 
be randomly chosen to receive either continued nCPAP with lucinactant for inhalation (study drug) or continued 
nCPAP alone. Your baby will also get the usual treatment and care given to all babies who are born before 36 
weeks gestational age at this hospital. All babies will be monitored with a transcutaneous carbon dioxide 
monitor, which is a heated sensor that measures carbon dioxide, or CO2, which is an indicator of how well the 
baby is breathing.  The carbon dioxide is measured through the skin so that it is not necessary to keep taking 
blood from the baby to measure his/her carbon dioxide. 
 
If your baby is chosen to receive study drug, your baby will receive one of two doses of the aerosolized 
lucinactant as a mist, or aerosol. The amount of aerosolized lucinactant your baby will receive will depend on 
which dose group your baby is assigned to. 
 
• 
Group 1 – aerosolized lucinactant (40 mg total phospholipids [TPL]/kg) for 25 minutes in conjunction 
with nCPAP (80 babies) 
 
• 
Group 2 – aerosolized lucinactant (80 mg TPL/kg) for 50 minutes in conjunction with nCPAP (80 babies) 
 
• 
Group 3 (Control Group) – continuous nCPAP alone (80 babies) 
 
Some of the lucinactant aerosol will not reach the baby’s lungs. It is possible that none of the lucinactant aerosol 
will reach the lungs. 
 
If your baby continues to experience difficulty breathing in the first 24 hours after receiving lucinactant for 
inhalation, your baby may receive  up to two additional doses of lucinactant that are equal to the first dose. 
 
Whether your baby gets nCPAP with lucinactant for inhalation or continuous nCPAP alone depends on a 
computer numbering system. This system chooses subjects by chance (like the flip of a coin). There is a 2 in 3 
chance that your baby will receive lucinactant for inhalation.  If you have twins, your babies will be randomized 
separately, so they may be in different study groups. 
 
Regardless of whether the baby gets nCPAP with lucinactant for inhalation or continuous nCPAP alone, if your 
baby develops more severe breathing problems, your baby’s doctor may place a tube in your baby’s windpipe 
and connect that tube to a breathing machine and may also give your baby liquid surfactant directly in your 
baby’s lungs through the tube in the windpipe. All babies enrolled in this research study will receive all routine 


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care and procedures regardless of whether the baby gets nCPAP with lucinactant for inhalation or continuous 
nCPAP alone. 
 
An independent safety review committee will review the study data at two times during the study.   All active 
completed assessments and procedures through 72 hours for enrolled patients will be reviewed.   Enrollment 
will continue throughout each review unless the committee recommends otherwise. 
 
This is a masked study. This means neither you will not know whether your baby receives continuous nCPAP 
with lucinactant for inhalation (study drug) or continuous nCPAP alone.  Alsoyour baby’s doctor or your study 
doctor may not know whether your baby receives continuous nCPAP with lucinactant for inhalation (study drug) 
or continuous nCPAP alone. Specific health care staff who have been educated and trained to use both the drug 
and the ADS will be assigned to prepare and give your baby’s treatment. The care your baby receives will not be 
affected by whether he or she receives aerosolized lucinactant. 
 
 
 
If you decide to allow your baby to participate in this study, you will be required to sign this Informed Consent 
Form.  Your medical records (related to your baby’s birth) will be reviewed, and your baby’s medical records 
will be reviewed. 
 
Your baby will have a physical exam and a chest x-ray done to see if he or she qualifies to be in the study.  In 
order for your baby to be considered for this study, he or she must be supported by supplemental oxygen and 
nCPAP for at least 30 minutes. The following procedures will be conducted if your baby qualifies for the study. 
 
1)   Lucinactant, a surfactant, is made into a mist, or aerosol, by the ADS 
2)   If your baby is assigned to receive lucinactant, your baby will receive his/her dose of aerosolized lucinactant 
as a mist, or aerosol, through nasal prongs placed in your baby’s nostril for the nCPAP. The nasal prongs 
and the CPAP machine used will both be devices that are commercially available and indicated for use in 
infants. 
3)   A tube, called an orogastric or nasogastric tube, will be placed through your baby’s mouth or nose and into 
his/her stomach to prevent too much air from accumulating in the stomach. This is often done for babies 
receiving CPAP alone. 
4)   Before, during, and after each dose of study drug, your baby’s vital signs, blood oxygen level, and 
nCPAP settings will be checked and documented. These assessments are part of the routine hospital care of 
babies born early. 
5)   Two blood samples will be taken: one blood sample to calibrate the transcutaneous monitor that records 
your baby’s carbon dioxide levels and one blood sample to measure sodium, chloride, potassium, and carbon 
dioxide levels. These samples will be taken from a catheter if the catheter is already in a blood vessel. A 
catheter is a device that is inserted into a blood vessel for a temporary period of time, that is used to help 
doctors, nurses, and other medical staff have access to draw blood more easily.  If there is no catheter in a 
blood vessel, or the catheter cannot be used to draw blood, the blood sample will be drawn from a vein by 
temporarily placing a needle into the vein, or by collecting the blood from a pinprick in the heel. The total 
amount of blood taken will be less than a quarter of a teaspoon, and your baby’s carbon dioxide level will 
continue to be monitored using the transcutaneous monitor and not by taking and testing the baby’s blood. 
6)   Your baby will be monitored and his or her vital signs, blood oxygen levels, and nCPAP settings will be 
checked and documented while in the hospital and up to 36 weeks gestational age. 
7) The number of stools in the first 24 hours following treatment group assignment will be recorded. 
8)  One additional chest x-ray may be done for the study if your child requires intubation (breathing tube 
placement) or if your baby is having increased respiratory problems. 


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9)    When  your baby reaches  36  weeks  gestational age,  or  is  discharged  or  transferred from the  hospital 
(whichever comes first), your baby will have a brief physical exam. 
10)  At 6 months corrected age, someone from the study team will contact you to ask you about if your baby has 
been in the hospital and if your baby has needed help with breathing.  You will also be asked about medications 
that your baby has taken. 
11)  At 1-year corrected age, your baby will be seen by the study team.  A physical exam and developmental exam 
will be done during that visit.  The study team will also ask you if your baby has been in the hospital and if your 
baby has needed help with breathing.  You will also be asked about the medications that your baby has taken. 
 
 
What will happen at the end of the study? 
After the study drug is stopped, your study doctor will decide what continued medical treatment your baby 
should receive. The care your baby receives will not be affected by whether he or she receives study drug. 
 
Following the end of the study, or after you have withdrawn your baby from the study before its conclusion if 
you decide to do so, your study doctor (or appointed delegate) may seek to establish your baby’s long term 
health status for a period of not more than 16 months, by accessing your baby’s hospital records, or publicly 
available sources such as national registries, newspaper obituaries and social networking websites.  Attempts 
may also be made to contact you or your relatives to ascertain this information.  If you do not want this 
information about you to be collected, you may record your objection with your study doctor at any time. 
 
What are the potential risks and discomforts? 
Babies who are born preterm are at risk for different complications related to preterm birth. The degree of risk is 
different for every baby and depends on several factors. These risks are present whether your baby participates 
in this study or not. Your baby’s doctor or the study doctor can talk to you about these risks. 
 
Babies who have RDS and who require supplemental oxygen and nCPAP for breathing support are at risk for 
developing more severe breathing problems that may require placing a tube in their windpipe and connecting 
that tube to a breathing machine. If this happens, your baby’s doctor may also decide to give your baby 
surfactant directly in your baby’s lungs through the tube in the windpipe. This risk is present whether your baby 
participates in this study or not. Your baby’s doctor or the study doctor can talk to you about these risks. 
 
Lucinactant for inhalation is an investigational drug-device combination that is being tested in humans. This 
means there may be unknown risks to your baby. It also means it is not known whether this drug will be of any 
benefit to your baby or make your baby’s problem worse. In previous studies in babies born as early as 26 weeks 
gestation, lucinactant, given as a liquid into a tube in the baby’s windpipe, did not increase the risk of babies 
developing complications or dying. 
 
Previous research in babies has shown that when lucinactant is delivered as a liquid through a tube in the baby’s 
windpipe, side effects commonly reported (10 or more people out of 100) or less likely reported (between 1 and 
9 people out of 100) include the following: 
Commonly reported (10 or more people out of 100; between 10% and 55%): 
• 
Oxyhemoglobin desaturation (a decrease in the oxygen level in the blood for a short period of time), 
• 
Apnea (stopping breathing for a few seconds), and 
• 
Bradycardia (a slowing of the heart). 
Less likely reported (between 1 and 9 people out of 100; less than 10%): 
• 
Gagging, which might occur when the surfactant first goes into the large airways of the lung, 
• 
Vomiting when drug is given, and 


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• 
Pallor (a lack of color in your baby’s skin). 
 
These side effects are generally seen with most of the surfactants used currently for respiratory diseases. These 
events may require your baby’s doctor and/or the study doctor to stop giving the study drug. Your baby’s doctor 
and/or the study doctor will stop treatment at any time if it is in your baby’s best interest. 


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Lucinactant, a surfactant, will be given after it has been made into a mist, or aerosol, using the ADS, an 
investigational device which has been specifically made to produce a lucinactant mist that contains very small 
particles of lucinactant. Delivering lucinactant as a mist may decrease the side effects described above, although 
this is not known for sure at this time. 
 
It is possible that your baby may not tolerate the delivery of the lucinactant mist and may develop some of the 
side effects listed above. Your baby will be monitored during the delivery of the lucinactant mist, and if your 
baby is not tolerating the delivery of the lucinactant mist, your baby’s doctor will stop the investigational 
treatment. 
 
It is possible that the lucinactant mist may partially or totally clog the inside of the nasal prongs. Your baby will 
be monitored during the delivery of the lucinactant mist and the caretakers will check the prongs during the 
delivery of the aerosolized lucinactant. 
 
To generate the mist, lucinactant is heated as it passes through the ADS. Although the device has been designed 
to generate a mist with a temperature that is safe for your baby, if the temperature safety controls of the device 
fail, it is possible that the mist might be too hot for your baby. 
 
The lucinactant mist carries a significant amount of fluid, and there is a potential risk that your baby would get 
too much fluid as a result of the investigational treatment.  A blood sample will be taken to measure the sodium, 
chloride, potassium, and carbon dioxide levels to check to see if your baby received too much fluid. 
 
A transcutaneous monitor will be placed on your baby prior to receiving the study drug and for at least 72 hours 
after. Such a monitor is frequently used for preterm infants to measure carbon dioxide levels. The use of this 
monitor may cause some temporary irritation on the skin of your baby and, rarely, can produce a burn. The skin 
irritation, if it happens, will go away soon after the monitor is removed. 
 
All babies enrolled in this study are required to be on nCPAP. This is a standard of care for babies who have 
respiratory distress. The  nCPAP devices used in this research study are commercially available and indicated 
for use in infants. The risks of nCPAP are minor, and include the following: 
 
• 
Excess air in the stomach, 
• 
Redness or irritation of the nose from the nasal prongs used to provide nCPAP, and 
• 
Congestion or runny nose. 
• 
Pneumothorax 
 
Your baby’s breathing problem may get worse over time, regardless of whether your baby receives nCPAP plus 
lucinactant for inhalation or continuous nCPAP alone. If your baby’s doctor decides that your baby needs more 
help breathing, your baby’s doctor may decide to place a tube in your baby’s windpipe and connect that tube to a 
breathing machine. Your baby’s doctor may also decide give your baby liquid surfactant directly in your baby’s 
lungs through the tube in the windpipe. This surfactant may be different from the lucinactant used in this study. 
 
As part of the study, a tube will be placed temporarily into the stomach, through either the mouth (orogastric) or 
nose (nasogastric). Orogastric and nasogastric tubes are generally very safe and effective. However, even if it is 
placed gently, this tube can irritate the nose, mouth, or stomach and cause some (usually minor) bleeding. If 
placed in the nose, it may cause some nasal stuffiness and occasionally a nasal infection. 


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Obtaining blood samples from babies born early is part of usual care. Obtaining blood samples is done using 
sterile materials and established techniques. Possible side effects from blood drawing include the following: 
• 
irritation of the vein, such as redness or swelling, 
• 
pain, and 
• 
bruising or bleeding at the blood draw site. 
There is also a slight possibility of infection. 
 
Your baby will be closely watched by his or her doctor and health care staff during the study. From the time of 
enrollment to the end of the study, all babies enrolled will be monitored for all possible side effects, and 
especially for signs that the baby’s breathing problem is getting worse. The performance of the investigational 
ADS device will also be monitored. This information will be closely followed by the Sponsor’s doctors. They 
will review the safety of the babies taking part in this study on an ongoing basis. An independent Safety Review 
Committee (also known as a Data Monitoring Committee) will also oversee this study and review this 
information. This committee is comprised of doctors who are not employed by the Sponsor. This committee will 
advise the Sponsor about the safety of current and future study subjects. They will also evaluate the ongoing 
scientific strength of the study. 
 
 
 
What are the advantages and disadvantages of participation in the study? 
As with any investigational product, there is no guarantee this treatment will help all or any of the babies in the 
study. New information about the benefits and safety of aerosolized lucinactant will be obtained from your 
baby’s participation in this study. This new information may benefit other babies in the future if aerosolized 
lucinactant  is  shown  to  be  safe  and  effective  in  babies  with  respiratory  distress  syndrome  who  require 
supplemental oxygen and nCPAP. 
 
Are there any alternative treatments? 
If you do not wish your baby to take part in the research, your baby will be provided with the established 
standard treatment available at this center. Babies diagnosed with respiratory distress syndrome usually receive 
nCPAP and sometimes receive liquid surfactant through a tube placed in the windpipe. Your study doctor will 
discuss these treatments with you. 
 
Will you be informed if new information becomes available during the study? 
The study doctor will inform you in a timely manner of any new information learned during the study that may 
affect your willingness to continue your baby’s participation. 
 
Who can you contact with further questions? 
You may ask questions about this consent form or the study at any time (before or during the course of the 
study).  If you have additional questions, or your baby experiences a research-related injury, contact the study 
doctor using the details provided in the table on the first page of this information sheet. 
 
If you have a complaint or question about your baby’s rights as a research subject, you may contact the [Ethics 
Committee (EC) or Institutional Review Board (IRB)] using the details provided in the table on the first page of 
this information sheet. This is a group of scientific and non-scientific individuals who review research studies 
with the safety and welfare of research subjects in mind. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by US Law. 
This Web site will not include information that can identify you/your baby.  At most, the Web site will include a 


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summary of the results. You can search this Web site at any time. This web site only shows data in English, but 
you can request information from the study staff at any time and have access to data that are publicly available. 
 
What happens if you change your mind? 
 
Your baby’s participation in this study is voluntary.  You do not have to allow your baby to take part, and you 
may discontinue your baby’s involvement at any time without penalty or loss of benefits to which you or your 
baby are otherwise entitled.  Refusing to allow your baby to participate will not affect your treatment or your 
baby’s treatment at this center in any way. You and your baby will still have all the benefits that you would 
otherwise have at this center. You may withdraw your baby from participating in the research at any time that 
you wish without either you or your baby losing any of your rights as a patient here. Neither your treatment nor 
your baby’s treatment at this center will be affected in any way. If you enroll your baby in this study and then 
later withdraw your baby from this study, any information obtained while your baby was enrolled in the study 
may be used to evaluate the safety and tolerability of aerosolized lucinactant. 
 
If you decide to leave the study before your baby has completed the study, tell the study doctor and follow 
instructions. It may be helpful if you could explain your reasons.  You may receive standard treatment and no 
prejudice will be shown towards you for medical care or participation in future research. 
 
In addition, the study doctor or the the Sponsor may withdraw your baby from the study for his or her own 
safety, even if you wish your baby to continue to participate, for example: 
• 
If your baby needs additional medication 
• 
If your baby experiences a study-related injury 
• 
If you do not follow the study rules 
 
If your baby’s participation in the study is stopped early, you may be asked to allow end of study procedures 
(such as a final medical examination and laboratory tests) to be completed on your baby, for your baby’s own 
safety. 
 
The remaining ICF content varies based on region-specific legislation & practices (see Text Conventions). 
•  The Master ICF must include & adapt the sections for ALL regions to be involved in the study. 
•  Country/Site-Specific ICFs must delete information not relating to their region. 
 
EMEA: 
Are there any costs if you decide to participate? 
You will not receive payment for allowing your baby to participate in this study, but the study drugs will be 
made available to you and your baby at no charge and you will not be required to pay for any study procedures. 
 
Who is funding this research? 
Discovery Laboratories, Inc. (a biotechnology company), will be organizing and funding this study.  Discovery 
Laboratories, Inc. will pay your baby’s study doctor and/or the study site to cover their costs of conducting this 
study. If applicable, your study doctor will disclose to you any financial links or other interests that he/she may 
have to the Sponsor. 
 
Are you insured when you participate in the study? 


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If your baby is injured because of his orher participation in this study, you will be entitled to receive 
compensation in accordance with [national] legislation.  Your baby’s study doctor will explain how you can 
obtain a copy of these guidelines. 
 
How will your confidentiality be respected and the privacy of your personal information maintained? You 
have the right to control the use and disclosure of your personal information and your baby’s personal 
information.  Basic personal information will be recorded including your and your baby’s name, contact details, 
gender, height, weight and racial origin (to be used only for clinical purposes), as well as information on your 
and your baby’s medical history, and clinical data collected about your baby’s participation in the study.  The 
following people may also access these records: 
• 
Study monitors and auditors, who may work for Discovery Laboratories, Inc. or its authorized 
representatives, who check that the study is being performed correctly and that the information collected 
about you and your baby is accurate; 
• 
The Ethical Committee that approved this study and ensures that your baby’s rights and well-being are 
safeguarded; 
• 
National and international regulatory authorities involved in keeping research safe for participants. 
All personnel accessing your and your baby’s records are required to respect your and your baby’s 
confidentiality at all times. 
 
To ensure privacy, your and your baby’s name and other identifying information will not be attached to records 
or samples released for research purposes.  Instead, your baby will only be identified by a code.  Only the study 
doctor and authorized personnel will be able to connect this code to your and your baby’s name, by a list that 
will be kept securely by the study site for "[insert retention period]" years.  Your baby’s date of birth may also 
be recorded to help identify your baby’s study record. Your baby’s coded data will be forwarded to Discovery 
Laboratories, Inc. and its service providers for activities related to the study e.g. laboratory analysis. It will be 
transferred into a computer database and processed to allow the results of this study to be analyzed and reported 
or published. If the results of the study are published, your and your baby’s identities will remain confidential. A 
list of companies to whom your coded information is transferred is available from Discovery Laboratories, Inc. 
via your study doctor. 
 
• 
* Delete sentence in bold unless PPD is contracted as privacy representative.  This wording should be 
incorporated in the country-specific ICFs for the relevant EU countries in the studies where PPD has this 
role. The list of studies where we are contracted, or about to be contracted in a study as representative is 
available at http://intranet.ppdi.com/policies_procedures/Data_Privacy_Rep_Service.htm If you are 
unsure, check with study PM which EU countries PPD acts in this role. 
• 
If PPD is not appointed, please make sure that the non-EU based Client Company is aware of the data 
protection law requirements of 1) appointing a privacy representative in each Member State and 2) 
mentioning its identity in the ICF. If Client Company has not appointed any privacy representative and/or 
doesn’t want to mention it in the ICF, this point can be omitted. Client Company is liable. 
Under data protection law [identification of national law] your study site and [Client Company legal entity 
name] shall be jointly responsible as ‘controllers’ for ensuring that your information is safeguarded. Discovery 
Laboratories, Inc. has appointed [PPD local company name] as its ‘representative’ in your country to fulfill its 
obligations under this law. You have the right to access, through your baby’s study doctor, all the information 
collected about you and your baby and, if applicable, ask for corrections. But, in order to protect the scientific 
integrity of the study, the treatment your baby received in this study needs to remain unknown (= masked) until 
the study data is analyzed. Recipients of your baby’s information may be in countries that do not have data 


Discovery Laboratories, Inc., Protocol Number 03-CL-1202, Amendment 1,  
Informed Consent Form 
Master_ICF_Final v1.2_25Feb2016 
Page 11 of 16 
WPD-SIA-01br00 
Effective Date: 13 January 2015 
 
 
 
protection safeguards and rights. [Client Company] and its authorized representatives, and regulatory 
authorities, shall anyway seek to maintain confidentiality within the limits of local laws in these countries. 
 
If you should withdraw your baby from the study, data collected prior to your withdrawal may still be processed 
along with other data collected as part of the study.  Normally no new information will be collected for the study 
database unless you specifically consent to that. However, the law does require that any side effects your baby 
may suffer are documented and reported. To complete the study findings, your baby’s long term health status 
may also be recorded (unless you object). You have the right to require that any previously retained samples are 
destroyed. 
 
• 
For signature page 
What will happen to your baby’s data? 
This clinical study may only be performed by collecting and using your baby’s medical information. Data 
protection laws give you the right to control the use of your personal information. Therefore, by signing this 
form you specifically authorize your baby’s information to be checked, transferred and processed as follows: 
• 
The authorized representatives of Discovery Laboratories, Inc., the Ethics Committee and regulatory 
authorities’ inspectors may review your baby’s medical information by direct access to your baby’s medical 
records. 
• 
Study data, including your baby’s coded medical information, may be used and shared for legitimate study 
and scientific purposes, including if you do not object, for future use in medical or pharmaceutical research. 
• 
Study data may be transferred to other countries for processing, including countries not covered by the data 
protection legislation. 
 
Has the study received medical or ethical approval? 
The Ethics Committee has given this study a positive opinion. 
 
 
 
 
 
 
 
 
 
NORTH AMERICA: 
Are there any costs if you decide to participate? 
The study drugs will be made available to your baby at no charge and you will not be required to pay for any 
study procedures. You or your insurance company may be billed for any standard medical care that is not 
required for the research study. 
 
Is there a payment if you decide to participate? 
You will not receive payment for participating in this study, but the study drugs will be made available to you at 
no charge and you will not be required to pay for any study procedures. 
 
Will you receive compensation if your baby is injured as a result of the study? 
If your baby is injured because of his or her participation in this study, treatment for the injury will be made 
available through [name of physician] and [institution]. The Sponsor will pay the costs of this treatment not paid 
by your medical insurance. No other payment is available from the Sponsor or the study doctor in the event of 


Discovery Laboratories, Inc., Protocol Number 03-CL-1202, Amendment 1,  
Informed Consent Form 
Master_ICF_Final v1.2_25Feb2016 
Page 12 of 16 
WPD-SIA-01br00 
Effective Date: 13 January 2015 
 
 
 
injury.  You are not waiving any legal rights by signing this form, accepting medical care or accepting payment 
for medical expenses. 
 
Will the personnel involved in the study receive any payment? 
The [institution] receives payment from Discovery Laboratories, Inc. who is the Sponsor of this study. 
 
•   The next section is applicable to the United States ONLY.  Remove this section if customizing ICF for 
Canada. 
What will happen to your baby’s data? 
•   Ensure statement regarding identifying information is correct for each study 
•   Please note: If sites are located in California, the HIPAA authorization must be separate from the ICF (at the 
end of the ICF document) with a separate signature and 14-point font under California’s medical privacy 
laws. See  CA template. 
 
This research study may be performed only by collecting and using your baby’s medical information.  Your 
baby’s study records will be kept as confidential as possible.  Only a number will be used to identify your baby. 
You or your baby will not be personally identified in any reports or publications that may result from this 
research study. 
 
Because of the research goals of this study, however, your study records cannot be kept completely confidential. 
The Sponsor of this study is Discovery Laboratories, Inc. 
 
The study personnel, the Sponsor and its agents and PPD will need to review the medical information collected 
from your baby for use in this study in order to accurately record information for this study.   In addition, in 
order to review the study findings, the U.S. Food and Drug Administration (FDA) and other regulatory agencies 
may review your baby’s medical records. The following sections provide a specific description of how your 
baby’s information will be used and disclosed if you consent for your baby to participate in this research study. 
By signing this consent form, you are authorizing such access. If you do not sign this form to authorize access, 
your baby will not be able to participate in this research study. 
 
The medical information that will be collected from you and your baby if your baby participates in the study 
includes: 
• 
Information obtained from procedures to determine your baby’s eligibility to participate in the study, 
including a routine medical history, physical exam, x-rays, and blood and breathing tests. 
• 
Information that is created or collected from your baby during your baby’s participation in the study, 
including the results of the tests included in the previous bullet point and any other procedures performed 
during the study. 
• 
Information contained in your baby’s underlying medical records related to your baby’s medical history and 
treatment. 
 
The above information may identify you and/or your baby by name, address, telephone number, social security 
number, health plan number, study number, date of birth, dates relating to various medical procedures, and/or 
other identifying information. 
 
If you sign this form and allow your baby to participate in the study, the study personnel will be authorized to 
use the information described above to carry out the purposes of the research study.  The study personnel will 
also be authorized to disclose the relevant information described above to the following parties involved in the 
research study: 
• 
Discovery Laboratories, Inc., PPD or other agents designated by Discovery Laboratories, Inc. to collect or 
review study data for verification of study procedures and/or adverse event reporting. 


Discovery Laboratories, Inc., Protocol Number 03-CL-1202, Amendment 1,  
Informed Consent Form 
Master_ICF_Final v1.2_25Feb2016 
Page 13 of 16 
WPD-SIA-01br00 
Effective Date: 13 January 2015 
 
 
 
• 
The Institutional Review Board (IRB) or Independent Ethics Committee (IEC) that oversees the research 
study at your site. 
• 
Government regulatory agencies including the FDA. 
 
Once your baby’s information is disclosed to the study Sponsors, its agents, the IRB/IEC or government 
agencies as described above, there is a potential that your baby’s medical information will be re-disclosed and 
will no longer be protected by U.S. federal privacy regulations.  In addition to disclosures to the entities 
identified above, PPD may further electronically disclose your coded health information to others involved in the 
research study, such as: 
 
• 
To laboratories or offsite testing facilities for clinical tests required by study protocols. 
• 
To approved offsite storage facilities or cloud service providers to meet study record retention and storage 
requirements. 
• 
To Discovery Laboratories, Inc., who will direct the research study. 
• 
To other third parties contracted by PPD and/or Discovery Laboratories, Inc., to provide services related to 
study. 
 
The study data may be transferred to other countries for processing, including countries not covered by data 
protection legislation. The laws of your state may provide further protection. 
 
While the study is in progress, your access to your baby’s study records will be temporarily suspended.  You 
will be able to access your baby’s information when the research study is completed.  You have the right to see 
and copy the medical information collected from your baby in the course of the study for as long as that 
information is maintained by the study personnel and other entities subject to federal privacy regulation. 
 
• 
*Edit the expiration date in the 2nd sentence of this paragraph if a specific date of expiration is required by 
state law (e.g., CA, MN, IL) 
Study data, including your coded medical information, may be used and shared for pharmaceutical research 
purposes related to this study. This authorization has no expiration date.  In signing this form, you authorize the 
use and disclosure of your baby’s information for purposes of the study at any time in the future. 
 
 
You may withdraw your authorization at any time by sending a written request to [insert name of responsible 
study personnel] at [insert address]. If you withdraw your authorization, data collected prior to your withdrawal 
may still be processed along with other data collected as part of the study.  Normally no new information will be 
collected for the study database unless you specifically authorize that.  However, the law does require that any 
side effects your baby may suffer are documented and reported. To complete the study findings, your baby’s 
long term health status may also be obtained from public sources. 
 
•   The next section is applicable to the Canada ONLY.  Remove this section if customizing ICF for United 
States. 
How will your confidentiality be respected and the privacy of your personal information maintained? 
You have the right to control the use and disclosure of your and your baby’s personal information. Basic 
personal information will be recorded, including your baby’s name, contact details, gender, height, weight and 
racial origin, as well as information on your baby’s medical history, and clinical data collected about your 
baby’s participation in the study.  Your baby’s confidentiality will be respected and no information that discloses 
you or your baby’s identity will be published without consent unless required by law.  However, your baby’s 
records may be given to and inspected by the following people: 


Discovery Laboratories, Inc., Protocol Number 03-CL-1202, Amendment 1,  
Informed Consent Form 
Master_ICF_Final v1.2_25Feb2016 
Page 14 of 16 
WPD-SIA-01br00 
Effective Date: 13 January 2015 
 
 
 
• 
Study monitors and auditors, who may work for Discovery Laboratories, Inc., or its authorized 
representatives, who check that the study is being performed correctly and that the information collected 
about you is accurate; 
• 
Ethical committee that approved this study and ensures that your rights and well-being are safeguarded; 
• 
Health Canada/Public Health Agency of Canada senior officials, and the REB members, for the purpose of 
monitoring the study. 
 
To ensure privacy, your and your baby’s name and other identifying information will not be attached to records 
or samples released for research purposes.  Instead, your baby will only be identified by a code. Only the study 
doctor and authorized personnel will be able to connect this code to your baby’s name.  Your baby’s coded data 
will be forwarded to Discovery Laboratories, Inc., and its service providers for activities related to the study (e.g. 
laboratory analysis). It will be transferred into a computer database and processed to allow the results of this 
study to be analyzed and reported or published. If the results of the study are published, your and your baby’s 
identity will remain confidential. 
 
Under federal data protection law, The Personal Information Protection and Electronic Documents Act (PIPEDA) 
and regional specific regulations, your study site shall be responsible for ensuring that your information is 
safeguarded. You have the right to access, through your study doctor, all the information collected about you and 
your baby and, if applicable, ask for corrections. But, in order to protect the scientific integrity of the study, the 
treatment your baby received in this study needs to remain unknown (i.e., masked) until the study data is 
analyzed.  Recipients of your information may be in countries that do not have data protection safeguards and 
rights.  Discovery Laboratories, Inc., and its authorized representatives, and regulatory authorities, shall anyway 
seek to maintain confidentiality within the limits of local laws. 
 
If you should withdraw your baby from the study, data collected prior to your withdrawal may still be processed 
along with other data collected as part of the study.  Normally no new information will be collected for the study 
database unless you specifically consent to that. However, the law does require that any side effects your baby 
may suffer are documented and reported. To complete the study findings, your baby’s long term health status 
may also be recorded (unless you object). You have the right to require that any previously retained samples are 
destroyed. 
 
•   The next section is applicable to the Canada ONLY.  Remove text if customizing ICF for United States. 
 
• 
For signature page 
What will happen to your baby’s data? 
This clinical study may only be performed by collecting and using your baby’s medical information. Therefore, 
by signing this form you specifically authorize your baby’s relevant information to be checked, transferred and 
processed as follows: 
• 
The authorized representatives of Discovery Laboratories, Inc., the Ethics Committee and regulatory 
authorities’ inspectors may review your baby’s medical information by direct access to your baby’s medical 
records. 
• 
Study data and all specified study-related documents, including your baby’s coded medical information, will 
be stored for a minimum of 25 years and may be used and shared for legitimate study and scientific purposes 
during this time. 
 
LATIN AMERICA: 
Are there any costs if you decide to participate? 


Discovery Laboratories, Inc., Protocol Number 03-CL-1202, Amendment 1,  
Informed Consent Form 
Master_ICF_Final v1.2_25Feb2016 
Page 15 of 16 
WPD-SIA-01br00 
Effective Date: 13 January 2015 
 
 
 
The study drugwill be made available to your baby at no charge and you will not be required to pay for any 
study procedures. You may be billed for any standard medical care that is not required for the study. 
 
Is there a payment if you decide to participate? 
You will not be paid to participate in this study. 
 
Will you receive compensation if your baby is injured as a result of the study? 
If your baby is injured because of your participation in this study, treatment for the injury will be made available 
through your study doctor and this institution. The Sponsor will pay the costs of this treatment [as well as the 
indemnification to which you would be legally entitled if you require it]. No other payment is available from the 
Sponsor or the study doctor in the event of injury.  You are not waiving any legal rights by signing this form or 
accepting medical care. 
 
How will your confidentiality be respected and the privacy of your personal information maintained? 
•   Data Protection is defined by national law; please refer to the ICF Country Specific Guidelines document for 
details.  In the case of any discrepancy, national laws supersede the standard template text 
Basic personal information will be recorded including your and your baby’s name, contact details, gender, 
height, weight and racial origin, as well as information on your baby’s medical history, and clinical data 
collected about your baby’s participation in the study.  The following people may also access these records: 
• 
Study monitors and auditors, who may work for Discovery Laboratories, Inc., or its authorized 
representatives, who check that the study is being performed correctly and that the information collected 
about you is accurate; 
• 
Ethical committee that approved this study and ensures that your rights and well-being are safeguarded; 
• 
National and international regulatory authorities involved in keeping research safe for participants. 
All personnel accessing your records are required to respect your confidentiality at all times. 
 
 
 
 
To ensure privacy, your baby’s name and other identifying information will not be attached to records or 
samples released for research purposes.  Instead, your baby will only be identified by a code.  Only the study 
doctor and authorized personnel will be able to connect this code to your baby’s name.  Your baby’s coded data 
will be forwarded to Discovery Laboratories, Inc., and its service providers for activities related to the study e.g. 
laboratory analysis. It will be transferred into a computer database and processed to allow the results of this 
study to be analyzed and reported or published. If the results of the study are published, your identity will remain 
confidential. 
 
• 
*Delete this paragraph if country does not have specific data protection legislation.  For details, please 
refer to: http://intranet.ppdi.com/policies_procedures/PrivMain_RC3_Data_Privacy_Laws_Per_Region.htm 
Under data protection law [identification of national law] your study site shall be responsible for ensuring that 
your and your baby’s named personal information is safeguarded. You have the right to access, through your 
study doctor, all the information collected about your baby and, if applicable, ask for corrections. But, in order 
to protect the scientific integrity of the study, the treatment your baby received in this study needs to remain 
unknown (= masked) until the study data is analyzed. Recipients of your information may be in countries that do 
not have data protection safeguards and rights.  Discovery Laboratories, Inc., and its authorized 
representatives, and regulatory authorities, shall anyway seek to maintain confidentiality within the limits of 
local laws. 


Discovery Laboratories, Inc., Protocol Number 03-CL-1202, Amendment 1,  
Informed Consent Form 
Master_ICF_Final v1.2_25Feb2016 
Page 16 of 16 
WPD-SIA-01br00 
Effective Date: 13 January 2015 
 
 
 
If you should withdraw your baby from the study, data collected prior to your withdrawal may still be processed 
along with other data collected as part of the study.  Normally no new information will be collected for the study 
database unless you specifically consent to that.  However, the law does require that any side effects your baby 
may suffer are documented and reported.  To complete the study findings, your baby’s long term health status 
may also be recorded (unless you object). You have the right to require that any previously retained samples are 
destroyed. 
 
• 
For signature page 
What will happen to your data? 
This clinical study may only be performed by collecting and using your baby’s medical information. Therefore, 
by signing this form you specifically authorize your baby’s information to be checked, transferred and processed 
as follows: 
• 
The authorized representatives of Discovery Laboratories, Inc., the Ethics Committee and regulatory 
authorities’ inspectors may review your medical information by direct access to your medical records. 
• 
Study data, including your baby’s medical information may be used and shared for legitimate study and 
scientific purposes, including if you do not object, for future use in medical or pharmaceutical research. 


Discovery Laboratories, Inc., Protocol Number 03-CL-1202, Amendment 1,  
Informed Consent Form 
Master_ICF_Final v1.2_25Feb2016 
Page 17 of 16 
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Effective Date: 13 January 2015 
 
 
 
Statement of Consent 
• 
Statements and signatures required may be adapted according to study population &/or local requirements 
• 
I have read and understand the statements in this informed consent form 
• 
I have had the opportunity to ask questions and I am satisfied with the explanations provided 
• 
I voluntarily agree to allow my baby to take part in this study 
• 
I understand that I and/or my legal representative will receive a copy of this signed and dated written consent 
form 
 
 
 
 
Subject 
Printed Name 
Signature 
Date 
 
The next signature line is applicable to the U.S. ONLY. Subjects should be made aware of this option when 
obtaining consent. 
 
• 
I  additionally  consent  to  the  use  of  my  baby’s  coded  medical  information  for  future  medical  or 
pharmaceutical research. 
 
 
 
 
Subject 
Printed Name 
Signature 
Date 
 
 
 
 
Parent or Legal Guardian (if subject is a minor) 
Printed Name 
Signature 
Date 
 
 
 
 
Witness (if applicable) 
Printed Name 
Signature 
Date 
 
• 
I have presented the study and answered the subject’s questions 
• 
I will give the subject/legal representative a copy of this signed and dated Informed Consent 
 
 
 
 
Presenter (Investigator/Delegate) 
Printed Name 
Signature 
Date 

Prot_000.pdf: 
 
 
A MULTINATIONAL, MULTICENTER, MASKED, RANDOMIZED, CONTROLLED 
STUDY TO ASSESS THE SAFETY AND EFFICACY OF LUCINACTANT FOR 
INHALATION IN PRETERM NEONATES 26 TO 32 WEEKS GESTATIONAL AGE 
WITH RESPIRATORY DISTRESS SYNDROME 
 
Protocol No.: 
03-CL-1202 
Study Phase: 
2b 
Investigational Product: 
AEROSURF® (lucinactant for inhalation) 
IND Number: 
119438 
ClinicalTrials.gov No 
EudraCT No. 
NCT02636868  
2015-003519-40 
 
 
Sponsor: 
Discovery Laboratories, Inc. 
Sponsor Contact: 
Steven G. Simonson, MD  
Sponsor’s Medical Officer: Steven G. Simonson, MD  
Senior Vice President and Chief Development Officer 
Address: 
2600 Kelly Road, Suite 100 
Warrington, PA 18976 
Phone No.: 
+1 (215) 488-9300  
Fax No.: 
+1 (215) 488-9301 
 
 
Date 
Original Protocol: 
11 August 2015 
Amendment 1 
11 March 2016 
Amendment 2 
19 April 2017 
 
 
 
This confidential information about an investigational product is provided for the exclusive use of investigators of 
this product and is subject to change at any time. The information in this document contains trade secrets and 
commercial information that are privileged or confidential and may not be disclosed unless such disclosure is 
required by federal or state law or regulations. In any event, persons to whom the information is disclosed must 
be informed that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you which is indicated as 
privileged or confidential. 


Lucinactant for Inhalation 
- CONFIDENTIAL - 
Discovery Laboratories, Inc. 
Protocol No.: 03-CL-1202 
 
Amendment 2, 19 April 2017 
 
 
Page 2 of 124 
 
A Multinational, Multicenter, Masked, Randomized, Controlled Study to Assess the Safety 
and Efficacy of Lucinactant for Inhalation in Preterm Neonates 26 to 32 Weeks Gestational 
Age with Respiratory Distress Syndrome 
 
Author: 
 
 
 
________________________________________ 
________________ 
 
Paul M. Shore, MD, MS, FAAP 
Date 
 
 
Senior Director, Clinical Research 
 
 
Approvals: 
 
 
 
________________________________________ 
________________ 
 
Robert Segal, MD, FACP 
Date 
 
 
Senior Vice President, Clinical Research and Academic Affairs 
 
 
 
________________________________________ 
________________ 
 
Steven G. Simonson, MD 
Date 
 
 
Senior Vice President and Chief Development Officer 
 
 
 
________________________________________ 
________________ 
 
Phillip D. Simmons 
Date 
 
 
Executive Director, Biostatistics & Data Management 
 
 


Lucinactant for Inhalation 
- CONFIDENTIAL - 
Discovery Laboratories, Inc. 
Protocol No.: 03-CL-1202 
 
Amendment 2, 19 April 2017 
 
 
Page 3 of 124 
 
LUCINACTANT FOR INHALATION PROTOCOL SUMMARY 
Protocol Number 
03-CL-1202 
Title: 
A Multinational, Multicenter, Masked, Randomized, Controlled Study to 
Assess the Safety and Efficacy of Lucinactant for Inhalation in Preterm 
Neonates 26 to 32 Weeks Gestational Age with Respiratory Distress 
Syndrome 
Phase: 
2b 
US IND Number: 
119438 
Sponsor: 
Discovery Laboratories, Inc. (Discovery), Warrington, PA, USA 
Committees: 
Steering Committee, Data Monitoring Committee (DMC) 
Study Drug and 
Device: 
Lucinactant for inhalation (an investigational, drug-device combination 
product) at 30 mg total phospholipids (TPL)/mL by the AEROSURF® 
Delivery System (ADS) utilizing a capillary-based aerosol generator 
(CAG). 
Active 
Ingredients: 
A 21-amino acid hydrophobic synthetic peptide (sinapultide, KL4 peptide), 
combined with the phospholipids dipalmitoylphosphatidylcholine (DPPC), 
palmitoyloleoyl-phosphatidylglycerol, sodium salt (POPG, Na), and the 
fatty acid palmitic acid (PA). 
Rationale: 
Respiratory distress syndrome of the newborn (RDS) is a disease that 
results from insufficiency of pulmonary surfactant in the immature neonatal 
lung, which occurs with high frequency in preterm infants and caries high 
morbidity and mortality, especially in very preterm infants. Exogenous 
surfactant replacement therapy (SRT) reduces mortality and morbidity in 
preterm infants with RDS and is recommended by multiple international 
guidelines. Currently, SRT requires endotracheal intubation to instill 
surfactant directly into the neonate’s lung, often with concomitant positive 
pressure mechanical ventilation (MV). However, both intubation and MV 
may have deleterious effects to the infant, potentially leading to short- or 


Lucinactant for Inhalation 
- CONFIDENTIAL - 
Discovery Laboratories, Inc. 
Protocol No.: 03-CL-1202 
 
Amendment 2, 19 April 2017 
 
 
Page 4 of 124 
 
long-term morbidities.  
In order to avoid endotracheal intubation and MV in preterm neonates with 
mild to moderate RDS, the use of non-invasive respiratory support with 
nasal continuous positive airway pressure (nCPAP) has become a widely 
accepted practice. SRT, however, cannot be delivered with nCPAP. 
Although sometimes successful, nCPAP will fail in approximately one-third 
to one-half of preterm neonates, who generally then require endotracheal 
intubation, MV, and in many cases delayed administration of SRT. Earlier 
SRT is more effective than later SRT; thus, the inability to administer SRT 
in conjunction with nCPAP may result in suboptimal timing for SRT to 
treat RDS.  
Therefore, an unmet medical need exists for a means to deliver SRT to 
preterm neonates with RDS supported with nCPAP early in the course of 
the disease. This strategy has the potential to improve RDS prior to the 
development of respiratory failure, thereby avoiding the need for 
endotracheal intubation and MV and the resultant potential for morbidity 
and complications. The ability to administer SRT via aerosol has the 
potential to address this unmet need.  
To address this unmet need, Discovery Laboratories, Inc. (Discovery) has 
developed lucinactant for inhalation, an investigational drug-device 
combination product, to deliver aerosolized SRT to preterm neonates with 
RDS who are being supported with nCPAP. The drug component of 
lucinactant for inhalation is lyophilized lucinactant, a lyophilized form of 
Surfaxin® (lucinactant) Intratracheal Suspension, an exogenous SRT 
approved by the U.S. Food and Drug Administration (NDA 021746). The 
device component, the Aerosurf® Delivery System (ADS), uses novel 
technology to aerosolize lucinactant for inhalation. 
Lucinactant for inhalation was studied in preterm neonates 29 to 34 weeks 
PMA in an open-label safety study (Protocol 03-CL-1201) at escalating 
dosages of 25, 50, 75, 100 and 150 mg total phospholipids (TPL)/kg. In 80 
neonates (8 in each of the 5 active groups and 40 in the control group), 
lucinactant for inhalation was generally well tolerated and there were 
generally no safety signals of concern with escalating doses. Complications 
of prematurity, including pulmonary air leak, were comparable between 
treatment and control groups. Exploratory assessment of clinical efficacy 
parameters suggests that lucinactant for inhalation may be providing 
beneficial effects.  


Lucinactant for Inhalation 
- CONFIDENTIAL - 
Discovery Laboratories, Inc. 
Protocol No.: 03-CL-1202 
 
Amendment 2, 19 April 2017 
 
 
Page 5 of 124 
 
A similar dose escalation study in preterm infants 26 to 28 weeks PMA has 
been initiated (Protocol 03-CL-1401) and is ongoing, using escalating 
dosages of, 50, 75, 100 and 150 mg total phospholipids (TPL)/kg. In 45 
neonates to date (8 each in the 50 and 75 mg TPL/kg groups, 6 in the 100 
mg TPL/kg group and 23 in the control group), lucinactant for inhalation 
has been generally well tolerated and there have been generally no safety 
signals of concern with escalating doses. Complications of prematurity, 
including pulmonary air leak, have so far been comparable between 
treatment and control groups. Exploratory assessment of clinical efficacy 
parameters to date suggests that it is likely that lucinactant for inhalation at 
a dosage greater than 100 mg TPL/kg (repeated more than 1 time) may be 
required in this population to provide beneficial effects. 
Going forward, Discovery has decided to develop and evaluate dosages of 
40 and 80 mg TPL/kg. Results from preclinical and clinical trials, including 
Study 03-CL-1201 and Study 03-CL-1401, support the safety and potential 
efficacy of initial and repeat administration with these dosages. 
Objectives: 
To evaluate the safety and efficacy of lucinactant for inhalation in 
conjunction with nCPAP, in comparison to nCPAP alone, in preterm 
neonates with RDS, as assessed by the incidence of and time to respiratory 
failure and/or death due to RDS in the first 72 hours of life, the incidence of 
bronchopulmonary dysplasia (BPD) at 36 weeks PMA, and change in 
physiologic parameters (fraction of inspired oxygen [FiO2] and partial 
pressure of carbon dioxide [PCO2]) over the first 72 hours of life.  
Primary Endpoint: The primary endpoint for this study is the incidence of respiratory failure or 
death due to RDS within the first 72 hours of life. A subject will be 
categorized as having respiratory failure due to RDS if either of the 
following occur: 
1. Intubation for MV and/or surfactant administration (with or without 
MV) within 72 hours of life 
2. The subject meets at least 1 of the following criteria, regardless of 
whether endotracheal intubation is performed: 
a. A sustained (≥ 60 minutes) need for FiO2 > 0.45 to maintain an SpO2 
> 90% to 95% 
 


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b. A sustained (on ≥ 2 consecutive observations > 60 minutes apart) 
transcutaneous PCO2 > 65 mm Hg  
c. nCPAP > 8 cm H2O 
Death due to RDS is any death whose primary cause is respiratory failure 
due to RDS. 
Secondary 
Endpoints: 
The secondary endpoints of this study include the evaluation of the 
following from the time of initiation of study treatment until study 
completion: 
1. Time to respiratory failure or death due to RDS 
2. Incidence rate of BPD at 36 weeks PMA 
3. All-cause mortality 
4. Incidence rate of survival without BPD at 36 weeks PMA 
5. Incidence rate of pulmonary air leak 
Tertiary 
Endpoints 
The tertiary endpoints of this study include the evaluation of the following 
from the time of initiation of study treatment until study completion: 
1. Incidence rates of common complications of prematurity other than air 
leak  
2. Change from baseline in FiO2 and/or transcutaneous PCO2 over the first 
72 hours of life 
Study Design: 
This study is a sequential, 2-part, multinational, multicenter, masked 
(Part A)/open-label (Part B), randomized, controlled study to evaluate the 
safety and efficacy of lucinactant for inhalation in conjunction with nCPAP 
compared with nCPAP alone, in preterm neonates 28 to 32 completed 
weeks PMA (Part A) and in preterm neonates 26 to 28 completed weeks 
PMA (Part B) who are being cared for in a neonatal intensive care unit 
(NICU), who had successful implementation of non-invasive respiratory 
support or ventilation within 90 minutes of birth (60 minutes for Part B), 
and who are candidates for SRT. The preferred initial mode of support is 
study nCPAP; however, other modes are acceptable if the investigator feels 
it is safe to switch the subject to study nCPAP following consent and 
screening. There will be 2 phases in Parts A and B of the study, a primary 
phase through 36 weeks PMA and a longer-term follow-up phase through 1-


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year corrected age. Data will be analyzed and reported at the completion of 
each respective study phase for Parts A and B of the study. 
Before study enrollment, legal guardians will provide a signed written 
informed consent form (ICF) for each potential subject. Qualification for 
study enrollment will be established after confirmation that the subject has 
met all of the inclusion criteria and none of the exclusion criteria. The 
clinical criteria for enrollment may be met prior to informed consent being 
obtained; however, no study-specific procedures that are not part of the 
usual standard care of the subject at the institution may be performed until 
the informed consent has been provided by a legally authorized 
representative of the subject.  
For Part A of the study, inclusion criteria to be met within the first 20 hours 
after birth include respiratory insufficiency with a requirement for nCPAP 
of 5 to 7 cm H2O with a FiO2 ≥0.25 (>0.21 for neonates 28 weeks PMA) to 
0.4 to maintain oxygen saturation measured by pulse oximetry (SpO2) 
of 90% to 95% for at least 30 minutes. For Part B of the study, inclusion 
criteria to be met within the first 12 hours after birth include respiratory 
insufficiency with a requirement for nCPAP of 5 to 7 cm H2O with a FiO2 
>0.21 to 0.4 to maintain SpO2 of 90% to 95% for at least 20 minutes. As 
soon as study qualification has been confirmed and the informed consent is 
signed, subjects will be randomized to an active treatment group (2 active 
groups in Part A; 1 active group in Part B) or to the control group (nCPAP 
only, with simulated [“sham”] study drug treatment in Part A). Study 
treatment (lucinactant for inhalation or sham/control) must be initiated as 
soon as possible and no more than 2 hours after randomization. 
Subjects in Part A may be eligible to receive up to 2 repeat doses of the 
treatment to which they are originally assigned, and subjects in Part B may 
receive up to 4 repeat doses. Repeat doses will be given for subjects in Part 
A as soon as 2 hours, and for subjects in Part B as soon as 30 minutes, from 
completion of the previous dose up to 36 hours after completion of 
randomization if subjects meet repeat dosing criteria (as described in the 
“Treatment Groups” section) unless it is unsafe to do so in the judgment of 
the investigator. Subjects randomized to the control group will be continued 
on nCPAP alone; subjects in Part A will receive repeated sham treatment to 
maintain study masking, while subjects in Part B will receive open label 
treatment. 
In both parts of the study, all subjects in the active treatment groups will 


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receive the same drug concentration of lucinactant for inhalation (30 mg 
TPL/mL) at the same rate of delivery (aerosolized concentration of 4.2 mg 
TPL/L in aerosol carrier gas flow of 3 L/min). The dosage will vary by the 
predetermined administration time for each dosage (25 minutes for the 40 
mg TPL/kg arm in Part A, 50 minutes for the 80 mg TPL/kg arm in Parts A 
and B). Lucinactant for inhalation will be delivered by the investigational 
ADS device in conjunction with a commercially available nCPAP generator 
and patient interface. Dose assignments in Part A will be masked from the 
principal investigator (PI), clinical and study staff (eg, site coordinator, 
bedside nurse), as applicable; sponsor as applicable; and subject’s 
parents/legal guardians. Dose assignments in Part B will be open label. 
All enrolled subjects will receive study treatment in a NICU: a specialized 
care center staffed by neonatologists, nurses, and respiratory therapists who 
are experienced in the delivery of emergent care to the preterm neonatal 
population. Neonates in the NICU are continuously monitored using 
advanced and sophisticated monitoring equipment, and there is ready and 
immediate access to equipment, medications, and skilled personnel that may 
be needed to address emergent developments. Interventions such as 
endotracheal intubation, MV, and surfactant administration will be readily 
available to all study subjects if clinically indicated in accordance with the 
high-level standard-of-care customary in the NICU. 
In both parts of the study, neonates will be followed for the primary phase 
efficacy and safety evaluations through 36 weeks PMA, NICU discharge, 
hospital transfer, or death (whichever occurs first). For the longer-term 
follow-up phase, neonates will be evaluated by phone or visit at 6-months 
corrected age and followed up to 1-year corrected age, at which time a 
physical examination will be performed, including an abbreviated 
neurologic assessment. 
Study Population: 
The study population will be comprised of preterm neonates 26 to 
32 completed weeks PMA who are receiving care in a NICU and are 
receiving nCPAP as the primary support modality for RDS. Enrollment will 
be conducted by strata: in Part A, approximately 5-10% of the subjects will 
be 28 completed weeks PMA and the remainder will be 29 to 32 completed 
weeks PMA, while in Part B randomization will be stratified by gestational 
age (26, 27, and 28 completed weeks PMA). 
 
 


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The study population in Part A will be randomized in a 1:1:1 ratio into 1 of 
3 treatment groups, and in Part B will be randomized in a 1:1 ratio into 1 of 
2 treatment groups (see “Treatment Groups” section). 
Study Sample 
Size: 
A total of up to 240 study subjects (up to 80 per treatment group) will be 
enrolled in Part A, and up to 80 subjects (up to 40 per treatment group) will 
be enrolled in Part B. For Part A, the sample sizes were calculated 
separately for incidence of respiratory failure due to RDS, time to 
respiratory failure or death due to RDS, and a reduction in FiO2. The sample 
size will have 90% power to detect the difference between treatment groups 
using a log-rank test for equality of time to event curves, assuming a 
constant hazard ratio of 0.500, within the first 72 hours of life. In addition, 
the sample size is sufficient to detect, separately, a reduction of 50% in the 
incidence of respiratory failure or death due to RDS within the first 
72 hours of life, or a reduction in FiO2 of 4 percentage points (eg, 30% to 
26%) within the first 24 hours following treatment. 
In addition, the sample size should be sufficient to provide a stable estimate 
of the size of the treatment effect (treatment delta). The efficacy estimate 
will be used to calculate the sample size for future studies. 
For Part B, formal sample size calculations have not been conducted. A 
total of 40 subjects per group should be sufficient to provide a stable 
estimate of the size of the treatment effect. 
Number of Sites: 
Approximately 60 study sites in North America, Europe, and South 
America. 
Study Duration: 
Overall, study enrollment will be completed in approximately 18 to 
20 months, with the last subject completing his or her last visit 
approximately 20 to 22 months from the time the first subject enrolled. 
Subject participation will be from 20 hours following birth until 36 weeks 
PMA, NICU discharge, death, or hospital transfer, whichever occurs first 
for the primary evaluation phase of the study. Follow-up through 1-year 
corrected age will be done for the secondary phase of the study. 


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Method of 
Administration: 
Subjects randomized to the active treatment groups will be administered an 
investigational drug-device combination product, lucinactant for inhalation, 
in conjunction with nCPAP. Reconstituted lyophilized lucinactant 
(reconstituted with sterile water for injection) will be aerosolized by the 
investigational ADS device and introduced into the nCPAP circuit. Those 
randomized to the control (nCPAP only) group will continue to receive 
nCPAP alone; in order to maintain masking in Part A, “sham” study drug 
treatment will be used: the ADS will be brought to the bedside but will not 
be used, and no active study drug will be administered. 
The theoretical inhaled dose (in mg TPL/kg) can be controlled based on the 
duration of exposure to the aerosol. This inhaled dose is a function of the 
concentration of lucinactant in the aerosol, the amount of aerosol inhaled by 
the subject (estimated by the subject’s minute ventilation, assuming that all 
gas inhaled by the subject contains the same concentration of aerosol), and 
the duration of exposure to the aerosol. Because of losses that occur as the 
lucinactant aerosol travels from the ADS to the patient interface, 
approximately 35% of the reconstituted lucinactant aerosolized by the ADS 
is emitted and available to be inhaled. 
Treatment 
Groups: 
Part A: 
40 mg/kg 
40 mg TPL/kg administered over 25 minutes in 
conjunction with nCPAP (n=80)  
 
Up to 2 repeat doses of 40 mg TPL/kg administered 
over 25 minutes will be given if repeat dosing criteria 
are met. 
80 mg/kg 
80 mg TPL/kg administered over 50 minutes in 
conjunction with nCPAP (n=80)  
 
Up to 2 repeat doses of 80 mg TPL/kg administered 
over 50 minutes will be given if repeat dosing criteria 
are met. 
 
Control 
Continuous nCPAP (n = 80) with sham drug treatment 
 
Up to 2 repeat sham treatments will be given if repeat 
dosing criteria are met. 


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Part B 
80 mg/kg 
80 mg TPL/kg administered over 50 minutes in 
conjunction with nCPAP (n = up to 40)  
 
Up to 4 repeat doses of 80 mg TPL/kg administered 
over 50 minutes will be given if repeat dosing criteria 
are met. 
 
Control 
Continuous nCPAP (n = up to 40)  
Repeat dosing will be given ≥2 hours (≥30 minutes for Part B) from 
completion of the previous dose up to 36 hours after completion of 
randomization if subjects have a sustained (≥30 minutes) need for FiO2 
above the qualifying FiO2 for study enrollment (≥0.25 for neonates 29-32 
weeks PMA, >0.21 for neonates 26-28 weeks PMA) to maintain SpO2 of 
90% to 95%, unless it is unsafe to do so in the judgment of the investigator. 
In Part A, masking procedures for the initial dose will be followed for 
repeat doses, including controls. 
Inclusion Criteria: 
Each subject must meet all of the following inclusion criteria to be enrolled 
in this study: 
1. Signed ICF from legally authorized representative (consent may be 
obtained prenatally, where allowed) 
2. Gestational age: 
a. Part A: 28 0/7 to 32 6/7 completed weeks’ gestation PMA 
b. Part B: 26 0/7 to 28 6/7 completed weeks’ gestation PMA 
3. Successful implementation of non-invasive support or ventilation 
(preferably bubble CPAP) within:  
a. Part A: 90 minutes after birth 
b. Part B: 60 minutes after birth 
4. Spontaneous breathing 
5. Chest radiograph consistent with RDS (may be deferred if in the best 
medical interest of the subject) 
6. Respiratory support: 
a. Part A: Within the first 20 hours after birth, requires an 
nCPAP of 5 to 7 cm H2O with an FiO2 ≥0.25 (>0.21 for 
neonates 28 weeks PMA) to 0.4 that is clinically indicated 
for at least 30 minutes to maintain SpO2 of 90% to 95%.  


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b. Part B: Within the first 12 hours after birth, requires an 
nCPAP of 5 to 7 cm H2O with an FiO2 of >0.21 to 0.4 that is 
clinically indicated for at least 20 minutes to maintain SpO2 of 
90% to 95%. 
Transient (<10 minutes) FiO2 excursions outside this range do not 
reset the time requirement. 
Exclusion 
Criteria: 
Subjects meeting any of the following exclusion criteria may not be 
enrolled in this study: 
1. A heart rate that cannot be stabilized above 100 beats per minute 
(bpm) within 5 minutes of birth 
2. Recurrent episodes of apnea requiring positive pressure ventilation 
(PPV) administered manually or mechanically through any patient 
interface 
3. A 5 minute Apgar score < 5 
4. Major congenital malformation(s) or craniofacial abnormalities that 
preclude the use of nCPAP, diagnosed antenatally or immediately 
after birth 
5. Clinically significant diseases or conditions other than RDS which 
could potentially interfere with cardiopulmonary function (eg, 
congenital heart disease, hydrops fetalis or congenital infection) 
6. A known or suspected chromosomal abnormality or syndrome 
7. Premature rupture of membranes (PROM) >3 weeks 
8. Hemodynamic instability requiring vasopressors or steroids for 
hemodynamic support and/or presumed clinical sepsis 
9. A need for intubation and/or invasive mechanical ventilation at any 
time before enrollment into the study 
10. The administration (or plan for administration) of any the following:  
a) Another investigational agent or investigational medical device  
b) Any other surfactant agent 
c) Systemic corticosteroids (other than antenatal steroids already 
received) 
11. Presence 
of 
air 
leak 
(pneumothorax, 
pneumomediastinum, 
pneumopericardium, subcutaneous emphysema, or definite evidence 
of pulmonary interstitial emphysema [PIE]) on the baseline chest 
radiograph  
 
 


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Concomitant 
Medications: 
All concomitant medications administered to the subject from birth until 
36 weeks PMA, NICU discharge, hospital transfer, or death (whichever 
occurs first) will be recorded in the electronic case report form (eCRF).  
Medications required for the general care of the subject are permitted with 
the exception of investigational agents, investigational medical devices, or 
any SRT before randomization. Commercially available SRTs, following 
study treatment, may be administered as medically indicated. Study subjects 
who receive any commercial SRT while on-study will be considered 
treatment failures but will continue to be followed until study completion. 
Postnatal steroids are not permitted unless clear medical need is determined. 
Caffeine or other methylxanthines are recommended. 
Safety and 
Tolerability 
Endpoints: 
The safety and tolerability endpoints will be assessed during the primary 
phase through 36 weeks PMA, NICU discharge, hospital transfer, or death, 
whichever occurs first, as described below. 
1. Survival (date and time of death, if applicable) 
2. AEs, including adverse device effects (ADEs) and AEs of special interest 
including peri-dosing events, complications related to placement of bi-
nasal prongs, and air leak 
3. Concomitant medications 
4. Use of respiratory support and supplemental O2, including the following: 
a. Need for endotracheal intubation and MV 
b. Mode of respiratory support (including supplemental oxygen) and 
important parameters for that mode 
5. Complications of prematurity 
6. Physical examinations 
7. Tolerability of lucinactant for inhalation 
8. Incidence of air leak 
9. Assessments of the following: 
a. Vital signs 
b. O2 saturation, as determined by pulse oximetry (SpO2) 
c. Serum electrolyte measurements 
d. Defecation 
e. Chest radiography prior to intubation 
 
 
 


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Early 
Discontinuation 
of Treatment: 
The administration of study treatment may be discontinued at any time prior 
to the completion of dosing if certain device error codes occur or based on 
the clinical judgment of the PI. Reasons for discontinuation of study 
treatment include, but are not limited to the following:  
1. A device failure or malfunction occurs, including certain error codes 
2. An AE or ADE which places subject safety occurs, eg pulmonary 
hemorrhage  
3. If, in the PI’s best medical judgment, initiating or continuing the 
subject’s exposure to study treatment is not in the best interest of the 
subject’s safety 
4. Signs of acute respiratory deterioration develop, as evidenced by a 
clinically significant increase in respiratory rate or effort (work of 
breathing) plus at least one of the following: 
a) An FiO2 ≥ 0.70 or sustained increase from baseline by ≥ 0.30 to 
maintain SpO2 90% to 95% 
b) A transcutaneous PCO2 > 70 mm Hg or a progressive increase from 
baseline to ≥ 20 mm Hg above baseline 
c) Recurring episodes of bradycardia 
d) A sustained apneic event 
Subjects whose treatment is discontinued based on the PI’s judgment will 
continue in the study. Subjects whose treatment is discontinued based on 
the parent/guardian’s wishes must be withdrawn from the study. 
Statistical 
Analysis 
The statistical analysis of both the primary and secondary objectives will be 
based on all enrolled preterm neonates. For the efficacy analysis, 
populations of all randomized subjects who received any treatment (intent-
to-treat [ITT]) and subjects with no major protocol deviations (per-protocol) 
will be evaluated, based upon the treatment group to which they were 
randomized. For the safety analysis, all subjects randomized to the control 
group or who received any lucinactant for inhalation (including partial 
doses) will be evaluated, based upon the treatment they actually received. 
All analyses will be performed for Parts A and B of the study for all 
subjects combined and by gestational age strata. 
The treatment difference (delta) between active and control treatments will 
be calculated for the primary and key secondary efficacy endpoints. The 
delta calculated will be used to plan additional studies and as supporting 
evidence of efficacy. 


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Interim Analyses: 
The data monitoring committee (DMC) will conduct 2 preplanned interim 
analyses during Part A of the study: 1) after approximately 25% of subjects 
have been enrolled and 2) after 66% of subjects have been enrolled. The 
DMC will be provided full safety tables and listings for review after 20 
subjects have been enrolled in Part B, but will not conduct a formal interim 
analysis. Study enrollment may be suspended if safety concerns are 
identified during the review. 
 
 


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TABLE OF CONTENTS 
LUCINACTANT FOR INHALATION PROTOCOL SUMMARY ........................................ 3 
TABLE OF CONTENTS ........................................................................................................... 16 
LIST OF ABBREVIATIONS .................................................................................................... 21 
1 
INTRODUCTION............................................................................................................... 23 
1.1 
Treatment of Neonatal Respiratory Distress Syndrome ............................................. 23 
1.1.1 
Continuous Positive Airway Pressure in Neonatal Respiratory Distress Syndrome 24 
1.1.2 
Unmet Medical Need for Aerosolized Surfactant Replacement Therapy ................ 25 
1.2 
Development of Aerosolized Surfactant with Lucinactant for Inhalation ................ 26 
1.3 
Clinical Experience with Aerosolized Lucinactant ...................................................... 27 
1.3.1 
Preliminary Studies Using Commercially Available Nebulizers.............................. 27 
1.3.2 
Clinical Studies using the AEROSURF Delivery System ........................................ 28 
2 
STUDY DESIGN AND RATIONALE .............................................................................. 38 
2.1 
Study Design .................................................................................................................... 38 
2.2 
Dose and Device Description and Rationale ................................................................. 41 
2.2.1 
General Description and Rationale for the ADS ....................................................... 41 
2.2.2 
Rationale for Study Control ...................................................................................... 42 
2.2.3 
Dosage Rationale ...................................................................................................... 42 
2.2.4 
Risk and Benefit of Study Interventions ................................................................... 53 
2.3 
Study Duration ................................................................................................................ 56 
2.3.1 
Duration of Subject Study Participation ................................................................... 56 
3 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 58 
3.1 
Objectives......................................................................................................................... 58 
3.2 
Efficacy Endpoints .......................................................................................................... 58 
3.2.1 
Primary Endpoint ...................................................................................................... 58 
3.2.2 
Secondary Endpoints ................................................................................................ 59 
3.2.3 
Tertiary Endpoints .................................................................................................... 59 
3.3 
Safety Endpoints ............................................................................................................. 59 
4 
STUDY POPULATION SELECTION ............................................................................. 61 


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4.1 
Study Population ............................................................................................................. 61 
4.2 
Inclusion Criteria ............................................................................................................ 61 
4.3 
Exclusion Criteria ........................................................................................................... 62 
5 
STUDY TREATMENT DOSING AND ADMINISTRATION ...................................... 64 
5.1 
AEROSURF Delivery System ........................................................................................ 64 
5.1.1 
AEROSURF Control Unit ........................................................................................ 66 
5.1.2 
AEROSURF Delivery Pack ...................................................................................... 66 
5.2 
Identity of Investigational Drug Product ...................................................................... 66 
5.2.1 
Formulation of Study Drug ....................................................................................... 66 
5.2.2 
Aerosol characteristics .............................................................................................. 67 
5.2.3 
Packaging and Labeling ............................................................................................ 67 
5.3 
Precautions for Aerosol Delivery and Device Usage .................................................... 67 
5.3.1 
Precautions for Aerosol Delivery.............................................................................. 68 
5.3.2 
Precautions for Device Usage ................................................................................... 68 
5.4 
Description of Treatment Groups ................................................................................. 68 
5.4.1 
Aerosol Delivery in the Active Treatment Groups ................................................... 69 
5.4.2 
Treatment in the Control Groups .............................................................................. 69 
5.5 
Treatment Groups and Method of Treatment Group Assignment ............................ 70 
5.6 
Study Masking ................................................................................................................. 71 
5.7 
Repeat Dosing .................................................................................................................. 72 
5.7.1 
Study Part A .............................................................................................................. 72 
5.7.2 
Study Part B .............................................................................................................. 73 
5.8 
Early Discontinuation of Study Treatment .................................................................. 73 
5.9 
Clinical Study Supplies at the Clinical Study Site ....................................................... 75 
5.9.1 
Investigational Study Drug and ADPs ...................................................................... 75 
5.9.2 
Ancillary Supplies ..................................................................................................... 75 
5.9.3 
Dispensing................................................................................................................. 75 
5.9.4 
Storage of Lucinactant and AEROSURF Delivery System ...................................... 75 
5.10 
Study Compliance ....................................................................................................... 76 
5.11 
Study Drug and Device Accountability ..................................................................... 76 
5.11.1 
Study Supply Accountability .................................................................................... 76 
6 
DATA MONITORING COMMITTEE ............................................................................ 78 


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6.1 
Safety Reviews ................................................................................................................. 78 
6.2 
Safety Enrollment Holds ................................................................................................ 78 
7 
STUDY PROCEDURES AND GUIDELINES ................................................................. 80 
7.1 
Clinical Assessments ....................................................................................................... 80 
7.1.1 
Vital Signs ................................................................................................................. 80 
7.1.2 
Body Weight ............................................................................................................. 80 
7.1.3 
Pulse Oximetry.......................................................................................................... 81 
7.1.4 
Apnea, Bradycardia and Desaturation ...................................................................... 81 
7.1.5 
Monitoring of Carbon Dioxide Levels ...................................................................... 81 
7.1.6 
Physical Examination................................................................................................ 82 
7.1.7 
Serum Electrolytes .................................................................................................... 82 
7.1.8 
Chest Radiograph ...................................................................................................... 82 
7.1.9 
Defecation ................................................................................................................. 82 
7.1.10 
Clinical Assessments during Each Study Treatment Administration ....................... 83 
7.2 
Medical Information ....................................................................................................... 83 
7.3 
Concomitant Medications .............................................................................................. 83 
7.3.1 
Use of Additional Surfactant Replacement Therapies .............................................. 83 
7.3.2 
Use of Caffeine Citrate or Systemic Corticosteroids ................................................ 84 
7.4 
Demographics .................................................................................................................. 84 
7.5 
Respiratory Support and Oxygen Delivery .................................................................. 84 
7.5.1 
General Principles for Respiratory Support .............................................................. 84 
7.5.2 
Emergent Respiratory Support .................................................................................. 85 
7.5.3 
Use of Nasal Continuous Positive Airway Pressure ................................................. 85 
7.5.4 
Use of Non-Invasive Support before and after Enrollment ...................................... 86 
7.5.5 
Documentation of Respiratory Support Parameters ................................................. 87 
7.6 
Assessment Parameters for Technical Performance of the Device ............................ 88 
8 
EVALUATIONS BY OBSERVATION PERIOD............................................................ 89 
8.1 
Screening Period ............................................................................................................. 89 
8.2 
Primary Phase ................................................................................................................. 89 
8.2.1 
Primary Observation Period ...................................................................................... 89 
8.2.2 
Extended Observation Period ................................................................................... 90 
8.2.3 
Final Observation Period (From Day 8 to 36 Weeks Postmenstrual Age/Final 
Observation [or NICU Discharge, Death, or Hospital Transfer]) ............................................ 90 
8.3 
Longer-Term Follow-Up Phase Through 1-Year Corrected Age .............................. 91 


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9 
ADVERSE EVENT REPORTING ................................................................................... 92 
9.1 
Adverse Events ................................................................................................................ 93 
9.1.1 
Causal Relationship of Adverse Events .................................................................... 94 
9.1.2 
Severity Grade Levels of Adverse Events ................................................................ 94 
9.1.3 
Adverse Event Procedures ........................................................................................ 94 
9.1.4 
Serious Adverse Events ............................................................................................ 95 
9.1.5 
Unanticipated Adverse Device Effects ..................................................................... 96 
9.2 
Discovery Contact Information ..................................................................................... 97 
9.2.1 
Trial-Related Questions ............................................................................................ 97 
9.2.2 
Medical Monitoring .................................................................................................. 97 
10 DISCONTINUATION AND REPLACEMENT OF SUBJECTS .................................. 99 
10.1 
Early Discontinuation of Study Treatment .............................................................. 99 
10.2 
Withdrawal of a Subject from the Study .................................................................. 99 
10.3 
Termination of the Study ........................................................................................... 99 
10.4 
Replacement of Subjects........................................................................................... 100 
11 PROTOCOL VIOLATIONS/DEVIATIONS ................................................................. 101 
12 ETHICS ............................................................................................................................. 102 
12.1 
Institutional Review Board/Independent Ethics Committee/Research Ethics 
Board 102 
12.2 
Informed Consent Form of Study Subject.............................................................. 103 
12.3 
Financial Disclosure .................................................................................................. 104 
13 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ............ 105 
13.1 
Statistical and Analytical Plans ............................................................................... 105 
13.2 
Interim Analyses ....................................................................................................... 106 
13.3 
Sample Size and Randomization ............................................................................. 106 
14 DATA COLLECTION, RETENTION AND MONITORING ..................................... 108 
14.1 
Protection of Subject Data and Confidentiality ..................................................... 108 
14.2 
Data Collection Instruments .................................................................................... 108 
14.3 
Data Management Procedures ................................................................................. 109 


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14.4 
Data Quality Control and Reporting ...................................................................... 109 
14.5 
Archival of Data ........................................................................................................ 109 
14.6 
Record Retention ...................................................................................................... 110 
14.7 
Monitoring ................................................................................................................. 110 
15 ADMINISTRATIVE AND REGULATORY CONSIDERATIONS ............................ 113 
15.1 
Protocol Amendments .............................................................................................. 113 
15.2 
End-of-Study Procedures ......................................................................................... 113 
15.3 
Study Report.............................................................................................................. 113 
15.4 
Publications ............................................................................................................... 113 
15.5 
Investigator Responsibilities .................................................................................... 114 
16 REFERENCES .................................................................................................................. 115 
17 APPENDICES ................................................................................................................... 118 
Appendix 1 
Protocol Definitions ...................................................................................... 119 
Appendix 2 
Protocol Event Schedule ............................................................................... 121 
Appendix 3 
Investigator Agreement Form ..................................................................... 123 
Appendix 4 
Investigator Agreement Form for Canada ................................................. 124 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ACU 
AEROSURF® Control Unit 
ADE 
Adverse device effect 
ADS 
AEROSURF® Delivery System 
ADP 
AEROSURF® Delivery Pack 
AE 
Adverse event 
BPD 
Bronchopulmonary dysplasia 
CAG 
Capillary-based aerosol generator 
CFR 
Code of Federal Regulations 
CPAP/nCPAP 
Continuous positive airway pressure/nasal CPAP 
CRF/eCRF 
Case report form/electronic CRF 
DMC 
Data Monitoring Committee 
DPPC 
dipalmitoylphosphatidylcholine 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GA 
Gestational age 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC/IRB/REB 
Independent Ethics Committee/Institutional Review 
Board/Research Ethics Board 
IMV 
Intermittent mechanical ventilation 
IND 
Investigational new drug 
IPP 
Intermittent positive pressure 
ITT 
Intent-to-Treat 
IVH 
Intraventricular hemorrhage 
IWRS 
Interactive web response system 


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Abbreviation 
Description 
KL4 
21-amino acid hydrophobic synthetic peptide, also known as 
sinapultide 
MMAD 
Mass median aerodynamic diameter 
NDA 
New drug application 
NEC 
Necrotizing enterocolitis 
NICU 
Neonatal intensive care unit 
NOAEL 
No observed adverse effect level 
PA 
Palmitic acid 
PCO2 
Partial pressure of carbon dioxide  
PDA 
Patent ductus arteriosus 
PI 
Principal Investigator 
PIF 
Peak inspiratory flow 
PMA 
Post-menstrual age 
POPG, Na 
Palmitoyloleoyl-phosphatidylglycerol, sodium salt 
PROM 
Premature rupture of membranes 
PVL 
Periventricular leukomalacia  
RDS 
Respiratory distress syndrome 
ROP 
Retinopathy of prematurity 
SAE 
Serious adverse event 
SIV 
Site initiation visit 
SpO2 
Oxygen saturation measured by pulse oximetry  
SRC 
Safety review committee 
SRT 
Surfactant replacement therapy 
TORCH 
Toxoplasmosis, rubella, cytomegalovirus, herpes simplex 
TPL 
Total phospholipids 
UADE 
Unanticipated adverse device effect 
US 
United States 
Vm 
Minute ventilation  
WMA 
World Medical Assembly 


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1 
INTRODUCTION 
The purpose of this study is to evaluate the safety and efficacy of lucinactant for inhalation used 
in conjunction with nasal continuous airway pressure (nCPAP), in comparison with nCPAP 
alone, in preterm neonates 26 to 32 completed weeks’ postmenstrual age (PMA) with respiratory 
distress syndrome (RDS) of the newborn. 
Aerosolized surfactant delivery potentially addresses an unmet medical need by providing a 
means to deliver surfactant to preterm neonates with RDS who are treated non-invasively with 
nCPAP, thereby providing surfactant replacement therapy (SRT) early in the disease course 
while avoiding the complications associated with endotracheal intubation and mechanical 
ventilation inherent in conventional surfactant delivery. 
This clinical study is intended for preterm neonates 26 to 32 completed weeks PMA and is 
designed to assess the safety and efficacy of a novel SRT, lucinactant for inhalation, 
administered at doses of 40 or 80 mg total phospholipids (TPL)/kg. A preceding dose-escalation 
safety study, Protocol 03-CL-1201, was conducted in preterm neonates 29 to 34 completed 
weeks PMA, whose intent was to establish that lucinactant for inhalation is generally well 
tolerated in dosages of 25, 50, 75, 100 and 150 mg TPL/kg. A similar dose-escalation safety 
study in preterm infants 26 to 28 weeks PMA has been initiated (Protocol 03-CL-1401). To date, 
there have been no safety signals of concern. Findings from these 3 studies (03-CL-1201, 03-CL-
1401, and 03-CL-1202) will contribute to the development and design of future investigations of 
this novel drug/device combination product.  
All study procedures and assessments are to be conducted in accordance with local and regional 
regulatory requirements, institutional review board (IRB)/independent ethics committee 
(IEC)/research ethics board (REB) requirements, International Conference on Harmonisation 
Good Clinical Practices (ICH GCP) Guidelines, and local institutional practices. 
Definitions of study terms are provided in Appendix 1. 
1.1 
Treatment of Neonatal Respiratory Distress Syndrome 
RDS of the newborn is a disease that results from insufficiency of pulmonary surfactant in the 
immature neonatal lung, which occurs with high frequency in preterm infants and caries high 
morbidity and mortality, especially in very preterm infants. Exogenous surfactant treatment 
reduces mortality and morbidity in preterm infants with RDS (1, 2). Intratracheal SRT has well-


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established benefits in infants with RDS and has become a standard, recommended therapy for 
this condition (3-6). Early SRT is more effective in reducing morbidity and mortality due to RDS 
than SRT delivered later (2), and multiple doses are sometimes necessary (1).  
Intratracheal instillation of surfactant into the lung requires endotracheal intubation, often with 
concomitant positive pressure mechanical ventilation (MV). However, endotracheal intubation is 
an invasive, painful procedure that itself has potential deleterious effects to the infant, including 
hypoxemia, bradycardia, hypertension, increases in intracranial pressure and cerebral blood flow 
which may increase the risk of intraventricular hemorrhage (IVH) (7, 8), and tracheal injury 
which may lead to the development of subglottic stenosis (9). Further, MV is associated with 
morbidities such as ventilator-associated lung injury and volutrauma/barotrauma resulting in air 
leak syndromes such as pneumothorax and/or pulmonary interstitial emphysema (PIE), and may 
also contribute to development of chronic lung disease (CLD) / bronchopulmonary dysplasia 
(BPD) (10). 
1.1.1 Continuous Positive Airway Pressure in Neonatal Respiratory Distress Syndrome 
In order to avoid endotracheal intubation and MV in preterm neonates with mild-to-moderate 
RDS, a strategy of using nasal continuous positive airway pressure (nCPAP) as an effective 
means of providing ventilatory support is now accepted practice (3-6, 11). nCPAP improves 
respiratory function in neonates by increasing functional residual capacity, improving lung 
compliance and dilating upper airway structures, thereby improving gas exchange and reducing 
work of breathing (11, 12).  
Devices that generate and deliver nCPAP, as well as patient interfaces such as nasal prongs, have 
been specifically designed, manufactured, and made commercially available for use in neonates. 
Devices to generate nCPAP include those with continuous humidified flow (eg, bubble CPAP, 
VapoTherm, SiPAP) and more complex devices with variable flow (eg, a mechanical ventilator 
set to CPAP mode). Because neonates are obligate nose breathers, several patient interface 
devices exist that can be used to deliver CPAP via the nose such as nasal masks, short bi-nasal 
prongs, and nasopharyngeal tubes. 
Studies in very preterm neonates of initial treatment of RDS with nCPAP alone (13-16), 
including meta-analyses (17, 18), have shown outcomes with this approach that are similar to 
traditional, early treatment with intratracheal surfactant. These studies have consistently shown 
that in neonates treated with nCPAP, the need for surfactant therapy is less than that of neonates 
treated with intubation and SRT, and that the important outcome of death or bronchopulmonary 


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dysplasia (BPD, defined as the need for oxygen [O2] treatment at day 28 after birth) is equal or 
less frequent with nCPAP. In neonates treated with nCPAP, approximately 33-67% of patients 
required intubation and intratracheal surfactant replacement, meaning that ⅓ to ⅔ of patients 
were able to avoid intubation altogether. Thus, the strategy of initially supporting neonates with 
nCPAP and reserving SRT only for those who require intubation appears to be reasonably 
effective and potentially safer by avoiding intubation. Two meta-analyses (10, 19) and a 
systematic review (20) have suggested that use of nCPAP as the primary respiratory support 
modality in preterm neonates reduces the need for intubation and the rate of BPD, with a number 
need to treat (NNT) of 25 for BPD (10). 
In neonates 24-28 weeks’ gestation, the rate of air leak (pneumothorax, pneumomediastinum or 
pulmonary interstitial emphysema) was generally low (3 to 9.6%), but in some reports was 
greater in the nCPAP groups compared to the intubation groups (12-14). Air leaks have been 
reported in as many as 21% of neonates in this gestational age range treated with a restrictive 
intubation strategy using nCPAP (21). 
Older gestational age infants treated with nCPAP may be at higher risk of air leak than younger 
infants (22). In a cohort of 297 neonates 25-32 weeks gestation with RDS initially treated with 
nCPAP alone, 65 (22%) overall required intubation (“nCPAP failure”). The rate of nCPAP 
failure was 45% in the subgroup 25-28 weeks’ gestation, consistent with prior reports, where 
only 15% of infants 29-32 weeks’ gestation had nCPAP failure. Notably, the rate of 
pneumothorax prior to intubation was 10% in the younger cohort (also consistent with most prior 
reports), but was 23% in the older gestational age infants as a whole and 47% in those older 
infants who failed nCPAP. 
1.1.2 Unmet Medical Need for Aerosolized Surfactant Replacement Therapy 
Several studies have demonstrated that earlier intratracheal SRT is more beneficial than later 
SRT (2). For this reason, guidelines recommend that when SRT is used it be given as early as 
possible (3-6). However, when nCPAP is used as initial respiratory support, SRT is necessarily 
delayed in those neonates who ultimately require endotracheal intubation. 
Thus, an unmet medical need exists for a means to deliver SRT to preterm neonates with RDS 
supported with nCPAP early in the course of the disease. This strategy has the potential to 
improve RDS prior to the development of respiratory failure, thereby avoiding the need for 
endotracheal intubation and MV and the resultant potential for morbidity and complications. The 
ability to administer SRT via aerosol has the potential to address this unmet need.  


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Efforts to aerosolize surfactants in clinical models have been largely unsuccessful to date (23) 
because of the limited capability of currently available aerosol generators to aerosolize 
surfactants in the amount needed to achieve a therapeutic benefit. Delivery of surfactant aerosol 
to the lungs has been limited by technical constraints of currently available aerosol generators 
and system configurations. Compared with surfactant administration via endotracheal 
instillation, surfactant administration via aerosolization is highly inefficient and dose delivery is 
limited (24). Newer aerosol generator technologies may allow for administration of aerosolized 
surfactant in sufficient quantities to achieve a therapeutic response. As with liquid surfactant, 
aerosolized surfactant is most likely delivered preferentially to the ventilated parts of the lungs 
(25). It is therefore likely that improving lung aeration by providing appropriate ventilatory 
support during aerosol delivery, as with nCPAP, would improve the delivery of aerosolized 
surfactant.  
1.2 
Development of Aerosolized Surfactant with Lucinactant for Inhalation 
To address this unmet need, Discovery Laboratories, Inc. (Discovery) has developed lucinactant 
for inhalation, an investigational drug-device combination product, to deliver aerosolized SRT to 
preterm neonates with RDS who are being supported with nCPAP. Lucinactant for inhalation is 
comprised of a drug component, lyophilized lucinactant, and a device component referred to as 
the AEROSURF® Delivery System (ADS). Lyophilized lucinactant is a lyophilized form of 
Surfaxin® (lucinactant) Intratracheal Suspension, an exogenous SRT approved by the U.S. Food 
and Drug Administration (NDA 021746). The ADS uses novel capillary-based aerosol generator 
(CAG) technology to aerosolize lucinactant for inhalation, providing a high-density surfactant 
aerosol output (1.2 mL/min), with an appropriate particle size (2 to 3 microns mass median 
aerodynamic diameter [MMAD]) for respiration and deposition within the neonatal lung. The 
ADS may allow aerosolized lucinactant to be deposited in the lungs of preterm neonates in 
sufficient quantities to effect a therapeutic response analogous to that of endotracheal instillation 
of surfactant.  
Nonclinical studies using the CAG technology in preterm lambs have demonstrated that 
aerosolized lucinactant significantly improved lung mechanics and gas exchange compared with 
preterm lambs receiving CPAP alone (26). In parallel, pilot clinical studies in neonates with RDS 
(Study KL4-CPAP-01) (27) as well as in adults with asthma and cystic fibrosis (Study KL4-
ASTH-01) have demonstrated that lucinactant aerosolized with commercially available 
nebulizers appears to be generally well-tolerated. The ADS represents the clinical version of the 


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CAG technology, which is being used in clinical trials, including the current study, to aerosolize 
lucinactant. 
1.3 
Clinical Experience with Aerosolized Lucinactant 
Two Discovery-sponsored clinical studies have been conducted using aerosolized lucinactant 
administered with standard, commercially available nebulizers (Studies KL4-CPAP-01 (27) and 
KL4-ASTH-01). Aerosolized lucinactant administered with the ADS has been investigated in 
one completed Discovery-sponsored clinical trial (Study 03-CL-1201) and one ongoing 
Discovery-sponsored clinical trial (Study 03-CL-1401). These studies are described below, and 
in further detail in the Investigator’s Brochure.  
1.3.1 Preliminary Studies Using Commercially Available Nebulizers 
Study KL4-CPAP-01 (27) was a Phase 2, multicenter pilot study in preterm neonates 
investigating the feasibility of delivering aerosolized lucinactant to preterm neonates at risk for 
RDS administered using the Aeroneb® Pro Nebulizer System in conjunction with nCPAP, which 
delivered a lucinactant output of approximately 4 μL/second. The majority (12, 70%) of the 17 
neonates studied received a single dose of study drug, with exposure dosage of approximately 72 
mg TPL of aerosolized lucinactant in a volume of 43 mL over the 3-hour treatment. No device-
related serious adverse events (SAEs) occurred. Adverse events during dosing (peridosing 
events) included oxygen desaturation (53% of patients), pallor (6%), nasal irritation (6%), skin 
irritation (6%), and apnea (29%); many of these are commonly observed in premature infants on 
nCPAP. Five subjects (30%) required subsequent endotracheal surfactant replacement, which is 
somewhat better than the rate reported in the literature (13, 14). The study demonstrated that it is 
feasible to deliver aerosolized lucinactant in conjunction with nCPAP and that the treatment was 
generally well-tolerated by preterm neonates. 
Study KL4-ASTH-01 was a Phase 1b study that assessed the safety and tolerability of 
aerosolized lucinactant in a placebo-controlled study of adults with mild persistent asthma. Six 
healthy adult volunteers and 9 adults with mild persistent asthma were administered aerosolized 
lucinactant by the Aeroneb® Pro Nebulizer System. In this study, ≤ 24.5 mg TPL was 
administered at approximately 1 mg/minute. The treatment was well-tolerated with no serious 
adverse events (SAEs). Pulmonary function and clinical signs and symptoms of asthma generally 
remained unchanged from baseline and were similar in both treatment groups.  


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The study demonstrated it is feasible to deliver aerosolized lucinactant to adults and that the 
treatment was generally well-tolerated. 
1.3.2 Clinical Studies using the AEROSURF Delivery System 
Lucinactant aerosolized using the ADS has been studied in a completed Phase 2a study in infants 
29 to 34 weeks PMA (Study 03-CL-1201). Results of this study are summarized in Section 
1.3.2.1, and results apropos to the selection of dosages in Part A of this study are summarized in 
Section 2.2.3.5. In addition, another study (Study 03-CL-1401) has been initiated to evaluate the 
safety and tolerability of lucinactant for inhalation in younger preterm infants 26-28 completed 
weeks PMA. Preliminary results of this study are summarized in Section 1.3.2.2, and results 
apropos to the selection of dosages in Part B of this study are summarized in Section 2.2.3.5. The 
current protocol (03-CL-1202) is designed to evaluate the size of the treatment effect for 
planning future studies. 
1.3.2.1 Study 03-CL-1201 
Study 03-CL-1201 was a Phase 2a, multicenter, randomized, open-label, controlled dose-
escalation study assessing the safety and tolerability of aerosolized lucinactant delivered using 
the ADS in preterm infants 29 to 34 completed weeks PMA. This study was conducted at 12 
study sites in the US and evaluated the safety of 5 dose-exposures of aerosolized lucinactant in 
conjunction with nCPAP: 25 mg TPL/kg, 50 mg TPL/kg, 75 mg TPL/kg, 100 mg TPL/kg and 
150 mg TPL/kg. Repeat doses were possible for the larger 2 dosages. Neonates treated with 
nCPAP alone served as the control group. 
A total of 80 neonates were enrolled, with 8 in each of the 5 dosing groups and 40 in the control 
group. Active and control subjects were similar in terms of gestational age, birth weight, gender, 
race and ethnic origin. One subject did not meet inclusion criteria but was enrolled in error; since 
this subject was randomized to the 100 mg TPL/kg group and briefly received study treatment, 
this subject was included in the safety analysis but not in the exploratory efficacy analyses. All 
active subjects received at least one treatment; 1 subject in the 100 mg TPL/kg group and 2 in the 
150 mg TPL/kg group received 2 treatments. Study drug treatment (initial or repeat) was 
discontinued early in 10 (25%) subjects: 6 (15%) due to “device failure or malfunction”; 2 (5%) 
due to signs of acute respiratory deterioration (including the subject enrolled in error); and 2 
(5%) due the principal investigator’s medical judgment. “Device failure or malfunction” was 
selected when the ADS terminated aerosol treatment early; however, these early stoppages were 
due to an error code being detected, such as an aerosol temperature outside of the preset 


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acceptable range. Thus, the device functioned as designed, but the full treatment was not 
delivered. 
The incidence of adverse events (AEs) was comparable between treatment and control groups, 
occurring in 39 (98%) active subjects and 37 (93%) controls. The incidence of AEs did not 
increase with dosage. The 3 most common AEs were neonatal jaundice, constipation and 
neonatal apnea. Complications of prematurity were comparable between treatment and control 
groups; the 3 most common were apnea (occurring in 23 [58%] active and 23 [58%] control 
subjects), air leak (9 [23%] active and 7 [18%] controls, discussed further below), and patent 
ductus arteriosus (5 [13%] active and 3 [8%] control subjects). Peri-dosing events were 
uncommon, occurring in 7 (18%) active subjects with no increase in incidence as dosage 
increased. The 3 most common peri-dosing events were transient desaturation in 5 (13%) 
subjects, nasal irritation in 2 (5%) subjects, and vomiting in 2 (5%) subjects. SAEs occurred in 
13 (33%) of active subjects, with no increase in incidence as dosage increased, and 7 (18%) of 
control subjects. Pneumothorax (a specific form of air leak, discussed further below) was the 
most commonly reported SAE, reported in 9 (23%) active subjects and 4 (10%) controls. Two 
subjects died: one subject in the 150 mg TPL/kg group experienced severe cardiopulmonary 
deterioration of unknown cause (suspected sepsis) 9 days after study treatment, and one control 
subject died of acute pulmonary hemorrhage related to RDS and treatment with poractant alfa 
(Curosurf) 2 days after randomization into the study; neither death was considered to be related 
to study treatment or procedures. 
When all forms of pulmonary air leak, including pneumothorax, pneumomediastinum and PIE 
(see Section 9), are considered together, the incidence in active and control groups was similar 
(Table 1-1). Overall, 9 (23%) active subjects experienced air leak, all of whom had 
pneumothorax with 2 (5%) experiencing PIE and 1 (3%) experiencing pneumomediastinum as 
well. The incidence across dosage groups was similar. In the control group, 7 (18%) were 
reported by the investigator as having air leak, 5 (13%) of whom had pneumothorax and 2 (5%) 
experiencing PIE.  
An independent review of all radiographs of all subjects confirmed the 9 air leaks in the active 
subjects, but identified an additional 2 air leaks (both PIE) in 2 control subjects. Thus, the 
independent review noted a total air leak incidence of 9 (23%) among both active and control 
subjects. 


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Table 1-1: Air Leaks Reported as Adverse Events in Study 03-CL-1201 
 
25 mg 
TPL/kg 
(N=8) 
50 mg 
TPL/kg 
(N=8) 
75 mg 
TPL/kg 
(N=8) 
100 mg 
TPL/kg 
(N=8) 
150 mg 
TPL/kg 
(N=8) 
Total 
Active 
(N=40) 
nCPAP 
Only 
(N=40) 
Total Air Leaks1 
2 (25%) 
2 (25%) 
1 (13%) 
2 (25%) 
2 (25%) 
9 (23%) 
7 (18%) 
   Pneumothorax 
2 (25%) 
2 (25%) 
1 (13%) 
2 (25%) 
2 (25%) 
9 (23%) 
5 (13%) 
   Pneumomediastinum 
0 
1 (13%) 
0 
0 
0 
1 (3%) 
0 
   PIE 
0 
0 
0 
0 
2 (25%) 
2 (5%) 
2 (5%) 
1Subjects may have had more than one type of air leak 
PIE = pulmonary interstitial emphysema 
Lucinactant for inhalation had no clinically important effect on serum electrolytes, gastric liquid 
volume, or defecation. Mean concentration of serum electrolytes (sodium, potassium, chloride, 
total carbon dioxide) was within normal range in active patients at 24 hours of life. AEs related 
to electrolyte disturbances were infrequent (≤13%) and similar between active and control 
subjects. Gastric liquid volume (residual) checked after dosing was physiologically normal for 
all active subjects, ranging from 0.00 to 8.00 mL; mean volume tended to increase with dosage 
(0.25±0.5 mL in the 25 mg TPL/kg group, 2.00±1.9 mL in the 150 mg TPL/kg group). Although 
constipation was reported an AE somewhat more frequently in active subjects (50%) vs controls 
(35%), active subjects had a physiologically normal number of stools (1.9) in the first 24 hours 
of life which was similar to the number in control subjects (1.7).  
Study 03-CL-1201 was neither designed nor powered to investigate efficacy. However, clinical 
parameters associated with efficacy (and safety) were measured. Preliminary results are 
described here for completeness and to inform dosage selection for the present study (see Section 
2.2.3). Overall, active subjects had a more rapid decrease in FiO2 than control subjects (Figure 
1-1): 1 hour after starting dosing, 11 (28%) active subjects were breathing room air (FiO2 0.21) 
vs 3 (8%) control subjects. Decreases in FiO2 were modest as expected (Figure 1-1), since most 
subjects were on relatively small amounts of supplemental oxygen (median FiO2 0.28 in active 
subjects, 0.30 in controls). Decreases in PCO2 were similarly modest and not different between 
actives and controls. 


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Figure 1-1 Change from baseline in FiO2 of all subjects in Study 03-CL-1201 
 
Intubation within 72 hours of life for any reason was considered a key efficacy parameter, since 
it generally indicates progression of RDS beyond the point where the subject can be supported 
on nCPAP alone and is the main intervention that aerosolized surfactant seeks to avoid. When 
limited to the initial 72 hour period, intubation occurred in 21 (53%) of control subjects (Figure 
1-2); the incidence was generally similar in each of the 5 individual control groups, thus all 
controls were pooled for comparison. Overall, 20 (50%) subjects in the active groups were 
intubated. However, notably fewer subjects were intubated with the higher 3 dosages (7/23, 
30%) than with the lower 2 dosages (11/16, 69%). Additionally, time to intubation was longer in 
active subjects (mean±SE of 55±36 hrs) than controls (19±4 hrs), particularly for subjects in the 
higher 3 dosage groups (Figure 1-3). 


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Figure 1-2 Incidence of Intubation for Any Reason within 72 Hours of Life (nCPAP 
Failure) in Study 03-CL-1201. 


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Figure 1-3 Kaplan-Meier plot showing proportion of subjects not intubated over the first 
12 hours after randomization into Study CL-03-1201. The higher 3 dosage groups (blue 
line) and lower 2 dosage groups (red line) are shown combined, vs all controls (black line). 
  
In conclusion, the results from Study 03-CL-1201 demonstrate that delivery of lucinactant as an 
aerosol using the ADS is feasible and that lucinactant for inhalation appears to be generally 
well-tolerated in infants 29-34 weeks PMA with RDS. Exploratory assessment of clinical 
efficacy parameters suggests that lucinactant for inhalation may be providing beneficial effects.  
1.3.2.2 Study 03-CL-1401 
Study 03-CL-1401 is a Phase 2a, multicenter, randomized, open-label, controlled dose-escalation 
study assessing the safety and tolerability of aerosolized lucinactant delivered using the ADS in 
preterm infants 26 to 28 completed weeks PMA. The planned intent is to evaluate the safety of 
up to 4 dose-exposures of aerosolized lucinactant in conjunction with nCPAP: 50 mg TPL/kg, 75 


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mg TPL/kg, 100 mg TPL/kg and 150 mg TPL/kg. One repeat dose is possible for all dosages. 
Neonates treated with nCPAP alone serve as the control group. A total of 22 study sites from the 
US, Canada, Poland and Chile have received IRB/REB/EC, health authority approval, where 
applicable, and sponsor approval for participation in the study. 
As of the data cut-off date for this Amendment (21 Feb 2017), 45 subjects have been enrolled, 
with 8 each in the 50 and 75 mg TPL/kg groups, 6 in the 100 mg TPL/kg group, and 23 in the 
control group; the 150 mg TPL/kg group is not yet open for enrollment. Active and control 
subjects have been similar in terms of gestational age, birth weight, gender, race and ethnic 
origin. All active subjects received at least one treatment, and 15 (68%) received a repeat 
treatment. Median time to initiation of study treatment was 5.3 hours after birth. 
Study drug treatment (initial or repeat) was discontinued early in 9 (41%) subjects: 8 (36%) due 
to “device failure or malfunction” and none due to signs of acute respiratory deterioration or 
investigator judgment. Most (5/8, 63%) of the device errors have been due to a “syringe pressure 
out of range” error, which likely resulted from micro-occlusions within the filter in the ADP, 
predominantly with certain manufacturing lots. When such errors occurred, supplemental 
lucinactant for inhalation was administered according to a schedule such that subjects received 
90-110% of the intended dosage. 
To date, the incidence of AEs and common complications of prematurity have been as expected 
for this population. AEs have been comparable between treatment and control groups, occurring 
in all active and control subjects. The 3 most common AEs have been neonatal apnea (occurring 
in 15 [68%] active and 17 [74%] control subjects), neonatal anemia (12 [55%] active and 9 
[39%] controls), and neonatal jaundice (9 [41%] active and 12 [52%] controls). The 3 most 
common complications of prematurity were apnea (16/22 [73%] active and 15/23 [65%] 
controls), PDA (10/22 [45%] active and 6/23 [26%] controls), and acquired sepsis (6/22 [27%] 
active and 3/23 [13%] control subjects). The small numbers of subjects in each group makes 
comparisons of these preliminary data difficult, but to date incidences appear to be generally 
comparable. Peri-dosing events have been uncommon, occurring in 7 (32%) active subjects with 
no clear increase in incidence as dosage has increased. The 3 most common peri-dosing events 
have been desaturation in 6 (27%) subjects, bradycardia in 3 (14%) subjects, and apnea in 3 
(14%) subjects. SAEs have occurred in 9 (41%) of active subjects, with no increase in incidence 
as dosage has increased, and 6 (26%) of control subjects. Lucinactant for inhalation has had no 
clinically important effect on serum electrolytes, gastric liquid volume, or defecation. 


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Air leaks have occurred in 4 (18%) active subjects and 2 (9%) control subjects (Table 1-2). Two 
of the subjects in the 50 mg TPL/kg group who experienced air leaks are twins who were 
subsequently diagnosed with Ehlers-Danlos syndrome, a genetic connective tissue disorder in 
which spontaneous pneumothorax in children can be a presenting sign.  
Table 1-2: Air Leaks Reported as Adverse Events in Study 03-CL-1401 
 
50 mg 
TPL/kg 
(N=8) 
75 mg 
TPL/kg 
(N=8) 
100 mg 
TPL/kg 
(N=6) 
150 mg 
TPL/kg 
(N=–) 
Total 
Active 
(N=22) 
nCPAP 
Only 
(N=23) 
Number of Subjects with an Air Leak1 
3 (38%) 
0 
1 (17%) 
— 
4 (18%) 
2 (9%) 
   Pneumothorax 
1 (13%) 
0 
1 (17%) 
— 
2 (9%) 
1 (4%) 
   PIE 
2 (25%) 
0 
0 
— 
2 (9%) 
1 (4%) 
1 Subjects may have had more than one type of air leak 
PIE = pulmonary interstitial emphysema 
 
After enrollment in each dosing group of Study 03-CL-1401 was completed, the Safety Review 
Committee (SRC) reviewed all safety data as specified in the study protocol. No findings of 
concern were identified, and the study was allowed to proceed to subsequent dosing groups. In 
addition, the SRC agreed that neonates 26-28 weeks PMA could be enrolled in the present study 
(Study 03-CL-1202). 
Study 03-CL-1401 was neither designed nor powered to investigate efficacy. However, clinical 
parameters associated with efficacy (and safety) were measured. Preliminary results are 
described here for completeness and to inform dosage selection for Part B of the present study 
(see Section 2.2.3). 
To date, active subjects have been no different from controls in change in FiO2 or PCO2 or in 
incidence of intubation within 72 hours of life (Figure 1-4). The reason for this apparent lack of 
effect is uncertain. As a safety study, Study 03-CL-1401 is not powered to detect efficacy so it 
may simply be too small to detect any difference in efficacy parameters, particularly since the 
likelihood of intubation in general rises with lower GA. Both active and control subjects were 
much more likely to be intubated if their baseline FiO2 was ≥0.35 (10/11 [91%] active and 9/9 
[100%] controls) vs <0.35 (7/12 [58%] active and 6/14 [43%] controls), suggesting that subjects 
whose baseline FiO2 was ≥0.35 were highly likely to be intubated regardless of treatment 
assignment. As a dose-escalation study, it is also possible that an effective dosage has not yet 
been reached, particularly since RDS is more common and often more severe in this immature 


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population than in neonates 29-34 weeks PMA, suggesting that they have a greater deficiency of 
surfactant and would require a higher dosage. Finally, since the literature supports administering 
SRT as early as possible especially in extremely preterm neonates (2-6), it is possible that the 
time between birth and treatment (5.3 hours) and the interval between treatments (4.6 hours) 
reduced the effectiveness of the treatment. This is supported by the observation that intubation 
occurred somewhat later in active patients vs controls (Figure 1-5). 
 
Figure 1-4. Incidence of Intubation for Any Reason within 72 Hours of Life (nCPAP 
Failure) in Study 03-CL-1401. 
 


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Figure 1-5: Time to Intubation for Any Reason within 72 Hours of Life (nCPAP Failure) in 
in Study 03-CL-1401. 
 
In conclusion, the preliminary results from Study 03-CL-1401 to date demonstrate that delivery 
of lucinactant as an aerosol using the ADS is feasible and that lucinactant for inhalation appears 
to be generally well-tolerated in infants 26-28 weeks PMA with RDS. Although the study is not 
powered for efficacy, it is likely that a total dosage greater than 100 mg TPL/kg (repeated more 
than 1 time) is required in this population. 


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2 
STUDY DESIGN AND RATIONALE 
This study will investigate the safety and efficacy of lucinactant for inhalation in conjunction 
with nCPAP compared to nCPAP alone. The study design is broken into 2 sequential parts. Part 
A will be masked and include neonates 28 to 32 completed weeks PMA. Part B will commence 
after completion of Part A, will include neonates 26 to 28 completed weeks PMA, and will be 
open-label. Part A will include 2 dosages of lucinactant for inhalation in 3 parallel treatment 
groups (40 mg TPL/kg lucinactant for inhalation, 80 mg TPL/kg lucinactant for inhalation, and 
nCPAP only; initial single dose with up to 2 repeat doses) in preterm neonates 28 to 
32 completed weeks PMA with RDS who are within the first 20 hours after birth, who had 
successful implementation of non-invasive support or ventilation within 90 minutes of birth, and 
who are candidates for SRT. Part B will include 1 dosage of lucinactant for inhalation in 2 
parallel treatment groups (80 mg TPL/kg lucinactant for inhalation and nCPAP only; single dose 
with up to 4 repeat doses) in preterm neonates 26 to 28 completed weeks PMA with RDS who 
are within the first 12 hours after birth, who had successful implementation of non-invasive 
support or ventilation within 60 minutes of birth, and who are candidates for SRT. 
2.1 
Study Design 
This study is a sequential 2-part, multinational, multicenter, masked (Part A)/open-label (Part B), 
randomized, controlled study to evaluate the safety and efficacy of lucinactant for inhalation in 
conjunction with nCPAP compared with nCPAP alone, in preterm neonates 28 to 32 completed 
weeks PMA (Part A) and in preterm neonates 26 to 28 completed weeks PMA (Part B). There 
will be 2 phases in Parts A and B of the study: a primary phase through 36 weeks PMA and a 
longer-term follow-up phase through 1-year corrected age. Data will be analyzed and reported at 
the completion of each respective study phase for Parts A and B of the study. 
Before study enrollment, parents or legal guardians will provide a signed written informed 
consent form (ICF) for each potential subject. Qualification for study enrollment will be 
established after informed consent has been provided and after confirmation that the subject has 
met all of the inclusion criteria and none of the exclusion criteria. The clinical criteria for 
enrollment may be met prior to informed consent being obtained; however, no study-specific 
procedures that are not part of the usual standard care of the subject at the institution may be 
performed until the informed consent has been provided by a legally authorized representative of 
the subject.  


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For Part A of the study, inclusion criteria to be met within the first 20 hours after birth include 
respiratory insufficiency with a requirement for nCPAP of 5 to 7 cm H2O and a fraction of 
inspired oxygen (FiO2) ≥0.25 (>0.21 for neonates 28 weeks PMA) to 0.4 to maintain oxygen 
saturation measured by pulse oximetry (SpO2) of 90% to 95% for at least 30 minutes. For Part B 
of the study, inclusion criteria to be met within the first 12 hours after birth include respiratory 
insufficiency with a requirement for nCPAP of 5 to 7 cm H2O with a FiO2 >0.21 to 0.4 to 
maintain SpO2 of 90% to 95% for at least 20 minutes. As soon as study qualification has been 
confirmed and the informed consent is signed, subjects will be immediately randomized to an 
active treatment group (2 active groups in Part A; 1 active group in Part B) or the control 
(nCPAP only, with simulated [“sham”] study drug treatment in Part A) group. Subjects in Part A 
will be enrolled by strata: approximately 5-10% (12-24) of the subjects will be 28 completed 
weeks PMA and approximately 206-228 of the subjects 29 to 32 completed weeks PMA. 
Randomization in Part B will be stratified by treatment within each gestational age (26, 27, and 
28 completed weeks PMA) and up to 80 patients will be enrolled. Study therapy (lucinactant for 
inhalation or sham/control) must be initiated as soon as possible after randomization. Treatment 
groups are outlined in Section 5.5. 
In Part A, subjects may be eligible to receive up to 2 repeat doses of the treatment to which they 
are assigned. Repeat doses will be given as soon as 2 hours from completion of the previous dose 
up to 36 hours after completion of randomization if subjects meet repeat dosing criteria, unless it 
is unsafe to do so in the judgment of the investigator, as described in Section 5.7. Should this 
situation arise the investigator will document the circumstances in the eCRF. Subjects 
randomized to a control group will be continued on nCPAP alone but will receive repeated sham 
treatment to maintain study masking. 
In Part B, subjects in the active group may be eligible to receive up to 4 repeat doses of the 
treatment to which they are assigned. Repeat doses will be given as soon as 30 minutes from 
completion of the previous dose up to 36 hours after completion of randomization if subjects 
meet repeat dosing criteria, unless it is unsafe to do so in the judgment of the investigator, as 
described in Section 5.7. 
In both parts of the study, all subjects in the active treatment groups will receive the same drug 
concentration of lucinactant for inhalation (30 mg TPL/mL) at the same rate of delivery 
(aerosolized concentration of 4.2 mg TPL/L in aerosol carrier gas flow of 3 L/min). The dosage 
will vary by the predetermined administration time for each dose. Lucinactant for inhalation will 
be delivered by the investigational ADS device in conjunction with a commercially available 


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nCPAP generator and patient interface. Details on dosage calculations and rationale are given in 
Section 2.2, and the drug delivery device is outlined in Section 5.1. 
In Part A, treatment assignments will be masked from the principal investigator (PI), clinical and 
study staff (eg, site coordinator, bedside nurse), as applicable; sponsor, as applicable; and 
subject’s parents/legal guardians. In Part B, treatment assignments will be open-label. 
All enrolled subjects will receive study treatment in a NICU, a specialized care center staffed by 
neonatologists, nurses, and respiratory therapists who are experienced in the delivery of 
emergent care to the preterm neonatal population. Neonates in the NICU are continuously 
monitored using advanced and sophisticated monitoring equipment, and there is ready and 
immediate access to equipment, medications, and skilled personnel that may be needed to 
address emergent developments. Interventions such as endotracheal intubation, MV, and 
traditional surfactant administration will be readily available to all study subjects if clinically 
indicated in accordance with the high-level standard-of-care customary in the NICU. 
In both parts of the study, neonates will be followed for the primary phase efficacy and safety 
evaluations through 36 weeks PMA, NICU discharge, hospital transfer, or death (whichever 
occurs first). For the longer-term follow-up phase, neonates will be evaluated by phone at 6-
months corrected age and followed up to 1-year corrected age, at which time a physical 
examination will be performed, including an abbreviated neurologic assessment. (See also 
Sections 7 and 8.) 
A schematic diagram of the study design is displayed in Figure 2-1. 


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Randomization 
Screening
40 mg/kg w/ 2 Poss. Repeats
(25 minutes)
nCPAP alone
36 Weeks PMA
80 mg/kg w/ 2 Poss. Repeats
(50 minutes)
1 Year Follow-up
28 to 32 Weeks PMA
Randomization 
Screening
nCPAP alone
36 Weeks PMA
80 mg/kg w/ 4 Poss. Repeats
(50 minutes)
1 Year Follow-up
26 to 28 Weeks PMA
Part A
Part B
 
Figure 2-1 Schematic of Study Design for 03-CL-1202 
 
2.2 
Dose and Device Description and Rationale 
In Part A of this study, up to 160 subjects (up to 80 in each of the 2 lucinactant for inhalation 
treatment groups) and in Part B up to 40 subjects will be randomized to an active treatment 
group and will receive aerosolized lucinactant through the ADS in conjunction with nCPAP. Up 
to 80 subjects in Part A and up to 40 in Part B will be randomized to the control group and will 
receive nCPAP alone with “sham” study drug treatment. 
2.2.1 General Description and Rationale for the ADS 
A full description of the ADS is given in Section 5.1. Briefly, reconstituted lyophilized 
lucinactant is pumped at high pressure and temperature through a capillary, which aerosolizes the 
lucinactant. The aerosolized lucinactant is propelled by gas flow and carried via an aerosol 
delivery tube where it joins the subject’s nCPAP system, allowing administration of aerosolized 
surfactant while maintaining respiratory support with nCPAP. 
Unlike prior attempts to aerosolize surfactants with conventional nebulizers, the ADS may 
aerosolize lucinactant in sufficient quantities to affect a therapeutic response sufficient to avoid 
endotracheal intubation. A device that permits effective surfactant aerosolization to neonates 
while receiving nCPAP support for the treatment of RDS may improve the success of nCPAP 
therapy and better avoid the potential deleterious effects of endotracheal intubation and 
mechanical ventilation. 


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2.2.2 Rationale for Study Control 
Preterm neonates who are treated for RDS initially with non-invasive ventilation (including 
nCPAP) are the appropriate controls for this study, since the addition of aerosolized surfactant 
would be the only difference in treatment in the active groups compared to the controls. Current 
guidelines allow use of non-invasive ventilation such as nCPAP as an initial modality for the 
treatment of RDS in preterm newborns, with the goal of avoiding endotracheal intubation (3-6, 
11). 
Initial treatment with brief intubation, surfactant delivery and extubation (the “INSURE” 
technique) or other forms of intratracheal (eg, the “LISA” or “MIST” techniques) or supraglottic 
(eg, via laryngeal mask airway) surfactant instillation represent potential alternative therapeutic 
strategies for SRT in RDS which would not demonstrate the effectiveness of aerosolized 
lucinactant in an isolated fashion, and thus would not be appropriate controls. 
Each of the 4 components of lucinactant (see Section 5.2.1) plays a role in its biological activity. 
Aerosolized vehicles (eg, sterile water or saline) may have an adverse effect on pulmonary 
function. Thus, no inert placebo exists. Therefore, “sham” treatment, in which the ADS is 
brought to the subject’s bedside but not used to deliver study drug, is the optimal control for the 
blinded Part A while continued nCPAP is the appropriate control for the open-label Part B. 
All study treatments (whether active or control) are given only if subjects are stable enough that 
they do not require intubation. Such subjects would typically be maintained on standard nCPAP 
or other forms of non-invasive ventilation. Since control/sham treatment is equivalent to standard 
care, it is therefore ethical to administer for initial or repeat dosing. 
2.2.3 Dosage Rationale 
2.2.3.1 General Considerations in Dosage Selection 
Lucinactant, administered as an intratracheal liquid bolus at a dose of 175 mg TPL/kg 
(5.8 mL/kg of a 30 mg TPL/mL suspension) has been demonstrated to be safe and effective in 
the prevention of RDS in preterm neonates at high risk for RDS and has been approved by the 
FDA (trade name SURFAXIN®, NDA 021746). However, the precise quantity of surfactant 
replacement required by any given neonate cannot be measured or known. The amount of 
surfactant needed by a neonate increases with alveolar surface area, which increases with weight 
and gestational age. The amount of endogenous surfactant available to a neonate depends 
critically on gestational age and lung maturation, but also on a number of other immeasurable 


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factors including lung inflammation, prenatal steroids, etc. Although neonates born at a lower 
gestational age are likely to be more surfactant deficient compared with neonates born at higher 
gestational ages, dosing algorithms based on gestational age or birth weight would be inadequate 
to estimate the dose of exogenous surfactant that should be administered to adequately replete 
surfactant and thereby treat RDS. 
Neonates at high risk for RDS are presumed to be substantially or wholly surfactant deficient; 
these neonates require immediate endotracheal intubation, SRT and MV. In contrast, the 
population of preterm neonates who can be sustained by nCPAP, rather than endotracheal 
intubation and MV, likely represent a broad spectrum of varying degrees of surfactant deficiency 
who may not require the full intratracheal dose of SRT. Study KL4-CPAP-01 (27) (Section 
1.3.1) suggested an appropriate dosage of aerosolized lucinactant (using the Aeroneb® Pro 
Nebulizer System) for premature neonates with RDS supported with nCPAP could be in the 
range of 75 mg TPL/kg, substantially lower than the intratracheal bolus lucinactant dosage of 
175 mg TPL/kg. Preclinical studies in animal models of RDS (28) and acute lung injury (29) 
suggest that the effective dosage of aerosolized surfactant may be as little as 5% that of the 
effective dosage of intratracheal surfactant. Thus, it is likely that preterm neonates on nCPAP 
will require substantially less than the intratracheal bolus dose of 175 mg TPL/kg of lucinactant.  
Inhalational delivery of drugs is extremely inefficient compared to most other modes of delivery. 
When delivered traditionally as an intratracheal bolus of liquid, it is highly likely that most, if not 
all, of the instilled surfactant will ultimately arrive at its site of action in the alveoli since 
surfactants tend to spread along surfaces. Studies in neonatal piglets have demonstrated that 
aerosolized surfactant is deposited in the lung much less efficiently than an equivalent 
intratracheal bolus (30) but with similar physiologic effects (31).  
Delivery of an aerosol to the alveoli will vary depending on the characteristics of the device (eg, 
condensation within tubing or impaction within the device), the aerosol itself (eg, particle size 
and rate of administration), and the breathing characteristics of the individual neonate (eg, 
inspiratory and expiratory patterns and ratios, frequency, tidal volume). To reach the alveoli and 
be deposited there, inhaled particles typically require a diameter ≤5 μm. Ideally, the rate of 
aerosol administration is kept constant and similar to the neonate’s inspiratory flow rate to 
maximize the amount of aerosol that is inhaled. Typically, inspiratory and expiratory patterns in 
preterm neonates vary from breath to breath, although are less variable than in older infants and 
children. Minute ventilation is the amount of air exchanged (inhaled and exhaled) in one minute, 
and is calculated as the product of breathing frequency and tidal volume. Minute ventilation 


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generally tends to be less variable than the pattern of individual breaths. Since minute ventilation 
is related to body surface area, which is in turn dependent on body weight (32, 33), it can be used 
to estimate the theoretical maximum inhalable dose of aerosolized surfactant normalized to body 
weight. The actual inhaled dose is likely to be less than the theoretical maximum since some 
aerosolized surfactant will be expelled during exhalation or will deposit in the naso- and 
oropharynx where it may then be swallowed. When lucinactant was aerosolized using the ADS 
and delivered via nCPAP (5 cmH2O) to cynomolgus macaques, whose airway anatomy is similar 
to that of preterm human neonates, the inhaled dose was deposited homogenously throughout the 
lungs (34). 
2.2.3.2 Calculation of the Theoretical Inhaled Dose 
The emitted dose of lucinactant for inhalation is the amount of aerosolized lucinactant delivered 
to the subject at the output of the aerosol tube where it joins the patient nCPAP interface. The 
theoretical inhaled dose is the amount of aerosolized lucinactant predicted to be inhaled by the 
subject. This inhaled dose is a function of the concentration of lucinactant in the aerosol, the 
amount of aerosol inhaled by the subject (estimated by the subject’s minute ventilation, assuming 
that all gas inhaled by the subject contains the same concentration of aerosol), and the duration 
of exposure to the aerosol. Thus, the dose can be estimated using the following equation:  
 
T
kg
Vm
C






=
Dose
 
Inhaled
 
Equation 1 
Where: C 
= Concentration of lucinactant in aerosol (in mg TPL/L) 
 
Vm/kg = Minute ventilation normalized to body weight (in L/min/kg) 
 
T 
= Dose duration (in minutes) 
 
All of the lucinactant that flows through the CAG is aerosolized; however, since much of the 
aerosolized drug impacts within the aerosol tubing only 35% reaches the patient interface. The 
emitted dose rate of the ADS is therefore the product of the flow rate of lucinactant through the 
CAG (1.2 mL/min), the concentration of the reconstituted lucinactant in the dosing syringe 
(30 mg TPL/mL) and the fraction of the aerosolized dose that is reaches the patient interface 
(35%) (see Investigator’s Brochure for further information): 
 
Emitted dose rate = 1.2 mL/min  30 mg TPL/mL  0.35 = 12.6 mg TPL/min  
Equation 2 


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The aerosolized lucinactant is carried to the patient interface by a gas (generally a mix of air and 
supplemental oxygen). The rate of flow of the carrier gas was chosen to be 3 L/min, which 
represents the typical peak inspiratory flow rate expected in the target population (33, 35). The 
concentration of aerosolized lucinactant in the carrier gas (C) is therefore the emitted dose rate 
(12.6 mg TPL/min) divided by the carrier gas flow rate (3 L/min). 
𝐶=
12.6 mg TPL/min
3 L/min
= 4.2 mg TPL/L 
Equation 3 
Minute ventilation (Vm) of preterm neonates can be estimated based on body weight, as shown 
in Table 2-1 (32, 33). When normalized to body weight, minute ventilation of the subjects 
expected to enroll in this study (750 to 2250 g) can be approximated as 0.4 L/min/kg. 
Table 2-1. Estimated Minute Ventilation of Preterm Neonates, by Weight 
 
Bide et al. (32) 
Bhutani et al. (33) 
 
Vm 
Vm (50th percentile) 
Weight (g) 
(L/min/kg)1 
(L/min) 
(L/min/kg) 
(L/min) 
750 
0.527 
0.3954 
0.4 
0.3000 
1000 
0.499 
0.4990 
0.4 
0.4000 
1250 
0.478 
0.5977 
0.4 
0.5000 
1500 
0.462 
0.6927 
0.4 
0.6000 
1750 
0.448 
0.7847 
0.4 
0.7000 
2000 
0.437 
0.8742 
0.4 
0.8000 
2250 
0.427 
0.9616 
0.4 
0.9000 
2500 
0.419 
1.0472 
0.3 
0.7500 
2750 
0.411 
1.1312 
0.3 
0.8250 
1 Calculated 
 
The time required to deliver the desired dose (T) can therefore be calculated by rearranging 
Equation 1 in terms of T; that is, dividing the desired theoretical inhaled dose by the product of 
C (4.2 mg TPL/L) and Vm (0.4 L/min/kg). For example, this calculation yields dose durations of 
50 minutes to achieve a target theoretical inhaled dose of 80 mg TPL/kg and 90 minutes for a 
dose of 150 mg TPL/kg. 
2.2.3.3 Rationale for Dosages Used in the Current Study 
The dosages used in completed study 03-CL-1201 were 25, 50, 75, 100 and 150 mg TPL/kg and 
in ongoing study 03-CL-1401 to date have been 50, 75, and 100 mg TPL/kg. From the practical 
standpoint, however, a dosage > 80 mg TPL/kg is cumbersome to administer. Two lucinactant 


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syringes of 60 mL each are required for these higher dosages, and the ADS system must be 
temporarily shut down during administration in order to change the syringe.  
To improve the practical viability of the program, Discovery has decided to develop and evaluate 
dosages of 40 and 80 mg TPL/kg. The higher dosage is the largest dosage that can be practically 
administered with a single 60 mL syringe. Using the dosage calculation in Section 2.2.3.2, the 
dosing durations for the 40 mg TPL/kg and 80 mg TPL/kg dosages would be 25 and 50 minutes, 
respectively. Dosages are approximate, as each neonate’s minute ventilation and pulmonary 
characteristics may vary slightly. If higher dosages are necessary, this can be achieved with 
repeat dosing, as is frequently done with intratracheal surfactant administration (1). Part A of this 
study will evaluate both dosages, while Part B will use only the 80 mg TPL/kg dosage. 
2.2.3.4 Nonclinical Experience Supporting Dose Rationale 
Study MB 04-12812.01 evaluated the toxic effects of orally administered lucinactant in adult 
rabbits. A total of 14 daily doses of 600 mg TPL/kg lucinactant (20 mL/kg) or 20 mL/kg 
Tris/NaCl buffer were administered orally by gavage in 2 equal volumes (10 mL/kg) at 
2- or 4-hour intervals to adult rabbits (2 males and 2 females per treatment group). A total of 
8400 mg TPL/kg of lucinactant was administered enterally. No evidence of any toxic effect was 
found in any animals in this study. 
Two completed nonclinical animal toxicology studies in pre-weaned rabbits (Study N107662) 
and pre-weaned rats (Study N107663) evaluated the acute toxicity of inhaled lucinactant 
(aerosolized by CAG technology). Rabbits and rats were exposed to aerosol on 2 consecutive 
days by a nose-only inhalation exposure system. Aerosolized lucinactant low-, mid-, and high-
dose groups were compared with air control and vehicle. Aerosolized lucinactant dose selections 
were based on the following; (1) potential human exposure (2) existing toxicity data (3) 
limitations imposed by the animal model (4) the exposure apparatus and its procedures, and (5) 
the stability of the experimental atmosphere. A total of 2716 mg TPL/kg of lucinactant aerosol 
was administered to rabbits over 2 days, and a total of 4252 mg TPL/kg of lucinactant aerosol 
was administered to rats over 2 days. A maximum feasible dose of aerosolized lucinactant was 
established based on these parameters and no observed adverse effect levels (NOAELs) were 
established to ensure adequate safety in preterm neonates. 
These nonclinical studies (Studies MB 04-12812.01, N107662, N107663) provide a safety 
margin of > 10:1 for the highest possible dose in Part A (240 mg TPL/kg) and > 6.75:1 for the 


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highest possible dose in Part B (400 mg TPL/kg), whether delivered to the lungs 
(> 2700 mg TPL/kg) or swallowed (8400 mg TPL/kg) (including volume load and sodium load). 
2.2.3.5 Clinical Experience Supporting Dose Rationale 
In neonates 28-34 weeks PMA, outcomes with a dose of 80 mg TPL/kg can be estimated by 
pooling the results of dosages immediately below (75 mg TPL/kg) and above (100 mg TPL/kg) 
in Study 03-Cl-1201 (see Section 1.3.2 for full description of this study). AEs, SAEs and 
complications of prematurity occurred at rates in these two groups similar to the remainder of the 
active cohort and controls, suggesting 80 mg TPL/kg would be well-tolerated. Dosages of 75 and 
100 mg TPL/kg reduced nCPAP failure: of the 15 subjects treated with these dosages, 4 (27%) 
had nCPAP failure within 72 hrs of life vs 53% of pooled controls (Figure 1-2). Further, dosages 
of 75 and 100 mg TPL/kg appeared to delay nCPAP failure as well, since none of the active 
subjects had nCPAP failure within 6 hours of dosing vs 18% of pooled controls (Figure 2-2, 
Figure 2-3). The reduction in nCPAP failure rate at 72 hours was seen both in subjects with 
lower (29-31 weeks PMA) and higher (32-34 weeks PMA) gestational age (Figure 2-4). These 
results suggest 80 mg TPL/kg dosage is likely to be effective. 


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Figure 2-2: Cumulative incidence of intubation for any reason within 72 hours of life 
(nCPAP Failure) in Study 03-CL-1201 among subjects receiving lucinactant for inhalation 
75 or 100 mg TPL/kg, by treatment group. 
 
0%
0%
27%
27%
27%
15%
18%
25%
30%
53%
0%
10%
20%
30%
40%
50%
60%
3 hrs
6 hrs
12 hrs
24 hrs
72 hrs
Cumulative % Intubated
Active
nCPAP


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Figure 2-3: Kaplan-Meier plot showing proportion of subjects not intubated over the first 
12 hours after randomization into Study CL-03-1201. Dosages of 75 and 100 mg TPL/kg 
are shown combined (red line), vs all controls (blue line). 
 
 


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Figure 2-4: Incidence of intubation for any reason within 72 hours of life (nCPAP Failure) 
in Study 03-CL-1201 among subjects receiving lucinactant for inhalation 75 or 100 mg 
TPL/kg, by gestational age group and by treatment group. 
 
In neonates 28-34 weeks PMA, outcomes with a dosage of 40 mg TPL/kg can be estimated by 
looking at results from subjects receiving the minimum dosage (25 mg TPL/kg) in Study 03-CL-
1201. AEs, SAEs and complications of prematurity occurred in this group at a rate similar to that 
of the remainder of the active cohort and controls, suggesting 40 mg TPL/kg would be well-
tolerated. FiO2 was observed to fall more quickly in this group than in controls (Figure 2-5), 
suggesting a positive physiological effect on lung compliance. The rate and timing of nCPAP 
failure was not observed to be different in this group from control; however, the study was not 
powered for efficacy evaluations. Repeat treatment of each dosage will also be available for each 
subject, which may improve efficacy at this dosage. Taken together, these results suggest the 40 
mg TPL/kg dosage is likely to be well-tolerated and to have the potential for efficacy, 
particularly with the ability to provide repeat doses. 


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Figure 2-5: Change from baseline in FiO2 of all subjects in Study 03-CL-1201, by 
treatment. Subjects receiving 25 mg TPL/kg are shown in orange vs control subjects in 
maroon. 
 
In neonates 26-28 weeks PMA, preliminary results from Study 03-CL-1401 are relevant. In this 
study, dosages up to 100 mg TPL/kg with a possible repeat dose have been administered. AEs, 
SAEs and complications of prematurity have occurred at rates in the active groups similar to the 
remainder of the active cohort and controls, suggesting that repeated doses of 80 mg TPL/kg 
would be well-tolerated. To date, nCPAP failure at 72 hours of life has occurred at a similar rate 
in active and control subjects even at the 100 mg TPL/kg dosage, but tends to occur later in 
active patients (Figure 1-5). There are several possible explanations for this observation (see 
Section 1.3.2.2), but the likelihood is that the dosages delivered to neonates 26-28 wks PMA in 
Study 03-CL-1401 have been inadequate to compensate for their greater surfactant deficiency 
relative to neonates 29-32 wks PMA. In addition, the observation that intubation in active 


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subjects occurred later than in controls in both Study 03-CL-1401 (Figure 1-5) and Study 03-CL-
1202 (Figure 2-2) suggest that lucinactant for inhalation may delay respiratory failure, raising the 
possibility that earlier and more frequently repeated doses may hold off respiratory failure until 
neonates begin manufacturing endogenous surfactant, which is the natural course of RDS. For 
this reason, Part B of this study focuses on administration of lucinactant for inhalation which 
begins as early and is repeated as often as practically possible, with as short a time between 
repeated doses as practically possible. 
Limited additional inferences can be made from prior clinical studies in which lucinactant was 
administered using aerosol generators other than the ADS or through non-aerosol administration. 
A prior clinical study of aerosolized lucinactant (Study KL4-CPAP-01) (27) using a 
commercially-available vibrating mesh nebulizer generated a theoretical inhaled dose of 
approximately 72 mg TPL/kg over a 3-hour period for RDS prophylaxis in preterm neonates 28 
to 32 weeks PMA (Section 1.3.1). In this cohort of 17 neonates, 5 (30%) required intratracheal 
SRT, suggesting that the dosage used may be efficacious.  
Subjects in Part A of this study may receive up to 2 repeat doses, and those in Part B may receive 
up to 4 repeat doses. Thus, the subjects in the 80 mg TPL/kg group of Part A could receive a 
total of 240 mg TPL/kg over approximately 6 to 36 hours, and active subjects in Part B could 
receive a total of 400 mg TPL/kg over a somewhat shorter interval. Repeated doses of 
intratracheal surfactant are often necessary and beneficial in neonates with RDS (1). In study 03-
CL-1201 (Section 1.3.2.1), 3 subjects received repeated doses: 1 subject in the 100 mg TPL/kg 
group (total dose of 200 mg TPL/kg) and 2 in the 150 mg TPL/kg group (total dose of 300 mg 
TPL/kg). In Study 03-CL-1401 (Section 1.3.2.2), 2 total doses of up to 100 mg TPL/kg (total 
dosage of 200 mg TPL/kg) have been administered over approximately 6 hours and have been 
well-tolerated. No AEs or ADEs related to study treatment occurred with repeat dosing in these 
subjects. For comparison, the dosage of lucinactant (Surfaxin®) approved by FDA for 
intratracheal administration is 175 mg TPL/kg, with up to 3 repeat doses (total dose of 700 mg 
TPL/kg) over 24-48 hours, each of which is administered over a few minutes. In addition, 
neonates with meconium aspiration syndrome have received doses of Surfaxin® 120 mg TPL/kg 
(36) by whole lung lavage, and adults with acute respiratory distress syndrome have received 
doses up to 8.55 g (114 mg TPL/kg) by bronchoscopic segmental lung lavage (37). Thus, 
dosages administered in both Parts A and B of this study are well within the FDA-approved 
dosage of intratracheal lucinactant. 


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2.2.4 Risk and Benefit of Study Interventions 
Risks and benefits of this study must be considered within the context of treating RDS in preterm 
infants (Section 1.1), which carries with it substantial risk of morbidity and mortality. These 
infants often require intratracheal SRT as well as MV in order to survive; however, both MV and 
endotracheal intubation are themselves associated with morbidity and mortality in this fragile 
population. Various types of non-invasive support and ventilation, including nCPAP, have been 
used to avoid endotracheal intubation and MV. However, nCPAP will be unsuccessful in about 
one third to one half of neonates with RDS, who will then require invasive MV and endotracheal 
intubation to receive SRT. Survivors are at risk of complications of prematurity including BPD, 
ROP, IVH and NEC. 
2.2.4.1 Risk and Benefit of Control Treatment 
As described in Section 5.4.2, control treatment in Part A of this study involves continuing 
subjects on nCPAP while the ADS is delivered to the bedside (in a blinded fashion) but is not 
used (“sham” treatment), and in Part B involves continuing nCPAP alone. Thus, control/sham 
treatment in both Part A and B of the study is identical to standard therapy with nCPAP. As 
described in Section 2.2.2, control/sham treatment in subjects who do not require endotracheal 
intubation is ethical. 
Known risks of standard nCPAP include nasal irritation/breakdown of the skin around the nose, 
apnea, oxygen desaturation, and air leak (eg, pneumothorax). Air leak with nCPAP has been 
reported in 3 to 47% of preterm neonates, and may be somewhat more common in neonates with 
greater gestational age (Section 1.1.1). The risk of requiring endotracheal intubation and SRT has 
been reported as 33-67% (Section 1.1.1). Risks of nCPAP in the prior clinical study using the 
ADS (Study 03-Cl-1201, Section 1.3.2) were consistent with those reported in the literature. 
Standard nCPAP, and therefore control treatment, has the benefit of providing respiratory 
support without the potential complications of invasive MV. The important outcome of survival 
without BPD is equal to or more frequent with nCPAP compared to with traditional treatment 
with endotracheal intubation and SRT (Section 1.1.1). 
2.2.4.2 Risk and Benefit of Active Treatment 
Because the ADS delivers lucinactant for inhalation via conventional nCPAP (Section 5.6), 
active treatment would include the same risks and benefits of respiratory support with standard 


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nCPAP therapy described above in Section 2.2.4.1. Active treatment would carry the additional 
risks and benefits of aerosolized SRT with lucinactant for inhalation. 
Lucinactant for inhalation is the reconstituted form of a lyophilized liquid surfactant (Surfaxin® 
[lucinactant]); therefore, the known class risks of SRT with liquid surfactant via the intratracheal 
route may be applicable. These risks are described in the Investigator’s Brochure and the 
Surfaxin® Product Insert, and include acute changes in lung compliance, bradycardia, oxygen 
desaturation, and airway obstruction. Rates of these adverse reactions and complications of 
prematurity were similar with Surfaxin® as with comparator surfactants. Pulmonary hemorrhage 
has been reported with intratracheal SRT, including with Surfaxin®.  
In the prior clinical study using aerosolized lucinactant for inhalation via the ADS (Study 03-CL-
1201, Section 1.3.2), the incidence of AEs was similar in subjects receiving active treatment 
compared to controls and were as expected for this population of premature neonates. The 3 most 
common AEs were neonatal jaundice, constipation and neonatal apnea, and the 3 most common 
peri-dosing events were transient desaturation in 5 (13%) subjects, nasal irritation in 2 (5%) 
subjects, and vomiting in 2 (5%) subjects. Obstruction of the nares or upper airway by condensed 
aerosol is a theoretical risk but was not observed in Study 03-CL-1201. To mitigate the risk of 
airway obstruction, all subjects are continuously attended by a qualified clinician during dosing 
and are continuously monitored for oxygen saturation (SaO2) and transcutaneous PCO2. 
Although the drug product is heated during aerosolization, it cools to 23-38°C during delivery 
and the ADS will shut down if aerosol temperature is >38°C; thermal injury to neonates was not 
observed in Study 03-CL-1201. The volume of aerosolized fluid administered to neonates could, 
in theory, affect fluid and electrolyte balance; however, no such problems were observed in 
Study 03-CL-1201 and electrolytes will be assessed in the present study. 
Risk of air leak was 23% in active treatment subjects vs 18% (23% based on independent 
radiologist review) among controls. Experience with repeated dosing is limited to 3 subjects in 
Study 03-CL-1201; although each received dosages higher than planned for the present study, 
incidence of AEs in these 3 subjects was similar to that in the remainder of the cohort. 
Automatic shutdown of the ADS was uncommon in study 03-CL-1201 (10% of subjects) and 
mostly (3/4 shutdowns) occurred at the highest dosage; only 1 shutdown occurred at a dosage 
(75 mg TPL/kg) similar to that proposed in the present study. All shutdowns resulted from error 
codes, and none resulted in any AE being reported. All subjects maintained nCPAP and 
inspiratory flow during active treatment, demonstrating the important safeguard that nCPAP is 


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maintained even if the ADS fails (Section 5.1). One ADE of nasal inflammation occurred; no 
other device-related performance issues resulted in any harm to subjects. A complete qualitative 
risk assessment has been completed to identify and mitigate potential safety risks associated with 
use of the ADS. 
In ongoing study 03-CL-1401, the incidence of AEs has been similar in subjects receiving active 
treatment compared to controls and has been as expected for this population of preterm neonates. 
The 3 most common AEs have been neonatal apnea, anemia and jaundice, and neither upper 
airway obstruction nor serious peri-dosing events have been observed. Risk of air leak has been 
lower than in Study 03-CL-1201: 18% in active subjects and 9% in controls. Automatic 
shutdown of the ADS has occurred in 41% of subjects; as with Study 03-CL-1201, most 
shutdowns resulted from error codes, and none resulted in loss of nCPAP or in any AE being 
reported related to the shutdown. The cause of one type of error code has been identified (syringe 
pressure out of range, mainly in certain ADP lots), and a corrective action has been undertaken 
(addition of a pre-filter for these lots of ADPs; see Investigator’s Brochure for details) in regions 
where these ADP lots have been distributed.  
2.2.4.3 Alternatives to Study Treatment 
Alternative approaches to treating neonates with (or at risk for) RDS, as described in Sections 
1.1 and 2.2.2, include attempting to support the neonate solely with a form of NIV (possibly 
including nCPAP) and without SRT; supporting the neonate with NIV and reserving 
intratracheal SRT (using various techniques) only for those who require intubation; and the 
traditional approach of supporting the neonate with invasive MV and intratracheal SRT. As 
described in Section 2.2.4.1 above, the former 2 approaches are identical to control treatment in 
the present study. Each of these approaches is supported by international guidelines (3-6, 11), 
and no strategy has yet been demonstrated as being superior in neonates who do not require 
immediate intubation. 
2.2.4.4 Summary of Risk-Benefit Assessment 
In summary, the potential benefit of lucinactant for inhalation delivered via the ADS is greater 
than the potential risk, especially when that risk is considered in the context of the risks of 
standard care of the premature newborn, including those of nCPAP. Further clinical study of this 
therapy in premature infants is therefore justified. 


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2.3 
Study Duration  
It is expected that recruitment will occur over a period of approximately 18 to 20 months for the 
sequentially conducted Part A and Part B of the study. It is estimated that the last subject 
enrolled will complete all assessments and procedures within approximately 20 to 22 months 
from the time of the first subject enrolled. 
Any adverse findings by the Data Monitoring Committee (DMC) may result in an extension of 
the study duration, early study closure, or early withdrawal of study subjects (Section 6).  
2.3.1 Duration of Subject Study Participation 
The total duration of study participation for each subject in the primary phase of both Parts A 
and B of the study will be from enrollment (≤ 20 hours from birth) to 36 weeks PMA. Each 
subject will participate in a follow-up phase through 1 year corrected age (1 year after the subject 
reaches 40 weeks PMA). All subjects who die or who complete all assessments and procedures 
up to and including the Final Observation (to occur at 36 weeks PMA or NICU discharge or 
hospital transfer, whichever occurs first) will be considered study completers. Details regarding 
subjects who withdraw from the study before completion are provided in Section 10.  
Study participation will consist of the following study phases and periods (assessments, 
procedures, and visits occurring in each of these phases can be found in Section 8):  
Primary Phase: 
• Screening Period: To occur in a timely manner to allow for study randomization 
≤ 20 hours from birth.  
o Study consent must be completed before any study-specific screening procedures that 
would not otherwise be performed in accordance with standard of care and local 
institutional practices.  
o Where permitted by the local ethics committee, consent may be obtained prenatally 
• Primary Observation Period: Time of randomization (T0 on study) to 72 hours (Day 3) 
from randomization.  
• Extended Observation Period:  Study Day 4 to completion on Study Day 7 (6 days after 
the day of randomization by calendar date). 
• Final Observation Period: ≥ Study Day 8 to Final Visit at 36 weeks PMA, NICU 
discharge, death, or hospital transfer (whichever occurs first). 


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Longer-Term Follow-Up Phase: 
• Longer-Term Follow-Up Period: Evaluations occur at 6 months and 1 year corrected age. 


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3 
STUDY OBJECTIVES AND ENDPOINTS 
This study is designed to investigate the safety and efficacy of lucinactant for inhalation in 
preterm neonates 26 to 32 completed weeks PMA. Efficacy and safety will be based on clinical 
evaluations (see Section 8). The endpoints specified are similar to those in Protocols 03-CL-1201 
and 03-CL-1401 to allow for potential comparison and pooling of results. 
3.1 
Objectives 
To evaluate the safety and efficacy of lucinactant for inhalation in conjunction with nCPAP, 
compared to nCPAP alone, in preterm neonates with RDS, as assessed by the time to and 
incidence of respiratory failure and/or death due to RDS over the first 72 hours of life, the 
incidence of BPD at 36 weeks PMA, and change in physiologic parameters (FiO2 and PCO2) 
over the first 72 hours of life. 
3.2 
Efficacy Endpoints 
3.2.1 Primary Endpoint 
The primary endpoint for this study is the incidence of respiratory failure or death due to RDS 
within the first 72 hours of life.  
A subject will be categorized as having respiratory failure due to RDS if either of the following 
occur:  
1. Intubation for MV and/or surfactant administration (with or without MV) within 72 hours 
of life, including SRT techniques such as INSURE, LISA and MIST 
2. The subject meets at least 1 of the following criteria, regardless of whether endotracheal 
intubation is performed: 
a. A sustained (≥ 60 minutes) need for FiO2 > 0.45 to maintain an SpO2 > 90% to 
95% 
b. A sustained (on ≥ 2 consecutive observations > 60 minutes apart) transcutaneous 
PCO2 > 65 mm Hg  
c. nCPAP > 8 cm H2O 
 
Death due to RDS is any death whose primary cause is respiratory failure due to RDS. 


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Respiratory failure due to RDS will be categorized as follows: 
• Respiratory failure, early 
Respiratory failure occurring ≤ 72 hours after birth 
• Respiratory failure, late 
Respiratory failure occurring > 72 hours and ≤ 7 days after 
birth 
Subjects meeting the criteria of respiratory failure due to RDS must continue to be followed for 
all safety evaluations as outlined in Appendix 2 until the time the subject completes the study or 
withdraws (Section 10.2). 
3.2.2 Secondary Endpoints 
The secondary endpoints of this study include the evaluation of the following from the time of 
initiation of study treatment until study completion: 
1. Time to respiratory failure or death due to RDS 
2. Incidence rate of BPD at 36 weeks PMA (defined in Appendix 1) 
3. All-cause mortality 
4. Incidence rate of survival without BPD at 36 weeks PMA 
5. Incidence rate of air leak (defined in Section 9) 
3.2.3 Tertiary Endpoints 
The tertiary endpoints of this study include the evaluation of the following from the time of 
initiation of study treatment until study completion: 
1. Incidence rates of common complications of prematurity other than air leak (defined in 
Section 9) 
2. Change from baseline in FiO2 and/or transcutaneous PCO2 over the first 72 hours of life 
3.3 
Safety Endpoints 
The following safety measures are to be documented in the electronic case report form (eCRF) in 
accordance with timings outlined in Appendix 2 and Section 8: 
1. Survival (date and time of death, if applicable) 
2. AEs, including adverse device effects (ADEs) and AEs of special interest including peri-
dosing events, complications related to placement of bi-nasal prongs, and air leak 
(Section 9) 


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3. Concomitant medications (Section 7.3) 
4. Use of respiratory support and supplemental O2 (Section 7.5), including the following:  
a) Need for endotracheal intubation and MV 
b) Mode of respiratory support (including supplemental oxygen) and important 
parameters for that mode (Section 7.5.5) 
5. Complications of prematurity (Section 9) 
6. Physical examinations (Section 7.1.6) 
7. Tolerability of lucinactant for inhalation 
8. Incidence of air leak (Section 9) 
9. Assessments of the following:  
a) Vital signs (Section 7.1.1) 
b) O2 saturation, as determined by pulse oximetry (SpO2) (Section 7.1.3) 
c) Serum electrolyte measurements (Section 7.1.7) 
d) Defecation (Section 7.1.9) 
e) Chest radiography prior to intubation (Section 7.1.8) 


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4 
STUDY POPULATION SELECTION 
This study is anticipated to enroll in Part A up to 240 preterm neonates (up to 80 per treatment 
group) 28 to 32 completed weeks PMA who are candidates for SRT and nCPAP in a NICU 
setting, and in Part B up to 80 preterm neonates (up to 40 per treatment group) 26 to 28 
completed weeks PMA who are candidates for SRT and nCPAP in a NICU setting.  
4.1 
Study Population 
This study population will be comprised of preterm neonates 26 to 32 completed weeks PMA 
who are receiving care in a NICU and are receiving nCPAP as the primary support modality for 
RDS. Part A of the study will enroll neonates 28 to 32 completed weeks PMA by strata: subjects 
28 completed weeks PMA will be defined as one stratum and subjects 29 to 32 completed weeks 
PMA will be defined as the other stratum. Part B of the study will enroll neonates 26 to 28 
completed weeks PMA, and will be stratified by treatment within each completed week PMA 
(26, 27, and 28 completed weeks PMA). 
The study population for Part A will be randomized in a 1:1:1 ratio into 1 of 3 treatment groups 
and the population for Part B will be randomized in a 1:1 ratio into 1 of 2 treatment groups (see 
Section 5.4). 
4.2 
Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be enrolled in this study: 
1. Signed ICF from legally authorized representative (consent may be obtained prenatally, 
where allowed) 
2. Gestational age: 
a) Part A: 28 0/7 to 32 6/7 completed weeks’ gestation PMA 
b) Part B: 26 0/7 to 28 6/7 completed weeks’ gestation PMA 
3. Successful implementation of non-invasive support or ventilation (preferably bubble 
CPAP) within  
a) Part A: 90 minutes after birth 
b) Part B: 60 minutes after birth 
4. Spontaneous breathing 


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5. Chest radiograph consistent with RDS (may be deferred if in the best medical interest of 
the subject) 
6. Respiratory support: 
a) Part A: Within the first 20 hours after birth, requires an nCPAP of 5 to 7 cm H2O with 
an FiO2 of ≥0.25 (>0.21 for neonates 28 weeks PMA) to 0.4 that is clinically indicated 
for at least 30 minutes to maintain SpO2 of 90% to 95%. 
b) Part B: Within the first 12 hours after birth, requires an nCPAP of 5 to 7 cm H2O with an 
FiO2 >0.21 to 0.4 that is clinically indicated for at least 20 minutes to maintain SpO2 of 
90% to 95%. 
Transient (<10 minutes) FiO2 excursions outside this range do not reset the time 
requirement. 
4.3 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria may not be enrolled in this study: 
1. A heart rate that cannot be stabilized above 100 bpm within 5 minutes of birth 
2. Recurrent episodes of apnea requiring positive pressure ventilation (PPV) administered 
manually or mechanically through any patient interface 
3. A 5 minute Apgar score < 5 
4. Major congenital malformation(s) or craniofacial abnormalities that preclude the use of 
nCPAP, diagnosed antenatally or immediately after birth 
5. Clinically significant diseases or conditions other than RDS which could potentially 
interfere with cardiopulmonary function (eg, congenital heart disease, hydrops fetalis or 
congenital infection) 
6. A known or suspected chromosomal abnormality or syndrome 
7. Premature rupture of membranes (PROM) > 3 weeks 
8. Hemodynamic instability requiring vasopressors or steroids for hemodynamic support 
and/or presumed clinical sepsis 
9. A need for intubation and/or invasive MV at any time before enrollment into the study 
10. The administration (or plan for administration) of any the following: 
a) Another investigational agent or investigational medical device  
b) Any other surfactant agent 
c) Systemic corticosteroids (other than antenatal steroids already received) 


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11. Presence of air leak (pneumothorax, pneumomediastinum, pneumopericardium, 
subcutaneous emphysema, or definite evidence of pulmonary interstitial emphysema 
[PIE]) on the baseline chest radiograph 


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5 
STUDY TREATMENT DOSING AND ADMINISTRATION 
Preterm neonates who meet all of the inclusion criteria and none of the exclusion criteria will be 
considered to be potential subjects. As soon as study qualification has been confirmed and 
parental consent obtained, subjects will be randomized to one of the active treatment groups or to 
the control group. All subjects will receive standard neonatal care in the NICU. Subjects 
randomized to an active group will receive lucinactant for inhalation via the ADS in conjunction 
with nCPAP. Subjects randomized to the control group will receive nCPAP only. In order to 
maintain masking in Part A of the study, control subjects will receive “sham” study drug 
treatment: the ADS will be brought to the bedside but will not be used, and no active study drug 
will be administered. In Part B of the study, control subjects will continue on nCPAP without 
sham treatment. All subjects, including controls, may receive repeat treatments if repeat dosing 
criteria are met (Part A: up to 2 repeat treatments; Part B: up to 4 repeat treatments). Subjects 
randomized to an active treatment group may be administered additional exposures of lucinactant 
for inhalation within 36 hours of randomization (Part A: up to 2 additional exposures; Part B: up 
to 4 additional exposures). Subjects in Part A randomized to control may receive an additional 1 
or 2 sham treatments while receiving nCPAP; those in Part B randomized to control will 
continue on nCPAP. 
To maintain masking in Part A, study treatment will occur behind a visual barrier; the PI, study 
staff (eg, site coordinator) (as applicable), and attending physician as appropriate will not be 
allowed to observe preparation of study materials, setup of the device, or to observe the subject 
during study treatment unless an emergent condition develops. The sponsor (as applicable) and 
the parents/legal guardian will also remain masked. Part B of the study will be open-label. (See 
also Section 5.6.) 
If at any point during the delivery of lucinactant for inhalation a potential safety risk to the 
subject is identified, aerosolization must be discontinued and local NICU procedures followed to 
ensure the safety of the subject. Any significant clinical findings or observations must be 
documented and communicated to Discovery at the earliest time point possible. 
5.1 
AEROSURF Delivery System 
The ADS creates and delivers aerosolized surfactant (lucinactant for inhalation) via 
2 components (Figure 5-1): the durable ACU (Section 5.1.1) and the disposable ADP 
(Section 5.1.2). The ADS is designed for bedside use and is mounted on a wheeled cart for easy 
transport.  


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Details for study drug preparation and ADS operation are provided in the AEROSURF 
Investigator’s Brochure and in the ADS Operator’s Manual. Briefly, lyophilized drug is 
reconstituted immediately before use by adding 10 mL of sterile water for injection to each of 
7 vials of lyophilized lucinactant, after which the vials are gently inverted to mix the suspension. 
The vials are drawn up into a single 60 mL syringe and transferred into the provided ADP 
syringe, which is then loaded into the ACU. The ADS is brought to the subject’s bedside and 
connected to the subject’s nCPAP via the patient interface connector. Carrier gas flow through 
the ADS is started at 3 L/min while the nCPAP gas flow is reduced by 3 L/min, which allows 
nCPAP to be maintained during treatment. 
A complete qualitative risk assessment has been completed to identify and mitigate potential 
safety risks associated with use of the ADS and is described in the Investigators’ Brochure. 
 
Figure 5-1. Schematic Diagram of the Aerosol Delivery System 
 


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The ADS aerosolizes lucinactant through heat and pressure created within the CAG located 
within the heater assembly. Together, the ADP and ACU produce, control and monitor the key 
elements necessary for the aerosolizing lucinactant.  
5.1.1 AEROSURF Control Unit  
The ACU contains a syringe pump mechanism and a temperature probe integrated with control 
electronics, which allows it to measure and control the heater to enable aerosol generation. The 
control electronics consist of embedded hardware and software with a touch screen interface that 
provides sequential instruction for ADS set-up and system operation, as well as safety 
interventions and control of the temperature of the heater. The syringe is contained within a 
chamber with a locking door, which prevents access to the syringe after aerosolization is started. 
A cart is provided for use with the ACU. Materials and dimensions for the ACU are consistent 
with equipment typically used in critical care environments. 
5.1.2 AEROSURF Delivery Pack 
The ADP is a single-use, disposable pack containing a 60-mL syringe, the carrier gas and the 
aerosol tube assemblies, and the heater assembly. The 60 mL syringe is filled with reconstituted 
lucinactant for inhalation, which pumped by the ACU through tubing to the heater assembly, 
which heats the lucinactant for inhalation and produces the aerosol. The carrier gas tube carries 
gas from an external source (usually a blend of air and oxygen) to the heater assembly, where it 
then drives the aerosol through the aerosol tube. Instructions for the proper set-up, connection, 
breakdown and return of ADP components are provided in the ADS Operator’s Manual. One 
ADP will be required for each treatment, with an additional ADP required for each repeat dose.  
Further information and instructions on ADP shipping and accountability are provided in the 
Study Manual. 
5.2 
Identity of Investigational Drug Product 
The complete list of ingredients for the drug product is shown in Table 5-1. 
5.2.1 Formulation of Study Drug 
The drug product (lucinactant) is supplied as a sterile, white, liposomal powder consisting of a 
21-amino acid hydrophobic synthetic peptide, (sinapultide, KL4 peptide), the phospholipids 
dipalmitoylphosphatidylcholine (DPPC) and palmitoyloleoyl-phosphatidylglycerol, sodium salt 


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(POPG, Na), and the fatty acid palmitic acid (PA). Immediately before dosing, the lyophilized 
product is reconstituted with sterile water for injection to a concentration of 30 mg TPL/mL.  
Table 5-1. Drug Description 
Ingredient 
Amount (mL) 
Sinapultide 
0.862 mg 
DPPC 
22.50 mg 
POPG, Na 
7.50 mg 
PA 
4.05 mg 
Note: Amounts reflect reconstituted product at 30 mg TPL/mL 
5.2.2 Aerosol characteristics 
The aerosol is generated at a formulation flow rate of approximately 1.2 mL/min. The mass 
mean aerodynamic diameter (MMAD) of the aerosol is below 5.0 m, which is considered an 
appropriate size to be deposited in the alveolus following inhalation. The carrier gas that carries 
the aerosol to the subject (typically a mixture of air and supplemental oxygen) has a nominal 
flow rate of 3 L/minute. Approximately 65% of the aerosolized dose condenses within the 
delivery tubing, leaving approximately 35% available for inhalation by the subject at the 
connection to the nCPAP patient interface. A disposable fluid trap collects the aerosol that 
condenses within the delivery tubing. Calculations for the theoretical maximum inhaled dose are 
given in Section 2.2.3.2. The specification for the aerosol temperature at the patient interface is 
25C to 38C.  
5.2.3 Packaging and Labeling 
Lucinactant is supplied in 30-mL glass vials packaged in cartons with foam inserts to reduce 
breakage. 
Lucinactant and the ADS will be appropriately labeled with the investigation caution statements 
required by the regional health authority (eg, FDA, EMA) to insure that users are aware that the 
product is limited by federal law to investigational use only.  
5.3 
Precautions for Aerosol Delivery and Device Usage 
The ADS, disposables and study drug are investigational materials which are to be used only for 
investigational studies with lucinactant for inhalation and not any other purpose. All equipment 
and supplies are to be returned to Discovery at the end of the study. 


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Sites must maintain accurate records and proper storage of all delivered and dispensed study 
drug vials and device components (including the AEROSURF® Delivery Packs [ADPs]). Details 
on study supply accountability and storage are provided in Section 5.9 and in the ADS 
Operator’s Manual.  
5.3.1 Precautions for Aerosol Delivery 
The nCPAP device used during aerosol delivery must be a continuous flow device and have a 
patient interface, both of which are commercially available for nCPAP delivery to neonates. An 
unmasked study-trained site designee (eg, respiratory therapist or nurse) must provide close 
monitoring of the subject and study device during aerosol delivery. 
Local NICU policies and procedures for nCPAP delivery are to be used, regardless of treatment 
group assignment. During study treatment delivery, clinical staff must ensure that the desired 
level of nCPAP is maintained. Typical maneuvers to improve the delivery of nCPAP, eg placing 
an oro- or nasogastric tube, securely but gently immobilizing the subject’s head, using pacifiers 
and/or chin strap, are encouraged during dosing. Subjects must be also closely monitored for 
complications related to placement of the patient interface (see Section 9). 
5.3.2 Precautions for Device Usage 
Before using the ADS on study subjects, clinicians must have completed all required study 
training. All local and regional NICU requirements for the operation of an investigational NICU 
device must be followed.  
If at any point during set-up, aerosol administration, or at finalization of aerosol delivery, an 
error screen or audible alarm is generated by the device that may signal a delivery malfunction, 
the user must contact Discovery immediately for further instructions (Section 9.2.1). In such 
cases, the subject must be removed from the device, and all local institutional procedures must 
be followed to ensure continued safety and observation of the subject. The ADS Operator’s 
Manual outlines audible alarms and visual displays that may indicate delivery failure.  
5.4 
Description of Treatment Groups 
The study treatment, ‘lucinactant for inhalation,’ consists of the investigational drug lucinactant 
and the delivery system ADS. The ADS has two components, the ADP and the AEROSURF® 
Control Unit (ACU), described fully in Section 5.1. The rationale for the selected device and 
study treatments, including active and control, is discussed in Section 2.2. 


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5.4.1 Aerosol Delivery in the Active Treatment Groups 
5.4.1.1 Study Part A 
Study treatment is to begin within 2 hours after randomization. For subjects randomized to the 
active study treatment groups, the duration of treatment is 25 or 50 minutes (corresponding to 40 
or 80 mg TPL/kg, respectively) in accordance with the subject’s treatment group. Repeat doses 
(up to 2) at the same dosage/duration are to be given if repeat dosing criteria are met unless it is 
unsafe to do so in the judgment of the investigator (see Section 5.7). All study treatments are 
masked (see Section 5.6). 
5.4.1.2 Study Part B 
Study treatment is to begin within 2 hours after randomization; however, every effort should be 
made to begin study treatment as soon after randomization as possible (ideally, within 30 
minutes). For subjects randomized to the active study treatment group, the duration of treatment 
is 50 minutes (corresponding to 80 mg TPL/kg). Repeat doses (up to 4) of 80 mg TPL/kg are to 
be given if repeat dosing criteria are met unless it is unsafe to do so in the judgment of the 
investigator (see Section 5.7). All study treatments are open-label. 
5.4.2 Treatment in the Control Groups 
As described in Section 2.2.2, no inert placebo exists. The appropriate control is to remain on 
nCPAP alone without study drug treatment, which is the control in Part B of the study. For Part 
A of the study, the optimal masked control, therefore, is to simulate study drug treatment in a 
masked fashion by bringing the ADS to the bedside but not administering any study drug, a 
procedure known as “sham” treatment. 
For sham treatment, no active drug will be prepared. Instead, the ADS will be prepared and 
delivered to the bedside along with an inactive syringe in a masked manner. Masking will occur 
as with active treatment (eg, behind a curtain). The ADS itself will be brought to the bedside but 
not used (since doing so would trigger alarms that would break masking). Control subjects in 
Part A of the study will be randomized to either a sham of 25 minutes or a sham of 50 minutes. 
The start time will be the time at which the sham setup is complete and the nCPAP circuit is 
interrupted; the stop time will be either 25 or 50 minutes later, depending upon the 
randomization. The subject will remain masked for the same duration as active subjects. At the 
end of the assigned sham treatment time, the subject will be switched to clean nCPAP 
equipment, as occurs at the end of active treatment. Masking equipment may then be removed. 


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As with active treatment, control/sham treatment in Part A of the study is to begin within 2 hours 
after randomization. Repeat control/sham treatments (up to 2) for the same duration as the initial 
treatment are to be given if repeat dosing criteria are met unless it is unsafe to do so in the 
judgment of the investigator (see Section 5.7). As described in Section 2.2.2, repeat treatment 
with control/sham in subjects who do not require intubation is ethical. 
Control subjects in Part B of the study will receive sham treatment (subject will be placed on the 
study interface); the ADS does not need to be brought to the bedside. Control subjects in Part B 
will not receive repeat treatments. 
5.5 
Treatment Groups and Method of Treatment Group Assignment 
Subjects will be assigned to receive either 40 or 80 mg/kg lucinactant for inhalation in 
conjunction with nCPAP or control (nCPAP only, with sham treatment of 25 or 50 minutes in 
Part A of the study) (Table 5-2). 
Table 5-2 Study Assignments by Treatment Groups 
Treatment  
Group 
Study Assignment 
Study Part Aa 
40 mg/kg 
Lucinactant for inhalation 40 mg TPL/kg (administered over 25 minutes) in conjunction 
with nCPAP (n = up to 80)  
Up to 2 repeat doses of lucinactant for inhalation 40 mg TPL/kg are to be given if repeat 
dosing criteria are met 
80 mg/kg 
Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction 
with nCPAP (n = up to 80)  
Up to 2 repeat doses of lucinactant for inhalation 80 mg TPL/kg are to be given if repeat 
dosing criteria are met 
Control 
Continuous nCPAP with sham drug treatment (n = up to 80)  
Study Part B 
80 mg/kg 
Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction 
with nCPAP (n = up to 40)  
Up to 4 repeat doses of lucinactant for inhalation 80 mg TPL/kg are to be given if repeat 
dosing criteria are met 
Control 
Continuous nCPAP (n = up to 40)  
aNote: In Part A of the study, masking procedures for the initial dose will be followed for all repeat doses in all 
treatment groups 
 
In Part A of the study, preterm neonates who successfully meet all eligibility criteria will be 
randomly assigned within their applicable stratum (28 completed weeks PMA or 29 to 32 


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completed weeks PMA) to one of the 3 treatment groups in a 1:1:1 ratio. In Part B of the study, 
preterm neonates who successfully meet all eligibility criteria will be randomly assigned within 
their applicable stratum (26, 27, and 28 completed weeks PMA) to one of the 2 treatment groups 
in a 1:1 ratio. 
Subjects will be randomized using centralized allocation electronically (eg, interactive web 
response system [IWRS]). Neonates from multiple births will be randomized independently. 
Randomization information will be provided to the study drug preparer (eg, pharmacist). The PI, 
study staff (eg, site coordinator) (as applicable), and attending physicians as appropriate will be 
masked to the treatment assignment, as described in the site’s blinding/masking plan.  
The randomization code list will be generated by Discovery Biometrics personnel. For Part A of 
the study, the code list will use a block size of 6 (40 mg TPL/kg 2, 80 mg TPL/kg 2, sham 
treatment of 25 minutes, sham treatment of 50 minutes), stratified by PMA. For Part B of the 
study, the code list will use a block size of 4 (80 mg TPL/kg 2, sham treatment of 50 minutes 
2). 
5.6 
Study Masking 
In order to minimize bias in subject assessments, study treatment masking (blinding) will be 
employed in Part A of the Study. Details of the masking procedure are provided in the 03-CL-
1202 Overall Blinding Plan, Blinding Procedure, Blinding Maintenance and Assurance Plan, and 
Statistical Analysis Plan documents. The blinding plan is outlined as follows: 
a. Subject safety takes precedence over maintenance of study masking. If at any 
point masking equipment interferes with emergent patient care or knowledge of 
study treatment assignment is required for patient management, then the blind 
may be broken. If this occurs, then Discovery must be notified as soon as possible 
(see Section 9.2.2). 
b. Personnel making or influencing clinical decisions – especially regarding 
intubation or the level of respiratory support until a subject reaches 72 hours of 
life – must be masked from treatment assignment. Every effort should be made to 
maintain study masking at all times unless the blind needs to be broken for 
reasons of subject safety. Clinicians may be masked for different subjects at 
different times, depending on the logistics at each site. 


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c. As there are potentially many ways in which treatment assignment might be 
masked, each site will create a site-specific blinding plan to be followed 
throughout the study that specifies which staff members (or types of staff 
members) are masked and which are not, and at what times. This blinding plan 
must be approved by Discovery prior to site’s participation in the study. 
d. Operational requirements of blinding are described in the Blinding Procedure 
document. Generally, active or sham drug syringes and materials will be prepared 
by an unmasked drug preparer at the time dosing is required and will be obscured 
from view when transported to the bedside with the ADS. Once at the bedside, 
visual barriers will be put in place to block dosing equipment from view outside 
the immediate bedside area. An unmasked dosing team will then administer active 
study drug or sham drug treatment (for controls). At the conclusion of treatment, 
the dosing team will replace any visibly soiled nCPAP equipment, break down the 
dosing equipment, remove all residual active drug, remove the visual barriers, and 
transport the waste (obscured from view) for disposal and the ADS back to 
storage. 
In order to facilitate administration of study treatment as early as possible in Part B of the study, 
study treatment will be open-label. As discussed in Section 1.3.2.2 and 2.2.3.5, it is likely that in 
neonates 26 to 28 weeks PMA study drug will need to be administered earlier and in higher 
dosages (or with more and earlier repeat doses) than has been done in Study 03-CL-1401 and in 
Part A of this study. Experience from Part A of this study to date has shown that set-up and 
breakdown of masking equipment has proven somewhat of a hindrance to early study treatment 
administration. Discovery has determined that the potential benefit of earlier study treatment 
administration outweighs the potential detriment of open-label administration compared to 
masked treatment. 
5.7 
Repeat Dosing 
5.7.1 Study Part A 
Up to 2 repeat doses will be administered to each subject, regardless of treatment group 
assignment, up to 36 hours following randomization. For each subject, repeat doses will consist 
of the same dosage/duration as the initial dose (including control/sham) and will occur if repeat 
dosing criteria are met, unless it is unsafe to do so in the judgment of the investigator. As 


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described in Section 2.2.2, repeat dosing with control/sham is ethical. Masking procedures used 
for the initial dose will be followed for repeat doses (see Section 5.6). 
The repeat dosing criteria for Part A of the study are defined as follows: 
a. Time: ≥2 hours from completion of the previous dose (up to 36 hours following 
randomization) 
b. Respiratory support: Subject has a sustained (≥30 minutes) need for FiO2 above 
the qualifying FiO2 for study enrollment (≥0.25 for neonates 29-32 weeks PMA, 
>0.21 for neonates 28 weeks PMA) to maintain SpO2 of 90% to 95%.  
As with the initial dose, the randomization system will be used to receive the study drug kit 
assignments, and all other procedures that were performed for the initial dose will be followed 
for the administration of the repeat doses. 
5.7.2 Study Part B 
Up to 4 repeat doses will be administered to each subject randomized to active treatment, up to 
36 hours following randomization. Repeat doses should be administered as soon as possible 
following the previous dose. Repeat doses will be administered if repeat dosing criteria are met, 
unless it is unsafe to do so in the judgment of the investigator. Repeat doses will be open-label. 
The repeat dosing criteria for Part B of the study are defined as follows: 
a. Time: ≥30 minutes from completion of the previous dose (up to 36 hours 
following randomization) 
b. Respiratory support: Subject has a sustained (≥30 minutes) need for FiO2 above 
the qualifying FiO2 for study enrollment (>0.21) to maintain SpO2 of 90% to 
95%.  
As with the initial dose, the randomization system will be used to receive the study drug kit 
assignments.  
5.8 
Early Discontinuation of Study Treatment 
The administration of study treatment may be discontinued at any time prior to the completion of 
dosing if certain device error codes occur or based on the clinical judgment of the PI. Reasons 
for discontinuation of study treatment include, but are not limited to the following:  


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1. 
Device failure or malfunction occurs, including certain error codes. If device failure or 
malfunction or error codes occur, Discovery personnel should be contacted 
immediately per Section 9.2.1).  
2. 
Automatic treatment interruption due to an error condition (eg, syringe pressure out of 
range error). If error codes occur, Discovery personnel should be contacted 
immediately per Section 9.2.1). 
3. 
An AE or ADE which places subject safety at risk occurs, eg, pulmonary hemorrhage. 
4. 
If, in the PI’s best medical judgment, initiating or continuing the subject’s exposure to 
study treatment is not in the best interest of the subject’s safety.  
5. 
Signs of acute respiratory deterioration develop, as evidenced by a clinically significant 
increase in respiratory rate or effort (work of breathing) plus at least one of the 
following: 
a. An FiO2 ≥ 0.70 or a sustained increase from baseline by ≥ 0.30 to maintain SpO2 
90% to 95% 
b. A transcutaneous PCO2 > 70 mm Hg or a progressive increase in PCO2 from 
baseline to ≥ 20 mm Hg above baseline  
c. Recurring episodes of bradycardia (see Section 7.1.4) 
d. A sustained apneic event (see Section 7.1.4) 
Subjects whose treatment is interrupted because of a device failure, malfunction, or error code 
may be administered a supplemental dose of lucinactant for inhalation in order to complete the 
interrupted dose with a total dosage as close to the initial target dosage as possible. Subjects 
whose treatment is discontinued based on the PI’s judgment will continue in the study. Subjects 
whose treatment is discontinued based on the parent/guardian’s wishes must be withdrawn from 
the study (see Section 10.2). 
In accordance with local institutional practices, an approved SRT must be made available to 
subjects demonstrating a clinical need if dosing is discontinued early. 


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5.9 
Clinical Study Supplies at the Clinical Study Site 
5.9.1 Investigational Study Drug and ADPs 
Lucinactant and ADPs will either be shipped directly to the investigational clinical study site 
pharmacies or to a designated location at the clinical study sites. A Clinical Supply Receipt Form 
will accompany the shipment. Study sites must verify each shipment via the Clinical Supply 
Receipt Form and study IWRS, and report study drug shipping temperatures to Discovery as 
outlined in the study manual.  
5.9.2 Ancillary Supplies 
Ancillary supplies (eg, nCPAP system, nasal prongs, and high pressure hoses) will be shipped 
directly to the investigational clinical study site NICU or to a designated location at the clinical 
study site. A Clinical Supply Receipt Form will accompany the shipment. Study sites must verify 
each shipment to Discovery via the Clinical Supply Receipt Form. 
5.9.3 Dispensing 
Study supplies (study drug/sham, ADP, and related study equipment) will be dispensed in 
accordance with the subject’s randomized treatment group (Section 5.5). The NICU pharmacist 
or designated study personnel will provide on-site storage, dispensing, reconciliation, and 
documentation of study supplies as outlined in the study manual. Study drug and 
ADP components (ie, ADP syringe and heater assembly) must be fully reconciled at the end of 
the study. The study clinical site monitor will provide oversight of these tasks and communicate 
any significant findings or indications of noncompliance to Discovery. 
5.9.4 Storage of Lucinactant and AEROSURF Delivery System 
Lucinactant must be stored in a secured area of the hospital pharmacy or NICU at 2°C to 8°C 
and protected from light until use. Study sites must monitor and log storage temperatures. All 
temperature excursions should be reported to Discovery as outlined in the study manual (see also 
Section 9.2). 
The ACU and ADPs will be delivered separately and must also be stored in a secure location 
under the recommended storage conditions outlined in the ADS Operator’s Manual. 


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5.10 Study Compliance 
Study compliance will be based on the timing and duration of actual study treatment delivered in 
comparison to the expected timing and duration based on the study treatment to which each 
subject was randomized. Aerosolization time and duration will be tracked by the ACU, which 
will display a continual count of lucinactant exposure time throughout the aerosol delivery 
period. Duration of sham treatment will be based on randomization of subjects to a sham of 25 or 
50 minutes. The duration of lucinactant exposure or sham treatment will be documented in the 
study eCRF.  
The number of subjects randomized but not treated, and the number of subjects whose study 
treatment is discontinued early will be recorded in the eCRF and summarized in the study report. 
5.11 Study Drug and Device Accountability 
It is the responsibility of the PI and designee to ensure that all study supplies (vials of lucinactant 
for inhalation, all components of the ADS, and related equipment) are inventoried and 
appropriately stored in accordance with study guidance documents (eg, study protocol, 
ACU Operator’s Manual), and used only for study subjects, by study trained staff.  
5.11.1 Study Supply Accountability 
The following guidelines must be followed to ensure the storage and accountability of the study 
supplies is consistent with the study protocol:  
1. Used or partially used vials of lucinactant for inhalation and ADPs must be kept separate 
from unused supplies throughout the life of the study. 
2. Designated study personnel will return all unused study drug vials and ADPs to the 
pharmacy or the clinical supply storage area immediately after the completion of study 
treatment.  
3. Reconciliation of study supplies will be performed at each study visit by the clinical site 
monitor and recorded appropriately in the pharmacy log and drug and device 
accountability records.  
4. Storage conditions, as described in the study manual, will be assessed and documented by 
the clinical site monitor at each study visit (ensuring all supplies are kept in a secure area 
with restricted access). 
5. Dispensing information must be recorded in the inventory log and kept with the study site 
records throughout the study.  


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6. Designated study personnel (eg, pharmacists) will not supply study drug, ADPs, and 
ancillary supplies to any person other than designated study staff. 
7. Study sites will not dispense the study supplies to any sites other than those listed on 
Form FDA 1572, Statement of Investigators. 


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6 
DATA MONITORING COMMITTEE 
The purpose of the DMC is to evaluate the degree of risk involved in study subject participation 
within each treatment group and to determine if study continuation in accordance with the 
current protocol holds the potential to institute any undue harm or threat to the safety and welfare 
of study subjects. Safety and tolerability data will be assessed at pre-specified enrollment 
milestones. Data from the time all active subjects complete assessments and procedures through 
72 hours of life will be reviewed. Enrollment will continue throughout each DMC review. 
The DMC will consist of 3 to 5 experts in the field of RDS; at least 2 of the experts must be 
neonatologists.  
6.1 
Safety Reviews 
The DMC reviews will consist of the evaluation of (1) all AEs, (2) ADEs relevant to potential 
subject safety issues, (3) case reviews of subjects with reported SAEs, and (4) summary tables of 
all safety endpoints (Section 3.3).  
In addition to discrete reviews by the DMC as a whole, the DMC chairman will receive safety 
updates at least every other week. Following a thorough independent review of available study 
data, the DMC will provide timely recommendations to the Discovery study team. 
Recommendations may consist of, but not be limited to the following:  
• Continue the study as planned 
• Suspend study enrollment, pending additional information 
• Close study enrollment  
An unmasked independent statistician, not a member of the committee, will be responsible for 
the statistical analysis of the data to be reviewed at each meeting.  
6.2 
Safety Enrollment Holds 
Failed tolerability will be established based on analysis of AEs. In particular, AEs related to the 
administration of lucinactant for inhalation are of particular interest. To prevent undue risk to 
subjects, ongoing review of combined AEs and SAEs will occur. If more than 3 subjects 
experience the same SAE related to study treatment (not including nCPAP failure), or the 
sponsor determines a pattern of SAE occurrence, the DMC chair will determine if an ad hoc 


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meeting of the DMC will occur to review the safety information from the study. Any death 
within 24 hours of study treatment will be communicated to the DMC chair at the time of 
regulatory agency reporting, if applicable, or if not applicable, when information is available. 


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7 
STUDY PROCEDURES AND GUIDELINES 
A table of study procedures and assessments is presented in Appendix 2.  
Before conducting any study-related activities, a signed written ICF and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization (where applicable) must be signed and 
dated by the subject’s parent or legally authorized guardian (Section 12.2). 
7.1 
Clinical Assessments 
The clinical assessments described below must be appropriately documented in the study eCRF. 
In addition, any clinical findings comprising an AE must be documented as such in the eCRF 
(Section 9).  
In addition to the clinical assessments outlined below, unmasked qualified medical personnel are 
to provide continual clinical assessment and monitoring during the active delivery of study 
treatment. If at any point during the delivery of study treatment a potential safety risk to the 
subject is identified, study treatment must be discontinued. Any significant clinical findings or 
observations must be documented and communicated to Discovery at the earliest time point 
possible (Section 9.2).  
7.1.1 Vital Signs  
Baseline vital signs (body temperature, respiratory rate, and heart rate) will be documented 
within 15 minutes ( 5 minutes) before randomization and at the following time points: 
• Study Days 1-2, hours (± window) after randomization: 1±0.25, 3±0.25, 6±1, 121, 
18±2, 24±2, 36±2, and 482 
• Study Days 3-7: daily at 0800 hours (±2 hours) 
In addition, vital signs (respiratory rate and heart rate only) will be documented during each 
study treatment (Section 7.1.10).  
7.1.2 Body Weight 
Birth weight will be documented in the study eCRF as part of the birth history.  


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7.1.3 Pulse Oximetry 
Oxygen (O2) saturations will be monitored by pulse oximetry (SpO2) continuously from the time 
of randomization until completion of Study Day 7. SpO2 will be documented in the study eCRF 
during each study treatment (Section 7.1.10). Additionally, SpO2 serves as part of the definition 
of apnea and desaturation (Section 7.1.4). 
7.1.4 Apnea, Bradycardia and Desaturation 
In this study, the following definitions are used for apnea, bradycardia, and desaturation. 
Occurrences of each must be recorded as an AE. 
Apnea is defined as a lack of inspiratory air movement sustained for ≥ 20 seconds and coincident 
with at least one of the following:  
1. SpO2 < 80% (not necessarily ≥20 seconds) 
2. HR < 100 bpm (not necessarily ≥20 seconds) 
3. Requirement for PPV administered manually or mechanically through any patient 
interface  
Bradycardia is defined as a heart rate < 100 bpm sustained for ≥ 20 seconds.  
Desaturation is defined as SpO2 < 80% sustained for ≥ 20 seconds. 
7.1.5 Monitoring of Carbon Dioxide Levels 
Serum partial pressure of carbon dioxide (PCO2) will be assessed for all subjects through the use 
of continuous transcutaneous monitoring. PCO2 monitoring will be initiated following 
randomization at least 30 minutes before the start of initial dosing and must continue for 
72 hours after randomization or until the subject is no longer receiving non-invasive support or 
ventilation, including nCPAP. The transcutaneous monitor must be calibrated for accuracy 
against a blood gas value (arterial, capillary, or venous) at the time of initial set-up and 
recalibrated, as necessary, in accordance with local institutional practices to ensure accuracy of 
the monitor output.  
Determinations of study conduct or classification, such as respiratory failure due to RDS 
(Section 3.2.1) or early stopping of study treatment (Section 5.8) may be made based on 
transcutaneous CO2 values. If the transcutaneous monitor is not available or cannot be used, 


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subjects may be enrolled and measurements per institutional practice for method (eg, heel stick) 
and time points may be used.  
PCO2 will be documented in the study eCRF during each study treatment (see Section 7.1.10) 
and every 6 hours from randomization through 72 hours. 
7.1.6 Physical Examination 
A complete physical examination will be performed by the PI or designee. The designee may be 
a qualified member of the site-based study staff (such as a nurse practitioner or physician 
assistant); physical examinations performed at screening must be reviewed and approved by the 
PI. Any new, clinically significant abnormal physical examination findings must be documented 
as AEs in the eCRF and will be followed by a physician or other qualified staff until resolution. 
7.1.7 Serum Electrolytes  
Serum electrolytes (Na+, Cl-, K+, and Total CO2) will be measured 24 hours from the time of 
randomization (± 6 hours). Values obtained in the course of clinical management may be used in 
lieu of obtaining samples specifically for this study. 
7.1.8 Chest Radiograph 
A chest radiograph for the diagnosis of RDS and exclusion of air leak will be performed as part 
of the screening assessment. A radiograph obtained in the course of clinical management may be 
used in lieu of obtaining samples specifically for this study. Diagnostic chest radiograph may be 
deferred until after enrollment if in the judgment of the investigator the diagnosis of RDS is 
nearly certain and it is the best medical interest of the subject to receive study treatment as soon 
as possible. A blinded review of all radiographs may be performed by Discovery or designee. 
A chest radiograph will also be required for study subjects who are intubated for any indication 
during the first 7 study days. All efforts must be made to obtain the chest radiograph prior to 
intubation, if the procedure does not delay or compromise the emergent care of the subject. 
7.1.9 Defecation 
The number of stools within the first 24 hours following randomization will be recorded in the 
study eCRF. 


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7.1.10 Clinical Assessments during Each Study Treatment Administration 
During administration of each study treatment (active or sham/control, initial or repeat dosing), 
vital signs (heart rate and respiratory rate), FiO2, SpO2, and PCO2 will be recorded at the start of 
study treatment and at 10, 20, 30, 40 and 50 minutes (±4 minutes) following the start of study 
treatment.  
7.2 
Medical Information 
The subject’s relevant medical information will be recorded at screening, including the 
following: 
• 
Maternal history, including rupture of membranes (time relative to birth, type), presence 
of clinical chorioamnionitis, use of antenatal steroids (number of doses, time relative to 
birth) 
• 
Birth history, including date and time of birth, mode of delivery (vaginal, Caesarian 
section), single or multiple birth (number), Apgar score (assessed at 1 and 5 minutes of 
life), presence of congenital anomalies, birth weight in grams (Section 7.1.2), use of 
Sustained Inflation resuscitation technique 
• 
Medical history from birth to randomization 
7.3 
Concomitant Medications 
Concomitant medications required for the general care of the subject are permitted, with the 
exception of investigational agents, investigational medical devices, or any SRT before 
randomization (see also Section 7.3.1). 
All concomitant medication and concurrent therapies will be documented from birth until the 
time the subject completes the primary phase of the study (36 weeks PMA), is discharged from 
the NICU, dies, or is transferred to another hospital (Section 10.2). Dose, route, unit, frequency 
of administration, indication for administration, and dates of medication will be captured on the 
eCRF. 
7.3.1 Use of Additional Surfactant Replacement Therapies 
Commercially available SRT may be administered to subjects whose respiratory status has 
deteriorated such that conventional SRT is in the subject’s best medical interest in the judgment 
of the investigator. Because conventional SRT requires endotracheal intubation (even if a tube 
other than an endotracheal tube is used), subjects receiving commercially available SRT will be 


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considered to have respiratory failure due to RDS (see Section 3.2.1). Such subjects remain in 
the study and are followed until study completion. 
7.3.2 Use of Caffeine Citrate or Systemic Corticosteroids 
Use of caffeine citrate or other methylxanthines is recommended and will be recorded as with 
any other concomitant medication. 
Use of prenatal steroids is permitted. Postnatal steroids are not permitted unless clear medical 
need is determined. 
7.4 
Demographics  
Demographic information (gestational age, sex, race & ethnicity) will be recorded at screening.  
7.5 
Respiratory Support and Oxygen Delivery 
7.5.1 General Principles for Respiratory Support 
For the purposes of this study, nCPAP refers to any device which maintains a constant airway 
pressure above ambient pressure and uses a patient interface on the subject’s face (eg, nasal 
prongs, mask, etc.). The study nCPAP device is the specific nCPAP device and interface 
supplied for use with the ADS. Non-invasive support and non-invasive ventilation (NIV) refer to 
any device which generates a constant or variable positive pressure and uses a patient interface 
on the subject’s face. nCPAP would therefore be a form of non-invasive support or ventilation 
with a constant airway pressure, while SiPAP, non-invasive positive pressure ventilation 
(NIPPV) and IPPB would be examples of NIV with variable pressures. MV refers to any device 
which generates a constant or variable positive pressure via an endotracheal tube or 
tracheostomy. Supplemental oxygen refers to delivery of oxygen without the generation of 
pressure above ambient pressure (eg, standard-flow nasal cannula). Although all forms of 
respiratory support may provide FiO2 >0.21, for this study supplemental oxygen refers only to 
modes that deliver oxygen without pressure. 
Study subjects must be maintained on study nCPAP from the time of randomization until at least 
6 hours after they have completed delivery of each dose of study treatment as outlined in 
Section 7.5.3. The management of respiratory support (including nCPAP) and oxygen delivery is 
otherwise at the discretion of the study PI, keeping in mind that repeat doses of lucinactant for 
inhalation can be delivered only on study nCPAP.  


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The study definition of respiratory failure due to RDS (Section 3.2.1) is used for analysis 
purposes only; it is not intended to mandate or guide clinical decision making. 
7.5.2 Emergent Respiratory Support 
Emergent endotracheal intubation and MV, in accordance with local institutional guidance, must 
be initiated at any time if deemed necessary for subject safety. Masking may be broken if 
necessary for subject safety. 
Any clinical event indicating a need for MV, additional ventilatory support or increases in 
supplemental oxygen must be evaluated as a potential AE (Section 9) and reported in the study 
eCRF as such, if applicable.  
7.5.3 Use of Nasal Continuous Positive Airway Pressure  
Study treatment may be delivered only via the study nCPAP device and interface. Subjects must 
remain on study nCPAP for at least 6 hours following each study treatment; 12 hours is strongly 
recommended, and ideally the subject will remain on study nCPAP until 36 hours following 
randomization when re-dosing is no longer permitted, unless the subject requires escalation in 
respiratory support to a different form of non-invasive ventilation or requires tracheal intubation. 
If a subject is switched from study nCPAP to an alternate form of non-invasive support within 12 
hours of dosing, the reason will be documented in the eCRF. Settings on nCPAP are left to the 
investigator’s judgment. 
Changing to an alternate form of nCPAP or other form of non-invasive support or ventilation in 
absence of escalating respiratory support requirements may on occasion be necessary, but is 
discouraged for a number of reasons. First, there are currently no definitive data to support that 
any form of non-invasive support or ventilation produces superior outcomes to any other form 
when used as a primary support modality. Second, each change in modality results in transient 
removal of positive airway pressure from the subject, which may cause alveolar derecruitment 
and subsequent respiratory deterioration, thereby presenting a safety risk. Third, use of 
modalities other than study nCPAP may pose a disincentive to re-dose, since in order to do so 
would require changing back to study nCPAP, which carries the risk of derecruitment as 
described, as well as additional logistical burden. 
The study nCPAP device and patient interface is commercially available and FDA-registered. 
On-site study and clinical staff will be trained by Discovery (or a qualified designee) on the use 
of the study nCPAP and interface. All local institutional policies and procedures relevant to the 


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administration and safety surveillance of nCPAP must be followed in conjunction with study 
specified procedures and assessments and in accordance with good clinical practice and 
judgment. During the nCPAP delivery, subjects must be monitored for complications related to 
placement of the patient interface (see Section 9).  
Procedures that may optimize nCPAP delivery include ensuring proper placement of the patient 
interface, inserting an oro- or nasogastric tube, maintaining the subject’s neck position in a mild 
extension that is comfortable for the subject, using pacifiers or chin strap, and suctioning the 
mouth and nose as needed.  
Initial nCPAP settings will depend on the subject’s clinical condition. Should the subject require 
increased respiratory support, incremental increases in FiO2 (to a maximum of 0.45) or nCPAP 
should be made by 1 cm H2O until a maximum nCPAP of 7 cm H2O is achieved. If a sustained 
nCPAP of >8 cm H2O or FiO2 ≥0.45 are necessary to maintain SpO2 90 to 95% or if 
PCO2 > 50 mm Hg, then other forms of non-invasive ventilation may be employed (see Section 
7.5.4). If unsuccessful, the subject should be evaluated for clinical signs and symptoms 
consistent with respiratory failure due to RDS (Section 3.2.1). 
7.5.4 Use of Non-Invasive Support before and after Enrollment 
In subjects eligible for this study, non-invasive support or ventilation must be implemented 
within 90 minutes of birth; however, modes of support other than study nCPAP are acceptable. 
In the delivery room, intermittent positive pressure breaths may be administered manually or 
mechanically through a noninvasive patient interface (eg, mask or nasal prongs) for no longer 
than 10 minutes after birth (eg, NeoPuff). Following delivery, any mode of non-invasive 
ventilation or patient interface may be used to support respirations as clinically indicated, 
including nasal cannula; high-flow nasal cannula (eg, VapoTherm); nCPAP generated by flow 
(eg, bubble CPAP or RAM cannula) or mechanical ventilator and using any interface (eg, RAM 
cannula, nasal prongs, face mask, etc); bi-level positive airway pressure (eg, SiPAP, BiPAP); 
neutrally-adjusted ventilatory assistance (NAVA); non-invasive positive-pressure ventilation 
(NIPPV); etc.  
Subjects are eligible for screening if any form of non-invasive support or ventilation is instituted 
within the required time period after birth (90 minutes for Part A of the study; 60 minutes for 
Part B) and the investigator feels it is safe to switch the subject to study nCPAP. After informed 
consent is obtained, subjects may be switched to study nCPAP/interface for screening. If the 
subject meets the inclusion criterion for respiratory support (Inclusion Criterion #6) and meets all 


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other inclusion/exclusion criteria, that subject may be enrolled. For Part A of the study, the 
respiratory support criterion requires that within the first 20 hours after birth the subject is stable 
for ≥30 minutes on nCPAP of 5-7 cm H2O with FiO2 0.25 (>0.21 for neonates 28 weeks PMA) 
to 0.4 to maintain SpO2 90%-95%. For Part B of the study, within the first 12 hours after birth 
the subject must be stable for ≥20 minutes on nCPAP of 5-7 cm H2O with FiO2 >0.21 to 0.4 to 
maintain SpO2 90%-95%. 
Particularly for the 26 to 28 week PMA neonates in Part B of the study, support as early as 
possible with NIV and transition to study nCPAP is emphasized. Ideally, subjects will be placed 
on NIV or study nCPAP within 15 to 30 minutes of birth, switched to study nCPAP shortly 
thereafter if not already on it, and will be randomized and receive study treatment within 1-2 
hours of birth. Such early treatment would likely require informed consent to be obtained 
prenatally. 
Following dosing, subjects must be maintained on study nCPAP for at least 6 hours; 12 hours is 
strongly recommended, and ideally the subject will remain on study nCPAP until 36 hours 
following randomization (Section 7.5.3). After at least 6 hours, other forms of non-invasive 
support or ventilation may be employed, particularly if a subject requires increased respiratory 
support but does not require intubation and SRT. Clinical judgment should be used to guide 
ventilatory management. If nCPAP has escalated to 7 cm H2O and subjects require additional 
support, non-invasive ventilation may be an option rather than increasing nCPAP further. 
Subjects requiring increased respiratory support should be considered for redosing if they are 
within the appropriate time frame and clinical conditions (Section 5.7). 
7.5.5 Documentation of Respiratory Support Parameters 
7.5.5.1 Documentation during the Primary and Extended Observation Periods 
From the time of randomization until completion of Study Day 7, respiratory support parameters 
must be evaluated and documented in the study eCRF:  
• The mode of respiratory support (including supplemental oxygen) and important 
parameters for that mode are documented at 0800 and 2000 daily. If the subject is on 
nCPAP, parameters are documented additionally at 1 and 3 hours following 
randomization, then every 6 hours until 48 hours following randomization. 
• FiO2 is documented every 6 hours from randomization through 72 hours along with 
transcutaneous PCO2 (Section 7.1.5) 


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• Vital signs, FiO2, SpO2, and PCO2 are documented during each study treatment (Section 
7.1.10) 
• Date and time are documented for each intubation and change of ventilatory support 
mode 
7.5.5.2 Documentation during Final Observation Period 
From Study Day 8 until the subject completes or withdraws from the study, the date and time of 
each intubation, change of ventilatory support mode (including supplemental oxygen), and 
important parameters for that mode must be evaluated and documented in the study eCRF.  
7.5.5.3 Documentation during Longer-Term Follow-up Phase 
During the longer-term follow-up phase, the start date/time and duration of each ventilatory 
support mode (including supplemental oxygen), and important parameters for that mode must be 
evaluated and documented in the study eCRF at 6 and 12 months corrected age (via telephone or 
report). 
7.6 Assessment Parameters for Technical Performance of the Device 
The following parameters will be captured in the eCRF in a blinded manner:  
• 
Any issues associated with device tubing (eg, ventilator/CPAP tubing detachments, 
aerosol tube detachments, proximal pressure port obstruction, aerosol tube condensate 
obstruction).  
• 
Approximate volume (in milliliters) of liquid in all the traps (at the completion of study 
drug administration) 
• 
Aerosol or study drug leakage before the subject interface (eg, disconnect of the 
inspiratory circuitry). 
• 
Occurrence of alarm signals before, during, or after dosing that may indicate a device 
malfunction. 
• 
Any automatic system shutdowns. 
• 
Loss of inspiratory flow to the neonate or inability to maintain nCPAP. 
• 
ADS temperature alerts (high or low). 
 


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8 
EVALUATIONS BY OBSERVATION PERIOD  
All of the assessments performed for each subject from screening until the time the subject 
completes the study (36 weeks PMA) or withdraws (Section 10.2) are presented below. A table 
of study procedures and assessments is presented in Appendix 2.  
8.1 
Screening Period 
The following information will be obtained for each subject before study enrollment: 
• 
A signed ICF 
• 
Inclusion and exclusion criteria (Sections 4.2 and 4.3) 
• 
Demographics (Section 7.4) 
• 
Maternal history (Section 7.2)  
• 
Birth history and birth weight (Section 7.2) 
• 
Medical History (Section 7.2) 
• 
Initial full physical examination findings (Section 7.1.6) 
• 
Chest radiograph (Section 7.1.8) 
• 
Respiratory support and O2 delivery (date and time of initial nCPAP or other type of non-
invasive ventilation) 
8.2 
Primary Phase 
8.2.1 Primary Observation Period  
The following will be documented for each randomized subject during the Primary Observation 
Period of the study (within first 72 hours of life): 
1. Date and time (T0) of randomization and assignment to study treatment group 
(Section 5.5) 
2. The date and time of the initiation and completion of each study drug or sham (control) 
treatment (Section 5) 
3. Technical performance of the device (Section 7.6) 
4. The use of pacifiers and/or chin strap during dosing (Section 5.3.1) 
5. The use of an oro- or nasogastric tube  
6. Vital signs (Sections 7.1.1 and 7.1.10) 


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7. SpO2 (Sections  7.1.3 and 7.1.10) 
8. Transcutaneous PCO2 values (Section 7.1.5 and 7.1.10) 
9. Assessment and documentation of respiratory support and supplemental oxygen 
(Section 7.5.5.1 and 7.1.10) 
10. Serum electrolytes (Section 7.1.7) 
11. Defecation (initial 24 hours following randomization) (Section 7.1.9) 
12. Chest radiograph, as applicable (Section 7.1.8) 
13. Incidence of all AEs, including ADEs, peri-dosing events, and complications related to 
placement of bi-nasal prongs (Section 9) 
14. Survival (date, time, and cause of death if applicable) 
15. Concomitant medications (Section 7.3) 
8.2.2 Extended Observation Period 
The following assessments are to be performed during the Extended Observation Period of the 
study (> 72 hours to ≤ 7 days after date of randomization). Daily measurements are to be 
obtained as close to 0800 as possible. 
1. Chest radiograph, as applicable (Section 7.1.8)  
2. Assessment and documentation of respiratory support and supplemental oxygen 
(Section 7.5.5.1) 
3. The use of an oro- or nasogastric tube  
4. Vital signs (Section 7.1.1) 
5. SpO2 (Section 7.1.3) 
6. Incidence of AEs (Section 9) 
7. Survival (date, time, and cause of death if applicable) 
8. Concomitant medications (Section 7.3) 
8.2.3 Final Observation Period (From Day 8 to 36 Weeks Postmenstrual Age/Final 
Observation [or NICU Discharge, Death, or Hospital Transfer]) 
The Final Observation Period from Day 8 to 36 weeks PMA/Final Observation, or NICU 
discharge, death, or hospital transfer (whichever occurs first), will include the following: 
1. Abbreviated physical examination (including changes from baseline examination) 
(Section 7.1.6) (final observation only) 


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2. Assessment and documentation of respiratory support and supplemental oxygen (Section  
7.5.5.1) 
3. Incidence of AEs (Section 9) 
4. Survival (date, time, and cause of death if applicable) 
5. Concomitant medications (Section 7.3)  
6. Incidence of BPD at 36 weeks PMA (see definition in Appendix 1) 
7. Occurrence or presence of  complications of prematurity (Section 9) and their treatments: 
8. Date and time of transfer or discharge from the current hospital (if applicable) 
8.3 
Longer-Term Follow-Up Phase Through 1-Year Corrected Age 
The following assessments are to be performed during the Longer-Term Follow-Up Phase from 
the final observation through 1-year corrected age. 
At 6 months corrected age (±2 weeks), the following will be assessed:  
1. Number of hospitalizations 
2. Time on respiratory support (Section 7.5.5.3) 
3. Concomitant medication: use of any bronchodilator or steroid 
At 1-Year corrected age (± 4 weeks), the following will be assessed: 
1. 
Number of hospitalizations 
2. 
Time on respiratory support (Section 7.5.5.3) 
3. 
Abbreviated physical examination 
4. 
Abbreviated neurologic assessment 
5. 
Concomitant medication: use of any bronchodilator or steroid 
 


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9 
ADVERSE EVENT REPORTING  
Information regarding the occurrence of AEs will be assessed from the time of randomization 
until completion of Final Study Observation. Incidence of ADEs will be assessed from the time 
of randomization until completion of the primary observation period. 
For purposes of this study, the following will be considered AEs of special interest if they occur 
within the primary observation period:  
1. Peri-dosing events, defined as the following AEs with an onset time ≤ 2 hours from the 
time of initiating study treatment:  
• Apnea (Section 7.1.4) 
• Bradycardia (Section 7.1.4) 
• Desaturation (Section 7.1.4) 
• Gagging/regurgitation 
• Pallor 
2. Apnea (Section 7.1.4), after the peri-dosing period 
3. Bradycardia (Section 7.1.4), after the peri-dosing period 
4. Desaturation (Section 7.1.4), after the peri-dosing period 
5. Complications related to placement of the patient interface as identified by the following:  
• Bleeding 
• Apparent obstruction of the nares  
• Occlusion of the interface requiring removal and replacement 
• Nasal irritation (erythema of nares or septum, inflammation of nares or septum) 
Air leak is considered an AE of special interest if it occurs at any time during the study. 
Examples of air leak include the following: 
• Pneumothorax 
• Pulmonary interstitial emphysema [PIE] 
• Pneumomediastinum 
• Pneumopericardium 
• Subcutaneous emphysema 


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Complications of prematurity include the following, but are not considered AEs of special 
interest: 
• Intraventricular hemorrhage [IVH] 
• Periventricular leukomalacia [PVL] 
• Pulmonary hemorrhage 
• Apnea 
• Necrotizing enterocolitis [NEC] 
• Patent ductus arteriosus [PDA] 
• Acquired sepsis 
• Retinopathy of prematurity [ROP] 
• BPD 
All AEs must be followed by the PI until resolution or for at least 30 days post-study if the 
subject is stable. 
Documentation of AEs in the eCRF must include the following parameters; (1) duration (time of 
onset and resolution), (2) severity or grade, (3) outcome, (4) action taken, and (5) relationship to 
study drug and/or device. AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), version 18.1 or above. 
9.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a study subject who is administered a 
pharmaceutical product that does not necessarily have a causal relationship with this product. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational product 
(drug and/or device), whether or not related to the investigational product (see ICH guideline 
E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
An ADE is an AE related to the use of the investigational device. ADEs are treated the same as 
all other AEs. For serious ADEs, see unanticipated adverse device effects (UADE) in 
Section 9.1.5. 


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9.1.1 Causal Relationship of Adverse Events 
The relationship of an AE to a study drug is assessed by the PI using the following definitions: 
• 
Not related: The AE is clearly related to other factors, such as the subject’s clinical state, 
therapeutic interventions, or concomitant drugs. 
• 
Unlikely Related: The AE was most likely produced by other factors, such as the subject’s 
clinical state, therapeutic interventions, or concomitant drugs, and does not follow a 
known response pattern to the study drug. 
• 
Possibly Related: The AE follows a reasonable sequence from the time of drug 
administration and/or follows a known response pattern to the study drug, but could have 
been produced by other factors, such as the subject’s clinical state, therapeutic 
interventions, or concomitant drugs. 
• 
Related: The AE follows a reasonable temporal sequence from the time of the drug 
administration and meets the following criteria;  
a) Follows a known response pattern to the study drug  
b) Cannot be reasonably explained by other factors such as the subject’s clinical 
state, therapeutic interventions, or concomitant drugs 
c) Meets one or more of the following:  
• occurs immediately following study drug administration 
• improves on stopping the drug 
• reappears on repeat exposure 
• there is a positive reaction at the application site 
9.1.2 Severity Grade Levels of Adverse Events 
The severity of an AE is assessed by the PI using the following definitions: 
• Mild: Symptoms causing no or minimal interference with usual social and functional 
activities  
• Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities  
• Severe: Symptoms causing inability to perform usual social and functional activities  
9.1.3 Adverse Event Procedures 
All AEs are to be assessed in all subjects throughout the study period (from enrollment to study 
withdrawal or completion) and documented in the study eCRF. Each AE should be reported 


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spontaneously or in response to general, non-directed discussion with the attending nurse or 
physician (eg, has there been any change in subject status since the last assessment period?). For 
each AE, the investigator should obtain all information required to complete the AE page of the 
eCRF, in accordance with eCRF completion guidelines (provided separately by Discovery). 
All AEs, regardless of seriousness, severity, or relationship to study participation, must be 
recorded (using medical terminology) in the source document and on the AE page of the eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology. 
All AEs must be followed until resolution or until a stable clinical end-point is reached, or for at 
least 30 days after the subject’s last day in the study if an AE is ongoing at the time the subject 
completes the study. All measures required for AE management and the ultimate outcome of the 
AE must be recorded in the source document and reported on the AE page of the eCRF. 
9.1.4 Serious Adverse Events 
A SAE is any untoward medical occurrence that, at any dose, meets one of the following criteria 
(ICH E2A, Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting): 
1. Results in death 
2. Is life-threatening 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. May be considered serious when based upon appropriate medical judgment 
When the investigator-trained designee becomes aware of an SAE, Discovery must be notified as 
soon as possible (and no later than 24 hours after the event has occurred) via telephone or fax, 
regardless of the relationship (or lack thereof) of the SAE to study participation. 
SAEs can be reported to the Discovery SAE reporting line, by country (see Section 9.2).  


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When reporting SAEs, the following information should be provided: 
1. Study identifier 
2. Study center 
3. Subject number 
4. A description of the event 
5. Date of onset 
6. Current status 
7. Clarification on whether study 
aerosol was discontinued 
8. The reason why the event is 
classified as serious 
9. The Investigator’s assessment of the 
association between the event and 
study participation 
All reports of SAEs must be followed up within 24 hours (or sooner at the request of the medical 
monitor) by the completion of the SAE form and signature by the person who completed the 
form and the PI. This should be emailed to the local clinical site monitor or faxed (Section 9.2.2). 
In accordance with Discovery’s standard operating procedures (SOPs) and regulatory agency 
(eg, FDA) regulations, investigators will be notified of the occurrence of serious, unexpected, 
related AEs. The PI must promptly inform the relevant IRB/IEC/REB in accordance with 
ICH E6 of all AEs that are deemed related to study participation (ie, there is a reasonable 
possibility that the AE may have been caused by the drug or device) and are thus deemed a 
significant new AE or risks with respect to the drug or device. 
9.1.5 Unanticipated Adverse Device Effects  
An UADE is defined as any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigator’s brochure, or 
any other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects.  
In such cases, Discovery must be notified immediately through the following procedures (see 
also Section 9.2): 
• Contact the clinical site monitor or designated contact person regarding the event 
immediately. 
• Complete all device reporting procedures detailed in the study manual. 


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9.2 
Discovery Contact Information 
The names, telephone, and fax numbers of the individuals who should be contacted regarding 
trial-related questions and safety are listed below. 
9.2.1 Trial-Related Questions 
For trial-related questions, including drug- or device-related issues, please call your clinical site 
monitor. 
9.2.2 Medical Monitoring 
FOR MEDICAL QUESTIONS, PLEASE CONTACT THE MEDICAL MONITOR: 
Steven G. Simonson, MD (Medical Officer) 
Office: (215) 488-9474 
Mobile: (267) 454-4931 
email: SSimonson@DiscoveryLabs.com 
Paul M. Shore, MD MS (Medical Monitor) 
Office: (215) 488-9465 
Mobile: (267) 663-3204 
email: PShore@DiscoveryLabs.com 
or, 
Robert Segal, MD, FACP (Safety Monitor) 
Office: (215) 488-9450 
Mobile: (267) 237-7576 
email: RSegal@DiscoveryLabs.com 
 
IN LATIN AMERICA, CONTACT: 
Carlos G. Guardia, MD 
Office: +1 717 300 1415 
Mobile: +56 9 4203 9028 
Email: CGuardia@Windtreetx.com 
 


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FOR SERIOUS ADVERSE EVENTS OR UNANTICIPATED ADVERSE DEVICE EFFECTS, 
PLEASE CONTACT DISCOVERY: 
North America:  
24 Hour Safety Hotline: +1 800 201 8725 
Safety Hotline Fax : +1 888 488 9697 
Latin America: 
24 Hour Safety Hotline Voice: +55 11 4504 4801 
Safety Hotline Fax: +55 11 3958 0983 
European Union: 
24 Hour Safety Hotline: +44 1223 374 240  
Safety Hotline Fax: +44 1223 374 102 
FOR ADDITIONAL ASSISTANCE, PLEASE CONTACT THE CLINICAL SITE MONITOR 
OR:  
Judy Varga (Associate Director, Clinical Sciences, Discovery) 
Mobile: (267) 614-2364 
email: JVarga@Windtreetx.com 


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10 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
10.1 Early Discontinuation of Study Treatment  
The administration of lucinactant for inhalation may be discontinued at any time prior to the 
completion of dosing based on certain criteria (Section 5.8) or the clinical judgment of the PI. 
Subjects whose treatment is discontinued based on the PI’s judgment will continue in the study. 
Subjects whose treatment is discontinued based on the parent/guardian’s wishes must be 
withdrawn from the study. 
10.2 Withdrawal of a Subject from the Study 
A subject may withdraw consent (through their legally authorized guardian) at any time without 
prejudice to further care. 
If a subject is discharged or transferred from the NICU before 36 weeks PMA, the clinical status, 
including presence or absence of BPD at 36 weeks PMA, should be obtained. If, for any reason, 
the status of a subject is unknown, every effort must be made to contact the subject’s legally 
authorized guardian to determine the status of the subject. If the status of the subject has not been 
established in 28 days after the subject reaches 36 weeks PMA, the subject will be considered 
lost to follow-up. Note: All attempts should be made to ensure that no subjects are lost to follow-
up. 
10.3 Termination of the Study 
The study may be terminated prematurely due to safety reasons by the DMC (Section 6).  
Additional reasons for study termination include, but are not limited to, the following: 
• The local or national regulatory agency requests a termination of the study. 
• It has been determined that the risk level associated with the experimental drug is 
significant and warrants termination of the study. 
• Discovery, for reasons other than safety, may terminate the study at any time by written 
notice of intended termination provided at least 30 days before termination. 
• The PI or IRB/IEC/REB, for reasons other than safety, may terminate participation of 
this clinical site in the study by written notice of intended termination provided at least 
30 days before termination. 


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• Any other clause described in the individual site Clinical Study Agreement (eg, if ICH 
GCP guidelines or other regulatory procedures are not followed or if enrollment rate is 
not sufficient to meet study goals). 
10.4 Replacement of Subjects 
Subjects who discontinue treatment early or who are withdrawn from the study will not be 
replaced, unless required by the DMC. 


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11 PROTOCOL VIOLATIONS/DEVIATIONS 
A protocol violation occurs when the PI fails to adhere to any significant protocol requirement 
affecting the inclusion, exclusion, subject safety, and primary endpoint criteria. Protocol 
violations include but are not limited to the following: 
• Failure to meet eligibility criteria 
• Use of a prohibited concomitant medication (Section 7.3) 
• Failure to comply with ICH GCP guidelines  
Discovery will determine if a protocol violation will result in withdrawal of a subject. 
A protocol deviation occurs when the PI fails to adhere to any protocol requirement that is not a 
protocol violation. Protocol deviations include collection of information outside a collection 
window or failure to collect non-critical information. 
When a protocol violation or deviation occurs, it will be discussed with the PI. All protocol 
violations and deviations will be documented and tracked. 


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12 ETHICS 
This study will be conducted according to the United States and ICH regulations and guidelines 
(21 Code of Federal Regulations [CFR] Part 50, Protection of Human Subjects, 21 CFR Part 56, 
Institutional Review Boards, 21 CFR Part 312, Investigational New Drug Application, and 
ICH E6, Guideline for Good Clinical Practice) as well as all applicable local, state, and federal 
regulations and guidelines regarding the conduct of clinical studies. In addition, this study will be 
conducted in accordance with the ethical principles included in the World Medical Assembly 
(WMA) Declaration of Helsinki, Ethical Principles for Medical Research Involving Human 
Subjects adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and 
amended most recently by the 59th WMA General Assembly, Seoul, Korea, October 2008. 
Throughout this section the term “Clinical Investigator” will be defined, in accordance with 
21 CFR 54, as any listed or identified PI or subinvestigator who is directly involved in study 
dosing or evaluation of research subjects. PIs or subinvestigators must be listed on Form FDA 
1572, if applicable, and also documented as appropriate on the delegation of authority signature 
log. 
12.1 Institutional Review Board/Independent Ethics Committee/Research Ethics Board 
The protocol, including any amendments and the ICF, will be submitted to the appropriate 
IRB/IEC/REB for each study site for approval to conduct the study. Before the initiation of the 
study at each study site, Discovery must be provided with a copy of the IRB/IEC/REB approval 
to conduct the study. This approval must refer to the study by exact protocol title and number 
and should identify the documents reviewed and the date of review. 
Protocol and ICF modifications or changes may not be initiated without prior written 
IRB/IEC/REB approval, except when necessary to eliminate immediate hazards to the study 
subjects or when the change(s) involves only logistical or administrative aspects of the study. 
Such modifications will be submitted to the IRB/IEC/REB and written verification that 
the modification was submitted and subsequently approved should be obtained. A site 
must receive approval from Discovery on any ICF modification before submission to 
the IRB/IEC/REB for approval and subsequent implementation at the study site. 
Protocol modifications (ie, amendments) may only be enacted by Discovery. 


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The IRB/IEC/REB must be informed of revisions to other study-related documents or study 
information that was originally submitted for review. Revised study documentation and related 
informational updates may include but are not limited to the following:  
1. Serious and/or unexpected AEs occurring during the study (reported in accordance with 
the SOPs and policies of the IRB/IEC/REB)  
2. Any new study information that may adversely affect subject safety or study conduct  
3. Annual study updates or IRB/IEC/REB requests for reassessment of the study  
4. Timely communication of significant actions and related findings from the DMC (to 
include study enrollment holds or expansion, protocol amendments, or early study 
closure). 
5. Notification of major study/site milestones to include study/site closure 
12.2 Informed Consent Form of Study Subject 
A signed written ICF will be obtained in accordance with the Declaration of Helsinki, ICH GCP, 
21 CFR 50 Subpart B, 2 and 21 CFR 56, Subpart A), HIPAA (where applicable), and local 
regulations. 
The PI will prepare the ICF (to include HIPAA authorization [where applicable]) based on an 
ICF template provided by Discovery. Completed site-based ICFs must be provided to Discovery 
or designee for approval before submission to the IRB/IEC/REB. The ICF generated by the PI 
must be acceptable to Discovery and be approved by the IRB/IEC/REB. The PI will send an 
IRB/IEC/REB approved copy of the ICF to Discovery for the study file. 
The subject’s legally authorized guardian will be provided a consent form describing this study 
and be provided sufficient information to make an informed decision about the subject’s 
participation in this study. The formal permission of a subject’s legally authorized guardian, 
documented on the IRB/IEC/REB-approved consent form (and any other locally required 
documents), must be obtained before the performance of any study-related activity, including the 
cessation of any medications or procedures. The consent form must be signed and dated 
including the time of consent by the subject’s legally authorized guardian, the investigator-
designated research professional obtaining the consent, and, if applicable, an impartial witness. If 
allowed by the IRB/IEC/REB, informed consent may be obtained prenatally. 
Assent of the subject will not be sought, since all subjects are neonates and not capable of 
providing assent. 


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12.3 Financial Disclosure 
The FDA has issued regulations (21 CFR Part 54, Financial Disclosure by Clinical 
Investigators) that require sponsors to submit complete and accurate certification or disclosure 
statements to certify the absence of certain financial interests of clinical investigators and/or to 
disclose those financial interests, as required, when clinical studies are submitted to FDA in 
support of marketing approval. These regulations are intended to ensure that financial interests 
and arrangements of clinical investigators, that could affect reliability of data submitted to FDA 
in support of marketing approval, are identified and disclosed by the sponsor. 
Clinical investigators will be asked to disclose proprietary (eg, patent, licensing agreement) and 
financial (eg, stock options, royalty) interests as they pertain to Discovery, before participating in 
the study. In addition, clinical investigators will be required to consult with Discovery before 
acquiring any financial interest in the company and must disclose any change in their proprietary 
or financial interests, if it occurs during the course of the study and for 1 year following study 
completion. The requirement for proprietary and financial disclosure also includes any 
ownership by the spouse or any dependent subject of the clinical investigator. 
If FDA determines that the financial interests of any clinical investigator raise serious questions 
about the integrity of the data, FDA will take any action it deems necessary to ensure the 
reliability of the data, including: 
1. Initiating agency audits of the data derived from the clinical investigator in question 
2. Requesting that the sponsor submit further data analyses (eg, to evaluate the effect of the 
clinical investigator’s data on overall study outcome) 
3. Requesting that the applicant conduct additional independent studies to confirm the results 
of the questioned study 
4. Refusing to treat the covered clinical study as providing data that can be the basis for an 
agency action 
If the sponsor does not include certification or disclosure, or both (as required), or does not 
certify that it was not possible to obtain the information, the FDA may refuse to file the New 
Drug Application (NDA). 


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13 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
It is anticipated that up to 240 subjects (up to 80 per treatment group) will be enrolled into the 
study in Part A, and up to 80 subjects (up to 40 per treatment group) will be enrolled into the 
study in Part B.  
A complete outline of the all planned analyses for the study, including the handling of missing 
data, is provided in the Statistical Analysis Plan for this protocol. 
13.1 Statistical and Analytical Plans 
The statistical analysis of both the primary and secondary objectives will be based on all enrolled 
preterm neonates. For the efficacy analysis, all randomized subjects (intent-to-treat [ITT]) and 
subjects with no major protocol deviations (per-protocol) will be evaluated, based upon the 
treatment group to which they were randomized. For the safety analysis, all control subjects and 
subjects who received any amount of aerosolized lucinactant will be evaluated, based upon the 
treatment they actually received. All analyses will be performed for Parts A and B of the study 
for all subjects combined by treatment group and by gestational age (for Part A only). 
All continuous variables (eg, weight, body temperature, transcutaneous PCO2) will be 
summarized using number (n), mean, standard deviation (SD), median, minimum, and 
maximum. All discrete variables (eg, sex, AEs, common complications of prematurity), will be 
summarized using frequency (n) and percent. Sites will be pooled for statistical analyses by 
geographic region. 
The primary endpoint (the incidence of respiratory failure or death due to RDS within 72 hours 
of life) is defined in Section 3.2.1. The incidence of respiratory failure or death due to RDS will 
be compared between each active treatment and control using the Cochran-Mantel-Haenszel test, 
controlling for pooled sites. 
Key secondary endpoints include the time to respiratory failure or death due to RDS, compared 
between each active treatment and control using the log-rank test. BPD, all-cause mortality, and 
common complications of prematurity (primarily air leak) will be compared using the Cochran-
Mantel Haenszel test. Physiologic parameters (ie, FiO2, transcutaneous PCO2) will be compared 
using ANOVA with treatment and pooled study site in the model. 


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The treatment difference (delta) between active and control treatments will be calculated for the 
primary and key secondary efficacy endpoints. The delta calculated will be used to plan 
additional studies and as supporting evidence of efficacy. 
Demographic parameters will be summarized by treatment group and assessed qualitatively for 
homogeneity of treatment groups. Concomitant medications will be classified using the 
WhoDrug dictionary and summarized using frequency and percent. 
AEs will be summarized by treatment group using frequency and percent, but will not be 
compared statistically. Physical examination and medical history will similarly be summarized. 
Vital signs (ie, body temperature, respiration rate, pulse) will be summarized as for continuous 
variables; vital signs will not be compared statistically. 
13.2 Interim Analyses 
The data monitoring committee (DMC) will conduct 2 preplanned interim analyses during Part A 
of the study: 1) after approximately 25% of subjects have been enrolled and 2) after 66% of 
subjects have been enrolled. The DMC will be provided full safety listings for review after 50% 
of subjects have been enrolled in Part B, but will not conduct a formal interim analysis. Study 
enrollment may be suspended if safety concerns are identified during any review (see Section 6).  
In addition, a review of the treatment effect may be conducted by an independent statistical 
analysis center (ISAC) after approximately 50% of the subjects have been enrolled in Part A. 
The ISAC will assess the time and incidence of respiratory failure due to RDS by treatment 
group. These results will be used to determine if adjustments to the doses being studied should 
be considered. The p-values may or may not be adjusted, as appropriate. 
13.3 Sample Size and Randomization 
A total of up to 240 study subjects (up to 80 per treatment group) will be enrolled in Part A of 
the study, and a total of up to 80 study subjects (up to 40 per treatment group) in Part B. For Part 
A, the sample sizes were calculated separately for incidence of respiratory failure or death due to 
RDS, time to respiratory failure or death due to RDS, and a reduction in FiO2. The sample size 
will have 90% power to detect the difference between treatment groups using a log-rank test for 
equality of time to event curves, assuming a constant hazard ratio of 0.500, within the first 
72 hours of life. In addition, the sample size is sufficient to, separately, detect a reduction of 50% 
in the incidence of respiratory failure due to RDS within the first 72 hours of life, or a reduction 


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in FiO2 of 4 percentage points (eg, 30% to 26%) within the first 24 hours following treatment 
(nQuery Advisor®, version 7.0).  
In addition, the sample size is sufficient to provide a stable estimate of the size of the treatment 
effect (treatment delta). The efficacy estimate will be used to calculate the sample size for future 
studies. 
For Part B, formal sample size calculations have not been conducted. A total of 40 subjects per 
group is sufficient to provide a stable estimate of the size of the treatment effect.    
Efficacy and safety will be assessed for each part separately and for all subjects combined. 


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14 DATA COLLECTION, RETENTION AND MONITORING 
All study data will be documented and reviewed within an eCRF, in accordance with local and 
regional regulatory requirements and ethical guidelines.  
Before site initiation, all participating PIs must agree to permit study-related monitoring, audits, 
IRB/IEC/REB reviews, as well as access and review of source data by Discovery or appointed 
designees.  
All study members involved in study data capture and review must complete eCRF training 
relevant to their role before study start. Further details on data capture and eCRF completion is 
provided in the eCRF Completion Guidelines. 
14.1 Protection of Subject Data and Confidentiality  
To maintain subject confidentiality, only the site number and subject number will be used to 
identify all subjects on eCRFs and other documentation submitted to Discovery. All evaluation 
forms, reports, and other records will be identified by a coded number only.  
All study records will be kept in a locked file cabinet and code sheets linking a subject’s name to 
a subject identification number will be stored separately in another locked file cabinet. Clinical 
information will not be released without written permission of the subject’s legally authorized 
representative, except as necessary for monitoring by the FDA. The investigators must also 
comply with all applicable privacy regulations (eg, HIPAA [US], EU Data Protection Directive 
95/46/EC). 
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement. 
14.2 Data Collection Instruments 
The investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject enrolled in this study. 
Study personnel at each site will enter data from source documents into the protocol-specific 
eCRF within 5 days of the information becoming available; however, data may be entered 
directly into the eCRF in fields which require free-text entries as directed by the sponsor. 
Subjects will not be identified by name in the study database or on any study documents to be 
collected by Discovery (or designee), but will instead be identified by a site and subject number. 


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Corrections for an existing eCRF record will automatically be recorded by the eCRF system 
(audit trail capturing the time, date, and the identification of the user who entered or updated 
eCRF data). Recorded corrections by the eCRF will create an electronic audit trail of study 
documentation. 
The PI is responsible for all study information obtained and documented on subjects. As such, 
the PI must review and verify all study data documented during the course of this study and 
ensure its completeness and accuracy.  
14.3 Data Management Procedures 
The data will be entered into a validated database. Members of Discovery’s Data Management 
department are responsible for data processing, in accordance with procedural documentation. 
Database lock will occur once all quality assurance procedures have been completed; this will 
include but not be limited to the following: (1) all site-based study data have been entered into 
the eCRF, (2) all entered data have been reconciled and reviewed by Discovery or designee, and 
(3) all data related queries have been rendered and resolved. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
14.4 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries will be 
entered, tracked, and resolved through the electronic data capture (EDC) system directly. The 
study database will be updated in accordance with the resolved queries. All changes to the study 
database will be documented. 
14.5 Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained. The 
databases will be backed up by a database administrator in conjunction with any updates or 
changes to the database. 
At critical junctures of the study (eg, production of interim reports and final reports), data for 
analysis will be locked and cleaned per established procedures. 


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At the conclusion of the study, each investigative site will receive a CD of their final data. 
14.6 Record Retention 
All records that support data entered into the eCRF of each subject must be retained in the files 
of the PI or the hospital for a minimum of 2 years (3 years for ICF) following notification by 
Discovery that all investigations have been discontinued or that the last approval of a marketing 
application has been obtained. Supporting documents will include but not be limited to the 
following:  
1. Copies of eCRFs (given to the site on a CD)  
2. All original source documents; these may include but not be limited to the following: 
a) ICFs 
b) laboratory reports 
c) progress notes 
d) medical histories 
e) physical and diagnostic findings  
f) diagnoses  
g) dates of therapy before and during this study 
h) drug and device dispensing/disposition records  
 
If the PI retires, relocates, or for other reason withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person who will accept the responsibility. 
Discovery must be notified in writing of the name and address of the new custodian. 
14.7 Monitoring 
Discovery or their designee will perform on-site monitoring visits as frequently as it is deemed 
necessary to ensure quality study data capture, and accurate adherence to the study protocol as 
outlined in the study Monitoring Plan. In order to protect the blind, records that could unblind the 
monitor will be reviewed by an “unblinded monitor.” 
Before enrollment, a clinical site monitor will complete a site initiation visit (SIV) at each study 
site. During SIVs, clinical site monitors will provide study training to site staff, ensure study 
drug storage is in accordance with the study protocol, and validate all other study requirements in 
accordance with the study monitoring plan.  
Clinical site monitors will schedule a study site visit as close as possible to the time of each site’s 
first enrolled study subject; periodic follow-up monitoring visits will ensure on a regularly 


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scheduled basis throughout the study, in accordance with enrollment at the study site. At these 
visits, the clinical site monitor will compare the data entered into the eCRF with the hospital or 
clinic records (source documents) and check for protocol compliance. Documentation reviews 
will include but not be limited to the evaluation and confirmation of the following:  
1. A record of informed consent 
2. Adherence to enrollment criteria 
3. Completion of all required study assessments 
4. Accurate and complete data capture of all AEs, concomitant medications, and safety and 
efficacy observations.  
5. Study drug and ADP storage and dispensing records maintained in accordance with study 
and regulatory requirements.  
Findings from these reviews will be discussed with the PI and study site staff. 
The dates of the monitoring visits will be recorded by the clinical site monitor in a sign-in log to 
be kept at the site. The study coordinator and PI are expected to be available for questions, have 
all source documentation readily available, and have a suitable environment provided for review 
of study-related documents. 
In accordance with ICH E6, Discovery will select (either directly or through a subcontract with a 
company specifically trained in the monitoring of clinical studies), qualified individuals to 
monitor study sites to ensure the quality of study progress and the close adherence of study sites 
to the study protocol and all related governing documents and SOPs. 
The clinical site monitor(s), before the initiation of each study site, will ensure each investigator 
and study staff understands the following: 
a) The investigational status of the study drug and device components and the 
requirements for its accountability 
b) The need to uphold all directives within the clinical protocol as it relates to study 
conduct and subject safety at the study site 
c) The obligation to obtain informed consent in accordance with the Declaration of 
Helsinki and ICH GCP guidelines before enrolling each subject in the study 
d) The obligation to obtain IRB/IEC/REB review and approval of the study before 
study initiation at his/her clinical site, and ensure timely updates to the 
IRB/IEC/REB as mandated by local and national regulatory requirements, and to 


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ensure timely communications to Discovery of all IRB/IEC/REB communications 
(to include reviews and subsequent actions) concerning the study. 
The clinical site monitor(s) will perform periodic visits to each clinical site during the course of 
the study to ensure the study protocol is being followed and that: 
a) Drug and device inventories are being properly maintained and documentation of 
vial usage is accurate and complete (unblinded monitor only). 
b) The PI is reporting all serious or fatal AEs (Section 9) as soon as possible, and in 
no case later than 24 hours after the event, to the medical monitor or designee at 
Discovery. 
c) Site reports temperature excursions for drug product; complaints for drug and 
device are reported (unblinded monitor only). 
The clinical site monitor(s) will perform an end-of-study visit to each clinical site to ensure that: 
a) All drug and ADP (including heater assembly [ADP] and syringe [ADPS] serial 
numbers) reconciliation forms, as provided in the study manual, are accurate and 
complete. 
b) All used and unused vials of study drug have been reconciled. 
c) All eCRFs are complete and all monitoring of eCRFs has been completed. 
 


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15 ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
This study will be conducted according to the US and ICH regulations and guidelines 
(21 CFR 50, 21 CFR 56, 21 CFR 312, and ICH E6) as well as all applicable local, state, and 
federal regulations and guidelines regarding the conduct of clinical studies. In addition, this 
study will be conducted in accordance with the ethical principles included in the WMA 
Declaration of Helsinki. 
15.1 Protocol Amendments 
Any amendments to the protocol will be written by Discovery. Protocol amendments will not be 
implemented without prior written IRB/IEC/REB approval except as necessary to eliminate 
immediate safety hazards to study subjects. A protocol amendment intended to eliminate an 
apparent immediate hazard to study subjects may be implemented immediately, provided the 
IRB/IEC/REB is notified within 5 working days. 
15.2 End-of-Study Procedures 
The PI will complete all required end-of-study procedures as outlined in the study manual and 
submit the final eCRFs (in satisfactory compliance with the protocol) within 1 week after the last 
subject has completed the study. Continuation of this study beyond this time must be agreed 
upon by both the PI and Discovery and may be implemented without amendment to the protocol. 
15.3 Study Report 
Discovery will take full responsibility for signing the final report following consultation with the 
steering committee. 
15.4 Publications  
The preparation and submittal for publication of a manuscript containing the study results shall 
be in accordance with a process determined by a mutual written agreement among Discovery and 
participating institutions. The publication or presentation of any study results shall comply with 
all applicable privacy laws, including but not limited to HIPAA. 


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15.5 Investigator Responsibilities 
By signing the Investigator Agreement Form (Appendix 3 and, in Canada, Appendix 4), the PI 
agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying 
Discovery or designee, except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Use the drug and/or device only for the purpose of investigational testing specified in the 
protocol, and not permit the device to be used by any other person except under my 
direction. 
4. Ensure that the requirements relating to obtaining informed consent and IRB/IEC/REB 
review and approval meet federal guidelines, as stated in 21 CFR 50 and 21 CFR 56. 
5. Report any AEs/SAEs that occur in the course of the study to Discovery or designee, in 
accordance with 21 CFR 312.64. 
6. Maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make 
records available for inspection by Discovery, designee, or Regulatory Agency. 
7. Ensure the study site is fully aligned with their local IRB/IEC/REB. 
8. Ensure the local IRB/IEC/REB complies with the requirements of 21 CFR 56 and/or ICH 
E6 guidelines and as such will be responsible for initial and continuing review and 
approval of the clinical study protocol and related documents. 
9. Promptly report to the IRB/IEC/REB and Discovery or designee all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include 
amendments and Investigational New Drug [IND] safety reports). 
10. Seek IRB/IEC/REB approval before any changes are made in the research study, except 
when necessary to eliminate hazards to the study subjects. 
11. Comply with all other requirements regarding the obligations of clinical investigators and 
all other pertinent requirements listed in 21 CFR 312 and in applicable local regulations. 
12. Ensure that all associates, colleagues, and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments. 
 


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16 REFERENCES 
 
1. 
Soll R, Ozek E. Multiple versus single doses of exogenous surfactant for the prevention 
or treatment of neonatal respiratory distress syndrome. Cochrane Database Syst Rev 
2009(1):CD000141. 
2. 
Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal 
respiratory distress syndrome. Cochrane Database Syst Rev 2012;11:CD001456. 
3. 
Polin RA, Carlo WA, Committee on F, Newborn, American Academy of P. Surfactant 
replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 
2014;133(1):156-63. 
4. 
Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European 
consensus guidelines on the management of neonatal respiratory distress syndrome in preterm 
infants--2013 update. Neonatology 2013;103(4):353-68. 
5. 
Walsh BK, Daigle B, DiBlasi RM, Restrepo RD, American Association for Respiratory 
C. AARC Clinical Practice Guideline. Surfactant replacement therapy: 2013. Respir Care 
2013;58(2):367-75. 
6. 
Davis DJ, Barrington KJ. Recommendations for neonatal surfactant therapy. Paediatr 
Child Health 2005;10(2):109-16. 
7. 
Schmid MB, Glossmann A, Hopfner RJ, Hummler HD, Fuchs H. Cerebral Oxygenation 
during Neonatal Endotracheal Intubation. E-PAS2014 2014:3843.563. 
8. 
Gleissner M, Jorch G, Avenarius S. Risk factors for intraventricular hemorrhage in a birth 
cohort of 3721 premature infants. J Perinat Med 2000;28(2):104-10. 
9. 
Talwar R, Virk JS, Bajaj Y. Paediatric subglottic stenosis - Have things changed? Our 
experience from a developing tertiary referral centre. Int J Pediatr Otorhinolaryngol 
2015;79(12):2020-2. 
10. 
Schmolzer GM, Kumar M, Pichler G, Aziz K, O'Reilly M, Cheung PY. Non-invasive 
versus invasive respiratory support in preterm infants at birth: systematic review and meta-
analysis. BMJ 2013;347:f5980. 
11. 
American Association for Respiratory Care. Application of Continuous Positive Airway 
Pressure to Neonates via Nasal Prongs, Nasopharyngeal Tube, or Nasal Mask—2004 Revision & 
Update. Respir Care 2004;49(9):1100-1108. 
12. 
Ho JJ, Subramaniam P, Davis PG. Continuous distending pressure for respiratory distress 
in preterm infants. Cochrane Database Syst Rev 2015;7:CD002271. 
13. 
SUPPORT Study Group, Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, et al. 
Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362(21):1970-9. 


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14. 
Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB, et al. Nasal CPAP or 
intubation at birth for very preterm infants. N Engl J Med 2008;358(7):700-8. 
15. 
Sandri F, Plavka R, Ancora G, Simeoni U, Stranak Z, Martinelli S, et al. Prophylactic or 
early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 
2010;125(6):e1402-9. 
16. 
Dunn MS, Kaempf J, de Klerk A, de Klerk R, Reilly M, Howard D, et al. Randomized 
trial comparing 3 approaches to the initial respiratory management of preterm neonates. 
Pediatrics 2011;128(5):e1069-76. 
17. 
Subramaniam P, Henderson-Smart DJ, Davis PG. Prophylactic nasal continuous positive 
airways pressure for preventing morbidity and mortality in very preterm infants. Cochrane 
Database Syst Rev 2005(3):CD001243. 
18. 
Isayama T, Chai-Adisaksopha C, McDonald SD. Noninvasive Ventilation With vs 
Without Early Surfactant to Prevent Chronic Lung Disease in Preterm Infants: A Systematic 
Review and Meta-analysis. JAMA Pediatr 2015;169(8):731-9. 
19. 
Fischer HS, Buhrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary 
dysplasia: a meta-analysis. Pediatrics 2013;132(5):e1351-60. 
20. 
Yee WH, Scotland J, Pham Y, Finch R, Evidence-based Practice for Improving Quality 
Evidence Review G. Does the use of primary continuous positive airway pressure reduce the 
need for intubation and mechanical ventilation in infants </=32 weeks' gestation? Paediatr Child 
Health 2011;16(10):633-7. 
21. 
Hummler HD, Parys E, Mayer B, Essers J, Fuchs H, Schmid M. Risk Indicators for Air 
Leaks in Preterm Infants Exposed to Restrictive Use of Endotracheal Intubation. Neonatology 
2015;108(1):1-7. 
22. 
Dargaville PA, Aiyappan A, De Paoli AG, Dalton RG, Kuschel CA, Kamlin CO, et al. 
Continuous positive airway pressure failure in preterm infants: incidence, predictors and 
consequences. Neonatology 2013;104(1):8-14. 
23. 
Abdel-Latif ME, Osborn DA. Nebulised surfactant in preterm infants with or at risk of 
respiratory distress syndrome. Cochrane Database Syst Rev 2012;10:CD008310. 
24. 
Berggren E, Liljedahl M, Winbladh B, Andreasson B, Curstedt T, Robertson B, et al. 
Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome. Acta 
Paediatr 2000;89(4):460-4. 
25. 
Lewis JF, McCaig L. Aerosolized versus instilled exogenous surfactant in a nonuniform 
pattern of lung injury. Am Rev Respir Dis 1993;148(5):1187-93. 
26. 
Wolfson MR, Wu J, Hubert TL, Mazela J, Gregory TJ, Clayton RG, et al. Aerosolized 
KL4 Surfactant Dose-Response in the Spontaneously Breathing CPAP-Supported Preterm Lamb. 
In: Pediatric Academic Society Conference; 2011. 


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27. 
Finer NN, Merritt TA, Bernstein G, Job L, Mazela J, Segal R. An open label, pilot study 
of Aerosurf(R) combined with nCPAP to prevent RDS in preterm neonates. J Aerosol Med Pulm 
Drug Deliv 2010;23(5):303-9. 
28. 
Lewis JF, Ikegami M, Jobe AH, Tabor B. Aerosolized surfactant treatment of preterm 
lambs. J Appl Physiol (1985) 1991;70(2):869-76. 
29. 
Lewis J, Ikegami M, Higuchi R, Jobe A, Absolom D. Nebulized vs. instilled exogenous 
surfactant in an adult lung injury model. J Appl Physiol (1985) 1991;71(4):1270-6. 
30. 
Linner R, Perez-de-Sa V, Cunha-Goncalves D. Lung deposition of nebulized surfactant in 
newborn piglets. Neonatology 2015;107(4):277-82. 
31. 
Rey-Santano C, Mielgo VE, Andres L, Ruiz-del-Yerro E, Valls-i-Soler A, Murgia X. 
Acute and sustained effects of aerosolized vs. bolus surfactant therapy in premature lambs with 
respiratory distress syndrome. Pediatr Res 2013;73(5):639-46. 
32. 
Bide RW, Armour SJ, Yee E. Allometric respiration/body mass data for animals to be 
used for estimates of inhalation toxicity to young adult humans. J Appl Toxicol 2000;20(4):273-
90. 
33. 
Bhutani VK, Sivieri EM. Pulmonary function and graphics. In: Goldsmith JP, Karotkin 
EH, editors. Assisted Ventilation of the Neonate. 4th ed. Philadelphia, PA: Saunders; 2003. p. 
293-309. 
34. 
Gregory TJ, Irshad H, Chand R, Kuehl P. Deposition of aerosolized lucinactant in non-
human primates (NHPs). In: Hot Topics in Neonatology. Washington, D.C.; 2017. 
35. 
Mazela J, Merritt TA, Finer NN. Aerosolized surfactants. Curr Opin Pediatr 
2007;19(2):155-62. 
36. 
Wiswell TE, Knight GR, Finer NN, Donn SM, Desai H, Walsh WF, et al. A multicenter, 
randomized, controlled trial comparing Surfaxin (Lucinactant) lavage with standard care for 
treatment of meconium aspiration syndrome. Pediatrics 2002;109(6):1081-7. 
37. 
Wiswell TE, Smith RM, Katz LB, Mastroianni L, Wong DY, Willms D, et al. 
Bronchopulmonary segmental lavage with Surfaxin (KL(4)-surfactant) for acute respiratory 
distress syndrome. Am J Respir Crit Care Med 1999;160(4):1188-95. 
 


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17 APPENDICES 
 


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Appendix 1 
Protocol Definitions 
Definitions 
 
Aerosol, study 
Output of ADS device (eg, aerosolized lucinactant) 
Aerosol, time 
Duration a subject is exposed to aerosolized lucinactant 
Air leak, pulmonary 
Chest radiographic evidence of air leak (pneumothorax, 
pulmonary interstitial emphysema, pneumomediastinum, 
pneumopericardium, subcutaneous emphysema). An air leak 
is considered an AE of special interest if it occurs at any time 
during the study. 
Apnea 
A lack of inspiratory air movement sustained for ≥20 seconds 
and coincident with at least one of the following: (a) SpO2 < 
80% (not necessarily ≥20 seconds), (b) HR < 100 bpm (not 
necessarily ≥20 seconds), or (c) requirement for positive 
pressure ventilation administered manually or mechanically 
through any patient interface. 
Bradycardia 
A heart rate < 100 bpm sustained for ≥ 20 seconds 
Bronchopulmonary dysplasia 
(BPD) at 36 weeks PMA 
The need for oxygen supplementation (FiO2 > 0.21) at 36 
weeks PMA. 
Corrected age 
Age of the subject from the date the subject reaches 40 weeks 
gestation. 
Desaturation 
SpO2 < 80% sustained for ≥ 20 seconds 
Final Observation 
The final study observation is to occur at 36 weeks PMA or at 
the time of NICU discharge or hospital transfer (whichever 
occurs first). If the neonate dies, the final observation will be 
considered the last study observation before death. 
Gestational age 
Gestational age of the subject based on the mother’s last 
menstrual period based on best obstetrical estimate or 
ultrasound. 
Non-invasive support 
Any respiratory support device which generates a constant 
positive pressure and uses a patient interface on the subject’s 
face. 
Non-invasive 
ventilation 
(NIV) 
Any respiratory support device which generates a variable 
(eg, bi-level) positive pressure regardless of whether 
synchronized to the subject’s inspirations, and uses a patient 
interface on the subject’s face. 


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Peri-dosing event 
One of the following AEs with an onset time ≤2 hours from 
the time of initiating study treatment: 
• Apnea 
• Bradycardia 
• Desaturation 
• Gagging/regurgitation 
• Pallor 
Period, extended 
observational  
The 
study 
timeframe 
occurring 
>72 
hours 
from 
randomization until ≤ Day 7  
Period, final observational 
The study timeframe occurring > day 7 to ≤ 36 weeks PMA 
Period, primary observational  The 
study 
timeframe 
occurring ≤72 
hours 
from 
randomization  
Physical exam 
Includes the following organ systems: cardiac, respiratory, 
abdomen, genitalia and perineum, skin, extremities, head, 
neck and mouth, and neurological. 
Study treatment 
Receipt of either active or sham/placebo dosing, either 
initially or as a repeat. Masking procedures for the initial 
dose will be followed for repeat doses. 
Supplemental oxygen 
Delivery of oxygen without the generation of pressure above 
ambient pressure (eg, standard-flow nasal cannula). Although 
all forms of respiratory support may provide FiO2 >0.21, for 
this study supplemental oxygen refers only to modes that 
deliver oxygen without pressure. 
 


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Appendix 2 
Protocol Event Schedule  
 
Primary Phase Through 36 Weeks PMA 
Longer-Term Follow-Up Phase 
Through 1-Year Corrected Age 
Measurement/Procedure 
Screening 
Primary 
Observation 
(Days 1 to 3) 
Extended 
Observation 
(Days 4 to 7) 
Final Observation 
(Day 8 to 36w PMA/ 
Final Observation) 
Informed Consent/HIPAA (or applicable local 
privacy regulations) 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Maternal History 
X 
 
 
 
 
Birth History and Birth Weight 
X 
 
 
 
 
Medical History  
X 
 
 
 
 
Physical Examination1 
X 
 
 
X 
 
Chest Radiograph2 
X 
X 
X 
 
 
Respiratory support and O2 delivery  
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
Study Treatment (drug or sham) Administration 
 
X3 
 
 
 
Technical Performance of Device 
 
X 
 
 
 
Use of pacifier and/or chin strap during dosing 
 
X 
 
 
 
Use of oro- or nasogastric tube 
 
X 
X 
 
 
Vital Signs3 
 
X 
X 
 
 
SpO2 
 
X 
X 
 
 
Transcutaneous PCO2 
 
X 
 
 
 
Serum Electrolytes 
 
X 
 
 
 
 Defecation 
 
X 
 
 
 
Adverse Events 
 
X 
X 
X 
 
Adverse Device Effects 
 
X 
 
 
 


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Primary Phase Through 36 Weeks PMA 
Longer-Term Follow-Up Phase 
Through 1-Year Corrected Age 
Measurement/Procedure 
Screening 
Primary 
Observation 
(Days 1 to 3) 
Extended 
Observation 
(Days 4 to 7) 
Final Observation 
(Day 8 to 36w PMA/ 
Final Observation) 
Survival 
 
X 
X 
X 
 
Concomitant Medication 
 
X 
X 
X 
X 
Incidence of BPD 
 
 
 
X 
 
Complications of Prematurity 
 
 
 
X 
 
Hospitalizations 
 
 
 
 
X 
Abbreviated physical and neurological exam 
 
 
 
 
X 
Note: Day 1 for all subjects is the day of study randomization. 
1 
Physical exam is performed at screening and at the final observation at the end of the Final Observation Period only 
2 
A chest radiograph will be performed as part of the screening assessment. An additional chest radiograph is required prior to intubation is required if such a procedure does not 
delay or compromise the emergent care of the subject. 
3  Body temperature, respiratory rate and heart rate are documented on a schedule based on the date and time of randomization. Respiratory rate and heart rate are additionally 
documented every 10 minutes during study treatment administration. 
 
 


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Appendix 3 
Investigator Agreement Form 
Study Title: 
A Multinational, Multicenter, Masked, Randomized, Controlled Study 
to Assess the Safety and Efficacy of Lucinactant for Inhalation in 
Preterm Neonates 26 to 32 Weeks Gestational Age with Respiratory 
Distress Syndrome 
Study Number: 
03-CL-1202 
I have read the foregoing protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study as outlined herein and will complete the study within the time 
designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure they 
are fully informed regarding the study drugs and/or devices and the conduct of the study. 
I will use only the informed consent form approved by the Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board and Discovery Laboratories, Inc. 
(Discovery) and will fulfill all responsibilities for submitting pertinent information to the 
IRB/IEC/REB responsible for the study. 
I further agree that authorized representatives of Discovery, the US Food and Drug 
Administration, or other regulatory agencies will have access to any source document from 
which eCRF information may have been generated. 
I agree that I and all subinvestigators listed on the delegation of authority form and/or Form FDA 
1572 shall inform Discovery of any equity interest in the company prior to participating in this 
study. I further agree that I and all subinvestigators listed will consult with Discovery before 
acquiring any financial interest in the company during the study and for one year after the 
study’s completion. 
 
Signed: 
 
 
Date:  
 
Printed Name:  
  
Title:  
  
Affiliation:  
  
Address:  
  
 
  
Phone Number: __________________ 


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Appendix 4 
Investigator Agreement Form for Canada 
Investigator’s Agreement in Accordance with Subsection 81(k) of the Medical Devices Regulations Canadian Sites 
Study Title: 
A Multinational, Multicenter, Masked, Randomized, Controlled Study to Assess the 
Safety and Efficacy of Lucinactant for Inhalation in Preterm Neonates 26 to 32 Weeks 
Gestational Age with Respiratory Distress Syndrome  
Study Number: 
03-CL-1202 
Device Name: 
AerosurfTM Delivery System 
I, as the qualified investigator for the above referenced clinical trial, undertake, as outlined in Subsection 81(k) of 
the Medical Devices Regulations, to: 
i. 
conduct the investigational testing in accordance with the protocol,  
ii. 
inform a patient who is to be diagnosed or treated with the device of the risks and benefits associated with 
its use and obtain the written consent of the patient, 
iii. 
not use the device or permit it to be used for any purpose other than the investigational testing specified in 
the protocol, 
iv. 
not permit the device to be used by any person other than myself, except under my direction, and 
v. 
in the event of an incident that is related to a failure of the device or a deterioration in its effectiveness, or 
any inadequacy in its labelling or in its directions for use and has led to the death or a serious deterioration 
in the state of health of a patient, user or other person, or could do so were it to recur, report the incident 
and the circumstances surrounding it to Discovery Laboratories, Inc. as soon as possible (and no later than 
24 hours after the event has occurred) and to the Canadian Medical Devices Bureau within 72 hours after it 
comes to my attention. 
 
Completed forms should be emailed to: mdpr-dimm@hc-sc.gc.ca or faxed to: 613-954-0941 or mailed to: 
Canada Vigilance - Medical Device Problem Reporting Program 
Marketed Health Products Directorate 
Health Canada 
Address Locator 0701E 
200 Tunney's Pasture Driveway 
Ottawa (Ontario) K1A 0K9 
 
Qualified Investigator and Site Information 
Printed Name 
Title 
Name of Site 
Address 
 
 
Signature 
Date 
 

SAP_001.pdf: 
DISCOVERY LABORATORIES, INC. 
Statistical Analysis Plan 
 
A Multinational, Multicenter, Masked, Randomized, Controlled Study to Assess the 
Safety and Efficacy of Lucinactant for Inhalation in Preterm Neonates 26 to 32 
Weeks Gestational Age with Respiratory Distress Syndrome 
 
 
Protocol Number: 03-CL-1202 
Amendment #2 
 
 
 
 
 
SAP Version: Final - Revision 2 
 
27 April 2017  
 
 
 


Protocol 03-CL-1202 
- CONFIDENTIAL - 
Discovery Laboratories, Inc. 
Statistical Analysis Plan 
 
Final - Revision 2, 27 April 2017 
 
 
2 
A Multinational, Multicenter, Masked, Randomized, Controlled Study to  
Assess the Safety and Efficacy of Lucinactant for Inhalation in Preterm Neonates  
26 to 32 Weeks Gestational Age with Respiratory Distress Syndrome 
 
Statistical Analysis Plan 
 
Author/Project Biostatistician 
 
 
 
 
 
 
  
Phillip D. Simmons 
 
Date 
Executive Director, Biostatistics and Data Management 
Discovery Laboratories, Inc. 
 
 
 
By signing below, I have read through the entire statistical analysis plan and agree to implement 
the plan. 
 
 
 
 
 
 
 
Robert Segal, MD 
 
Date 
Senior Vice President, Clinical Development & Academic Affairs 
Discovery Laboratories, Inc. 
 
 
 
 


Protocol 03-CL-1202 
- CONFIDENTIAL - 
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Statistical Analysis Plan 
 
Final - Revision 2, 27 April 2017 
 
 
3 
EXECUTIVE SUMMARY 
The objectives of this study are to evaluate the safety and efficacy of lucinactant for inhalation, 
in comparison to nasal continuous positive airway pressure (nCPAP) alone, in preterm neonates 
with RDS, as assessed by the time to, and incidence of, respiratory failure and/or death due to 
RDS, incidence of bronchopulmonary dysplasia (BPD), and change in physiologic parameters 
(fraction of inspired oxygen [FiO2] and partial pressure of carbon dioxide [PCO2]) over the first 
72 hours of life. 
This is a multinational, multicenter, randomized, 2-part (A, B), double-blind (masked)/open 
label, controlled study comparing lucinactant for inhalation (AEROSURF®) administered with 
nCPAP to treatment with nCPAP alone for the treatment of RDS in 26 to 32 completed weeks 
post-menstrual age (PMA) preterm infants. For Part A (masked), infants 28 to 32 weeks PMA 
will be randomized into 1 of 3 parallel treatment groups, with 2 repeat doses allowed if the repeat 
dose criterion is met. For Part B (open-label), infants 26 to 28 weeks PMA will be randomized 
into 1 of 2 parallel treatment groups, with 4 repeat doses allowed if the repeat dose criterion is 
met. Reconstituted lyophilized lucinactant (reconstituted with sterile water for injection) will be 
aerosolized by the investigational device, the Aerosurf Delivery System (ADS), using the 
capillary aerosol generator and introduced into the nCPAP circuit. Those infants randomized to 
the control arm will receive nCPAP alone.  
Exposure, defined as the emitted dose, is the amount of lucinactant that is delivered at the 
connection to the patient interface by the ADS at a constant rate of flow. The theoretical inhaled 
dose – the fraction of the aerosolized lucinactant that the infant is exposed to that is likely to be 
inhaled – is estimated by product of: 1) the aerosol concentration, 2) the minute ventilation of the 
infant, and 3) the administration time of the aerosol.  


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Statistical Analysis Plan 
 
Final - Revision 2, 27 April 2017 
 
 
4 
Treatment  
Group 
Study Assignment 
Study Part Aa 
40 mg/kg 
Lucinactant for inhalation 40 mg TPL/kg (administered over 25 minutes) in conjunction with 
nCPAP (n = up to 80)  
Up to 2 repeat doses of 40 mg TPL/kg are to be given if repeat dosing criteria are met 
80 mg/kg 
Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction with 
nCPAP (n = up to 80)  
Up to 2 repeat doses of 80 mg TPL/kg are to be given if repeat dosing criteria are met 
Control 
Continuous nCPAP with sham drug treatment (n = up to 80)  
Study Part B 
80 mg/kg 
Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction with 
nCPAP (n = up to 40)  
Up to 4 repeat doses of 80 mg TPL/kg are to be given if repeat dosing criteria are met 
Control 
Continuous nCPAP (n = up to 40)  
a In Part A of the study, masking procedures will be followed for all doses in all treatment groups. 
 
The data monitoring committee (DMC) will conduct 3 preplanned interim analyses: 1) after 
approximately 25% of subjects in Part A have been enrolled, 2) after 67% of subjects in Part A 
have been enrolled, and 3) after approximately 20 subjects in Part B have been enrolled. The 
DMC will review all available safety data for each interim analysis; if there are safety concerns, 
a recommendation may be made to suspend study enrollment. 
Repeat dosing will be allowed in each dosing group. Subjects meeting the repeat dosing criterion 
will receive up to 2 (Part A) or 4 (Part B) additional treatments of the same dose. For the control 
subjects that meet the repeat dosing criteria, all the procedures conducted for the active subjects 
will be carried out (without delivering a dose) to protect study blinding (Part A). 
Primary Study Period: 
For the primary study period, subjects will be followed for safety and efficacy evaluations 
(including, but not limited to, the incidence and timing of intubation, mechanical ventilation 
and/or surfactant administration; AEs; concomitant medications; physiological assessments; 
incidence of BPD) until the subject is 36 weeks PMA, is discharged, is transferred, or has died. 
Descriptive statistics (number of subjects, percent, mean, standard deviation, median, minimum, 
maximum) will be presented by treatment group, defined as each of the active doses (n = 80, 160 
subjects total for Part A; n ≤ 80 subjects for Part B) and the all controls combined (n = 80 for 
Part A and n ≤ 80 for Part B). A final visit will occur at 36 weeks PMA or at the time of 
discharge or transfer (whichever occurs first) for all subjects. 


Protocol 03-CL-1202 
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Statistical Analysis Plan 
 
Final - Revision 2, 27 April 2017 
 
 
5 
Efficacy endpoints in the study include: 
1. Incidence of respiratory failure or death due to RDS within the first 72 hours of life  
Respiratory failure due to RDS will be defined as follows: 
a. 
any subject receiving intubation for mechanical ventilation (MV) and/or 
surfactant administration within 72 hours of life or death due to RDS; or 
b. 
if the subject meets at least 1 of the following criteria, regardless of whether 
endotracheal intubation is performed: 
• a sustained need for FiO2 > 0.45 to maintain an SpO2 > 90% to 95%  
• a sustained (on ≥ 2 consecutive observations > 60 minutes apart) 
transcutaneous PCO2 > 65 mmHgnCPAP > 8 cm H2O 
Death due to RDS is any death whose primary cause is respiratory failure due to RDS 
2. Incidence rate of death due to RDS 
3. Time to respiratory failure due to RDS within 72 hours of life 
4. Incidence rate of late (> 72 hours of life through Day 7) respiratory failure due to RDS 
5. Incidence rate of BPD and rate of survival without BPD at 36 weeks PMA 
6. Observed FiO2 and PCO2 values and change from baseline values in FiO2 and PCO2 over 
the first 72 hours of life 
7. Incidence rate of pulmonary air leak, especially pneumothorax 
Safety endpoints in the study include: 
1. Survival (all-cause mortality; date and time of death, if applicable) 
2. AEs, including adverse device effect (ADEs) and AEs of special interest, including peri-
dosing events, complications related to placement of binasal prongs, and air leaks 
3. Concomitant medications 
4. Use of respiratory support and supplemental O2 
5. Common complications of prematurity 
6. Physical examinations 
7. Tolerability of lucinactant for inhalation  
8. Incidence rate of air leak 
9. Assessments of the following:  


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a) Vital signs  
b) O2 saturation, as determined by pulse oximetry (SpO2) 
c) Serum electrolyte measurements  
d) Defecation 
e) Chest radiograph prior to intubation 
Follow-Up Period: 
Neonates may be followed up to 1 year corrected age (based on 40 weeks PMA), at which time a 
physical examination will be performed, including an abbreviated neurologic assessment. Also, 
the number of hospitalizations, need for and duration of ventilator support, and use of 
bronchodilators or steroids will be recorded. An interim 6-month corrected age follow-up (via 
telephone or visit) will include number and reasons for hospitalizations, need for and duration of 
ventilator support, and/or oxygen supplementation requirements 
Analysis Populations: 
The statistical analysis of both the primary and secondary objectives will be based on all enrolled 
preterm neonates. For the efficacy analysis, the primary analysis will be based on a modified 
intent-to-treat (mITT) population, defined as subjects who received treatment. In addition, 
populations of all randomized subjects (ITT), subjects with no treatment interruptions, and 
subjects with no major protocol deviations (per-protocol) will be evaluated based upon the 
treatment group to which they were randomized. For the safety analysis, all subjects randomized 
to the control group or who received any lucinactant for inhalation (including partial doses) will 
be evaluated based upon the treatment they actually received. 
The treatment difference (delta) between active and control treatments will be calculated for the 
primary and key secondary efficacy endpoints for each country and/or region. The delta 
calculated will be used to plan additional studies and to evaluate regional care contribution 
variations that may occur in the study. 


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TABLE OF CONTENTS 
EXECUTIVE SUMMARY .......................................................................................................... 3 
1 
OVERVIEW ........................................................................................................................ 11 
1.1 
BACKGROUND ................................................................................................................ 11 
1.1.1 Treatment of Neonatal Respiratory Distress Syndrome ........................................... 11 
1.1.2 Development of Aerosolized Device for Lucinactant Delivery ................................. 12 
1.2 
OBJECTIVES ................................................................................................................... 13 
1.2.1 Efficacy Objective ..................................................................................................... 14 
1.2.2 Primary Endpoint...................................................................................................... 14 
1.2.3 Secondary Endpoints ................................................................................................ 14 
1.2.4 Tertiary Endpoints .................................................................................................... 15 
1.2.5 Safety Evaluations ..................................................................................................... 15 
1.3 
HYPOTHESES .................................................................................................................. 16 
2 
INVESTIGATIONAL PLAN ............................................................................................ 17 
2.1 
STUDY POPULATION ...................................................................................................... 17 
2.1.1 Inclusion criteria ....................................................................................................... 17 
2.1.2 Exclusion Criteria ..................................................................................................... 18 
2.2 
STUDY DESIGN AND RANDOMIZATION ........................................................................... 18 
2.2.1 Treatment Groups ..................................................................................................... 20 
2.2.2 Repeat Dosing ........................................................................................................... 20 
2.2.3 Sample Size Justification........................................................................................... 21 
2.2.4 Study Schedule .......................................................................................................... 22 
3 
STUDY SUBJECT CHARACTERISTICS ...................................................................... 23 
3.1 
SUBJECT DISPOSITION .................................................................................................... 23 
3.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...................................................... 23 
3.2.1 Demographics ........................................................................................................... 23 
3.2.2 Medical, Birth and Maternal History ....................................................................... 23 
3.3 
STUDY AND CONCOMITANT MEDICATION...................................................................... 24 
3.3.1 Compliance ............................................................................................................... 24 
3.3.2 Number of Doses ....................................................................................................... 24 
3.3.3 Previous and Concomitant Medication .................................................................... 24 
3.4 
PROTOCOL VIOLATIONS/DEVIATIONS ............................................................................ 24 
4 
EFFICACY ANALYSIS ..................................................................................................... 25 
4.1 
EFFICACY POPULATIONS ................................................................................................ 25 
4.1.1 Modified Intent-to-Treat Population ......................................................................... 25 
4.1.2 ITT Population .......................................................................................................... 26 
4.1.3 Without Treatment Interruptions Population............................................................ 26 
4.1.4 Per-Protocol Population ........................................................................................... 26 
4.2 
STATISTICAL ANALYSIS ................................................................................................. 26 


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4.2.1 Primary Efficacy Endpoint ....................................................................................... 27 
4.2.2 Key Secondary Endpoints ......................................................................................... 27 
4.2.3 Physiological Assessments ........................................................................................ 28 
4.2.4 BPD and Survival without BPD ................................................................................ 29 
4.2.5 Concordance between Intubation and Respiratory Failure Criteria ....................... 29 
4.2.6 Late Respiratory Failure or Death Due to RDS ....................................................... 29 
4.2.7 Complications of Prematurity ................................................................................... 29 
4.3 
MISSING DATA ............................................................................................................... 29 
4.4 
SUBGROUP ANALYSES ................................................................................................... 30 
5 
TECHNICAL PERFORMANCE OF THE DEVICE ..................................................... 30 
6 
SAFETY ANALYSES ........................................................................................................ 31 
6.1 
SAFETY POPULATION ..................................................................................................... 31 
6.2 
EXTENT OF EXPOSURE ................................................................................................... 31 
6.3 
ADVERSE EVENTS .......................................................................................................... 31 
6.3.1 Peri-Dosing AEs ....................................................................................................... 31 
6.3.2 AEs Related to Surfactant Administration (AEs of Special Interest) ........................ 32 
6.3.3 Other TEAEs ............................................................................................................. 32 
6.3.4 Serious Adverse Events ............................................................................................. 32 
6.3.5 Unexpected Adverse Device Effects .......................................................................... 32 
6.3.6 Deaths ....................................................................................................................... 33 
6.4 
CLINICAL ASSESSMENTS OF SAFETY .............................................................................. 33 
6.4.1 Vital Signs ................................................................................................................. 33 
6.4.2 Physical Examination ............................................................................................... 33 
6.4.3 Serum Electrolytes .................................................................................................... 33 
6.4.4 Defecation ................................................................................................................. 33 
6.4.5 Respiratory Support and Supplemental Oxygen ....................................................... 33 
6.5 
LONG-TERM FOLLOW-UP .............................................................................................. 34 
6.5.1 6-Month Follow-Up .................................................................................................. 34 
6.5.2 One-Year Follow-Up ................................................................................................ 34 
7 
INTERIM ANALYSES AND DATA MONITORING .................................................... 35 
7.1 
DATA MONITORING COMMITTEE ................................................................................... 35 
7.2 
INTERIM ANALYSES ....................................................................................................... 35 
7.3 
DATA MONITORING ................................................................................................... 35 
8 
STATISTICAL TECHNICAL ISSUES ............................................................................ 36 
8.1 
METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................... 36 
8.2 
BLINDING/MASKING ...................................................................................................... 36 
8.3 
DETAILS ON STATISTICAL METHODS .............................................................................. 36 
8.3.1 Logistic Regression for Testing Incidence of Event .................................................. 36 
8.3.2 Log-Rank Test for Testing Time to Event ................................................................. 38 
8.3.3 Generalized Linear Modeling using Poisson Distribution ....................................... 39 


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8.4 
MULTIPLICITY ................................................................................................................ 40 
9 
GENERAL ANALYSIS DEFINITIONS .......................................................................... 40 
9.1 
BASELINE DEFINITION ................................................................................................... 41 
9.2 
WINDOWS FOR VISITS .................................................................................................... 41 
9.3 
SITE POOLING METHODS ............................................................................................... 41 
10 REFERENCES .................................................................................................................... 42 
11 LIST OF SUMMARY TABLES, LISTINGS, AND FIGURES ..................................... 44 


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ABBREVIATIONS 
Abbreviation 
Description 
ADE 
Adverse device effect 
ADS 
Aerosurf® Delivery System 
AE 
Adverse event 
BPD 
Bronchopulmonary dysplasia 
CAG 
Capillary aerosol generator 
Cl/Cl- 
Chloride/Chloride ion 
DMC 
Data monitoring committee 
FiO2 
Fraction of inspired oxygen 
IMV 
Intermittent mechanical ventilation 
IP 
Investigational product 
ITT 
Intent-to-treat 
IVH 
Intraventricular hemorrhage 
IWRS 
Interactive web-response system 
K/K+ 
Potassium/Potassium ion 
MAP 
Mean airway pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAD 
Mass median aerodynamic diameter 
MV 
Mechanical ventilation 
Na/Na+ 
Sodium/Sodium Ion 
nCPAP 
Nasal continuous positive airway pressure 
NEC 
Necrotizing enterocolitis 
NICU 
Neonatal intensive care unit 
PCO2 
Arterial carbon dioxide 
PDA 
Patent ductus arteriosus 
PMA 
Post-menstrual age 
PVL 
Periventricular leukomalacia 
RDS 
Respiratory distress syndrome 
ROP 
Retinopathy of prematurity 
SAE 
Serious adverse event 
SpO2 
Oxygen saturation as measured by pulse oximetry 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event 
TPL 
Total phospholipids 
UADE 
Unanticipated adverse device effect 
WHO 
World Health Organization 
 
 
 


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1 
OVERVIEW 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of 
strategy, rationale, and statistical techniques to be used to assess safety and efficacy in the 
03-CL-1202 study of lucinactant for inhalation in preterm neonates. The purpose of the SAP is to 
ensure the credibility of the study findings by pre-specifying the statistical approaches to the 
analysis of study data prior to database lock. This SAP provides additional details concerning the 
statistical analyses that are outlined in the protocol. 
1.1 
BACKGROUND 
1.1.1 Treatment of Neonatal Respiratory Distress Syndrome 
Exogenous surfactant treatment reduces mortality and morbidity in preterm infants with 
respiratory distress syndrome (RDS) (1,2). Intratracheal SRT has well-established benefits in 
infants with RDS and has become a standard, recommended therapy for this condition (3,4,5,6). 
Early SRT is more effective in reducing morbidity and mortality due to RDS than SRT delivered 
later (2), and multiple doses are sometimes necessary (1).  
Intratracheal instillation of surfactant into the lung requires endotracheal intubation, often with 
concomitant positive pressure mechanical ventilation (MV). However, endotracheal intubation is 
an invasive, painful procedure that itself has potential deleterious effects to the infant (7,8), and 
tracheal injury which may lead to the development of subglottic stenosis (9). Further, MV is 
associated with morbidities such as ventilator-associated lung injury and volutrauma/barotrauma 
resulting in air leak syndromes such as pneumothorax and/or pulmonary interstitial emphysema 
(PIE), and may also contribute to development of chronic lung disease (CLD) / 
bronchopulmonary dysplasia (BPD) (10). 
In order to avoid endotracheal intubation and MV in preterm neonates with mild-to-moderate 
RDS, a strategy of using nasal continuous positive airway pressure (nCPAP) as an effective 
means of providing ventilatory support is now accepted practice (3,4,5,6,11). nCPAP improves 
respiratory function in neonates by increasing functional residual capacity, improving lung 
compliance and dilating upper airway structures, thereby improving gas exchange and reducing 
work of breathing (11,12). Devices that generate and deliver nCPAP, as well as patient interfaces 
such as nasal prongs, have been specifically designed, manufactured, and made commercially 
available for use in neonates.  
 


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Studies in very preterm neonates of initial treatment of RDS with nCPAP alone (13,14,15,16), 
including meta-analyses (17,18), have shown outcomes with this approach that are similar to 
traditional, early treatment with intratracheal surfactant. These studies have consistently shown 
that in neonates treated with nCPAP, the need for surfactant therapy is less than that of neonates 
treated with intubation and SRT, and that the important outcome of death or bronchopulmonary 
dysplasia (BPD, defined as the need for oxygen [O2] treatment at day 28 after birth) is equal or 
less frequent with nCPAP. In neonates treated with nCPAP, approximately 33-67% of patients 
required intubation and intratracheal surfactant replacement, meaning that ⅓ to ⅔ of patients 
were able to avoid intubation altogether. Thus, the strategy of initially supporting neonates with 
nCPAP and reserving SRT only for those who require intubation appears to be reasonably 
effective and potentially safer by avoiding intubation. Two meta-analyses (10,19) and a systematic 
review (20) have suggested that use of nCPAP as the primary respiratory support modality in 
preterm neonates reduces the need for intubation and the rate of BPD, with a number need to 
treat (NNT) of 25 for BPD (10). 
Older gestational age infants treated with nCPAP may be at higher risk of air leak than younger 
infants (21). In a cohort of 297 neonates 25-32 weeks gestation with RDS initially treated with 
nCPAP alone, 65 (22%) overall required intubation (“nCPAP failure”). The rate of nCPAP 
failure was 45% in the subgroup 25-28 weeks’ gestation, consistent with prior reports, where 
only 15% of infants 29-32 weeks’ gestation had nCPAP failure. Notably, the rate of 
pneumothorax prior to intubation was 10% in the younger cohort (also consistent with most prior 
reports), but was 23% in the older gestational age infants as a whole and 47% in those older 
infants who failed nCPAP. 
1.1.2 Development of Aerosolized Device for Lucinactant Delivery 
Discovery Laboratories, Inc. (Discovery) has developed a capillary-based aerosol generator 
(CAG) device to aerosolize lucinactant (lucinactant for inhalation). Nonclinical studies using the 
CAG technology in spontaneously breathing preterm lambs have demonstrated that lambs 
receiving aerosolized lucinactant demonstrated significant improvements in lung mechanics and 
gas exchange compared with lambs receiving CPAP alone. In addition, pilot clinical studies 
using aerosolized lucinactant in neonates with RDS, as well as in adults with asthma and cystic 
fibrosis, have demonstrated that aerosolized lucinactant appears to be generally safe and well-
tolerated. Data from a large neonatal database support the assumption that prophylactic use of 
aerosolized surfactant and nCPAP may reduce the need for intubation by 36% in neonates with a 
birth weight of 1001 to 1500 grams(3). 
 


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Discovery Laboratories, Inc. (Discovery) has developed lucinactant for inhalation, an 
investigational drug-device combination product, to deliver aerosolized SRT to preterm neonates 
with RDS who are being supported with nCPAP. Lucinactant for inhalation is comprised of a 
drug component, lyophilized lucinactant, and a device component referred to as the 
AEROSURF® Delivery System (ADS). The ADS uses novel capillary-based aerosol generator 
(CAG) technology to aerosolize lucinactant for inhalation, providing a high-density surfactant 
aerosol output (1.2 mL/min), with an appropriate particle size (2 to 3 microns mass median 
aerodynamic diameter [MMAD]) for respiration and deposition within the neonatal lung.  
Nonclinical studies using the CAG technology in preterm lambs have demonstrated that 
aerosolized lucinactant significantly improved lung mechanics and gas exchange compared with 
preterm lambs receiving CPAP alone (23). In parallel, pilot clinical studies in neonates with RDS 
(Study KL4-CPAP-01) (24) as well as in adults with asthma and cystic fibrosis (Study KL4-
ASTH-01) have demonstrated that lucinactant aerosolized with commercially available 
nebulizers appears to be generally well-tolerated. The ADS represents the clinical version of the 
CAG technology, which is being used in clinical trials, including the current study, to aerosolize 
lucinactant. 
The purpose of this study is to evaluate the safety and efficacy of lucinactant for inhalation used 
in conjunction with nCPAP, in comparison to nCPAP alone, in preterm neonates 26 to 32 
completed weeks postmenstrual age (PMA) with RDS. 
1.2 
OBJECTIVES 
This study is designed to investigate the safety and efficacy of lucinactant for inhalation in 
preterm neonates 26 to 32 (28 to 32 [Part A]; 26 to 28 [Part B]) completed weeks PMA. Efficacy 
and safety will be based on clinical evaluations. The endpoints specified are similar to those in 
Protocols 03-CL-1201 and 03-CL-1401 to allow for potential comparison and pooling of results. 
The objectives of this study are to evaluate the safety and efficacy of lucinactant for inhalation in 
conjunction with nCPAP, compared to nCPAP alone, in preterm neonates with RDS, as assessed 
by the incidence of, and the time to, respiratory failure and/or death due to RDS over the first 
72 hours of life, the incidence of BPD at 36 weeks PMA, and change in physiologic parameters 
(fraction of inspired oxygen [FiO2] and partial pressure of carbon dioxide [PCO2]) over the first 
72 hours of life. 
In addition, the results of the study should to provide a stable estimate of the size of the treatment 
effect (treatment delta). The efficacy estimate will be used to calculate the sample size for future 
studies. 


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Part A will be unblinded and fully analyzed when enrollment in this part is complete. All 
relevant data from these subjects will be reviewed, cleaned, and locked. In addition, Part A will 
not be unblinded until all decisions on site pooling and per-protocol assessments have been 
completed. An analysis database will be created with the locked data. 
Part B will be fully analyzed when enrollment in this part is complete and the database is locked. 
1.2.1 Efficacy Objective 
The efficacy objective is to assess the size of the clinical effect of lucinactant for inhalation in 
comparison to nCPAP alone, as demonstrated by the incidence of and time to respiratory failure 
due to RDS, incidence of BPD at 36 weeks PMA, physiologic parameters (FiO2 and PCO2), and 
incidence rate of survival without BPD at 36 weeks PMA. 
1.2.2 Primary Endpoint 
The primary endpoint for this study is the incidence rate of respiratory failure or death due to 
RDS within the first 72 hours of life.  
A subject will be defined as having respiratory failure due to RDS if either of the following 
occur: 
1. Intubation for MV and/or surfactant administration within 72 hours of life. MV for non-
respiratory failure reasons will be excluded (eg, surgery). 
2. The subject meets at least 1 of the following criteria, regardless of whether endotracheal 
intubation is performed: 
a. A sustained ( 60 minutes) need for FiO2 > 0.45 to maintain an SpO2 > 90% to 
95% 
b. A sustained (on ≥ 2 consecutive observations > 60 minutes apart) transcutaneous 
PCO2 > 65 mmHg 
c. nCPAP > 8 cm H2O 
3. Death due to RDS. Death due to RDS is any death whose primary cause is respiratory 
failure due to RDS 
1.2.3 Secondary Endpoints 
The secondary endpoints of this study include the evaluation of the following from the time of 
initiation of study treatment until study completion: 
1. Time to respiratory failure due to RDS 


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2. Incidence rate of BPD and rate of survival without BPD at 36 weeks PMA 
3. All-cause mortality 
4. Incidence rate of pulmonary air leak, especially pneumothorax 
1.2.4 Tertiary Endpoints 
The tertiary endpoints of this study include the evaluation of the following from the time of 
initiation of study treatment until study completion: 
1. Incidence rates of common complications of prematurity other than air leak 
2. Change from baseline in FiO2 and/or transcutaneous PCO2 over the first 72 hours of life 
1.2.5 Safety Evaluations 
The following measures are to be documented in the electronic case report form (eCRF) in 
accordance with timings outlined in protocol event schedule: 
1. Survival (date and time of death, if applicable) 
2. AEs, including adverse device effects (ADEs) and AEs of special interest, including peri-
dosing events, complications related to placement of bi-nasal prongs, and air leak.  
3. Concomitant medications 
4. Use of respiratory support and supplemental O2, including the following:  
a) Need for endotracheal intubation and MV 
b) Mode or respiratory support (including supplemental oxygen) and important 
parameters for that mode 
5. Complications of prematurity (ie, intraventricular hemorrhage [IVH], periventricular 
leukomalacia [PVL], pulmonary hemorrhage, necrotizing enterocolitis [NEC], patent 
ductus arteriosus [PDA], acquired sepsis, retinopathy of prematurity [ROP], and BPD) 
6. Physical examinations 
7. Tolerability of lucinactant for inhalation 
8. Incidence of air leak 
9. Assessments of the following:  
a) Vital signs 
b) O2 saturation, as determined by pulse oximetry (SpO2) 
c) Serum electrolyte measurements 
d) Defecation 


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e) Chest radiography, at baseline and prior to intubation 
1.3 
HYPOTHESES 
A total of 2 null hypotheses are defined for this study: 
1. There is no difference between active treatment and control (40 mg TPL/kg vs. 80 mg 
TPL/kg vs. Control – Part A; 80 mg TPL/kg vs. control – Part B) in the incidence of 
respiratory failure or death due to RDS within 72 hours of life. The incidence of 
respiratory failure or death due to RDS will be compared between both active treatments 
and control using logistic regression. Pairwise testing between each active treatment and 
control, and for both active groups combined versus control, will be conducted in Part A. 
2. There is no difference between active treatment and control (40 mg TPL/kg vs. control 
and 80 mg TPL/kg vs. control – Part A; 80 mg TPL/kg vs. control – Part B) for the time 
to respiratory failure or death due to RDS. The time to respiratory failure or death due to 
RDS will be compared for both active treatments and for each active treatment separately 
versus control using the log-rank test. 
Part A only: In order to examine the concordance between subjects receiving intubation for MV 
and/or surfactant administration and subjects who meet respiratory failure criteria (sustained 
FiO2 > 0.45, sustained PCO2 > 65 mmHg, or nCPAP > 8 cm H2O), the subjects receiving 
intubation, the subjects who meet criteria, and the subjects who both received intubation and met 
criteria will be summarized. 
In addition, the treatment difference (delta) between active and control treatments will be 
calculated for the primary and key secondary efficacy endpoints (eg, incidence of respiratory 
failure of death due to RDS, incidence of BPD) for each country and/or region. The delta 
calculated will be used to plan additional studies and to evaluate regional care contribution 
variations that may occur in the study.  


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2 
INVESTIGATIONAL PLAN 
2.1 
STUDY POPULATION 
The study population will be comprised of preterm neonates 26 to 32 completed weeks PMA 
who are receiving care in a NICU and are receiving nCPAP as the primary support modality for 
RDS. Enrollment will be conducted by strata: in Part A, approximately 5-10% of the subjects 
will be 28 completed weeks PMA and the remainder will be 29 to 32 completed weeks PMA, 
while in Part B randomization will be stratified by gestational age (26, 27, and 28 completed 
weeks PMA). 
The study population in Part A will be randomized in a 1:1:1 ratio into 1 of 3 treatment groups, 
and in Part B will be randomized in a 1:1 ratio into 1 of 2 treatment groups. 
A subject will be enrolled at 1 of approximately 50 study sites in the US, Canada, Poland, 
Netherlands, Ireland, Colombia, and Chile. It is anticipated that approximately 2400 subjects will 
be screened to meet the enrollment goal of approximately 240 subjects (10:1 ratio of screened to 
enrolled). 
2.1.1 Inclusion criteria 
Each subject must meet all of the following inclusion criteria to be enrolled in this study: 
1. 
Signed ICF from legally authorized representative (consent may be obtained prenatally, 
where allowed) 
2. 
Gestational age: 
a. Part A: 28 0/7 to 32 6/7 completed weeks’ gestation PMA 
b. Part B: 26 0/7 to 28 6/7 completed weeks’ gestation PMA 
3. 
Successful implementation of non-invasive support or ventilation (preferably bubble 
CPAP) within: 
a. Part A: 90 minutes after birth 
b. Part B: 60 minutes after birth 
4. 
Spontaneous breathing 
5. 
Chest radiograph consistent with RDS (may be deferred if in the best medical interest 
of the subject) 
6. 
Respiratory support: 
a. Part A: Within the first 20 hours after birth, requires an nCPAP of 5 to 7 cm H2O 
with an FiO2 ≥0.25 (>0.21 for neonates 28 weeks PMA) to 0.4 that is clinically 
indicated for at least 30 minutes to maintain SpO2 of 90% to 95%. 


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b.  Part B: Within the first 12 hours after birth, requires an nCPAP of 5 to 7 cm H2O 
with an FiO2 of >0.21 to 0.4 that is clinically indicated for at least 20 minutes to 
maintain SpO2 of 90% to 95%. 
Transient (<10 minutes) FiO2 excursions outside this range do not reset the time 
requirement. 
2.1.2 Exclusion Criteria  
Subjects meeting any of the following exclusion criteria may not be enrolled in this study: 
1. 
A heart rate that cannot be stabilized above 100 beats per minute (bpm) within 5 
minutes of birth 
2. 
Recurrent episodes of apnea requiring positive pressure ventilation (PPV) administered 
manually or mechanically through any patient interface 
3. 
A 5 minute Apgar score < 5 
4. 
Major congenital malformation(s) and cranial/facial abnormalities that preclude the use 
of nCPAP, diagnosed antenatally or immediately after birth 
5. 
Clinically significant diseases or conditions other than RDS which could potentially 
interfere with cardiopulmonary function (eg, congenital heart disease, hydrops fetalis, 
or congenital infection) 
6. 
A known or suspected chromosomal abnormality or syndrome 
7. 
Premature rupture of membranes (PROM) > 3 weeks 
8. 
Hemodynamic instability requiring vasopressors or steroids for hemodynamic support 
and/or presumed clinical sepsis 
9. 
A need for intubation and/or invasive mechanical ventilation at any time before 
enrollment into the study 
10. The administration (or plan for administration) of any the following:  
a) Another investigational agent or investigational medical device  
b) Any other surfactant agent 
c) Systemic corticosteroids (other than antenatal steroids already received) 
11. Presence of air leak (pneumothorax, pneumomediastinum, pneumopericardium, 
subcutaneous emphysema, or definite evidence of pulmonary interstitial emphysema 
[PIE]) on the baseline chest radiograph 
 
2.2 
STUDY DESIGN AND RANDOMIZATION 
This study is a multinational, multicenter, 2-part (A, B), masked/open-label, randomized, 
controlled study to evaluate the safety and efficacy of lucinactant for inhalation in conjunction 


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with nCPAP compared with nCPAP alone. For Part A (masked), preterm neonates 28 to 
32 completed weeks PMA who are being cared for in a neonatal intensive care unit (NICU) and 
who are within the first 20 hours after birth, who had successful implementation of noninvasive 
respiratory support within 90 minutes of birth, and who are candidates for SRT will be enrolled. 
For Part B (open-label), preterm neonates 26-28 completed weeks PMA who are being cared for 
in a NICU and who are within the first 12 hours after birth, who had successful implementation 
of noninvasive respiratory support within 60 minutes of birth, and who are candidates for SRT 
will be enrolled. The preferred initial mode of noninvasive support is study nCPAP; however, 
other modes are acceptable if the investigator feels it is safe to switch the subject to study 
nCPAP following consent and screening. There will be 2 phases in the study, a primary phase 
through 36 weeks PMA and a longer-term follow-up phase through 1-year corrected age. Data 
analyses and presentations will be conducted after each phase. 
For Part A, subjects may be eligible to receive up to 2 repeat doses of study treatment, whether 
active or control. Repeat doses will be allowed 2 hours from completion of the previous dose up 
to 36 hours after completion of randomization if subjects meet repeat dosing criteria. Subjects 
randomized to the control group will be continued on nCPAP alone, but will receive sham 
treatment as detailed in the Blinding Plan. 
For Part B, subjects may be eligible to receive up to 4 repeat doses of study treatment for 
subjects randomized to the active group. Repeat doses will be allowed 30 minutes from 
completion of the previous dose up to 36 hours after completion of randomization if subjects 
meet repeat dosing criteria. Subjects randomized to the control group will be continued on 
nCPAP alone. 


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2.2.1 Treatment Groups 
Treatment  
Group 
Study Assignment 
Study Part Aa 
40 mg/kg 
Lucinactant for inhalation 40 mg TPL/kg (administered over 25 minutes) in conjunction with 
nCPAP (n = up to 80)  
Up to 2 repeat doses of 40 mg TPL/kg are to be given if repeat dosing criteria are met 
80 mg/kg 
Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction with 
nCPAP (n = up to 80)  
Up to 2 repeat doses of 80 mg TPL/kg are to be given if repeat dosing criteria are met 
Control 
Continuous nCPAP with sham drug treatment (n = up to 80)  
Study Part B 
80 mg/kg 
Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction with 
nCPAP (n = up to 40)  
Up to 4 repeat doses of 80 mg TPL/kg are to be given if repeat dosing criteria are met 
Control 
Continuous nCPAP (n = up to 40)  
a In Part A of the study, masking procedures will be followed for all doses in all treatment groups. 
 
To maintain the masking, study treatment for Part A will occur behind movable partitions or 
curtains (or some equivalent barrier to prevent unblinding); the PI, study staff (eg, site 
coordinator) (as applicable), and any applicable attending physician as appropriate will not be 
allowed to observe preparation of study materials, setup of the device, or to observe study 
treatment unless an emergent condition develops. The sponsor and the parents/legal guardian 
will also remain masked. Each site will develop and submit a blinding plan that must be 
approved by Discovery prior to screening and enrollment of subjects. 
If at any point during the delivery of lucinactant for inhalation a potential safety risk to the 
subject is identified, aerosolization must be discontinued by activating the ADS ‘Stop Treatment’ 
interface.  
2.2.2 Repeat Dosing 
Up to 2 (Part A) or 4 (Part B) repeat doses will be allowed for each treatment group. The repeat 
doses will consist of repeating the same dose and will occur if repeat dosing criteria are met. The 
repeat dosing criterion is defined as 2 hours (Part A) or 30 minutes (Part B) from completion of 
the previous dose up to 36 hours after completion of randomization, and the subject must require 
a sustained need for supplemental oxygen at or above the qualifying FiO2 for study entry (ie, 
≥ 0.25 for neonates 29 to 32 weeks PMA, > 0.21 for neonates 26 to 28 weeks PMA) for at least 
30 minutes to maintain SpO2 of 90% to 95%. Masking procedures for the initial treatment will be 
followed for repeat doses, including for control patients (Part A). 


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As with the initial dose, the randomization system will be used to receive the study drug 
assignments, and all other procedures that were performed for the initial dose will be followed 
for the administration of the repeat doses. 
If, in the opinion of the PI, repeat dosing would compromise the safety of the subject, repeat 
dosing will not occur. If a subject qualifies for repeat dosing but does not receive repeat dosing, 
the reason for this will be documented. 
2.2.3 Sample Size Justification 
A total of approximately 240 study subjects (approximately 80 per treatment group) will be 
enrolled for Part A. Sample size assumptions were determined by previous data, by medical 
judgment, and by pragmatic considerations of study feasibility. The sample sizes were calculated 
separately for incidence of respiratory failure due to RDS and time to intubation. All sample size 
calculations were two-sided and assumed and an alpha level of 5%. 
The sample size for Part A is sufficient at approximately 90% power to detect a reduction of 
50% in the incidence of respiratory failure due to RDS within the first 72 hours of life (nQuery 
Advisor®, version 7.0).  
The sample size, with a total number of events required of 81 and an alpha level of 5%, for the 
log-rank test for equality of event curves, will have approximately 90% power to detect the 
difference between an event proportion of 0.75 and an event proportion of 0.50 (a constant 
hazard ratio of 0.415), within the first 72 hours of life.  
For Part B, formal sample size calculations have not been conducted. A total of 40 subjects per 
group are sufficient to provide a stable estimate of the size of the treatment effect.   
In addition, the sample size is sufficient to provide a stable estimate of the size of the treatment 
effect (treatment delta). The efficacy estimate will be used to calculate the sample size for future 
studies. 


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2.2.4 Study Schedule 
Protocol Event Schedule Summarization 
 
Phases Through 36 Weeks PMA 
Longer-Term 
Follow-Up  
Measurement/Procedure 
Screening 
Primary 
Observation 
(Days 1 to 3) 
Extended 
Observation 
(Days 4 to 7) 
Final 
Observation 
(to 36w PMA) 
Informed Consent/HIPAA 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Maternal/Birth History 
X 
 
 
 
 
Birth Weight 
X 
 
 
 
 
Physical Examination 
X 
 
 
X 
 
Chest Radiograph 
X 
X 
X 
 
 
Randomization 
 
X 
 
 
 
Study Drug Administration 
 
X 
 
 
 
Use of Pacifier and/or Chin Strap 
during Dosing 
 
X 
 
 
 
Use of oro- or nasogastric tube 
 
X 
X 
 
 
Defecation 
 
X 
 
 
 
Vital Signs 
 
X 
X 
 
 
Monitoring of SpO2 
 
X 
X 
 
 
Monitoring of transcutaneous PCO2 
 
X 
 
 
 
Resp. support and O2 delivery  
X 
X 
X 
X 
X 
Serum Electrolytes 
 
X 
 
 
 
Technical Performance of Device 
 
X 
 
 
 
Incidence of BPD 
 
 
 
X 
 
Peri-Dosing Events 
 
X 
 
 
 
Complications of Prematurity 
 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
Adverse Device Effects 
 
X 
 
 
 
Survival 
 
X 
X 
X 
 
Concomitant Medication 
 
X 
X 
X 
X 
Hospitalizations 
 
 
 
 
X 
Abbrev. physical and neuro. exam 
 
 
 
 
X 
Note: Day 1 for all subjects is the day of study randomization. See protocol for schedule details. 


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3 
STUDY SUBJECT CHARACTERISTICS 
3.1 
SUBJECT DISPOSITION 
Subject disposition (overall and by country) will be summarized by treatment group using 
frequency and percent. The number of subjects screened, randomized (intent-to-treat [ITT] 
population), randomized and received study medication (modified ITT [mITT] population), 
administered study medication (safety population), without treatment interruptions, and without 
protocol violations (per-protocol population) will be described. 
The number of subjects who completed the study or died will be summarized using frequency 
and percent by treatment group and overall. Reasons for early discontinuation from the study 
include withdrawal of consent, and lost-to-follow up. A subject may withdraw consent (through 
their legally authorized guardian) at any time without prejudice to further care. 
The number of subjects who discontinued treatment early will be summarized using frequency 
and percent by treatment group and overall. Reasons for early discontinuation of treatment 
include device failure or malfunction, AE or ADE, PI’s best medical judgment, respiratory 
deterioration. 
3.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
3.2.1 Demographics 
Continuous variables (eg, gestational age, birth weight) will be summarized using mean, 
standard deviation (SD), median, minimum, and maximum. Categorical variables (eg, sex, race, 
ethnicity) will be summarized by treatment group using frequency and percent. 
Race categories with small numbers (frequencies of percentages of < 10%) will be combined as 
‘Other’ for summary displays. 
3.2.2 Medical, Birth and Maternal History 
The mode of delivery (vaginal, c-section), type of birth (single, multiple), and incidence of 
congenital anomalies will be summarized by treatment group using frequency and percent.  
The Apgar score at 1 and 5 minutes and antenatal steroid use will be summarized by treatment 
group using mean, SD, median, minimum, and maximum. 


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Incidence of medical history findings, incidence and type of ruptured membranes, incidence of 
clinical chorioamnionitis, and the incidence and number of doses of antenatal steroids will be 
summarized by treatment group using frequency and percent. 
3.3 
STUDY AND CONCOMITANT MEDICATION 
3.3.1 Compliance 
Compliance summary for this study is not applicable as all subjects will be administered at least 
one dose by study staff in the NICU. The number of subjects who experienced treatment 
interruptions for the initial or repeat doses will be summarized by treatment group. 
3.3.2 Number of Doses 
The number of doses (treatments) received by subjects in the active arms and the number of 
times a subject qualified for a repeat dose will be summarized by treatment group. 
3.3.3 Previous and Concomitant Medication 
Medications taken since birth and concomitant medications will be coded according to the World 
Health Organization (WHO) drug dictionary, version DDE September 2013 or later. Medications 
will be summarized using frequency and percentages for each treatment group by drug category 
and generic name. 
3.4 
PROTOCOL VIOLATIONS/DEVIATIONS 
A protocol violation occurs when the PI fails to adhere to any significant protocol requirement 
affecting the inclusion, exclusion, subject safety, and primary endpoint criteria. A protocol 
deviation is any deviation from the protocol that does not rise to the level of a protocol violation. 
All protocol violations/deviations will be summarized by treatment group and listed by subject. 
Subjects with protocol violations will not be included in the per-protocol population (see Section 
4.1.4). 
 


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4 
EFFICACY ANALYSIS  
The efficacy objective is to assess the size of the clinical effect of lucinactant for inhalation in 
comparison to nCPAP alone, as demonstrated by the incidence of and time to respiratory failure 
due to RDS, incidence of BPD at 36 weeks PMA, physiologic parameters (FiO2 and PCO2), and 
incidence rate of survival without BPD at 36 weeks PMA. 
Hypothesis testing will be done for incidence of respiratory failure due to RDS and time to 
respiratory failure due to RDS. Due to the preliminary nature of this study and the uncertainty 
around baseline rates of failure, all analyses, unless otherwise specified, will be conducted at an 
alpha level of 10%. 
4.1 
EFFICACY POPULATIONS 
For efficacy analyses, subjects will be summarized according to their assigned (randomized) 
treatment. In addition, for the primary and key secondary endpoints, subjects will be summarized 
according to the amount of total study therapy received (eg, 25 minutes of aerosol treatment with 
a repeat would be combined with a 50 minute treatment) for within-group correlations. Within-
group correlations will also be used to identify baseline variables to include as independent 
predictors in the logistic regression (logit) and generalized linear model analyses. 
The statistical analysis of both the primary and secondary objectives will be based on all enrolled 
preterm neonates. For the efficacy analysis, the primary analysis will be based on a modified 
intent-to-treat population (mITT), defined as subjects who received treatment and completed the 
50 minute post initiation of dose vital signs assessments. In addition, populations of all 
randomized subjects (ITT) and subjects with no major protocol deviations (per-protocol) will be 
evaluated (as described in Section 3.4), based upon the treatment group to which they were 
randomized. For the safety analysis, all subjects randomized to the control group or who received 
any lucinactant for inhalation (including partial doses) will be evaluated, based upon the 
treatment they actually received. 
4.1.1 Modified Intent-to-Treat Population 
The mITT population is the primary efficacy analysis population and is defined as subjects who 
were randomized and received study treatment (any aerosol delivered to infant) 
.  


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4.1.2 ITT Population 
The ITT population is defined as all subjects who were randomized in the study, regardless of 
receipt of study treatment. 
4.1.3 Without Treatment Interruptions Population 
This population is defined as all subjects who received treatment without a treatment interruption 
(eg, study device shut-down prior to completion of dose). 
4.1.4 Per-Protocol Population 
The per-protocol population will be used for all efficacy endpoints as a supportive analysis. The 
per-protocol population is defined as all randomized subjects who received at least one dose of 
study drug and who do not have a protocol violation which would be considered a reason for 
exclusion from this population. 
Protocol violations which may lead to exclusion from the per-protocol population include, but 
are not limited to: 
• Inclusion and/or exclusion criteria not met. 
• Initial dose was not completed. 
• Subject was given repeat dose, but did not meet repeat dose criteria. 
• Blinded personnel performed unblinded task or activity. 
• Subject received the wrong study treatment or incorrect dose. 
At the end of the study, but prior to unblinding, the list of protocol violations and deviations will 
be provided by Data Management. The list will be reviewed by the Medical Monitor and other 
study personnel, as appropriate, for determination of inclusion into and/or exclusion from the 
per-protocol population. The complete list of all protocol violations, along with a per-protocol 
population inclusion indication, will be included in the final data analysis. 
4.2 
STATISTICAL ANALYSIS 
All analyses will be performed for all subjects combined and by country or region.  
All continuous variables (eg, birth weight, body temperature, PCO2) will be summarized using 
number (n), mean, standard deviation (SD), median, minimum, and maximum. All discrete 
variables (eg, sex, AEs, common complications of prematurity), will be summarized using 
frequency (n) and percent.  


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Sites will be pooled for statistical analyses by geographic region, as described in a separate 
analysis memo. Site pooling decisions will be made at the end of the study, but prior to 
unblinding. 
The treatment difference (delta) between active and control treatments will be calculated for the 
primary and secondary efficacy endpoints. The delta calculated will be used to plan additional 
studies and as supporting evidence of efficacy. 
See Section 8, Statistical Technical Issues, for details on statistical methods and calculations. 
4.2.1 Primary Efficacy Endpoint 
The primary endpoint is the incidence of respiratory failure or death due to RDS, defined as the 
number of subjects who need intubation for surfactant administration and/or MV or meet the 
criteria for respiratory failure due to RDS within 72 hours of life, or who die due to RDS-related 
respiratory failure within 72 hours of life. The incidence of respiratory failure or death due to 
RDS will be compared between each active treatment and control using logistic regression, 
controlling for pooled study sites, gender, birth weight, and baseline FiO2. Additional terms (eg, 
time to treatment from birth) will be evaluated for appropriateness to include in model. The 
comparison results will be presented as incidence and percent with associated p-value, at an α-
level of 10%. 
4.2.2 Key Secondary Endpoints 
The key secondary endpoint will be based on the log-rank test for time to respiratory failure or 
death due to RDS, adjusting for pooled study center. The primary endpoint is defined as the time 
from randomization to when subjects need intubation for surfactant administration and/or MV 
(for respiratory failure, not for elective procedures), or to when subjects meet the criteria for 
respiratory failure due to RDS within 72 hours of life, or who die due to RDS-related respiratory 
failure.  
A Kaplan-Meier graph for time to respiratory failure will be produced. Descriptive statistics of 
the log-rank test (number of subjects, mean, standard error [SE], and median point estimate) will 
be presented by treatment group. Both the log-rank test and the Wilcoxon test (another test of 
time to failure) will be conducted. An α-level of 10% will be considered evidence of clinical 
effect. The Hochberg modification of the Bonferroni correction will be used to adjust for 
multiple comparisons. Applying the Hochberg modification means that if both p-values are less 
than or equal to 0.10, then both comparisons will be considered statistically significant; if one 
greater than 0.10, the other must be less than 0.05 to be considered statistically significant. 


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In addition, for Part A, generalized linear models will be used to model occurrence of an event 
(intubation for surfactant administration and/or MV) against subject, dose number (1, 2, or 3), 
treatment regimen (study treatment group), time at risk, and any applicable covariates based 
upon a Poisson distribution. This model will allow for assessing treatment only and treatment 
with repeats, and determining if there is a treatment by repeat interaction term. See Section 8 for 
additional details. 
Explanations and/or descriptions related to respiratory failure will be listed. 
4.2.3 Physiological Assessments 
Change in FiO2 is defined as the change from baseline (initiation of treatment for active subjects 
or completion of patient interface setup for control subjects) through 72 hours post-
randomization. Change in FiO2 will be compared between each active treatment and control 
using ANOVA with treatment and pooled study site in the model. The comparison results will be 
presented as LS mean and standard error, 95% CI, and two-sided p-value. 
Change in transcutaneous PCO2 is defined as the change from baseline (initiation of treatment 
for active subjects or completion of patient interface setup for control subjects) through 72 hours 
post-randomization. Change in PCO2 will be compared between each active treatment and 
control using ANOVA with treatment and pooled study site in the model. The comparison results 
will be presented as LS mean and standard error, 95% CI, and two-sided p-value. 
Individual timepoint assessments (eg, 1, 3, 6, 12 hours from randomization) may be performed 
for change from baseline for both FiO2 and PCO2. Comparisons of the individual timepoint 
assessments will be performed using mixed-model ANOVA with treatment and pooled study 
center in the model. The comparison results will be presented as LS mean and standard error, 
95% CI, and two-sided p-value. 
Area under the curve (AUC) analyses for FiO2 and PCO2 change from baseline will be 
conducted. The AUC will be calculated using the trapezoidal rule and will be compared between 
treatment groups using ANOVA with treatment and pooled study site in the model. The 
comparison results will be presented as LS mean and standard error, 95% CI, and two-sided p-
value 
Line graphs by treatment for observed and change from baseline values will be produced for 
both PCO2 and FiO2. 


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4.2.4 BPD and Survival without BPD 
BPD is defined as the need for supplemental oxygen above room air (21%) at 36 weeks PMA. 
The number and percent of subjects who develop BPD by 36 weeks PMA will be summarized by 
treatment group. The number and percent of subjects who are alive and without BPD at 36 weeks 
PMA will be summarized by treatment group. 
Comparisons between treatment groups for the total number of subjects with BPD will be carried 
out using the CMH test, controlling for pooled study sites. 
4.2.5 Concordance between Intubation and Respiratory Failure Criteria 
In order to examine the concordance between subjects receiving intubation for MV (for 
respiratory failure) and/or surfactant administration and subjects who meet respiratory failure 
criteria (sustained FiO2 > 0.45, sustained PCO2 > 65 mmHg, or nCPAP > 8 cm H2O), the 
subjects receiving intubation, the subjects who meet criteria, and the subjects who both received 
intubation and met criteria will be summarized. 
This examination will be done for both the time to intubation or meeting respiratory failure 
criteria and the incidence of intubation or meeting respiratory failure criteria. 
4.2.6 Late Respiratory Failure or Death Due to RDS 
Late respiratory failure or death due to RDS is defined as defined as the number of subjects who 
need intubation or meet the criteria for respiratory failure between 72 hours of life through Day 
7, and after Day 7 through Day 28. The incidence of late respiratory failure or death due to RDS 
will be compared between each active treatment and control using the CMH test, controlling for 
pooled study sites. The comparison results will be presented as incidence and percent with 
associated p-value. 
4.2.7 Complications of Prematurity 
Common complications of prematurity (apnea, air leak, IVH, PVL, pulmonary hemorrhage, 
NEC, PDA, acquired sepsis, and ROP) will be summarized by treatment group using frequency 
and percent by treatment group and compared using the CMH test, controlling for pooled study 
sites. 
4.3 
MISSING DATA 
Missing values represent a potential source of bias in a clinical trial. Hence, every effort will be 
undertaken to fulfill all the requirements of the protocol concerning the collection and 


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management of data; however, some missing data is inevitable. Handling of missing data, as 
applicable, is described with the analysis for specific parameters (see Section 4.2). No 
imputation, including last observation carried forward, will be done for the any parameters; only 
available data will be considered.  
4.4 
SUBGROUP ANALYSES 
Presentations by subgroup (sex, race, ethnic origin, country/region) will be considered for the 
primary endpoint if sufficient numbers allow. 
Analysis of results by gestational age strata may be performed as an exploratory analysis. 
5 
TECHNICAL PERFORMANCE OF THE DEVICE 
The technical performance of the device will be summarized for each active treatment. The 
incidence of the following will be summarized: ventilator/CPAP tubing detachments, aerosol 
tube detachments, aerosol tube condensate obstruction, proximal pressure port obstructions, 
study drug leakage (either liquid or aerosol), occurrence of any alarm signals (before, during, and 
after dosing), automatic system shutdowns, loss of inspiratory flow, inability to maintain nCPAP, 
occurrence of any error codes. In addition, the weight and/or volume of liquid in all traps will be 
summarized as continuous variables. Statistical comparisons between active treatment groups are 
not planned. 
Incomplete treatments with reasons and/or explanations will be listed. 


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6 
SAFETY ANALYSES 
6.1 
SAFETY POPULATION 
The safety population is defined as all subjects who received any study medication, active or 
sham. Subjects will be included in the treatment group for the treatment actually received (if 
different than the group that they were randomized). All safety assessments will be based on this 
population. 
Safety analyses will be summarized by all subjects combined and by country or region. 
6.2 
EXTENT OF EXPOSURE 
All subjects randomized to active treatment are to receive at least one dose of study medication. 
Subjects will receive 25 or 50 minutes of aerosolized lucinactant. The number of subjects who 
receive a repeat dose, the number of doses received, the amount of treatment received (based on 
time of treatment), and the number of subjects whose study treatment is terminated early will be 
summarized. 
6.3 
ADVERSE EVENTS 
All treatment-emergent AEs (TEAEs; AEs occurring at or after randomization) will be coded by 
preferred term and system organ class (SOC) from the Medical Dictionary for Regulatory 
Activities (MedDRA), version 16.1 or above, and will be reviewed by the medical monitor or 
designee. All TEAEs will be summarized as categorical variables (frequency and percent) by 
treatment group unless otherwise indicated. TEAEs that are related to the device (ADEs) will be 
summarized with all AEs and separately. TEAEs will not be compared between treatment 
groups. 
6.3.1 Peri-Dosing AEs 
The incidence of peri-dosing events (ie, bradycardia, desaturation, gagging/regurgitation, apnea, 
and pallor) will be summarized. 
In addition, the incidence of complications related to the placement of bi-nasal prongs (bleeding, 
apparent obstruction to the nares, occlusion of the prongs, nasal irritation, and other) will be 
summarized by treatment group. 


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6.3.2 AEs Related to Surfactant Administration (AEs of Special Interest) 
Individual air leaks (eg, pneumothorax, pulmonary interstitial emphysema, pneumo-
mediastinum, pneumopericardium, and subcutaneous emphysema) will be identified by medical 
review of all AEs and summarized by treatment group.  
Occurrences of apnea, bradycardia, and desaturation after the peri-dosing period will be 
summarized by treatment group. 
6.3.3 Other TEAEs 
TEAEs, other than those listed above, will be summarized by treatment group by the MedDRA 
preferred term and SOC for all TEAEs, regardless of relationship to study drug, and for TEAEs 
at least remotely related. If a TEAE occurs multiple times for the same subject within the same 
term or body system, only the most severe occurrence for that term or body system will be 
counted. 
In addition, all TEAEs will be summarized by severity (mild, moderate, severe), relationship to 
the study drug (unrelated, unlikely related, possibly related, related), whether or not the TEAE 
was device related, and, if sufficient number of subjects warrant, by gender, race, and ethnic 
origin. 
6.3.4 Serious Adverse Events 
All SAEs will be listed and summarized by treatment group using frequency counts and 
percentages. If the same SAE occurs multiple times for the same subject, the most severe 
occurrence will be counted.  
SAEs, including multiple occurrences, will also be listed, to include severity, relationship to the 
study drug, gender, race, and ethnic origin. 
6.3.5 Unexpected Adverse Device Effects  
Unexpected adverse device effects (UADEs) will be listed and summarized by treatment group 
using frequency counts and percentages. If the same UADE occurs multiple times for the same 
subject, the most severe occurrence will be counted.  


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6.3.6 Deaths 
All-cause mortality and deaths due to RDS during the study will be summarized by treatment 
group using frequency counts and percentages. Deaths by subject will also be listed and will 
include primary cause, date and time of death, gender, race, and ethnic origin. 
6.4 
CLINICAL ASSESSMENTS OF SAFETY 
6.4.1 Vital Signs 
Vital signs, including body temperature, respiration rate, and heart rate, will be summarized at all 
pre-specified time points. Clinically significant vital signs will also be recorded as AEs. 
6.4.2 Physical Examination 
For each body system evaluated at screening and at the final physical examination, frequency 
counts and percentages of normal and abnormal results will be summarized by treatment group. 
In addition, a shift table to describe the changes in normal/abnormal results between screening 
and the final visit will be presented. Any new abnormal physical examination findings must be 
documented as AEs. 
6.4.3 Serum Electrolytes 
Serum electrolytes (Na+, CL-, K+) and total serum carbon dioxide (CO2) will be measured at 24 
hours from the time of randomization (± 6 hours) and will be summarized as continuous 
variables and presented by treatment group. Clinically significant values will also be recorded as 
AEs. 
6.4.4 Defecation 
The number of stools occurring within 24 hours from the time of randomization will be 
summarized by treatment group as a discrete variable using frequency and percent. 
6.4.5 Respiratory Support and Supplemental Oxygen 
Pressure support, including respiratory rate, CPAP, and FiO2 (as appropriate) at all time points 
will be summarized as continuous variables. For subjects receiving mechanical ventilation (MV) 
through Day 7, the mode, mean airway pressure (MAP), respiratory rate, and FiO2 will be 
summarized. For subjects receiving supplemental oxygen through Day 7, the mode and the FiO2 
will be summarized. All MV and supplemental oxygen data, including other settings (eg, tidal 
volume, PIP, PEEP, flow rate, mode of delivery) will be listed by subject. 


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The number of subjects requiring respiratory support in the delivery room, including sustained 
inflation, will be summarized using frequency and percent. 
6.5 
LONG-TERM FOLLOW-UP 
6.5.1 6-Month Follow-Up 
The assessments conducted at the 6-month follow-up (number of hospitalizations, need for and 
duration of ventilator support, and oxygen supplementation requirements) will be summarized 
and presented as a listing. 
6.5.2 One-Year Follow-Up 
Summary tables will be produced for the one-year follow-up to summarize physical 
examinations, bronchodilator or steroid use, neurologic assessments, the number of 
hospitalizations, and need for and duration of ventilator support, after all subjects have 
completed the study. 
 


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7 
INTERIM ANALYSES AND DATA MONITORING 
7.1 
DATA MONITORING COMMITTEE 
The purpose of the DMC is to evaluate the degree of risk involved in study subject participation 
within each treatment group and to determine if study continuation in accordance with the 
current protocol holds the potential to institute any undue harm, or threat to the safety and 
welfare of study subjects. The DMC will consist of 3 to 5 experts in the field of RDS; at least 2 
of the experts must be neonatologists. 
The DMC reviews will consist of the evaluation of (1) all AEs, (2) ADEs relevant to potential 
subject safety issues, (3) case reviews of subjects with reported SAEs, and (4) summary tables of 
all safety endpoints. Safety and tolerability data will be assessed at the time all active subjects in 
each dose group completes assessments and procedures through 72 hours. Enrollment will 
continue throughout each DMC review. 
Following a thorough independent review of available study data, the DMC will provide timely 
recommendations to the Discovery study team. 
7.2 
INTERIM ANALYSES 
The data monitoring committee (DMC) will conduct 2 preplanned interim analyses during Part A 
of the study: 1) after approximately 25% of subjects have been enrolled and 2) after 66% of 
subjects have been enrolled. The DMC will be provided full safety listings for review after 
approximately 20 subjects have been enrolled in Part B, but will not conduct a formal interim 
analysis. Study enrollment may be suspended if safety concerns are identified during any review.  
7.3 
DATA MONITORING  
The data will be entered into a validated database. Members of Discovery’s Data Management 
department are responsible for data processing, in accordance with procedural documentation. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries will be 
entered, tracked, and resolved through the electronic data capture (EDC) system directly. The 
study database will be updated in accordance with the resolved queries. All changes to the study 
database will be documented. 


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8 
STATISTICAL TECHNICAL ISSUES 
8.1 
METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
For each treatment group, preterm neonates who successfully meet all eligibility criteria within 
the enrollment period will be randomly assigned to either 40 or 80 mg TPL/kg lucinactant for 
inhalation (80 mg TPL/kg only in Part B) or control (nCPAP only) within their applicable strata 
(26-28 completed weeks PMA or 29 to 32 completed weeks PMA). Subjects will be randomized 
using a web-based centralized allocation. Neonates from multiple births will be randomized 
independently. In Part A, randomization information will be provided to unblinded site personnel 
(eg, pharmacist); site staff responsible for care decisions of the neonates will be masked to the 
treatment assignment as described in the blinding plan. In Part B, open-label randomization 
information will be provided to designated site personnel. Subjects that discontinue the study (ie, 
withdrawn consent) or treatment prematurely will not be replaced. 
The randomization code list will be generated by Discovery Biometrics personnel. The code list 
will use a block size of 6 for Part A (40 mg/kg  2, 80 mg/kg  2, Sham 40 mg/kg  1, Sham 80 
mg/kg  1) or a block size of 4 for Part B (80 mg/kg  2, Sham  2), stratified by PMA. 
8.2 
BLINDING/MASKING  
In order to minimize bias in subject assessments, study treatment masking will be employed for 
Part A. Details on blinding can be found in the Blinding Plan for 03-CL-1202. 
Part B is open label; no masking will be employed. 
8.3 
DETAILS ON STATISTICAL METHODS 
8.3.1 Logistic Regression for Testing Incidence of Event  
Logistic regression is being used to investigate the relationship between the dichotomous 
primary endpoint and a set of explanatory variables. For binary response models, the response, 
Y, of an individual or an experimental unit can take on one of two possible values, denoted by 1 
and 2 (eg, Y = 1 if respiratory failure has occurred, other Y = 2). Suppose xi is a vector of 
explanatory variables and p = Pr(Y = 1 | xi) is the response probability to be modeled. The linear 
logistic model has the form 
logit(𝑝) ≡ln (
𝑝
1 −𝑝) = 𝛼+ 𝛽′𝑥𝑖 


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where α is an intercept parameter and β is the vector of slope parameters (14). 
The likelihood function expresses the probability of observing the data in hand as a function of 
the unknown parameters. The likelihood of observing the values of y for all the observations can 
be written as L = Pr(y1, y2, …, yn). Because of the assumption that observations are independent, 
the overall probability of observing all the yi’s can be factored into the product of the individual 
probabilities: 
𝐿= Pr(𝑦1)Pr(𝑦2) … Pr(𝑦𝑛) = ∏Pr(𝑦𝑖)
𝑛
𝑖=1
, 
where Π indicates repeated multiplication. By definition, Pr(yi = 1) = pi and Pr(yi = 0) = 1 – pi.  
That implies  
Pr(𝑦𝑖) = 𝑝𝑖
𝑦𝑖(1 −𝑝𝑖)1−𝑦𝑖. 
The logarithm of the equation produces 
ln 𝐿= ∑𝑦𝑖
𝑖
ln (
𝑝𝑖
1 −𝑝𝑖
) + ∑ln(1 −𝑝𝑖)
𝑖
. 
Substituting this expression in the logit model, the likelihood function can be simplified to 
ln 𝐿= ∑𝛽𝑥𝑖𝑦𝑖
𝑖
−∑ln(1 + 𝑒𝛽𝑥𝑖)
𝑖
. 
We now choose values of β that make the equation as large as possible (15). 
The regression will be performed within the SAS System® using the LOGISTIC procedure; 
models will be fit by the method of maximum likelihood. 
Baseline factors, such as gender or gestational age, will be tested to determine if they are 
correlated with study therapy and thus have a significant impact in the model. Factors that are 
correlated will be included in the model as covariates. At a minimum, pooled study sites, gender, 
birth weight, and baseline FiO2 will be included. 
The summary table format for the primary efficacy analysis for Part A is given below. 


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Treatment 
Logistic Regression 
Respiratory Failure due to RDS 
40 mg/kg 
(N=80) 
80 mg/kg 
(N=80) 
nCPAP 
Only 
(N=80) 
Overall 
40 mg/kg vs. 
Control 
80 mg/kg vs. 
Control 
Number of Subjects 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Number of Subjects with 
Respiratory Failure 
xx (yy%) 
xx (yy%) 
xx (yy%) 
x.xxx 
x.xxx 
x.xxx 
8.3.2 Log-Rank Test for Testing Time to Event  
The rank statistics used to test homogeneity between the strata (treatments) have the form of a c 
 1 vector v = (v1, v2, …, vc) with  
𝑣𝑗= ∑𝑤𝑖
𝑘
𝑖=1
(𝑑𝑖𝑗−𝑛𝑖𝑗𝑑𝑖
𝑛𝑖
) 
where c is the number of strata , and the estimated covariance matrix, V = (Vjl), is given by 
𝑉𝑗𝑙= ∑𝑤𝑖
2𝑑𝑖𝑠𝑖(𝑛𝑖𝑛𝑖𝑙𝛿𝑗𝑙−𝑛𝑖𝑗𝑛𝑖𝑙)
𝑛𝑖
2(𝑛𝑖−1)
𝑘
𝑖=1
 
where i labels the distinct event times, jl is 1 if j = l and 0 otherwise, nij is the size of the risk set 
in the jth stratum at the ith event time, dij is the number of events in the jth stratum at the ith 
time, and 
𝑛𝑖= ∑𝑛𝑖𝑗
𝑐
𝑗=1
 
𝑑𝑖= ∑𝑑𝑖𝑗
𝑐
𝑗=1
 
𝑠𝑖= 𝑛𝑖−𝑑𝑖 
The term vj can be interpreted as a weighted sum of observed minus expected numbers of failure 
under the null hypothesis of identical survival curves. The weight wi is 1 for the log-rank test and 
ni for the Wilcoxon test. The overall test statistic for homogeneity is vV–v, where V– denotes a 
generalized inverse of V. This statistic is treated as having a Χ 2 distribution with degrees of 
freedom equal to the rank of V for the purposes of computing an approximate probability 
level(14). 
The summary table format for this efficacy analysis is given below. 


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Treatment 
Log-Rank/Wilcoxon 
Respiratory Failure or 
Death due to RDS 
Statistics 
40 mg/kg 
(N=80) 
80 mg/kg 
(N=80) 
nCPAP 
Only 
(N=80) 
Overall 
40 mg/kg vs. 
Control 
80 mg/kg vs. 
Control 
Time to Respiratory Failure 
or Death 
n 
xx 
xx 
xx 
 
 
 
(hours from treatment 
initiation) 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
 
Min,Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
Estimated Time-to-Event 
Mean 
xx.x 
xx.x 
xx.x 
x.xxx 
x.xxx 
x.xxx 
 
SE 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
If significant differences are noted in baseline factors, such as gender or birth weight, a 
supportive exploratory analysis will be done to determine if any of these factors have a 
significant impact in the model using standard step-up and step-down methodology. The 
variables selected by the two methods are then compared and a new model is constructed with 
the selected factors included and the primary analysis is evaluated as indicated above. 
8.3.3 Generalized Linear Modeling using Poisson Distribution 
Occurrence of events can be modeled using generalized linear models with a Poisson 
distribution. Random variables that have a number of X occurrences of some phenomenon during 
a fixed period of time have a Poisson distribution. Thus, the Poisson distribution is appropriate 
for testing the number of events of respiratory failure over 72 hours between study therapies. 
Suppose that a response variable Y is distributed as Poisson and has expected value µ. Recall that 
the variance of a Poisson variable is also µ. If you have a single explanatory variable x, you can 
write a regression model for µ as 
𝑔(𝜇) = 𝛼+ 𝑥𝛽, 
where g is a link function, in terms of a generalized linear model (GLM). Usually, g is taken to 
be the log function. If so, you have a loglinear model 
ln(𝜇) = 𝛼+ 𝑥𝛽. 
You can rewrite this model as 
𝜇= 𝑒𝛼𝑒𝑥𝛽. 


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If you increase the explanatory variable x by one unit, it has a multiplicative effect of e β on µ. 
Since this model is specified as a GLM, with a log link and a Poisson distribution, you can fit it 
with the GENMOD procedure and use the deviance and likelihood ratio tests to assess model fit 
and use Wald or score statistics to assess the model effects. 
Frequently, discrete counts represent information collected over time (days, years), and interest 
lies in modeling rates. If the exposure time is denoted as N, you write the rate as Y / N and write 
the expected value as µ / N. Modeling this rate with a loglinear model is written 
ln 𝜇
𝑁= 𝛼+ 𝑥𝛽, 
which can be rearranged as 
ln 𝜇= 𝛼+ 𝑥𝛽+ log (𝑁). 
The term log(N) is called an offset and must be accounted for in the estimation process(15). In our 
case, N represents “time at risk.” For first dose, time at risk is from treatment initiation to the 
start of the second dose or time of event or 72 hours; for the second dose, time at risk is from 
treatment initiation for the second dose to third dose or time of event or 72 hours; for the third 
dose, time at risk is from treatment initiation for the third dose to time of event or 72 hours. 
Baseline factors, such as gender or gestational age, will be tested to determine if they are 
correlated with study therapy and thus have a significant impact in the model. Factors that are 
correlated will be included in the model as covariates. 
8.4 
MULTIPLICITY 
Time to respiratory failure or death due to RDS, is a single hypothesis with two comparisons: 40 
mg TPL/kg vs. nCPAP Only and 80 mg TPL/kg vs. nCPAP Only. To adjust for multiple 
comparisons, a Hochburg modification of the Bonferroni correction will be performed. Applying 
the Hochberg modification means that if both p-values are less than or equal to α, then both 
comparisons will be considered statistically significant; if one is greater than α, the other must be 
less than α /2 to be considered statistically significant.  
No other adjustments for multiple comparisons will be done. 
9 
GENERAL ANALYSIS DEFINITIONS 
All summaries and statistical analyses will be generated using SAS® System for Windows, 
version 9.1 or higher. 


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9.1 
BASELINE DEFINITION 
Baseline is defined as the measurement at the start of study drug administration for subjects 
randomized to the active group, and time of patient interface change for subjects randomized to 
the control group (both recorded as “initiation of study treatment” on several forms).  
9.2 
WINDOWS FOR VISITS 
Accurate clock times will be recorded for each timed event in military time (24-hour clock). 
Day 1 is the day on which randomization occurs; Day 2 begins at midnight following 
randomization; Day 3 is the 2nd day following randomization; Day 7 will be the sixth day after 
the day of randomization. 
All assessments at pre-specified time points are to be conducted within the windows specified in 
the protocol. The windows for the the 6-month and 12-month visits will be ±2 weeks (not 
specified in protocol). Summary tables will use the pre-specified time points, not the actual 
times, to summarize the data. 
9.3 
SITE POOLING METHODS 
Pooled centers are used in all analyses where control by center is warranted (eg, CMH tests, 
ANOVA models). Pooling of centers is done in order to ensure similar sizes of centers and so 
that testing of treatment by center interaction can be accomplished. Centers will be pooled based 
on a geographic basis to ensure there is no center that has less than 5 subjects. In order to keep 
center sizes from being too disparate, pooling will try to balance the enrollment; however, this 
will be done in a blinded manner. The specific pooling of sites and the rationale will be described 
prior to unmasking of the study. 


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10 
REFERENCES 
1. Soll RF, Özek E. Multiple versus single doses of exogenous surfactant for the prevention or 
treatment of neonatal respiratory distress syndrome. Cochrane Database of Systematic 
Reviews. 2009;(1). 
2. Bahadue F, Soll R. Early versus delayed selective surfactant treatment for neonatal 
respiratory distress syndrome. Cochrane Database of Systematic Reviews. 2012; 11. 
3. Polin RA, Carlo WA, Committee on F, Newborn, American Acadamy of Pediatrics. 
Surfactant replacement therapy for preterm and term neonates with respiratory distress. 
Pediatrics. 2014; 133(1): p. 156-163. 
4. Sweet D, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European consensus 
guidelines on the management of neonatal respiratory distress syndrome in preterm infants - 
2013 update. Neonatology. 2013; 103(4): p. 353-368. 
5. Walsh B, Daigle B, DiBlasi R, Restrepo R. AARC Clinical Practice Guideline. Surfactant 
replacement therapy. Respiratory Care. 2013 Feb; 58(2): p. 367-375. 
6. Davis D, Barrington K. Recommendations for neonatal surfactant therapy. Paediatr Child 
Health. 2005; 10(2): p. 109-116. 
7. Schmid M, Glossmann A, Hopfner R, Hummler H, Fuchs H. Cerebral oxygenation during 
neonatal endotracheal intubation. E-PAS2014. 2014; 3843.563. 
8. Gleissner M, Jorch G, Avenarius S. Risk factors for intraventricular hemorrhage in a birth 
cohort of 3721 premature infants. J Perinat Med. 2000; 28(2): p. 104-110. 
9. Talwar R, Virk J, Bajay Y. Paediatric subglottic stenosis - Have things changed? Our 
experience from a developing tertiary referrel centre. Int J Pediatr Otorhinolaryngol. 2015; 
79(12): p. 2020-2022. 
10. Schmolzer G, Kumar M, Pichler G, Aziz K, O'Reilly M, Cheung P. Non-invasive versus 
invasive respiratory support in preterm infants at birth: systemic review and meta-analysis. 
BMJ. 2013; 347: p. f5980. 
11. AARC Clinical Practice Guidelines. Application of continuous positive airway pressure to 
neonates via nasal prongs, nasopharyngeal tube, or nasal mask. ; 2004. 
12. Ho J, Subramaniam P, Davis P. Continuous distending pressure for respiratory distress in 
preterm infants. Cochrane Database of Systematic Reviews. 2015; 7. 
13. SUPPORT Study Group, Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, et al. Early 
CPAP versus surfactant in exptremely preterm infants. N Engl J Med. 2010; 362(21): p. 
1970-1979. 
14. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB, COIN Trial 
Investigators. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 
2008 Feb 14; 358(7): p. 700-708. 
15. Sandri F, Plavka R, Ancora G, Simeoni U, Stranak Z, Martinelli S. Prophylactic or early 
selective surfactant combined with nCPAP in very preterm infants. Pediatrics. 2010; 125(6): 


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43 
p. e1402-1409. 
16. Dunn M, Kaempf J, de Klerk A, de Klerk R, Reilly MHD. Randomized trial comparing 3 
approaches to the initial respiratory management of preterm neonates. Pediatrics. 2011; 
128(5): p. e1069-1076. 
17. Subramaniam P, Henderson-Smart D, Davis P. Prophylactic nasal continuous positive 
airways pressure for preventing morbidity and mortality in very preterm infants. Cochrane 
Database Syst Rev. 2005 Jul 20;(3). 
18. Isayama T, Chai-Adisaksopha C, McDonald S. Noninvasive ventilation with vs. without 
early surfactant to prevenet chronic lung disease in preterm infants: A systematic review and 
meta-analysis. JAMA Pediatr. 2015; 169(8): p. 731-739. 
19. Fischer H, Buhrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary 
dysplasia: a meta-analysis. Pediatrics. 2013; 132(5): p. e1351-1360. 
20. Yee WH, Scotland J, Pham Y, Finch R, Evidence-Based Practice for Improving Quality 
Eveidence Review. Does the use of primary continuous positive airway pressure reduce the 
need for intubation and mechanical ventilation in infants > 
21. Dargaville P, Aiyappan A, De Paoli A, Dalton R, Kuschel C, Kamlin C, et al. Continuous 
positive airway pressure failure in preterm infants: incidence, predictors and consequences. 
Neonatology. 2013; 104(1): p. 8-14. 
22. Vermont Oxford Network. Expanded database summary. ; 2003. 
23. Wolfson M, Wu J, Hubert T, Mazela J, Gregory T, Clayton R, et al. Aerosolized KL4 
surfactant dose-response in the spontaneously breathing CPAP-supported preterm lamb. In 
Pediatric Academic Society Conference; 2011. 
24. Finer N, Merritt T, Bernstein G, Job L, Mazela J, Segal R. An open-label, pilot study of 
Aerosurf® combined with nCPAP to prevent RDS in preterm neonates. J Aerosol Med Pulm 
Drug Delliv. 2010; 23(5): p. 303-309. 
25. SAS Institute Inc. SAS/STAT® User's Guide, Version 8. Cary, NC: SAS Institute Inc.; 1999. 
26. Allison PD. Logistic Regression Using the SAS System: Theory and Application. Cary, NC: 
SAS Institute Inc.; 1999. 
27. Stokes ME, Davis CS, Koch GG. Categorical Data Analysis Using SAS®, Third Edition 
Cary, NC: SAS Institute Inc.; 2012. 


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11 
LIST OF SUMMARY TABLES, LISTINGS, AND FIGURES 
Table 
Title 
 
1.1 
Subject Disposition – Study Populations – All Subjects 
1.2 
Subject Disposition – Study Completion/Termination Status – All Subjects 
1.3 
Subject Disposition – Number of Subjects who Discontinued Early – All Subjects 
1.4 
Subject Disposition – Protocol Deviations/Violations – All Subjects 
2.1 
Subject Demographics – Intent-to-Treat Population 
2.2 
Medical Information – Maternal History – Intent-to-Treat Population 
2.3 
Medical Information – Birth History – Intent-to-Treat Population 
2.4 
Medical Information – Medical History – Intent-to-Treat Population 
3.1 
Concomitant Medications – Intent-to-Treat Population 
3.2 
Number of Treatments Received – Intent-to-Treat Population 
3.3 
Number of Subjects with Protocol Deviations – Intent-to-Treat Population 
4.1.1 
Efficacy Analysis – Incidence of Respiratory Failure or Death Due to RDS – 
Modified Intent-to-Treat Population 
4.1.2 
Efficacy Analysis – Incidence of Respiratory Failure or Death Due to RDS – Intent-
to-Treat Population 
4.1.3 
Efficacy Analysis – Incidence of Respiratory Failure or Death Due to RDS – Per-
Protocol Population 
4.1.4 
Efficacy Analysis – Incidence of Respiratory Failure or Death Due to RDS - by Any 
Intubation or Physiological Criteria  – Intent-to-Treat Population – Intent-to-Treat 
Population [if applicable] 
4.1.5 
Efficacy Analysis – Incidence of Respiratory Failure or Death Due to RDS - by Any 
Intubation or Physiological Criteria – Per-Protocol Population [if applicable] 
4.2.1 
Efficacy Analysis – Time to Respiratory Failure or Death Due to RDS – Modified 
Intent-to-Treat Population 
4.2.2 
Efficacy Analysis – Time to Respiratory Failure or Death Due to RDS – Intent-to-
Treat Population 
4.2.3 
Efficacy Analysis – Time to Respiratory Failure or Death Due to RDS – Per-Protocol 
Population 
4.2.4 
Efficacy Analysis – Time to Respiratory Failure or Death Due to RDS - by Any 
Intubation or Physiological Criteria  – Intent-to-Treat Population – Intent-to-Treat 
Population [if applicable] 
4.2.5 
Efficacy Analysis – Time to Respiratory Failure or Death Due to RDS - by Any 
Intubation or Physiological Criteria – Per-Protocol Population [if applicable] 
4.3.1 
Efficacy Analysis – Incidence of Respiratory Failure or Death Due to RDS by 
Poisson Modeling – Modified Intent-to-Treat Population 


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4.3.2 
Efficacy Analysis – Incidence of Respiratory Failure or Death Due to RDS by 
Poisson Modeling – Intent-to-Treat Population 
4.3.3 
Efficacy Analysis – Incidence of Respiratory Failure or Death Due to RDS by 
Poisson Modeling – Per-Protocol Population 
4.4.1 
Efficacy Analysis – Incidence of Late Respiratory Failure or Death Due to RDS – 
Modified Intent-to-Treat Population 
4.4.2 
Efficacy Analysis – Incidence of Late Respiratory Failure or Death Due to RDS – 
Intent-to-Treat Population 
4.4.3 
Efficacy Analysis – Incidence of Late Respiratory Failure or Death Due to RDS – 
Per-Protocol Population 
4.5.1 
Efficacy Analysis – Physiological Parameters – PCO2 – Modified Intent-to-Treat 
Population 
4.5.2 
Efficacy Analysis – Physiological Parameters – PCO2 – Intent-to-Treat Population 
4.5.3 
Efficacy Analysis – Physiological Parameters – PCO2 – Per-Protocol Population 
4.6.1 
Efficacy Analysis – Physiological Parameters – FiO2 – Modified Intent-to-Treat 
Population 
4.6.2 
Efficacy Analysis – Physiological Parameters – FiO2 – Intent-to-Treat Population 
4.6.3 
Efficacy Analysis – Physiological Parameters – FiO2 – Per-Protocol Population 
4.7.1 
Efficacy Analysis – BPD and Survival Without BPD at 36 Weeks PMA – Modified 
Intent-to-Treat Population 
4.7.2 
Efficacy Analysis – BPD and Survival Without BPD at 36 Weeks PMA – Intent-to-
Treat Population 
4.7.3 
Efficacy Analysis – BPD and Survival Without BPD at 36 Weeks PMA – Per-
Protocol Population 
4.8.1 
Efficacy Analysis– Complications of Prematurity – Modified Intent-to-Treat 
Population 
4.8.2 
Efficacy Analysis– Complications of Prematurity – Intent-to-Treat Population 
4.8.3 
Efficacy Analysis– Complications of Prematurity – Per-Protocol Population 
5.1.1 
Investigational Device – Technical Performance of Device – Initial Dose – Safety 
Population 
5.1.2 
Investigational Device – Technical Performance of Device – Repeat Dose – Safety 
Population 
5.2.1 
Investigational Device – Investigational Product Administration – Initial Dose – 
Safety Population 
5.2.2 
Investigational Device – Investigational Product Administration – Repeat Dose – 
Safety Population 
6.1.1 
Peri-Dosing Adverse Events – Initial Dose – Safety Population 
6.1.2 
Peri-Dosing Adverse Events – Repeat Dose – Safety Population 
6.2 
Air Leaks – Safety Population 
6.3.1 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term – 
Safety Population 


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6.3.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Severity – Safety Population 
6.3.3 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Relationship to Study Treatment – Safety Population 
6.3.4 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Severity and Relationship to Study Treatment – Safety Population 
6.3.5 
Treatment-Emergent Adverse Events in Descending Order of Frequency – Safety 
Population 
6.4.1 
Serious Adverse Events by System Organ Class and Preferred Term – Safety 
Population 
6.4.2 
Serious Adverse Events by System Organ Class and Preferred Term by Severity – 
Safety Population 
6.4.3 
Serious Adverse Events by System Organ Class and Preferred Term by Relationship 
to Study Treatment – Safety Population 
6.4.4 
Serious Adverse Events by Preferred Term Displayed in Descending Order of 
Frequency – Safety Population 
6.5 
Adverse Device Effects in Descending Order of Frequency – Safety Population  
6.6 
All-Cause Mortality – Safety Population 
7.1.1.1 
Clinical Assessments – Vital Signs – Body Temperature – Observed Values and 
Change from Baseline – Safety Population 
7.1.1.2 
Clinical Assessments – Vital Signs During Dosing – Body Temperature – Observed 
Values and Change from Baseline – Safety Population 
7.1.2.1 
Clinical Assessments – Vital Signs – Respiration Rate – Observed Values and 
Change from Baseline – Safety Population 
7.1.2.2 
Clinical Assessments – Vital Signs During Dosing – Respiration Rate – Observed 
Values and Change from Baseline – Safety Population 
7.1.3.1 
Clinical Assessments – Vital Signs – Heart Rate – Observed Values and Change from 
Baseline – Safety Population 
7.1.3.2 
Clinical Assessments – Vital Signs During Dosing – Heart Rate – Observed Values 
and Change from Baseline – Safety Population 
7.2 
Clinical Assessments – Vital Signs – Birth Weight – Safety Population 
7.3 
Clinical Assessments – Serum Electrolytes – Safety Population 
7.4 
Clinical Assessments – Number of Defecations – Safety Population 
7.5.1 
Clinical Assessments – Physical Examination – Safety Population 
7.5.2 
Clinical Assessments – Physical Examination: Shift Table – Safety Population 
7.6.1 
Clinical Assessments – Respiratory Support in the Delivery Room and Mechanical 
Ventilation – Safety Population 
7.6.2 
Clinical Assessments – Respiratory Support – Supplemental Oxygen – Safety 
Population 
7.6.3 
Clinical Assessments – Respiratory Support – nCPAP Settings – Safety Population 
7.7.1 
Six-Month Follow-Up – General Health Assessments – Safety Population 


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7.7.2 
One-Year Follow-Up – General Health Assessments – Safety Population 
7.7.3 
One-Year Follow-Up – Neurologic and Growth Assessments – Safety Population 
 
Listing 
Title 
 
1.1 
Protocol Violations/Deviations 
2.1 
All-Cause Mortality 
2.2 
Serious Adverse Events 
3.1 
Pre-Study/Concomitant Medications 
4.1 
Description of Respiratory Failure 
5.1 
Description of Early Termination of Aerosol Treatment 
6.1 
Mechanical Ventilation Information by Subject 
6.2 
Supplemental Oxygen Information by Subject 
 
Figure 
Title 
 
1.1 
Time to Respiratory Failure or Death Due to RDS – Modified Intent-to-Treat 
Population 
1.2 
Time to Respiratory Failure or Death Due to RDS – Intent-to-Treat Population 
1.3 
Time to Respiratory Failure of Death Due to RDS – Per-Protocol Population 
2.1.1 
FiO2 Observed Values by Treatment Group 
2.1.2 
FiO2 Change from Baseline Values by Treatment Group 
2.2.1 
PCO2 Observed Values by Treatment Group 
2.2.2 
PCO2 Change from Baseline Values by Treatment Group