A Multicenter, Randomized, Open-label, Controlled Trial To Assess The Safety And Tolerability Of Lucinactant For Inhalation In Preterm Neonates 26 to 28 Weeks PMA
Phase: PHASE2
Conditions: Respiratory Distress Syndrome
Sponsor: Windtree Therapeutics

 
 
A MULTICENTER, RANDOMIZED, OPEN-LABEL, CONTROLLED TRIAL TO 
ASSESS THE SAFETY AND TOLERABILITY OF LUCINACTANT FOR 
INHALATION IN PRETERM NEONATES 26 TO 28 WEEKS PMA 
 
Protocol No.: 
03-CL-1401 
Study Phase: 
2a 
Investigational Product: 
Aerosurf® (lucinactant for inhalation) 
IND Number: 
119438 
 
 
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.: 
(215) 488-9300  
Fax No.: 
(215) 488-9301 
 
 
Date 
Original Protocol: 
4 May 2015 
Amendment 1 
2 September 2015 
 
 
 
 
 
 
 
This confidential information about an investigational product is provided for the exclusive use of investigators of 
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A Multicenter, Randomized, Open-Label, Controlled Trial to Assess the Safety and Tolerability 
of Lucinactant for Inhalation in Preterm Neonates 26 to 28 Weeks PMA 
 
Author: 
 
 
 
________________________________________ 
________________ 
 
Phillip D. Simmons 
Date 
 
Executive Director, Biostatistics and Data Management 
 
Approvals: 
 
 
 
________________________________________ 
________________ 
 
Steven G. Simonson, MD 
Date 
 
Senior Vice President and Chief Development Officer 
 
 
 
________________________________________ 
________________ 
 
Robert Segal  
Date 
 
Senior Vice President, Clinical Development & Academic Affairs 
 
 

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AEROSURF PROTOCOL SUMMARY 
Protocol Number 
03-CL-1401 
Title: 
 
A Multicenter, Randomized, Open-Label, Controlled Trial to Assess the 
Safety and Tolerability of Lucinactant for Inhalation in Preterm 
Neonates 26 to 28 Weeks PMA 
Phase: 
2a 
US IND Number: 
119438 
Sponsor: 
Discovery Laboratories, Inc. (Discovery), Warrington, PA, USA 
Committees: 
Steering Committee, Safety Review Committee (SRC) 
Study Drug and 
Device 
Lucinactant for inhalation (an investigational, drug-device combination 
product) at 30 mg total phospholipids (TPL)/ml delivered 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 dipalmitoylphosphatidyl-
choline (DPPC) and palmitoyloleoyl-phosphatidylglycerol, sodium salt 
(POPG, Na), and the fatty acid palmitic acid (PA). 
Rationale: 
Preterm neonates are often surfactant deficient and receive surfactant 
replacement therapy (SRT) to treat respiratory distress syndrome 
(RDS). Currently, the preterm infant has SRT instilled directly into the 
lung through an endotracheal tube while receiving positive pressure 
mechanical ventilation. However, data from studies in animal models of 
RDS suggest that endotracheal intubation and positive pressure 
mechanical ventilation administered by an endotracheal tube may be 
injurious to the preterm lung. Therefore, clinical practice has evolved 
over the past decade toward avoidance of the use of endotracheal 
intubation, thereby foregoing SRT, and instead utilizes non-invasive 
means to provide ventilatory support, including nasal continuous 
positive airway pressure (nCPAP), to support preterm newborns with 
mild to moderate RDS. However, large multicenter trials have 

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demonstrated respiratory deterioration in one-third to one-half of 
preterm neonates receiving nCPAP, who then progress to requiring 
endotracheal intubation, mechanical ventilation, and in many cases 
SRT. Meta-analyses of clinical surfactant studies indicate that SRT is 
most effective when administered early in the course of RDS, and the 
therapeutic benefit of SRT can diminish substantially when 
administered later in the course of the disease. Therefore, the inability to 
administer SRT without endotracheal intubation results in suboptimal 
timing for SRT in preterm infants who are initially supported with 
nCPAP who then deteriorate and require endotracheal intubation and 
SRT to treat RDS.  
The inability to administer SRT without the need for endotracheal 
intubation represents an unmet medical need. Aerosolized surfactant 
delivery potentially addresses this unmet medical need by providing a 
means to deliver SRT to preterm neonates with RDS supported with 
nCPAP, thereby providing SRT early in the disease course while 
avoiding the need for endotracheal intubation. 
The lucinactant for inhalation clinical program is intended to study 
preterm infants 26 to 28 completed weeks post-menstrual age (PMA). 
Currently, preterm infants 29 to 34 completed weeks PMA are being 
studied in Protocol 03-CL-1201. To date, lucinactant for inhalation has 
been shown to be generally safe and well-tolerated. Since there have 
been no safety signals of concern in later preterm infants, this study (03-
CL-1401) will evaluate earlier preterm infants (26 to 28 completed 
weeks PMA) for safety and tolerability. 
Primary Objective: 
The primary objective of this study is to evaluate the safety and 
tolerability of lucinactant for inhalation, administered as an aerosolized 
dose in 4 escalating doses to a preterm, neonatal population 26 to 28 
completed weeks PMA receiving nCPAP for RDS compared with 
neonates receiving nCPAP alone. Safety and tolerability will be 
evaluated using the same measures and assessments that have been used 
in Protocol 03-CL-1201, which has shown lucinactant for inhalation to 
be generally safe and well-tolerated in infants 29 to 34 completed weeks 
PMA. 
Secondary Objective: 
The secondary objectives of this study are to determine the maximum 
tolerated dose of lucinactant as determined by the safety evaluations 

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obtained within each dosing group, and to assess the feasibility of 
evaluating physiological pulmonary function parameters as a measure of 
improvement in clinical status in preterm neonates 26 to 28 completed 
weeks PMA who are receiving nCPAP for RDS, compared with 
neonates receiving nCPAP alone. 
Study Design: 
This multicenter, randomized, controlled, dose-escalation study, will 
evaluate the safety and tolerability of lucinactant for inhalation in 
conjunction with nCPAP in comparison with nCPAP alone in preterm 
infants 26 to 28 completed weeks PMA with RDS. For this study, 
lucinactant for inhalation refers to the active investigational agent, 
lyophilized lucinactant, in combination with the investigational delivery 
device, ADS.  
Preterm neonates between 26 and 28 completed weeks PMA who are 
within the first 20 hours after birth and who had successful 
implementation of controlled nCPAP within 90 minutes of birth will be 
considered to be potential subjects. Before study enrollment, legal 
guardians will provide a 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. Inclusion criteria to be met within the first 20 hours after birth 
includes a required nCPAP of 5 to 6 cm H2O to maintain SpO2 
of 88% to 95% with a fraction of inspired oxygen (FiO2) within a range 
of 0.25 to 0.50 for at least 30 minutes. As soon as study eligibility has 
been confirmed and the informed consent is signed, subjects will be 
randomized to either an active arm or a control arm. Subjects 
randomized to an active arm will receive 1 dose of lucinactant for 
inhalation within 2 hours of randomization; subjects must continue to 
meet entry criteria at the time of initiation of study therapy. Active study 
therapy will be administered through the investigational ADS device 
over 30, 45, 60, or 90 minutes in conjunction with nCPAP support.  
Subjects may be eligible to receive a repeat dose between 2 and 24 
hours after the initial dose if subjects meet repeat dosing criteria, as 

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described in the “Treatment Groups” section. Subjects randomized to a 
control arm will be continued on nCPAP alone. 
A safety assessment will be performed by an independent SRC after 
each group has been enrolled. All subjects on the active arm will receive 
the same drug concentration of lucinactant for inhalation at the same 
rate. The dose will vary by the volume of the nominal dose of 
lucinactant (30 mg TPL/ml) aerosolized and introduced into the nCPAP 
circuit, given over a predetermined time for each dose. The lucinactant 
for inhalation delivery will be facilitated by the investigational ADS 
device in conjunction with a commercially available nCPAP generator 
and patient interface. 
Dose assignments will be un-blinded, as the primary objective of this 
study is safety and tolerability. Preliminary efficacy endpoints will be 
assessed as an exploratory objective. 
All enrolled subjects will receive study treatment in a neonatal intensive 
care unit (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. Infants 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, mechanical ventilation, 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.  
Neonates will be followed through the primary phase evaluations 
through 36 weeks PMA, NICU discharge, hospital transfer, or death, 
whichever occurs first. 
Study Population: 
This study will be comprised of preterm neonates 26 to 28 completed 
weeks PMA who are receiving care in a NICU and are eligible to 
receive nCPAP support for RDS.  
The study population will consist of 4 escalating dose groups with an 
allowed repeat dose if repeat dose criteria are met. Repeat dosing is to 
ensure subjects with a demonstrated need will receive additional 
treatment, as is done with bolus dosing. 

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Study Sample Size: 
It is anticipated that approximately 64 subjects will be enrolled. 
Approximately 32 subjects will be randomized to the active arm 
(drug/device combination) and approximately 32 subjects will be 
randomized to the control arm (nCPAP alone). 
The sample size is based on the number of subjects necessary to 
evaluate safety and tolerability of lucinactant for inhalation. Sample size 
calculations to demonstrate a clinical effect will not be performed as 
efficacy is an exploratory objective. Subjects that do not complete the 
administered dose of lucinactant for inhalation, or withdraw from the 
study will not be replaced, unless required by the SRC in order to 
adequately assess safety in the dose group. 
Number of Sites: 
Up to approximately 25 clinical sites in the US; sites outside the US 
may also be used.  
Study Duration: 
Overall study enrollment will be completed in approximately 7 months, 
with the last subject completing their last visit approximately 9 months 
from the time of the first subject enrolled. 
Subject participation will be from ≤ 20 hours following birth until 
36 weeks PMA or discharge, whichever comes first.  
Method of 
Administration: 
Subjects randomized to the active study arm 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 device, ADS (using the CAG), and 
introduced into the nCPAP circuit. Those randomized to the control arm 
will continue to receive nCPAP alone.  
The exposure time will be based on the nominal dose, defined as the 
volume of lucinactant aerosolized by the ADS. 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. 
Because of losses that occur as the lucinactant aerosol travels from the 
ADS to the patient interface, the emitted dose is approximately 35% of 
the nominal dose. 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 the aerosol concentration, the minute 
ventilation of the infant, and the administration time of the aerosol.  

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Dosing Groups: 
 
 
Dosing Group I 
Active Arm (n = 8): 50 mg TPL/kg administered over 30 
minutes in conjunction with nCPAP   
 
1 Repeat dose of 50 mg TPL/kg administered over 30 minutes 
is allowed if repeat dosing criteria are met. 
 
Control Arm (n = 8): Continuous nCPAP  
 
 
Dosing Group II 
Active Arm (n = 8): 75 mg TPL/kg administered over 45 
minutes in conjunction with nCPAP   
 
1 Repeat dose of 75 mg TPL/kg administered over 45 minutes 
is allowed if repeat dosing criteria are met. 
 
Control Arm (n = 8): Continuous nCPAP 
 
 
Dosing Group III 
Active Arm (n = 8): 100 mg TPL/kg administered over 60 
minutes in conjunction with nCPAP   
 
1 Repeat dose of 100 mg TPL/kg administered over 60 minutes 
is allowed if repeat dosing criteria are met. 
 
Control Arm (n = 8): Continuous nCPAP  
 
 
Dosing Group IV 
Active Arm (n = 8): 150 mg TPL/kg administered over 90 
minutes in conjunction with nCPAP   
 
1 Repeat dose of 150 mg TPL/kg administered over 90 minutes 
is allowed if repeat dosing criteria are met. 
 
Control Arm (n = 8): Continuous nCPAP 
 
 
Each dosing group will complete study dosing and all active subjects will 
complete 72 hour safety assessments and procedures before the SRC 
review. The SRC will review all available safety data (to include study-
related adverse events [AEs], including adverse device effects [ADEs], 
serious adverse events [SAEs], and additional safety endpoints). 
Enrollment will continue in the next dosing group without pause from the 
previous dosing group; however, if the SRC identifies safety concerns 
that would preclude dosing, enrollment will stop until these safety 
concerns are addressed and the SRC recommends resuming enrollment.  
Repeat dosing will be allowed in each dosing group. Subjects meeting 
the repeat dosing criterion will receive an additional treatment of the 
same dose. Repeat dosing will be allowed between 2 hours and 24 hours 
after completion of the initial dose if subjects require a sustained need for 
supplemental oxygen at or above the qualifying  FiO2 level for study 
entry (ie, 0.25) for at least 30 minutes to maintain SpO2 of 88% to 95%.  
Subjects will be followed for safety evaluations (including, but not 
limited to, AEs and concomitant medications) until the subject is 

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36 weeks PMA or is discharged. A final visit will occur at 36 weeks 
PMA or at the time of discharge or withdrawal (whichever occurs first) 
for all subjects. 
Inclusion Criteria: 
1. Signed ICF from legally authorized representative; 
2. Gestational age 26 to 28 completed weeks PMA; 
3. Successful implementation of controlled nCPAP within 90 minutes 
after birth; 
4. Spontaneous breathing; 
5. Chest radiograph consistent with RDS; 
6. Within the first 20 hours after birth, requires an nCPAP of 
5 to 6 cm H2O to maintain SpO2 of 88% to 95% with an FiO2 of 
0.25 to 0.50 that is clinically indicated for at least 30 minutes. 
Transient (<10 minutes) FiO2 excursions below 0.25 or above 0.50 
do not reset the 30 minute requirement. 
Exclusion Criteria: 
 
1. Heart rate that cannot be stabilized above 100 beats per minutes 
within 5 minutes of birth; 
2. Recurrent episodes of apnea occurring after the initial newborn 
resuscitation period (ie, 10 minutes after birth) requiring 
intermittent positive pressure breaths using inflating pressures 
above the set CPAP pressure 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 nCPAP, diagnosed antenatally or immediately after 
birth; 
5. Other diseases or conditions potentially interfering with 
cardiopulmonary function (eg, hydrops fetalis or congenital 
infection such as TORCH); 
6. Known or suspected chromosomal abnormality or syndrome; 
7. Premature rupture of membranes (PROM) > 2 weeks; 
8. Evidence of hemodynamic instability requiring vasopressors or 
steroids for hemodynamic support and/or presumed clinical sepsis; 
9. Need for endotracheal intubation and/or mechanical ventilation; 
10. Has been administered any the following:  
a) Another investigational agent or investigational medical 

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device, 
b) Administration of any other surfactant agent, 
c) Steroid treatment (exposure before birth is acceptable). 
Note: All subjects must continue to meet entry criteria at the time of 
initiation of study therapy. 
Concomitant 
Medications: 
All concomitant medications administered to the subject from birth until 
36 weeks PMA, NICU discharge, hospital transfer, or death (whichever 
comes 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 lucinactant for inhalation administration or control, 
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 (as per 
the protocol). Postnatal steroids are not permitted unless clear medical 
need is determined. 
Safety and Tolerability 
Measures: 
 
Primary and Secondary Safety and Tolerability Measures: 
• Primary Observation Period (Day 1 and 2):  
1. Survival 
2. Use of respiratory support and supplemental oxygen 
3. Incidences leading to early discontinuation of 
aerosolized lucinactant administration  
4. Incidence of worsening respiratory status 
5. Incidence of air leak  
6. AEs, including ADEs (specifically including peri-dosing 
events and nasal excoriations) 
7. Complications of prematurity 
8. Concomitant medication 
9. Physical exam findings 
10. Tolerability of lucinactant for inhalation  
11. Assessments of the following:  
a) Vital signs  
b) Oxygen saturations (SpO2) 

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c) Partial pressure of carbon dioxide (PCO2) values 
d) FiO2 values 
e) Serum electrolyte measurements  
f) Body weight  
g) Gastric liquid volume 
h) Defecation 
12. Chest radiography prior to non-emergent intubation, or 
in cases of worsening respiratory status, if such a 
procedure does not delay or compromise the emergent 
care of the subject  
 
• Extended Observation Period (Day 3 until Day 7):  
1. Survival 
2. Incidences leading to withdrawal from study  
3. Incidence of worsening respiratory status 
4. AEs, including ADEs 
5. Complications of prematurity  
6. Concomitant medication 
7. Assessment of the following:  
• Vital signs  
• O2 saturation values 
• FiO2 values through 72 hours 
• PCO2 values through 72 hours 
8. Chest radiography prior to non-emergent intubation, or 
in cases of worsening respiratory status, if such a 
procedure does not delay or compromise the emergent 
care of the subject. 
9. Use of respiratory support and supplemental oxygen 
• Final Observation Period (Day 8 to 36 Weeks PMA or 
discharge): 
1. Survival 
2. Incidences leading to withdrawal from study  
3. Incidence of worsening respiratory distress 
4. AEs, including ADEs 
5. Physical exam findings 

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6. Concomitant medications 
7. Use of respiratory support and supplemental oxygen 
8. Complications of prematurity  
 
Efficacy Measures 
(Exploratory) 
1. Technical performance of the ADS 
The efficacy of the device delivery of lucinactant for inhalation 
will be characterized indirectly through the subject’s response 
to treatment and solicited feedback from the principal 
investigators (PIs) and relevant site-based study staff. 
2. Incidence of bronchopulmonary dysplasia (BPD) 
3. Rate of survival without BPD at 36 weeks PMA (as applicable) 
4. Worsening respiratory status either during or after exposure to 
lucinactant for inhalation  
A. A subject will be categorized as having worsening respiratory 
status if they meet at least 1 of the following criteria: (1) need 
for additional surfactant therapy following exposure to 
lucinactant for inhalation; (2) a sustained (> 30 minutes) 
FiO2 > 0.50 to maintain an SpO2 > 90%; (3) a 
PCO2 > 65 mm Hg on ≥ 2 consecutive observations; (4) 
persistent, arterial pH  < 7.20 (if blood gas values are available 
and obtained for non-study related clinical assessment); (5) any 
sustained apneic event, defined as ≥ 20 seconds and at least one 
of the following: (a) HR < 100 bpm, (b) desaturation (oxygen 
saturation < 80%), (c) requirement for intermittent positive 
pressure (IPP) breaths using inflating pressures above the set 
CPAP pressure administered manually or mechanically 
through any patient interface; (6) intubation for any reason 
(except for elective surgical procedures); (7) 
nCPAP > 7 cm H2O; (8) initiation of IPP breaths using 
inflating pressures above the set CPAP pressure administered 
manually or mechanically through any patient interface; (9) 
death while on study; or (10) the study PI determines the 
subject to have worsening respiratory status based on their best 
clinical judgment. 
B. Early worsening: worsening respiratory status occurring  ≤ 72 
hours after birth 
C. Late worsening: worsening respiratory status occurring > 72 

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hours and ≤ 7 days after birth 
All subjects meeting the criteria of worsening respiratory status 
will continue to be followed for safety evaluations until 
36 weeks PMA or discharge. 
5. Physiological Parameters 
FiO2 and PCO2 will be evaluated as potential efficacy 
parameters. 
Stopping Rules: 
The discontinuation of lucinactant for inhalation and the criteria for 
enrollment hold are the same as those used in Protocol 03-CL-1201. 
The administration of lucinactant for inhalation may be discontinued at 
any time in accordance with the clinical judgment of the PI or the 
wishes of the subject’s legal guardian. In accordance with local 
institutional practices, SRT must be made available to subjects 
demonstrating a clinical need following exposure to lucinactant for 
inhalation. 
 
Reasons for discontinuation from study drug administration include the 
following:  
• Device failure or malfunction, including error codes or 
treatment interruptions; 
• Pulmonary hemorrhage or other AE/ADE; 
• In the PI’s best medical judgment, initiating or continuing the 
subject’s exposure to lucinactant for inhalation is not in the best 
interest of the subject’s safety, such as hemodynamic instability. 
• Signs of acute respiratory deterioration as evidenced by an 
increased respiratory rate or an observed increase in respiratory 
effort (work of breathing) plus at least one of the following: 
a) An FiO2  ≥ 0.70 or a sustained ( 10 minutes) increase from 
baseline by ≥ 0.30 to maintain adequate oxyhemoglobin 
saturation (SpO2  88%), 
b) A PCO2 > 70 mm Hg or a progressive increase from 
baseline to ≥ 20 mm Hg above baseline and confirmed with 
a blood gas, 
c) Recurring episodes of bradycardia defined as a heart rate 
< 100 bpm for ≥ 20 seconds, 
d) A sustained apneic event, defined as apnea for at least 20 

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seconds in duration and meeting at least one of the 
following: (1) HR < 100 bpm, (2) desaturation (oxygen 
saturation < 80%), (3) requirement for IPP breaths using 
inflating pressures above the set CPAP pressure 
administered  manually or mechanically through any 
patient interface. 
 
Enrollment hold criteria: 
The study will be placed on enrollment hold until further evaluation 
by the SRC if one of the following criteria are met:  
• If > 2 subjects per dosing group experience a SAE related to 
lucinactant for inhalation administration 
• If ≥ 1 subject dies during first 12 hours following and related to 
lucinactant for inhalation administration 
Statistical Analysis: 
The statistical analysis of both the primary and secondary safety and 
tolerability objectives will be based on all randomized preterm neonates 
in the study. In addition, data from all evaluable preterm neonates will 
be analyzed for efficacy signals as an exploratory endpoint. No 
hypothesis testing or statistical comparisons will be performed. 
Interim Analyses: 
All available safety endpoint data captured from randomization to 
completion of 72 hours for active subjects, and all available safety 
endpoint data for control subjects, will be evaluated by the SRC. As this 
is an open-label study with no hypothesis testing, no adjustments for 
p-values are required or employed for the interim analyses. 
 
 

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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
AEROSURF PROTOCOL SUMMARY .................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 15 
LIST OF ABBREVIATIONS .................................................................................................... 20 
1 
INTRODUCTION............................................................................................................... 22 
1.1 
Treatment of Neonatal Respiratory Distress Syndrome ............................................. 22 
1.1.1 Continuous Positive Airway Pressure in Neonatal Respiratory Distress Syndrome .... 23 
1.2 
Development of Aerosolized Device for Lucinactant Delivery ................................... 23 
1.2.1 Non-invasive Surfactant Delivery................................................................................. 24 
1.3 
Clinical Experience with Aerosolized Lucinactant ...................................................... 24 
1.3.1 Study KL4-CPAP-01 .................................................................................................... 25 
1.3.2 Study KL4-ASTH-01 .................................................................................................... 25 
1.3.3 Study 03-CL-1201 ........................................................................................................ 26 
1.4 
Regulatory Agency Meetings ......................................................................................... 26 
2 
STUDY DESIGN AND RATIONALE .............................................................................. 28 
2.1 
Study Design .................................................................................................................... 28 
2.2 
Dose and Device Description .......................................................................................... 30 
2.2.1 Capillary-based Aerosol Generating Systems .............................................................. 30 
2.2.2 Rationale for Study Control .......................................................................................... 30 
2.2.3 Dose Rationale .............................................................................................................. 30 
2.3 
Study Duration ................................................................................................................ 36 
2.3.1 Duration of Subject Study Participation ....................................................................... 36 
3 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 37 
3.1 
Primary Objective ........................................................................................................... 37 
3.1.1 Primary Endpoints ........................................................................................................ 37 
3.2 
Secondary Objective ....................................................................................................... 37 
3.3 
Safety Evaluations ........................................................................................................... 37 

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3.4 
Exploratory Efficacy Objective ..................................................................................... 39 
3.4.1 Efficacy Endpoints ........................................................................................................ 39 
4 
STUDY POPULATION SELECTION ............................................................................. 40 
4.1 
Study Population ............................................................................................................. 40 
4.2 
Inclusion Criteria ............................................................................................................ 40 
4.3 
Exclusion Criteria ........................................................................................................... 40 
5 
STUDY DOSING AND ADMINISTRATION ................................................................. 42 
5.1 
Precautions for Aerosol Delivery and Device Usage .................................................... 42 
5.1.1 Precautions for Aerosol Delivery.................................................................................. 43 
5.1.2 Stopping Criteria for Aerosol Delivery......................................................................... 43 
5.1.3 Precautions for Device Usage ....................................................................................... 44 
5.1.4 Assessment Parameters for Technical Performance of the Device .............................. 44 
5.2 
Description of Study Assignment and Aerosol Delivery ............................................. 45 
5.2.1 Aerosol Delivery ........................................................................................................... 45 
5.2.2 Study Assignment; Dosing Groups ............................................................................... 46 
5.2.3 Method of Assigning Study Subjects to Dosing Groups .............................................. 47 
5.2.4 Sequential Dosing Scheme ........................................................................................... 47 
5.2.5 Repeat Dosing ............................................................................................................... 47 
5.3 
Aerosurf Delivery System ............................................................................................... 48 
5.3.1 Aerosurf Control Unit ................................................................................................... 50 
5.3.2 Aerosurf Delivery Pack................................................................................................. 50 
5.4 
Delivery of On-Study Continuous Positive Airway Pressure ..................................... 51 
5.4.1 Set-up of Continuous Positive Airway Pressure System .............................................. 52 
5.5 
Identity of Investigational Drug Product ...................................................................... 53 
5.5.1 Formulation of Study Drug ........................................................................................... 53 
5.5.2 Packaging and Labeling ................................................................................................ 54 
5.6 
Clinical Study Supplies at the Clinical Study Site ....................................................... 54 
5.6.1 Investigational Study Drug and ADPs .......................................................................... 54 
5.6.2 Ancillary Supplies ......................................................................................................... 54 
5.6.3 Dispensing..................................................................................................................... 54 
5.6.4 Storage of Lucinactant and Aerosurf Delivery System ................................................ 55 
5.7 
Study Compliance ........................................................................................................... 55 
5.8 
Study Drug and Device Accountability ......................................................................... 55 

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5.8.1 Study Supply Accountability ........................................................................................ 56 
6 
SAFETY REVIEW COMMITTEE .................................................................................. 57 
6.1 
Safety Reviews ................................................................................................................. 57 
6.2 
Safety Enrollment Holds ................................................................................................ 57 
7 
STUDY PROCEDURES AND GUIDELINES ................................................................. 59 
7.1 
Clinical Assessments ....................................................................................................... 59 
7.1.1 Vital Signs ..................................................................................................................... 59 
7.1.2 Body Weight ................................................................................................................. 60 
7.1.3 Pulse Oximetry.............................................................................................................. 60 
7.1.4 FiO2 ............................................................................................................................... 60 
7.1.5 Monitoring of Carbon Dioxide Levels .......................................................................... 60 
7.1.6 Physical Examination.................................................................................................... 61 
7.1.7 Serum Electrolytes ........................................................................................................ 61 
7.1.8 Chest Radiograph .......................................................................................................... 61 
7.1.9 Gastric Liquid Volume ................................................................................................. 61 
7.1.10 
Defecation ................................................................................................................. 62 
7.2 
Medical Information ....................................................................................................... 62 
7.3 
Concomitant Medications .............................................................................................. 62 
7.3.1 Use of Additional Surfactant Replacement Therapies .................................................. 62 
7.4 
Demographics .................................................................................................................. 62 
7.5 
Worsening Respiratory Status ....................................................................................... 62 
7.5.1 Worsening Respiratory Status Criteria ......................................................................... 63 
7.5.2 Worsening Respiratory Status Categories .................................................................... 63 
7.6 
Respiratory Support and Oxygen Delivery .................................................................. 63 
7.6.1 Emergent Respiratory Support ...................................................................................... 64 
7.6.2 Documentation During Primary and Extended Observation Period ............................. 64 
7.6.3 Documentation During Final Observation Period ........................................................ 65 
7.7 
Criteria for Acute Respiratory Deterioration .............................................................. 65 
8 
EVALUATIONS BY VISIT ............................................................................................... 67 
8.1 
Screening Period ............................................................................................................. 67 
8.2 
Primary Observation Period .......................................................................................... 68 
8.3 
Extended Observation Period:....................................................................................... 69 

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8.4 
Final Visit ......................................................................................................................... 69 
9 
ADVERSE EVENT REPORTING ................................................................................... 71 
9.1 
Adverse Events ................................................................................................................ 71 
9.1.1 Causal Relationship of Adverse Events ........................................................................ 72 
9.1.2 Severity Grade Levels of Adverse Events .................................................................... 72 
9.1.3 Adverse Event Procedures ............................................................................................ 73 
9.1.4 Serious Adverse Events ................................................................................................ 73 
9.1.5 Unanticipated Adverse Device Effects ......................................................................... 74 
9.2 
Medical Monitoring ........................................................................................................ 75 
10 DISCONTINUATION AND REPLACEMENT OF SUBJECTS .................................. 76 
10.1 
Early Discontinuation of Lucinactant for Inhalation .................................................. 76 
10.2 
Study Withdrawal ........................................................................................................... 76 
10.3 
Early Study Termination ............................................................................................... 76 
10.4 
Replacement of Subjects................................................................................................. 77 
11 PROTOCOL VIOLATIONS ............................................................................................. 78 
12 ETHICS ............................................................................................................................... 79 
12.1 
Institutional Review Board ............................................................................................ 79 
12.2 
Informed Consent Form of Study Subject.................................................................... 80 
12.3 
Financial Disclosure ........................................................................................................ 80 
13 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .............. 82 
13.1 
Statistical and Analytical Plans ..................................................................................... 82 
13.2 
Interim Analyses ............................................................................................................. 82 
13.3 
Sample Size and Randomization ................................................................................... 83 
14 DATA COLLECTION, RETENTION AND MONITORING ....................................... 84 
14.1 
Protection of Subject Data and Confidentiality ........................................................... 84 
14.2 
Data Collection Instruments .......................................................................................... 84 
14.3 
Data Management Procedures ....................................................................................... 85 

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14.4 
Data Quality Control and Reporting ............................................................................ 85 
14.5 
Archival of Data .............................................................................................................. 85 
14.6 
Record Retention ............................................................................................................ 86 
14.7 
Monitoring ....................................................................................................................... 86 
15 ADMINISTRATIVE AND REGULATORY CONSIDERATIONS .............................. 89 
15.1 
Protocol Amendments .................................................................................................... 89 
15.2 
End-of-Study Procedures ............................................................................................... 89 
15.3 
Study Report.................................................................................................................... 89 
15.4 
Publications ..................................................................................................................... 89 
15.5 
Investigator Responsibilities .......................................................................................... 90 
16 REFERENCES .................................................................................................................... 91 
 
APPENDICES 
Appendix 1 
Protocol Definitions .............................................................................................93 
Appendix 2 
Protocol Event Schedule Summarization ..........................................................96 
Appendix 3 
Papile Scoring System for Intraventricular Hemorrhage (IVH) ....................98 
Appendix 4 
Scoring System of Bell for Necrotizing Enterocolitis (NEC) ...........................99 
Appendix 5 
International Classification of Retinopathy of Prematurity (ROP) ..............101 
Appendix 6 
Investigator Agreement Form ..........................................................................102 

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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ABG 
Arterial blood gas 
ACU 
Aerosurf Control Unit 
AE 
Adverse event 
ADE 
Adverse device effect 
ADS 
Aerosurf Delivery System 
ADP 
Aerosurf Delivery Packet 
BPD 
Bronchopulmonary dysplasia 
CAG 
Capillary aerosol generator 
CFR 
Code of Federal Regulations 
CPAP/nCPAP 
Continuous positive airway pressure/nasal CPAP 
CRF/eCRF 
Case report form/electronic CRF 
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 
NOEL 
No observed adverse effect level 
PA 
Palmitic acid 
PCO2 
Partial pressure of carbon dioxide  
PaO2 
Partial pressure of oxygen dissolved in arterial blood   
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 tolerability of a sequential, escalating dose 
of lucinactant for inhalation (a non-invasive, investigational drug-device combination product ) 
administered in preterm neonates 26 weeks to 28 completed weeks (28 weeks 6 days) 
post-menstrual age (PMA) with respiratory distress syndrome (RDS) treated with nasal 
continuous positive airway pressure (nCPAP), in comparison with nCPAP alone.  
Non-invasive surfactant delivery potentially addresses an unmet medical need by providing a 
means to deliver surfactant to preterm neonates with RDS treated with nCPAP, thereby 
providing surfactant therapy early in the disease course while avoiding the complications 
associated with endotracheal intubation for surfactant delivery. 
This phase 2a study is designed to assess the safety and tolerability of a novel surfactant 
replacement therapy (SRT), lucinactant for inhalation, administered at select doses in preterm 
infants 26 to 28 completed weeks PMA. A similar study, Protocol 03-CL-1201, in preterm 
neonates 29 to 34 completed weeks PMA, was conducted first to establish that lucinactant for 
inhalation is generally safety and well tolerated. Similar to this study (03-CL-1401), Protocol 03-
CL-1201 evaluated lucinactant for inhalation in a dose-escalation manner up to 75 mg total 
phospholipids (TPL)/kg, with a currently ongoing study extension in that population up to 150 
mg TPL/kg. Findings from these two studies (03-CL-1201 and 03-CL-1401) 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) 
requirements, International Conference on Harmonisation Good Clinical Practices (ICH GCP) 
Guidelines, and local institutional practices. In addition, the study procedures and assessments 
are designed to mimic those of Protocol 03-CL-1201. 
Definitions of study terms are provided in Appendix 1. 
1.1 
Treatment of Neonatal Respiratory Distress Syndrome 
Surfactant treatment has reduced mortality and morbidity in newborns with RDS. Intratracheal(1) 
instillation of exogenous surfactant is a standard treatment for the treatment of RDS, and the 
benefits of surfactant treatment, specifically early surfactant treatment, are well established(2). 

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However, instillation of surfactant into the lung requires endotracheal intubation, an invasive 
procedure that has potential deleterious effects.  
1.1.1 Continuous Positive Airway Pressure in Neonatal Respiratory Distress Syndrome 
Efforts by neonatologists to avoid endotracheal intubation to reduce the volutrauma and 
barotrauma associated with airway inflation and deflation have focused on the use of nCPAP, 
reserving intubation and surfactant administration for the most severely ill neonates.  
The use of nCPAP in preterm neonates with RDS has become widely accepted(3) and national 
guidelines (American Association for Respiratory Care)(4) exist for treatment of respiratory 
distress in preterm newborns. These guidelines outline several patient interface devices that can 
be used to deliver continuous airway pressure such as nasal masks, short bi-nasal prongs, and 
nasopharyngeal tubes. It has been demonstrated that nCPAP is effective in increasing functional 
residual capacity by stabilizing and improving alveolar function(5) and in dilating the larynx(6). 
Devices that generate and deliver nCPAP, including patient interfaces such as nasal prongs, are 
specifically designed, manufactured, and commercially available for use in neonates.  
While the use of nCPAP in preterm infants is common, studies of nCPAP alone, including a 
meta-analysis of prophylactic nCPAP for preventing morbidity and mortality in very preterm 
neonates, have not shown a clear benefit of this approach(7). A large, multicenter, randomized 
clinical study (N = 610) was performed to compare the effects of nCPAP alone versus 
intermittent mechanical ventilation (IMV) for very preterm neonates at birth. This study showed 
that in the nCPAP group, the need for surfactant therapy was half of that compared to subjects in 
the intubation group, and death or oxygen treatment at day 28 after birth was less frequent 
(p = 0.006). However, there were no differences in survival or supplemental oxygen therapy at 
36 weeks, overall mortality, days of respiratory support, oxygen treatment, hospital stay, or other 
secondary outcomes. Of note, a higher rate of pneumothorax in the nCPAP group compared to 
the intubation group (9% versus 3%) was observed, and over 50% of infants in the nCPAP group 
required endotracheal intubation(8). Other studies comparing nCPAP to endotracheal intubation 
and surfactant administration have also demonstrated a relatively high rate of endotracheal 
intubation in the group receiving nCPAP. 
1.2 
Development of Aerosolized Device for Lucinactant Delivery 
Discovery Laboratories, Inc. (Discovery) has developed a capillary aerosol generator (CAG) 
device to aerosolize lucinactant (lucinactant for inhalation). Pre-clinical studies using the CAG 

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technology in spontaneously breathing preterm lambs receiving aerosolized lucinactant have 
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. 
1.2.1 Non-invasive Surfactant Delivery 
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). 
Because aerosolized surfactant is preferentially delivered to the ventilated parts of the lungs, it is 
essential to provide appropriate ventilatory support during aerosol delivery. Distribution of 
aerosol in the lungs has been limited by the technical constraints of currently available aerosol 
generators and system configurations. Compared with the endotracheal instillation surfactant 
administration route, efforts to aerosolize surfactants in clinical models have been largely 
unsuccessful because of the highly inefficient and limited dose delivery compared with the bolus 
administration route of currently available aerosol generators (9,10). However, the CAG technology 
may allow for administration of aerosolized lucinactant to be deposited in the lungs of preterm 
neonates in potentially sufficient quantities to affect a therapeutic response analogous to that of 
endotracheal instillation surfactant administration. An investigational device, Aerosurf Delivery 
System (ADS) utilizing the CAG has been developed and provides a high-density surfactant 
aerosol output (20 μl/sec), with an appropriate particle size (2 to 3 microns mass median 
aerodynamic diameter [MMAD]). The ADS will be used in 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 commercially available nebulizers (KL4-CPAP-01, KL4-ASTH-01). These 
studies demonstrated that delivery of lucinactant as an aerosol is technically feasible and that it is 
generally safe and well-tolerated in both adult patients and preterm neonates. In addition, one 
study (03-CL-1201) is being conducted with aerosolized lucinactant administered using the 
ADS. The preliminary results from 03-CL-1201 demonstrate that delivery of lucinactant as an 
aerosol using the CAG technology is feasible and that lucinactant for inhalation appears to be 
generally safe and well-tolerated in infants 29 to 34 weeks PMA. 

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1.3.1 Study KL4-CPAP-01 
KL4-CPAP-01 was a phase 2, multicenter pilot study in preterm neonates investigating the 
feasibility of prophylactic, aerosolized lucinactant administered in conjunction with nCPAP. The 
study was designed to establish the feasibility of delivering prophylactic aerosolization of 
lucinactant to preterm neonates at risk for RDS(11). A total of 17 neonates were enrolled and 
evaluated through 28 days of age. 
The drug-device combination study consisted of a conditioning system and in-line Aeroneb® Pro 
Nebulizer System, which aerosolized lucinactant that was diluted from 30 mg/ml TPL to 
20 mg/ml TPL. Treatment delivery was administered in conjunction with a nCPAP system and 
short bi-nasal prongs. The predetermined, theoretical maximum aerosolized, inhaled dose was 
0.4 mg TPL per minute. Therefore, over a 3-hour period, the total, potential maximum 
lucinactant inhaled dose under breathing conditions of 6.4 ml tidal volume and 54 breaths per 
minute was 72 mg TPL. The predetermined Aeroneb Pro Nebulizer System output rate based on 
bench testing was approximately 4 μL/second. Thus, the total drug dispensed volume was 43 ml 
over 3 hours. With 3 re-treatments, the total potential drug exposure was up to 288 mg and 
172 ml over a 48-hour period which, when calculated based on the average weight of the 
subjects entered into the trial would translate to approximately 192 mg/kg and 115 ml/kg, 
respectively. Since the majority of infants received only a single dose of study drug, most infants 
received approximately 72 mg TPL of aerosolized lucinactant in a volume of 43 ml over the 3 
hour treatment. 
The study demonstrated it is feasible to deliver aerosolized lucinactant in conjunction with 
nCPAP and that the treatment was generally safe and well tolerated by preterm neonates.  
1.3.2 Study KL4-ASTH-01 
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. 
The study demonstrated it is feasible to deliver aerosolized lucinactant to adults and that the 
treatment was generally safe and well tolerated.  

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1.3.3  Study 03-CL-1201 
03-CL-1201 is a phase 2a multicenter, randomized, open-label, controlled study assessing the 
safety and tolerability of aerosolized lucinactant delivered using the ADS in preterm infants 29 to 
34 completed weeks PMA. This is a dose-escalation study has recently completed enrollment in 
Dosing Group IV (100 mg TPL/kg and control [nCPAP only]). As the extension phase of this 
study is ongoing, full results are not yet available; however, preliminary results from Dosing 
Groups I, II, III, and IV indicate tolerability with the combination product. Reviews of the data 
conducted by the Safety Review Committee (SRC) for Dosing Groups I, II, III, and IV indicate 
that lucinactant delivered via the ADS is safe and well tolerated and the SRC has recommended 
continuing to the final extension dosing group (Dosing Group V) (see Section 2.2.3.2). The 
dosing regimen for the extension phase of the study by protocol amendment includes two 
additional dosing groups: Dosing Group IV, 100 mg TPL/kg with a possible repeat dose and 
Dosing Group V, 150 mg TPL/kg with a possible repeat dose. 
This current protocol (03-CL-1401) has been designed to use the same procedures and 
assessments as Study 03-CL-1201, but in a younger patient population. 
1.4 
Regulatory Agency Meetings 
Two meetings (1 pre-investigational new drug [pre-IND] meeting and 1 type C meeting) were 
held with the US Food and Drug Administration (FDA) on April 5, 2006, and July 18, 2007 to 
discuss the proposed development program for lucinactant for inhalation. During these meetings, 
Discovery agreed to perform 2 toxicology studies using lucinactant and the CAG technology in 2 
species, with 1 of the species being non-rodent. These studies were completed and yielded a no-
observed-adverse-effect–level (NOAEL) at the maximum feasible dose, as described in Section 
2.2.3.1. 
Discovery also acknowledged that the study population for the clinical program would be 
preterm neonates at risk for or with RDS. Discovery further acknowledged that the lucinactant 
aerosolized by the CAG technology would be tested for safety in a dose escalation study, and 
that testing would first be conducted in neonates at approximately 30 weeks PMA before testing 
in neonates at lower gestational ages. This dose-escalation study (Protocol 03-CL-1201) has 
recently completed enrollment through Dosing Groups I, II and III (25, 50 and 75 mg TPL/kg, 
respectively), and preliminary results indicate that lucinactant for inhalation is generally safe and 
tolerated. As was originally planned, with the conclusion of enrollment in Dosing Group III and 

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approval by the SRC to proceed to study a younger preterm population (ie, 26 to 28 completed 
weeks PMA), enrollment in Protocol 03-CL-1401 will begin. 

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2 
STUDY DESIGN AND RATIONALE 
This study will investigate the safety and tolerability of up to 4 escalating exposures with a 
potential repeat dose of lucinactant for inhalation. The study design will include up to 4 dosing 
groups consisting of preterm neonates 26 to 28 completed weeks PMA with RDS who are 
candidates for nCPAP and SRT.  
2.1 
Study Design  
This study is a multicenter, randomized, open-label, controlled study to evaluate the safety and 
tolerability of a novel drug-device combination investigational product (lucinactant for 
inhalation) administered in conjunction with nCPAP, in preterm neonates with RDS who are 
under the care and observation of a neonatal intensive care unit (NICU). The study will explore 
escalating exposures of lucinactant for inhalation in a sequential manner through 4 unique dosing 
groups. All subjects randomized to the active study arm will receive the same concentration of 
study drug to provide the same total dose exposure. Subjects randomized to the control arm will 
receive nCPAP alone. Dosing groups are outlined in Section 5.2.2. 
The lucinactant for inhalation delivery will be facilitated by the investigational ADS device in 
conjunction with a commercially-available nCPAP generator and patient interface. Details on the 
drug delivery device are outlined in Section 5.3. 
Eligible neonates will be randomized within 20 hours after birth. Aerosolization of lucinactant 
will be initiated within 2 hours after randomization.  
The study is designed to sequentially increase dose exposure. After each sequential dose, an 
independent SRC will review all adverse events and specified safety parameters (Section 6) 
(Figure 2.1-1). 

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Figure 2.1-1 Schematic of Study Design for 03-CL-1401 
 

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2.2 
Dose and Device Description 
In this study, approximately 32 subjects will be randomized to an active arm and will receive 
aerosolized lucinactant through the ADS (utilizing CAG technology) in conjunction with 
nCPAP. Approximately 32 subjects will be randomized to the control arm and will receive 
nCPAP alone.  
2.2.1 Capillary-based Aerosol Generating Systems 
Newer technologies, such as the CAG system, may allow for administration of aerosolized 
surfactant to preterm neonates in sufficient quantities to affect a therapeutic response similar to 
the response demonstrated in surfactants administered by endotracheal instillation. A device that 
permits effective surfactant aerosolization to neonates receiving nCPAP support for the treatment 
of RDS may improve the success of nCPAP therapy. 
2.2.2 Rationale for Study Control 
The use of nCPAP in the US is widely utilized for the treatment of RDS in preterm newborns, 
and current guidelines outline several patient interface devices that can be used to deliver 
continuous airway pressure such as nasal masks, short bi-nasal prongs, and nasopharyngeal 
tubes(4). Thus, preterm neonates who, in accordance with current treatment practice, would be 
treated with nCPAP are appropriate controls for this study. 
2.2.3 Dose Rationale   
Lucinactant, administered as an intratracheal 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 infants at high risk for RDS. Infants at high risk for RDS are presumed to be 
substantially or wholly surfactant deficient and require endotracheal intubation and mechanical 
ventilation. In contrast, the population of preterm infants who can be sustained by nCPAP, rather 
than endotracheal intubation and mechanical ventilation, likely represent a broad spectrum of 
varying degrees of surfactant insufficiency. While infants born at a lower gestational age are 
likely to be more surfactant insufficient compared with infants born at higher gestational ages, a 
myriad of factors can also influence these degrees of surfactant insufficiency. Therefore, dosing 
algorithms based on gestational age, or birth weight as a surrogate for gestational age, would not 
necessarily represent the optimal method for estimating the dose of surfactant that should be 
administered to adequately treat RDS. Nevertheless, preterm infants who can be sustained by 
nCPAP are unlikely to require a full replacement dose of SRT. Thus, it is likely that preterm 

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infants on nCPAP will require substantially less than the intratracheal bolus dose of 175 mg 
TPL/kg of lucinactant. In fact, based on a previously conducted clinical study of aerosolized 
lucinactant (KL4-CPAP-01), the target theoretical inhaled dose is likely to be in the range of 
75 mg TPL/kg or higher.  
The relative inefficiency of inhalation therapy must also be considered. Due to the viscoelastic 
properties of surfactant, it is highly likely that most, if not all, of the surfactant delivered as a 
bolus to the trachea will ultimately arrive in the alveoli, the site of action for surfactant. 
However, the entrainment of surfactant administered as an aerosol into the subglottic airway to 
the nasopharynx will vary depending on the characteristics of the aerosol, such as particle size 
and rate of administration, and the breathing characteristics of the individual neonate (eg, 
inspiratory and expiratory patterns, frequency, and tidal volume). The aerosol particle size and 
rate of administration can be kept constant; however, the rate of administration should be 
representative of the infant’s inspiratory flow to optimize the efficiency of aerosol entrainment. 
Typically, inspiratory and expiratory patterns in preterm infants will vary from breath to breath. 
However, breathing frequencies and tidal volumes are less variable in preterm populations. 
Minute ventilation, which is related to body surface area and therefore indirectly related to body 
weight, is the product of frequency and tidal volume. Therefore, minute ventilation can be used 
to estimate the theoretical maximum inhaled dose of aerosolized surfactant normalized to body 
weight. The actual inhaled dose is likely to be less since some aerosolized surfactant will be 
expelled during exhalation or will deposit in the oropharynx and be swallowed into the stomach.  
The safety of the total TPL load and volume of fluid that infants will receive (and any potential 
for impact on serum electrolytes and acid-base balance) is supported both by prior toxicology 
studies and by preclinical and clinical experience. 
2.2.3.1 Preclinical 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 lavage 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 non-clinical animal toxicology studies in pre-weaned rabbits (N107662) and 
pre-weaned rats (N107663) evaluated the acute toxicity of inhaled lucinactant (aerosolized by 

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CAG technology). Rabbits and rats were exposed to aerosol on 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 NOAELs were established to ensure adequate safety in preterm neonates. 
Preclinical studies provide a safety margin of > 15:1 for the highest dose (150 mg TPL/kg), 
whether delivered to the lungs (> 2700 mg TPL/kg) or swallowed (8400 mg TPL/kg) (including 
volume load and sodium load). 
2.2.3.2 Clinical Experience Supporting Dose Rationale 
Human subjects have been exposed to both high doses and large volumes of lucinactant 
administered by intratracheal bronchial lavage. In addition, study populations consisting of 
neonates with meconium aspiration syndrome and adults with acute respiratory distress 
syndrome have received doses up to 1710 ml(12,13). 
In addition, lucinactant for inhalation in doses up to 75 mg TPL/kg has been administered in 
Study 03-CL-1201 in infants 29 to 34 weeks PMA. Currently, subjects are being enrolled into 
the extension phase of the study (Dose group IV; 100 mg TPL/kg or control). This study (03-CL-
1401) includes the same entry criteria and the same assessments at the same evaluation times. 
Protocol 03-CL-1201 
Doses of lucinactant for inhalation up to 150 mg TPL/kg have been administered and the safety 
and tolerability drug-device combination product reviewed by an independent safety committee. 
Through doses up to 100 mg TPL/kg, lucinactant for inhalation appears generally safe and 
tolerated with no specific safety issues noted. Preliminary information suggests that 25 mg 
TPL/kg may be a sub-therapeutic dose based on physiological assessments compared with the 
nCPAP control group; as a result, the proposed starting dose for neonates with a greater degree 
of surfactant insufficiency is 50 mg TPL/kg for this study (03-CL-1401). 
Primary safety and tolerability measures include survival, air leak, complications of prematurity, 
and AEs. In addition, assessments on vital signs, PCO2, FiO2, serum electrolytes, and gastric 

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liquid volume will be performed.  A summary of selected measures is provided in the Aerosurf 
investigator’s brochure. 
To date, one death has occurred; the subject expired 9 days following aerosolized lucinactant 
administration of 150 mg/kg due to sudden, unexplained, cardiopulmonary deterioration not 
related to study drug or study protocol. All subjects randomized received study treatment. No 
clinically meaningful difference between any of the active groups and the nCPAP Only group 
have been observed for complications of prematurity, though sample sizes are small. 
There appeared to be a higher rate for several AEs, including airleak, in the Group I active group 
compared with the control group; however, small numbers make these comparisons difficult. 
Moreover, data for Dosing Groups II, III, and IV do not suggest clinically relevant areas of 
concern. The most common type of air leak reported has been pneumothorax. No clinically 
relevant differences have been observed between the active groups and the control group on 
completion of dosing Groups II, III, and IV. 
The subjects in the active and control groups exhibit results for serum electrolytes that are very 
similar, indicating that the investigational product has had no demonstrable impact on serum 
electrolytes. 
In summary, the preliminary data for Protocol 03-CL-1201 indicate that there are no specific 
safety concerns and that the doses studied are generally safe and tolerated. The SRC has 
reviewed all safety data from Dosing Groups I through IV, and in each case recommended that 
the study continue. The results also indicate that the dose of 25 mg TPL/kg is likely a 
subtherapeutic dose. After evaluation of the data by the steering committee and discussion with 
Discovery, it was determined that the appropriate starting dose of for this study (03-CL-1401) 
should be 50 mg TPL/kg. 
2.2.3.3 Dose Exposure and Delivery 
The inhaled doses for this dose escalation study are based on a previously conducted clinical 
study of aerosolized lucinactant (KL4-CPAP-01) that consisted of a theoretical inhaled dose of 
aerosolized lucinactant 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). The initial dose will be 
approximately one third of the theoretical inhaled dose of the previous study. 
The theoretical inhaled dose can be estimated using the following equation:  

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T
kg
Vm
C







Dose
 
Inhaled
 
Where: C 
= Aerosol concentration 
 
Vm/kg = Minute ventilation per kg of body weight  
 
T 
= Dose duration in minutes 
• C: the aerosol concentration is calculated by dividing the emitted dose by the flow rate of 
the carrier gas used to drive the aerosol to the patient interface;  
• Vm/kg : the subject’s Vm can be calculated based on the patient’s weight(14), or based on 
direct neonatal lung function measurements of newborns(15). Table 2.2-1 shows the 
comparison of Vm values derived from these two sources; 
• T: the duration of aerosol exposure in minutes is a modifiable, external factor that is 
determined by the target inhaled dose as a function of the CAG output; once this is 
known, the nominal dose can be calculated. 
The emitted dose of the ADS is the product of the CAG output (1.2 ml/min), the concentration of 
the lucinactant (30 mg TPL/ml) and the fraction of the nominal dose that is delivered at the 
patient interface is 0.35: 
Emitted dose = 1.2 ml/min x 30 mg TPL/ml x 0.35 = 12.6 mg TPL/min 
The aerosol concentration (C) is the emitted dose (12.6 mg TPL/min) divided by the carrier gas 
flow rate (3 L/min). This flow rate was chosen because it best represents the range of inspiratory 
flow rates observed in the target population. 
𝐶= 12.6 mg TPL/min
3 L/min
= 4.2 mg TPL/L 
Estimates of minute ventilation (Vm) within the range of body weights of preterm infants 
expected to enroll in the study are listed in Table 2.2-1, based on the work of Bide, et al. and 
Bhutani, et al (14,15). When normalized to body weight, the Vm/kg is consistent across the range 
of weights at approximately 0.4 L/min/kg. 

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Table 2.2-1. Minute Ventilation Comparison Between Bide and Bhutani 
 
Bide et al. 
Bhutani et al. 
 
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 four levels for the theoretical inhaled dose are 50, 75, 100, and 150 mg TPL/kg. By using 
these values, the dose duration (T) is calculated by dividing the target inhaled dose by the 
product of C (4.2 mg TPL/L) and Vm (0.4 L/min/kg). This calculation yields dose durations of 
30, 45, 60 and 90 minutes to achieve target theoretical doses. 
2.2.3.4 Dose Durations 
The dosing duration for the 50 mg/kg, 75 mg/kg, 100 mg/kg, and 150 mg/kg inhaled doses have 
been established at 30, 45, 60, and 90 minutes.  
Table 2.2-2 provides a summary of the dosing durations for each dosing group. Calculations used 
to derive these aerosolization times are outlined in this section. 
Table 2.2-2. Dosing Duration in Minutes for Each Dosing Group 
Dose and Dosing Time (min) 
Weight (g) 
50 mg/kg 
75 mg/kg 
100 mg/kg 
150 mg/kg 
750 – 2750 
30 
45 
60 
90 
Note: Based on Bhutani, et al. (15) 
Neonates of low weight will receive slightly more study drug, while those with a higher weight 
will receive slightly less.  

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2.3 
Study Duration  
It is expected that recruitment will occur over a period of 7 months, with an average of 1 subject 
enrolled per 4 weeks for each of the approximately 12 study sites (actual subject recruitment 
period may vary). It is estimated that the last subject enrolled will complete all assessments and 
procedures within 9 months from the time of the first subject enrolled. Thus the total duration of 
the study is expected to be approximately 9 months. 
Any adverse findings by the SRC may result in early study closure and early withdrawal of study 
subjects (Section 6).  
2.3.1 Duration of Subject Study Participation  
The total duration of study participation for each subject will be from enrollment (≤ 20 hours 
from birth) to 36 weeks PMA. All subjects who complete all assessments and procedures up to 
and including the Final Visit (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 periods (assessments, procedures, and 
visits associated with each of these phases can be found in Section 7.1):  
• 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.  
• Primary Observation Period: time of randomization (T0 on study) to 48 hours from 
randomization.  
o To include: pre-treatment assessment, treatment period (30, 45, 60, or 90 minutes), 
followed by continual safety monitoring in accordance with local NICU procedures. 
o Study treatment must be initiated ≤ 22 hours from the time of birth 
• Extended Observation Period: > 48 hours on study to completion on Study Day 7 (6 days 
after the day of randomization by calendar date) or until time of death or hospital 
transfer/discharge, whichever comes first. 
• Final Observation Period: ≥ Study Day 8 to 36 weeks PMA or discharge or until of death 
or hospital transfer/discharge, whichever comes first. 

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3 
STUDY OBJECTIVES AND ENDPOINTS 
This study is designed to investigate the safety and tolerability of lucinactant for inhalation in 
preterm infants of gestational age 26 to 28 completed weeks PMA. Safety and tolerability will be 
based on clinical evaluations (Section 8). Efficacy will be an exploratory objective. The 
endpoints specified are the same endpoints as Protocol 03-CL-1201, to allow for potential 
comparison and pooling of results. 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of lucinactant for 
inhalation, administered as an aerosolized dose in 4 escalating doses to a preterm, neonatal 
population 26 to 28 completed weeks PMA receiving nCPAP for RDS compared with neonates 
receiving nCPAP alone. 
Safety and tolerability will be evaluated using the same measures and assessments that have been 
used in Protocol 03-CL-1201, which has shown lucinactant for inhalation up to 75 mg/kg to be 
generally safe and well-tolerated in infants 29 to 34 completed weeks PMA. 
3.1.1 Primary Endpoints 
The primary endpoints of this study will be derived from the safety evaluations, including 
adverse device effects (ADEs) reported from the time of randomization until 36 weeks PMA of 
upon discharge (Section 3.3). 
3.2 
Secondary Objective 
The secondary objective of this study is to determine the maximum tolerated dose of lucinactant 
as determined by the safety evaluations obtained within each dosing group (Section 3.3), and to 
assess the feasibility of evaluating physiological pulmonary function parameters as a measure of 
improvement in clinical status (Section 3.4) in preterm infants 26 to 28 completed weeks PMA 
who are receiving nCPAP for RDS, compared with preterm infants receiving nCPAP alone. 
3.3 
Safety Evaluations 
The following measures are to be documented in the electronic case report form (eCRF) in 
accordance with timings outlined in Appendix 2 and Section 7: 
1. Survival (date and time of death if applicable) 

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2. AEs, including ADEs  
• To include: nasal excoriations by examination ( ≥ 24 hours to ≤ 7 days following 
aerosol exposure) and evidence of lung air leak (especially pneumothorax) 
(Section 7.1.8) 
• To be categorized as a peri-dosing events if onset of event is  ≤ 2 hours from the 
time of initiating administration of lucinactant for inhalation [Section 9]) 
3. Signs consistent with worsening respiratory status (Section 7.5) 
4. Concomitant medications (Section 7.3) 
5. Use of respiratory support and supplemental oxygen (Section 7.6), to include:  
• Need for endotracheal intubation and mechanical ventilation 
• Need for intermittent positive pressure breaths using inflating pressures above the 
set CPAP pressure administered  manually or mechanically through any patient 
interface 
• nCPAP and fraction of inspired oxygen (FiO2) requirements (Section 5.4.1), 
(Section 7.6.2) 
6. Complications of prematurity (ie, IVH, periventricular leukomalacia [PVL], pulmonary 
hemorrhage, NEC, patent ductus arteriosus [PDA], sepsis, ROP, BPD) 
7. Physical examinations (Section 7.1.6) 
8. Tolerability of lucinactant for inhalation 
9. Incidence leading to withdrawal from study 
10. Incidence of air leak  
11. Assessments of the following:  
a) PCO2 (Section 7.1.5) 
b) Serum electrolyte measurements (Section  7.1.7) 
c) Body weight (Section  7.1.2) 
d) Vital signs (Section 7.1.1) 
e) Gastric liquid volume (Section 7.1.9) 
f) Defecation (Section 7.1.10) 
g) Oxygen (O2) saturation, as determined by pulse oximetry (SpO2) (Section 7.1.3) 
h) Chest radiography, as applicable (Section 7.1.8) 

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3.4 
Exploratory Efficacy Objective 
To demonstrate the ability to measure clinical effect. 
3.4.1 Efficacy Endpoints 
Exploratory efficacy endpoints will be evaluated from the time of lucinactant for inhalation 
initiation until study completion (non-hypothesis testing) and will include the following: 
1. 
Incidence of BPD  
2. 
Rate of survival without BPD at 36 weeks PMA or upon discharge 
3. 
Worsening of respiratory status (Section 7.5) 
4. 
Technical performance of the ADS 
• The efficacy of the device delivery of lucinactant for inhalation will be 
characterized indirectly through the subject’s response to treatment and solicited 
feedback from the PIs and relevant site-based study staff. 
5. 
Physiological parameters (eg, FiO2, PCO2) 

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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will consist of approximately 64 preterm neonates from 26 to 28 completed 
weeks PMA with RDS who are candidates for SRT and nCPAP in a NICU setting. A subject will 
be enrolled at 1 of approximately 25 study sites in the US. 
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; 
2. 
Gestational age 26 to 28 completed weeks PMA; 
3. 
Successful implementation of controlled nCPAP within 90 minutes after birth; 
4. 
Spontaneous breathing; 
5. 
Chest radiograph consistent with RDS; and 
6. 
Within the first 20 hours after birth, requires an nCPAP of 5 to 6 cm H2O to maintain SpO2 
of 88% to 95% with an FiO2 of 0.25 to 0.50 that is clinically indicated for at least 
30 minutes. Transient (<10 minutes) FiO2 excursions below 0.25 or above 0.50 do not reset 
the 30 minute 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 beats/minutes within 5 minutes of birth; 
2. Recurrent episodes of apnea occurring after the initial newborn resuscitation period (ie, 10 
minutes after birth) requiring intermittent positive pressure breaths using inflating pressures 
above the set CPAP pressure 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 nCPAP, 
diagnosed antenatally or immediately after birth; 
5. Other diseases or conditions potentially interfering with cardiopulmonary function (eg, 
hydrops fetalis or congenital infection such as TORCH); 
6. Known or suspected chromosomal abnormality or syndrome; 

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7. Premature rupture of membranes (PROM) > 2 weeks; 
8. Evidence of hemodynamic instability requiring vasopressors or steroids for hemodynamic 
support and/or presumed clinical sepsis; 
9. A need for endotracheal intubation and/or mechanical ventilation; and 
10. Has been administered any the following:  
a) Any investigational agent or exposure to a medical device, 
b) Any other surfactant agent, or 
c) Steroid treatment (steroid exposure before birth is acceptable). 
Note: All subjects must continue to meet entry criteria at the time of initiation of study therapy. 

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5 
STUDY DOSING AND ADMINISTRATION 
Preterm neonates between 26 and 28 completed weeks PMA who are within the first 20 hours 
after birth and who had successful implementation of controlled nCPAP within 90 minutes of 
birth will be considered to be potential subjects. 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 (eg, FiO2, heart rate, O2 saturation) 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. As 
soon as study eligibility has been confirmed and the informed consent is signed, subjects will be 
randomized. All study subjects are to be randomized within 20 hours after birth to either an 
active study arm or a control arm. Subjects randomized to an active arm will receive 1 dose of 
lucinactant for inhalation, initiated within 2 hours of randomization through the investigational 
ADS device administered over 30, 45, 60, or 90 minutes in conjunction with nCPAP support. 
One additional treatment is allowed if subjects meet the repeat dose criterion. Subjects 
randomized to a control arm will be continued on nCPAP alone.  
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. Local NICU procedures should be followed in the event of early discontinuation of 
lucinactant for inhalation to ensure the safety and care of the subject. Any significant clinical 
findings or observations must be documented and communicated to Discovery at the earliest 
time point possible. 
5.1 
Precautions for Aerosol Delivery and Device Usage 
The ADS, disposables, and study drug are investigational materials, and are to be used only for 
lucinactant for inhalation investigational studies, and are not to be used for any other purpose. 
All equipment and supplies are to be returned to Discovery at the end of the study. 
Sites must maintain accurate records and proper storage of all delivered and dispensed study 
drug vials and device components (including the ADPs). Details on study supply accountability 
and storage are provided in Section 5.6 and in the ADS Operator’s Manual.  
The PI or study-trained designee must provide close monitoring of the subject and study device 
during aerosol delivery. 

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5.1.1 Precautions for Aerosol Delivery 
The device and interface used for nCPAP delivery during aerosol delivery must be commercially 
available for nCPAP delivery to neonates. During the nCPAP delivery, subjects must be closely 
monitored for complications related to placement of the patient interface. Assessment must 
include, but not be limited to, evaluations for the following conditions: bleeding, apparent 
obstruction of the nares, occlusion of interface requiring removal and replacement, nasal 
irritation (erythema of nares or septum, inflammation of nares or septum). 
Local NICU policies and procedures for nCPAP delivery are to be used to deliver both the study 
drug and nCPAP, regardless of randomization (ie, active arm or control arm). After connecting 
the aerosol tube to the CPAP adapter and initiating aerosolization, the PI must ensure that the 
desired CPAP is maintained. During the dosing period, the subject’s head should be securely but 
gently immobilized. Pacifiers can be used during dosing periods. 
5.1.2 Stopping Criteria for Aerosol Delivery  
The administration of lucinactant for inhalation may be discontinued at any time in accordance 
with the clinical judgment of the PI or the wishes of the subject’s legal guardian. In accordance 
with local institutional practices, a proven SRT must be made available to subjects demonstrating 
a clinical need following exposure to lucinactant for inhalation. Reasons for discontinuation of 
lucinactant for inhalation may be related to but not limited to the following:  
1. 
Device failure or malfunction, including error codes or treatment interruptions; 
2. 
Pulmonary hemorrhage or other AE/ADE; 
3. 
In the PI’s best medical judgment, initiating or continuing the subject’s exposure to 
lucinactant for inhalation is not in the best interest of the subject’s safety, such as 
hemodynamic instability. (Note: When medical judgment is the sole criteria for 
stopping therapy, a detailed narrative describing the clinical events and observations 
supporting the decision to stop therapy needs to be documented.); 
4. 
Signs of respiratory deterioration as evidenced by an increased respiratory rate or an 
observed increase in respiratory effort (work of breathing) plus at least one of the 
following: 
• An FiO2  ≥ 0.70 or a sustained (≥ 10 minutes) increase from baseline by ≥ 0.30 to 
maintain oxyhemoglobin saturation (SpO2 ≥ 88%),   

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• A PCO2 > 70 mm Hg or a progressive increase in  PCO2 from baseline 
to ≥ 20 mm Hg above baseline and confirmed with a blood gas, 
• Recurring episodes of bradycardia defined as a heart rate of  < 100 bpm for ≥ 20 
seconds, 
• A sustained apneic event, defined as apnea at least 20 seconds in duration and 
meeting at least one of the following: (1) HR < 100 bpm, (2) desaturation (oxygen 
saturation < 80%), (3) requirement for IPP breaths using inflating pressures above 
the set CPAP pressure administered  manually or mechanically through any 
patient interface. 
5.1.3 Precautions for Device Usage 
Before aerosol activation with the ADS, 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, to include any emergent or routine medical needs of the subject during and 
following aerosol delivery with the device.  
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 immediately contact the clinical site monitor and call Discovery’s reporting line 
(855-4ACTADS [855-422-8237]). A representative from Discovery will call with further 
instructions. In such cases, the subject should 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 be 
indicate delivery failure.  
5.1.4 Assessment Parameters for Technical Performance of the Device 
The following parameters will be captured in the eCRF:  
1. Any issues associated with device tubing (eg, ventilator/CPAP tubing detachments, 
aerosol tube detachments, proximal pressure port obstruction, aerosol tube condensate 
obstruction).  
2. Approximate volume (in ml) of liquid in all the traps. 

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3. Aerosol or study drug leakage before the subject interface (eg, disconnect of the 
inspiratory circuitry). 
4. Occurrence of alarm signals before, during, or after dosing that may indicate a device 
malfunction. 
5. Any automatic system shutdowns. 
6. Loss of inspiratory flow to the neonate or inability to maintain nCPAP. 
7. ADS temperature alerts (high or low). 
5.2 
Description of Study Assignment and Aerosol Delivery 
The study treatment, ‘lucinactant for inhalation,’ consists of the investigational drug lucinactant 
and the delivery system ADS. The ADS has two components, the Aerosurf® Delivery Pack 
(ADP) and the Aerosurf® Control Unit (ACU). The rationale for the selected treatment and 
device technology is discussed in Section 2.2. 
5.2.1 Aerosol Delivery 
Preterm neonates between 26 and 28 completed weeks gestational age who are within the first 20 
hours after birth and who had successful implementation of controlled nCPAP within 90 minutes 
of birth will be considered to be potential subjects. 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 (eg, FiO2, heart rate, O2 saturation) 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 may be performed until the informed consent has 
been provided by a legally authorized representative of the subject. As soon as study eligibility 
has been confirmed and the informed consent is signed, subjects will be randomized. All study 
subjects are to be randomized within 20 hours after birth to either an active study arm (consisting 
of lucinactant for inhalation in conjunction with nCPAP) or a control study arm (consisting of 
nCPAP alone).  
Details for study drug preparation are provided in the Aerosurf Investigator’s Brochure and in 
the ADS Operator’s Manual. Briefly, 10 ml of sterile water for injection are added to each of 7 
vials and the vials are gently inverted to mix the suspension. A total of approximately 60 ml of 
solution are drawn up into the provided ADP syringe, which is loaded into the ACU. 
Study treatment is to begin within 2 hours after randomization. For subjects randomized to the 
active study arm, the treatment dose (ie, drug exposure) will be 50, 75, 100, or 150 mg 

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TPL/kg (delivered over 30, 45, 60, or 90 minutes, respectively) in accordance with the subject’s 
dosing group. A repeat dose at the same level is allowed if the repeat dosing criterion is met (see 
Section 5.2.5). 
The carrier gas flow rate for the ADS is 3 L/min. This is consistent with the anticipated peak 
inspiratory flow (PIF) of preterm neonates (between 26 and 28 weeks PMA) and therefore will 
reduce potential aerosol dilution.  
A summary of dose selection for this study is provided in Section 2.2.3. 
5.2.2 Study Assignment; Dosing Groups 
Subjects will be assigned to 1 of 4 dosing groups (Table 5.2-1). 
Table 5.2-1 Study Assignments by Dosing Groups 
Dosing  
Group 
Study Assignment 
Dosing Group I 
Active Arm: (n = 8 subjects) 
Lucinactant for inhalation: 50 mg TPL/kg administered over 30 minutes with nCPAP 
1 repeat dose is allowed if repeat dosing criteria are met 
 
Control Arm: (n = 8 subjects) 
Continuous nCPAP 
Dosing Group II 
Active Arm: (n = 8 subjects) 
Lucinactant for inhalation: 75 mg TPL/kg administered over 45 minutes with nCPAP  
1 repeat dose is allowed if repeat dosing criteria are met 
 
Control Arm: (n = 8 subjects) 
Continuous nCPAP 
Dosing Group III 
Active Arm: (n = 8 subjects) 
Lucinactant for inhalation: 100 mg TPL/kg administered over 60 minutes with nCPAP  
1 repeat dose is allowed if repeat dosing criteria are met 
 
Control Arm: (n = 8 subjects) 
Continuous nCPAP 
Dosing Group IV 
Active Arm: (n = 8 subjects) 
Lucinactant for inhalation: 150 mg TPL/kg administered over 90 minutes with nCPAP  
1 repeat dose is allowed if repeat dosing criteria are met 
 
Control Arm: (n = 8 subjects) 
Continuous nCPAP 
Note: Eligible subjects 26 to 28 weeks PMA will be randomized into either the active or control arm in 
accordance with the dosing group enrolling at the time of subject randomization: 

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5.2.3 Method of Assigning Study Subjects to Dosing Groups 
For each dosing group, preterm neonates who successfully meet all eligibility criteria within the 
enrollment period (20 hours) will be randomly assigned to 1 of 2 study arms (active or control) 
(Section 5.2.2). Subjects will be randomized using centralized allocation by an interactive web 
response system (IWRS). Infants from multiple births will be randomized independently. 
The randomization code list will be generated by Discovery Biometrics personnel and 
transmitted to the IWRS vendor. The code list will use a block size of 4 for each dosing group. 
5.2.4 Sequential Dosing Scheme 
The study dosing will initiate in Dosing Group I (the lowest dose), and continue to Dosing Group 
II after completion of enrollment. Each dosing group will enroll sequentially following 
completed enrollment of the previous dosing group. After all active subjects within each dosing 
group have completed 72 hours, the SRC will review the safety and tolerability of this dose. 
If there appears to be intolerability with a given dose or operational challenges administering a 
dose, the remaining subjects may have the dose decreased to a previously administered dose, 
after consultation with the SRC. 
Further details on the dosing for each dosing group are provided in Section 5.2.2. 
5.2.5 Repeat Dosing 
In order to ensure the safety of repeat dosing, specifically in regards to AEs and electrolyte 
changes (such as sodium and potassium levels), and to ensure subjects with a demonstrated need 
receive treatment, 1 repeat dose will be allowed for all dosing groups. The repeat dose will 
consist of repeating the same dose and will occur between 2 and 24 hours after the initial dose, if 
the repeat dosing criterion is met. The repeat dosing criterion is defined as at least 2 hours, but no 
more than 24 hours, after dosing and the subject must require a sustained need for supplemental 
oxygen at or above the qualifying FiO2 level for study entry (ie, 0.25) for at least 30 minutes to 
maintain SpO2 of 88% to 95%. 
As with the initial dose, the IWRS 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 dose. 

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If, in the opinion of the PI, repeat dosing would compromise the safety of the subject, repeat 
dosing will not occur. 
5.3 
Aerosurf Delivery System 
The ADS creates and controls aerosolized surfactant (lucinactant for inhalation) through 2 
components, the ACU (Section 5.3.1) and the disposable ADP (Section 5.3.2). At the patient 
interface, two external flow sources are combined: humidified air from the CPAP system and 
carrier gas flow from the ADS (Figure 5.3-1). The entire ADS is a device designed for bedside 
use, and is mounted on a wheeled cart for easy transport. 
A complete qualitative risk assessment has been completed to identify and mitigate potential 
safety risks associated with use of the ADS. 

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Figure 5.3-1. Aerosol Delivery System 
 
 
The ADS produces the aerosolized form of lucinactant through heat and pressure created within 
the CAG located within the heater assembly. The ADP is in-line to the ACU, and jointly these 
two components produce, control and monitor the key elements necessary for the production of 
aerosolized surfactant (lucinactant for inhalation). A summary of the key functions each of the 
Aerosurf Control Unit 
Airway 
Connector 
Humidifier & CPAP 
Patient 
Interface 
Aerosurf 
Delivery Pack 
Inspiratory Flow 
Filled Syringe 
Carrier Gas from External Source 
Expiratory Flow 
Heater 
Assembly 
Temperature probe 
Aerosol 
Elbow 
Capillary Aerosol Generator (CAG) 
Syringe 
Pump 
Transition 
Adapter 
Control 
Software 
Condensation 
Trap 

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ADS components (ACU and ADP) contributes to the aerosolization of lucinactant is provided in 
Table 5.3-1. 
Table 5.3-1 Key Function of Aerosurf Control Unit and Aerosurf Delivery Pack 
Key Component 
Aerosurf Control Unit 
Aerosurf Delivery Pack 
Carrier Gas1  
N/A 
Contains the carrier gas tube 
assembly that is connected to an 
external gas source1. 
Heater 
Measures and controls the heater, which 
enables aerosol generation 
Contains the heater assembly, 
placed in line with the Aerosol 
Control Unit to heat lucinactant for 
inhalation. 
Lucinactant  
Contains a chamber with a locking door 
mechanism to accept the filled syringe; 
prevents access to syringe chamber after 
aerosolization is started. 
Includes a 60 ml syringe, which is 
filled to the maximum volume with 
lucinactant for inhalation. 
1 Carrier gas is an external flow source of oxygen and room air blends, at percentages that are in accordance with the study 
protocol, subject safety, and best medical judgment as directed by the PI.  
5.3.1 Aerosurf Control Unit  
The ACU contains a syringe pump mechanism integrated with control electronics and a 
temperature probe. The control electronics consists of embedded hardware and software with a 
touch screen interface that provides sequential instruction for (1) ADS set-up, (2) system 
operation, (3) safety interventions, and (4) temperature control. A cart is provided for use with 
the ACU. Materials and dimensions for the ACU are consistent with similar equipment used in 
critical care environments. 
5.3.2 Aerosurf Delivery Pack 
The ADP is a single-use, disposable pack containing a 60 ml syringe, the tube assembly, and the 
heater assembly. A summary of the ADP functions are provided in Table 5.3-1. 
5.3.2.1 ADP Set-up 
Instructions for the proper set-up and connections of ADP components are provided in the ADS 
Operator’s Manual. Depending upon the dose, 1 or 2 ADPs will be required for each treatment. 
The syringe is filled to maximum volume with the lucinactant suspension and placed in the 
syringe sleeve located in the ACU. To ensure full aerosol delivery, and proper functionality of 

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the device, it is imperative that the syringe is filled to the maximum volume and all air bubbles 
are removed before placement into the device.  
5.3.2.2 ADP Post Delivery Procedures 
The ADP must be disengaged from the ADS and returned to Discovery after completion of 
aerosol delivery (as indicated on the ACU screen). All fluid should be removed from the aerosol 
tubing and fluid traps in accordance with local institutional practices before shipping.  
Instructions on proper removal of the ADP from the ADS are provided in the ADS Operator’s 
Manual. 
Study ADPs are required to be returned to 1 of 3 return facilities in accordance to the following 
categories. 
1. Unused ADPs are shipped to Battelle at the time of site closure or at the request of 
Discovery (clinical site monitors will provide additional information to study sites on 
associated shipping procedures and addresses); 
2. Used ADPs that are not associated device errors are picked-up by a specified vendor 
for destruction; 
3. ADPs associated with device errors are shipped to Battelle, when requested by 
Discovery (further information regarding associated shipping procedures is made 
available to study sites at the time of the request). 
Further information and instructions on ADP shipping and accountability are provided in the 
Study Manual.  
5.4 
Delivery of On-Study Continuous Positive Airway Pressure  
The use of nCPAP will be implemented within 90 minutes of birth. On-site study staff will be 
trained on the use and functionality of the nCPAP device for use during this study. The nCPAP 
device and training will be provided by Discovery or qualified designee. 
The use of nCPAP can be preceded by intermittent positive pressure breaths using inflating 
pressures above the set nCPAP pressure administered manually or mechanically through a non-
invasive patient interface (mask, nasal prongs) for no longer than 10 minutes after birth (eg, 
NeoPuff). 

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All local institutional policies and procedures relevant to the 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 closely monitored for complications related to 
placement of the patient interface (eg, bi-nasal prongs). Assessment must include but not be 
limited to evaluations for the following conditions: bleeding, apparent obstruction of the nares, 
occlusion of interface requiring removal and replacement, nasal irritation (erythema of nares or 
septum, inflammation of nares or septum). 
5.4.1 Set-up of Continuous Positive Airway Pressure System 
The CPAP Operator’s Manual provides details on the proper set-up and operation of the nCPAP 
device. These procedures, in conjunction with local institutional practices, must be followed to 
optimize subject safety, and to ensure consistent, therapeutic pressure that minimizes resistance 
in the artificial and preterm infant airways. 
The essential procedures to further minimize resistance during nCPAP delivery are as follows: 
1. 
Ensure proper placement of the patient interface  
Note: the device and subject interface used for nCPAP delivery during aerosol delivery 
must be commercially available and specifically for nCPAP delivery in neonates 
2. 
Insert a gastric tube (open to air) after proper placement of the patient interface has been 
assessed. 
3. 
Maintain the subject’s neck position in a mild extension that is comfortable for the subject 
4. 
Assess the need for nasal and oral airway suctioning and administer as needed  
5.4.1.1 Initial nCPAP Settings 
The initial nCPAP settings will depend on the subject’s clinical condition and may be adjusted in 
accordance with Section 5.4.1.2; however, the following are the recommendations for initial 
nCPAP settings: 
• FiO2 ≥ 0.25 (based on inclusion criteria met; refer to Section 4.2) and < 0.50 (Section 7.6) 
• CPAP = 5 to 6 cm H2O  

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5.4.1.2 Adjustments to nCPAP Settings 
Incremental increases in nCPAP should be made by 1 cm H2O until a maximum nCPAP of 
6 cm H2O is achieved and the following subject parameters are maintained for the duration of 
aerosol administration:  
• 
SpO2 ≥ 88 and ≤ 95% 
• 
FiO2  ≥  0.25 and < 0.50 (Section 7.6) 
• 
PCO2 < 50 mm Hg (Section 7.1.5) 
• If a sustained nCPAP of ≥ 7 cm H2O is necessary to maintain SpO2 88 to 95% or 
PCO2 > 50 mm Hg, then the subject should be evaluated for clinical signs and 
symptoms consistent with worsening of respiratory status (Section 7.5). 
5.4.1.3 Documentation of nCPAP Settings 
nCPAP settings must be documented in the study eCRF at the time of initial randomization and 
at the following timeframes: 1, 3 ( 15 minutes), 6, 12 ( 1 hour), 18, 24, 36, and 48 hours ( 2 
hours) after randomization.  
5.5 
Identity of Investigational Drug Product 
The complete list of ingredients for the drug product is shown in Table 5.5-1. 
5.5.1 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 
dipalmitoyl-phosphatidylcholine (DPPC) and palmitoyloleoyl-phosphatidylglycerol, sodium salt 
(POPG, Na), and the fatty acid palmitic acid (PA). Immediately before dosing, the lyophilized 
product is reconstituted with sterile water for injection at a concentration of 30 mg TPL/ml.  
Table 5.5-1. 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/ml 

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5.5.1.1 Aerosol characteristics 
The aerosol is generated at a formulation flow rate of approximately 20 L/second. The mass 
median aerodynamic diameter (MMAD) of the aerosol is below 5.0 m. The ventilated gas that 
carries the aerosol to the subject has a nominal flow rate of 3 L/minute. A disposable fluid trap 
collects the condensed aerosol that is not transferred to the ventilation circuit (Figure 5.3-1). The 
specification for the aerosol temperature at the patient interface is 25C to 38C. 
5.5.2 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 required FDA caution 
statements, to insure that users are aware that the product is limited by federal law to 
investigational use only.  
5.6 
Clinical Study Supplies at the Clinical Study Site 
5.6.1 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.  
5.6.2 Ancillary Supplies 
Ancillary supplies (eg, CPAP system, nasal prongs, 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. 
5.6.3 Dispensing 
Study supplies (study drug, ADP, and related study equipment) will be dispensed in accordance 
with the subject’s randomized dosing group (Section 5.2.2). The NICU pharmacist or designated 
study personal 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 

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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. 
5.6.4 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. 
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. 
5.7 
Study Compliance 
Study compliance will be based on the actual delivery time of lucinactant for inhalation in 
comparison to the subject’s randomized aerosolization time. Aerosolization time will be tracked 
by the ACU, which will display a continual count of lucinactant exposure time throughout the 
aerosol delivery period. The length of lucinactant exposure time (as observed through aerosol 
delivery and ACU display) will be documented in the study eCRF. The ACU will also display an 
interface to allow for emergent aerosol discontinuation. PIs are to discontinue aerosol delivery if 
a potential safety risk to the subject is identified at any point during the aerosol delivery period. 
The number of subjects randomized but not treated, and the number of subjects prematurely 
discontinued from aerosol delivery will be recorded in the eCRF and summarized in the study 
report. 
No diaries will be required since lucinactant for inhalation will be administered at the clinical 
site.  
5.8 
Study Drug and Device Accountability 
It is the responsibility of the PI and trained 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.  

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5.8.1 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 study 
aerosol delivery.  
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.  
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 
SAFETY REVIEW COMMITTEE 
The purpose of the SRC is to evaluate the degree of risk involved in study subject participation 
within each dosing group 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 the time all active subjects in each 
dose group completes assessments and procedures through 72 hours.  
The SRC 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 SRC 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).  
Following a thorough independent review of available study data, the SRC will provide timely 
recommendations to the Discovery study team. Recommendations may consist of, but not be 
limited to the following:  
• Continue enrollment at the next higher dose level, which includes a potential repeat dose,  
• Suspend or close study enrollment  
At each review, the control subjects will be summarized in aggregate. 
An 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, if more than 2 subjects per dosing group experience an SAE related to dosing, 
enrollment and dosing will be suspended and further enrollment and dosing will proceed only if 
and when the SRC deems it to be appropriate. 
In addition, if a treated subject dies during the first 12 hours following and related to lucinactant 
for inhalation administration, then an unscheduled meeting of the SRC will be called. Safety and 

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tolerability data will be presented to the SRC for their immediate review. Study enrollment will 
be suspended until such time that a safety assessment has been completed. Enrollment and 
dosing will proceed only if and when the SRC deems it to be appropriate. If the SRC deems it to 
be appropriate to re-initiate enrollment after an enrollment hold, IRB approvals will be obtained 
before the re-initiation of subject screening and enrollment activities. 

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7 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is outlined in tabular form in Appendix 2.The required testing procedures 
for this protocol are the same as the procedures in Protocol 03-CL-1201. 
Before conducting any study-related activities, a written informed consent form (ICF) and the 
Health Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject’s legally authorized guardian (Section 12.2). 
7.1 
Clinical Assessments 
The following clinical assessments must be appropriately documented in the study eCRF. In 
addition, any clinical findings that are consistent with an AE must be documented as such in the 
eCRF (Section 9).  
In addition to the clinical assessments outlined below, PIs are to provide continual clinical 
assessment and monitoring during the active delivery of lucinactant for inhalation. If at any point 
during the delivery of lucinactant for inhalation, a potential safety risk to the subject is identified, 
aerosol delivery must be discontinued by activating the ACU ‘stop treatment’ interface. Any 
significant clinical findings or observations must be documented and communicated to 
Discovery at the earliest time point possible.  
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 from the 
time of randomization: 1, 3 ( 15 minutes), 6, 12 ( 1 hour), 18, 24, 36, and 48 hours ( 2 hours) 
post-randomization. 
Subjects randomized to the active study arm will have additional vital signs (respiratory rate and 
heart rate) documented every 5 minutes ( 2 minutes) during the administration of lucinactant for 
inhalation for Dosing Group I and II. For Dosing Groups III and IV, vital signs will be 
documented every 15 minutes ( 5 minutes) after randomization.  
For all dosing groups, subjects randomized to the nCPAP only arm will have additional vital 
signs (respiratory rate and heart rate) documented 15 minutes ( 5 minutes) after randomization. 

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For all randomized subjects, daily vital sign assessments (body temperature, respiratory rate, and 
heart rate) must be performed at 0800 hours ( 2 hours) from Study Day 3 to the completion of 
Study Day 7. 
Sustained heart rate < 100  bpm for ≥ 20 seconds must be noted as an AE of bradycardia in the 
study eCRF. 
In this study, a sustained apnea event is defined as lasting ≥ 20  seconds and is coincident with at 
least one of the following: (1) HR < 100 bpm, (2) desaturation (oxygen saturation < 80%), (3) 
requirement for intermittent positive pressure breaths using inflating pressures above the set 
CPAP pressure administered  manually or mechanically through any patient interface.  
7.1.2 Body Weight 
The first body weight measurement obtained after randomization must be recorded in the study 
eCRF. In addition, birth weight will be documented in the study eCRF as part of the birth 
history.  
7.1.3 Pulse Oximetry 
SpO2 will be monitored continuously from the time of randomization until completion of Study 
Day 7. 
Sustained SpO2 < 80% for ≥ 20 seconds must be recorded as an AE in the study eCRF. 
7.1.4 FiO2 
FiO2 values will be recorded at different times throughout the study. At a minimum, FiO2 values 
are: 1) recorded at specified time points while a subject is receiving nCPAP, 2) recorded every 
12 hours when a subject is receiving other types of respiratory support or supplemental oxygen, 
3) recorded every 15 minutes for 3 hours after randomization, and 4) recorded every 6 hours 
from randomization through 72 hours. 
7.1.5 Monitoring of Carbon Dioxide Levels 
PCO2 measurements for subjects in both the active and control groups will be resulted through 
the use of continuous transcutaneous monitor.  
PCO2 monitoring must be initiated following randomization (for subjects randomized to the 
active study arm, monitoring must be initiated at least 30 minutes before the start of ADS 

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delivery) and continue for 72 hours post randomization. The transcutaneous monitor must be 
calibrated for accuracy against blood gas values (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.  
In the eCRF, PCO2 values will be recorded every 15 minutes through 3 hours after 
randomization, and every 6 hours from randomization through 72 hours. 
7.1.6 Physical Examination 
A complete physical examination will be performed by either the PI or designee. The designee 
may be a qualified member of the site-based study staff (such as a nurse practitioner, NICU 
nurse, or physician assistant); physical examinations performed at screening must be reviewed 
and approved by the PI. Any new 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). 
7.1.8 Chest Radiograph 
A chest radiograph for the diagnosis of RDS will be performed as part of the screening 
assessment. 
A chest radiograph will also be required during the first 7 study days for study subjects who meet 
1 or both of the following: (1) non-emergent intubation for any indication (in such instances, all 
efforts must be made to obtain the chest radiograph prior to intubation, if the procedure does not 
delay or compromise the care of the subject); or, (2) worsening of respiratory status in 
accordance to Section 7.5. 
7.1.9 Gastric Liquid Volume 
Gastric liquid volume will be assessed 30 minutes (± 15 minutes) following completion of 
lucinactant for inhalation administration. Enteral feedings are to be held during administration 
and for at least 1 hour following completion of lucinactant for inhalation administration. 

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7.1.10 Defecation 
The number of stools within the first 24 hours following randomization will be recorded in the 
study eCRF. 
7.2 
Medical Information 
Relevant medical information, including maternal-birth history, pertinent respiratory history, 
medical history (from birth to randomization) and information regarding underlying diseases will 
be recorded at screening. 
7.3 
Concomitant Medications 
Concomitant medications required for the general care of the subject are permitted, with the 
exception of investigational agents and investigational medical devices. 
All concomitant medication and concurrent therapies will be documented from birth until the 
time the subject completes the study (36 weeks PMA or discharge) or withdraws (Section 10.2). 
Dose, route, unit, frequency of administration, indication for administration, and dates of 
medication will be captured. 
7.3.1 Use of Additional Surfactant Replacement Therapies 
Following lucinactant for inhalation administration, commercially available SRTs consistent 
with the current standard of care may be administered only in circumstances where it is in the 
best interest of subject’s safety, and in the PI’s best medical judgment.  
Subjects receiving commercially available SRT during study participation will be considered 
treatment failures, and as such, will continue to be followed for safety follow-up until study 
completion. 
The study criteria for worsening of respiratory status are outlined in Section 7.5. 
7.4 
Demographics  
Demographic information (eg, gestational age, sex, race) will be recorded at screening.  
7.5 
Worsening Respiratory Status 
Subjects meeting the criteria of worsening respiratory status (outlined within this section) 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). 

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Refer to Section 7.1.8 for required chest radiograph. 
7.5.1 Worsening Respiratory Status Criteria 
A subject will be categorized as having worsening respiratory status if they meet at least 1 of the 
following criteria: 
1. The need for additional surfactant therapy following exposure to lucinactant for inhalation 
2. A sustained FiO2 > 0.50 for > 30 minutes to maintain an SpO2 > 90% 
3. A PCO2 > 65  mm Hg on ≥ 2 consecutive occasions 
4. Persistent, arterial pH  < 7.20 (if blood gas values are available and obtained for non-study 
related clinical assessment) 
5. Any sustained apneic event defined as ≥ 20  seconds and meeting at least one of the 
following: (a) HR < 100 bpm, (b) desaturation (oxygen saturation < 80%), (c) requirement 
for intermittent positive pressure breaths using inflating pressures above the set CPAP 
pressure administered manually or mechanically through any patient interface 
6. Intubation for any reason (except for elective surgical procedures) 
7. nCPAP > 7 cm H2O 
8. Initiation of intermittent positive pressure breaths using inflating pressures above the set 
CPAP pressure administered manually or mechanically through any patient interface 
9. Death while on study 
10. The study PI determines that the subject has worsening respiratory status based on their 
best clinical judgment. 
7.5.2 Worsening Respiratory Status Categories 
Worsening respiratory status will be categorized as follows: 
• Early worsening : worsening respiratory status occurring  ≤ 72 hours after birth 
• Late worsening: worsening respiratory status occurring > 72 hours and  ≤ 7 days after birth 
7.6 
Respiratory Support and Oxygen Delivery 
Study subjects must be maintained on nCPAP from the time of randomization until they have 
completed delivery of lucinactant for inhalation as outlined in Section 5.4. The management of 
respiratory support (to include nCPAP) and oxygen delivery after the completion of lucinactant 
for inhalation delivery will be at the discretion of the study PI.  

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During nCPAP delivery subjects must be closely monitored for complications related to 
placement of the patient interface (eg, bi-nasal prongs). Assessment must include but not be 
limited to evaluation for the following conditions: bleeding, apparent obstruction of the nares, 
occlusion of interface requiring removal and replacement, nasal irritation (erythema of nares or 
septum, inflammation of nares or septum). Evidence of these conditions should be reported as an 
AE and treated in accordance with local institutional practice.  
FiO2 values (regardless of mode of delivery) will be recorded following randomization and will 
continue for 72 hours post randomization. 
7.6.1 Emergent Respiratory Support 
Emergent endotracheal intubation and mechanical ventilation, in accordance with local 
institutional guidance, must be initiated at any time if deemed necessary for subject safety. In 
such instances, the subject must be evaluated for worsening of respiratory status (Section 7.5.2).  
Any clinical event indicating a need for mechanical ventilation, additional pressure 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.   
7.6.2 Documentation During Primary and Extended Observation Period 
From the time of randomization until completion of Study Day 7 the following must be evaluated 
and documented in the study eCRF:  
1. Mechanical ventilation: date and time of initiation and discontinuation, the mode, mean 
airway pressure, respiratory rate, set tidal volume (if appropriate), and FiO2 
• To be documented every 12 hours ( 1 hour) until mechanical ventilation has 
been discontinued for > 24 hours  
2. Pressure support (to include nCPAP): date and time of initiation and discontinuation, PIP, 
respiratory rate, CPAP, flow rate, and FiO2, as appropriate. 
• Primary Observation Period: document at 1, 3 ( 15 minutes), 6, 12 ( 1 hour), 
18, 24, 36, and 48 hours ( 2 hours) post-randomization 
• Extended Observation Period: document every 12 hours ( 1 hour) until nCPAP 
has been discontinued for > 24 hours 
3. Supplemental oxygen (FiO2 > 21%): date and time of initiation and discontinuation, mode 
of delivery (eg, nasal cannula, oxygen hood), and FiO2, as appropriate. 

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• After the administration of lucinactant for inhalation, FiO2 must be documented 
every 12 hours ( 1 hour) until supplemental oxygen has been discontinued for 
> 24 hours 
4. Intubation: the date and time of intubation for any reason must be documented.  
If respiratory support or oxygen delivery is reinitiated following discontinuation, then parameters 
must again be captured every 12 hours until discontinuation. 
7.6.3 Documentation During Final Observation Period 
From Study Day 8 until the subject completes or withdraws from the study, the following must 
be evaluated and documented in the study eCRF:  
• 
Intubation and mechanical ventilation: date and time of initiation and discontinuation 
• 
Pressure support (to include nCPAP): date and time of initiation and discontinuation 
• 
Supplemental oxygen: date and time of initiation and discontinuation, mode of delivery 
and FiO2 
• 
Intubation: the date and time of intubation for any reason 
7.7 
Criteria for Acute Respiratory Deterioration 
Subjects must be closely monitored for signs and symptoms of acute respiratory deterioration 
throughout the study period. Any clinical signs of acute respiratory deterioration must be treated 
in accordance with local institutional practices and under the best medical judgment of the study 
PI.  
Acute respiratory deterioration must be reported as an AE and, for study purposes, is defined by 
an increased respiratory rate or an observed increase in respiratory effort (work of breathing) 
plus at least one of the following criteria:  
1. An FiO2 ≥ 0.70 or a sustained increase from baseline by ≥ 0.30 to maintain 
oxyhemoglobin saturation  
2. A PCO2 > 70 mm Hg or a progressive increase from baseline to ≥ 20 mm Hg above 
baseline and confirmed with a blood gas 
3. Recurring episodes of bradycardia defined as a heart rate < 100 bpm for ≥ 20 seconds 
4. A sustained apnea event, defined as apnea for at least 20  seconds in duration and meeting 
at least one of the following: (1) HR < 100 bpm, (2) desaturation (oxygen saturation 
< 80%), (3) requirement for intermittent positive pressure breaths using inflating pressures 

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above the set CPAP pressure administered  manually or mechanically through any patient 
interface 
5. Endotracheal intubation for any reason (with the exception of elective surgical procedures) 
6. Initiation of intermittent positive pressure breaths using inflating pressures above the set 
CPAP pressure administered  manually or mechanically through any patient interface 
7. nCPAP > 7 cm H2O 
8. Death while on study 
9. The study PI determines that the subject has worsening respiratory status based on their 
best clinical judgment (Note: When medical judgment is the sole criteria for stopping 
therapy, a detailed narrative describing the clinical events and observations supporting the 
decision to stop therapy needs to be documented.) 

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8 
EVALUATIONS BY VISIT  
All of the following assessments will be performed until the time the subject completes the study 
(36 weeks PMA) or withdraws (Section 10.2). 
A Schedule of Events representing the required testing procedures and the associated timeframe 
to be performed for the duration of the study is outlined in Appendix 2.  
8.1 
Screening Period 
The following information will be obtained for each subject before study enrollment: 
• 
A signed ICF 
• 
Maternal history, to include (Section 7.2):  
a) Rupture of membranes (time relative to birth, type) 
b) Chorioamnionitis (clinical) 
c) Antenatal steroids (number of doses, time relative to birth) 
• 
Birth history, to include (Section 7.2): 
a) Date and time of birth 
b) Mode of delivery (vaginal, C-section) 
c) Single or multiple birth (number) 
d) Apgar score (assessed at 1 and 5 minutes) 
e) Congenital anomaly 
• 
Medical History (Section 7.2) 
• 
Demographics, to include Section 7.4: 
a) Sex 
b) Race 
c) Ethnic origin 
d) Birth weight (grams) (Section 7.1.2) 
e) Gestational age (weeks)  
• 
Initial physical examination findings (Section 7.1.6) 
• 
Inclusion and exclusion criteria (Sections 4.2 and 4.3) 
• 
Chest radiograph  (Section 7.1.8) 
• 
Date and time of initial nCPAP or other type of controlled positive pressure ventilation 

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8.2 
Primary Observation Period  
The following will be documented for each randomized subject during the Primary Observation 
Period of the study (≤ 48 hours after randomization [T0]): 
1. Date and time (T0) of randomization and the study dosing group assignment 
(Section 5.2.2) 
2. The date and time of the initiation and completion of aerosol delivery (Section 5) 
3. All AEs, including ADEs (Section 9) 
Peri-dosing events (defined as an AE with an onset time ≤ 2 hours from the time of 
initiating administration of lucinactant for inhalation) may include but not be limited to:  
• Bradycardia (as noted by HR < 100 bpm for ≥ 20 seconds) (Section 7.1.1) 
• Desaturation (as noted by O2 saturation < 80% for ≥ 20 seconds) (Section 7.1.3) 
• Gagging/regurgitation 
• Apnea (central, obstructive, or combined) (Section 7.1.1) 
• Pallor 
• Complications related to placement of bi-nasal prongs (bleeding, apparent 
obstruction of the nares, bi-nasal prongs occlusion requiring removal and 
replacement, nasal irritation). 
4. Respiratory support and supplemental oxygen as outlined in Section 7.6  
5. nCPAP settings (Section 5.4), (Section 7.6) 
6. FiO2 values (Section 7.1.4) 
7. Signs and symptoms consistent with worsening of respiratory status (Section 7.5) 
8. Vital signs and SpO2 (Section 7.1.1, Section 7.1.3) 
9. PCO2 values (Section 7.1.5) 
10. Chest radiograph, as applicable (Section 7.1.8)  
11. Gastric liquid volume (Section 7.1.9) 
12. Serum electrolytes (Section  7.1.7) 
13. Defecation (initial 24 hours following radomization) (Section 7.1.10) 
14. Concomitant medications (Section 7.3) 
15. Technical performance of the device (Section 5.1.4) 
16. The use of pacifiers 

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8.3 
Extended Observation Period:  
The following assessments are to be performed during the Extended Observation Period of the 
study (> 48 hours to ≤ 7 days after date of randomization). Daily measurements are to be 
obtained as close to 0800 as possible. 
1. Assessment and documentation of respiratory support and supplemental oxygen 
(Section 7.6) 
2. Signs and symptoms consistent with worsening of respiratory status (Section 7.5) 
3. Vital signs (Section 7.1.1) 
4. SpO2 (Section 7.1.3) 
5. Chest radiograph, as applicable (Section 7.1.8)  
6. Incidence of AEs, including ADEs (Section 9) 
7. Concomitant medications (Section 7.3) 
8.4 
Final Visit 
The Final Visit (36 weeks PMA or discharge, whichever comes first) will include the following: 
1. Documentation of respiratory support and supplemental oxygen (Section 7.6) 
2. AEs, including ADEs (Section 9) 
3. Physical examination (including changes from baseline exam) (Section 7.1.6) 
4. Occurrence or presence of the following (as applicable): 
a) IVH (worst grade during hospitalization) 
b) Cystic PVL during hospitalization 
c) PDA and related treatments (surgery or pharmacologics) 
d) NEC (stage and related treatments) 
e) Lung air leaks 
f) Pulmonary hemorrhage 
g) Acquired sepsis 
h) Apnea 
5. Incidence of BPD 
6. The incidence of ROP (Appendix 5) (document onset and severity throughout study 
participation) 
7. Survival (date, time, and cause of death if applicable) 

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8. Date and time of transfer or discharge from the current hospital (if applicable) 
9. Concomitant medications (Section 7.3) 

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9 
ADVERSE EVENT REPORTING  
Information regarding the occurrence of AEs, including ADEs, will be assessed from the time of 
randomization until completion of Final Study Visit.  
For purposes of this study, the following will be considered AEs of special interest if they occur 
within the primary observation period:  
1. Bradycardia: defined as a heart rate < 100 bpm for > 20 seconds 
2. Desaturation: defined as SpO2 < 80% for > 20 seconds 
3. A sustained apnea event defined as lasting ≥ 20  seconds and is coincident with at least 
one of the following: (1) HR < 100 bpm, (2) desaturation (oxygen saturation < 80%), (3) 
requirement for intermittent positive pressure breaths using inflating pressures above the 
set CPAP pressure administered  manually or mechanically through any patient interface.  
4. Air leak, including pneumothorax and pneumomediastinum. 
 
Complications related to placement of bi-nasal prongs 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) 
 
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. 
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). 

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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. 
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  

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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 
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) by telephone, 
regardless of the relationship (or lack thereof) of the SAE to study participation. 
SAEs should be reported to Discovery’s reporting line (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 to Discovery at 
888-527-9512 (USA). 
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 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: 
• 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 
Medical Monitoring 
The names, telephone, and fax numbers of the individuals who should be contacted regarding 
safety issues are listed below. 
FOR MEDICAL QUESTIONS, PLEASE CONTACT THE MEDICAL MONITOR: 
Steven G. Simonson, MD (Medical Monitor) 
Office: (215) 488-9474 
Cell: (267) 454-4931 
email: SSimonson@DiscoveryLabs.com 
or, 
Robert Segal, MD, FACP (Safety Monitor) 
Office: (215) 488-9450 
Cell: (267) 237-7576 
email: RSegal@DiscoveryLabs.com 
FOR SERIOUS ADVERSE EVENTS OR UNANTICIPATED ADVERSE DEVICE EFFECTS, 
PLEASE CONTACT DISCOVERY: 
Reporting Line (24/7/365): (855) 4ACTADS (422-8237) (USA) 
Fax Number: (888) 527-9512 (USA) 
FOR ADDITIONAL ASSISTANCE, PLEASE CONTACT YOUR CRA OR:   
Christine E. Buben (Director, Clinical Operations, Discovery) 
Office: (215) 488-9479 
Cell: (215) 527-5618 
email: CBuben@DiscoveryLabs.com 

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10 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
10.1 
Early Discontinuation of Lucinactant for Inhalation  
The PI or the subject’s legal guardian may discontinue the administration of lucinactant for 
inhalation at any time point before or during the administration of lucinactant for inhalation. 
Discontinuation may be based on but not limited to the criteria outlined in Section 5.1.2.  
1. Device failure or malfunction, including error codes or treatment interruptions 
2. Pulmonary hemorrhage or other AE/ADE 
3. In the PI’s best medical judgment, initiating or continuing the subject’s exposure to 
lucinactant for inhalation is not in the best interest of the subject’s safety. 
4. Signs of respiratory deterioration as evidenced by an increased respiratory rate or an 
observed increase in respiratory effort (work of breathing) plus at least one of the 
following: an FiO2  ≥ 0.70 or a sustained increase from baseline by ≥ 0.30 to maintain 
oxyhemoglobin saturation; a PCO2 > 70 mm Hg or a progressive increase in  PCO2 from 
baseline to ≥ 20 mm Hg above baseline and confirmed with a blood gas; recurring episodes 
of bradycardia defined as a heart rate of  < 100 bpm for ≥ 20 seconds; a sustained apneic 
event, defined as apnea at least 20 seconds in duration and meeting at least one of the 
following: (1) HR < 100 bpm, (2) desaturation (oxygen saturation < 80%), (3) requirement 
for IPP breaths using inflating pressures above the set CPAP pressure administered  
manually or mechanically through any patient interface. 
10.2 
Study Withdrawal 
A subject may withdraw consent (through their legally authorized guardian) at any time without 
prejudice to further care. 
If, at the end of the Final Study Period, 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 following exposure to study aerosol, 
the subject will be considered lost to follow-up. 
10.3 
Early Study Termination 
The study may be terminated prematurely due to safety reasons by the SRC (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. 

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• 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, 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. 
• 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 SRC in order to adequately assess safety in the dose group. 

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11 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or 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. 
When a protocol violation occurs, it will be discussed with the PI. All protocol violations 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  
The protocol, including any amendments and the ICF, will be submitted to an IRB at each 
investigational site for approval to conduct the study. Before the initiation of the study at each 
investigational site, a designee at the site will forward to Discovery a copy of the site’s local IRB 
approval to conduct study 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 
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 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 for approval and subsequent implementation at 
the study site. Protocol modifications (ie, amendments) may only be enacted by Discovery. 
The IRB 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:  

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1. Serious and/or unexpected AEs occurring during the study (reported in accordance with 
the SOPs and policies of the IRB)  
2. Any new study information that may adversely affect subject safety or study conduct  
3. Annual study updates or IRB requests for reassessment of the study  
4. Timely communication of significant actions and related findings from the SRC (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 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, and local regulations. 
The PI will prepare the ICF and HIPAA authorization 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. The ICF generated by the PI must be acceptable to Discovery and 
be approved by the IRB. The PI will send an IRB-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 consent of a subject’s legally authorized guardian, using 
the IRB-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. 
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 

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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 approximately 64 subjects will be enrolled into the study with approximately 
32 subjects randomized to the active surfactant arm. The sample size is based on the number of 
subjects necessary to evaluate the safety and tolerance of lucinactant for inhalation.  
Sample size calculations to demonstrate clinical effect will not be performed as efficacy is an 
exploratory objective.  
A complete outline of the all planned analyses for the study, to include the handling of missing 
data, is provided in Statistical Analysis Plan. 
13.1 
Statistical and Analytical Plans 
The statistical analysis will be based on all randomized subjects in the study, ie, the Intent-to-
Treat (ITT) population. In addition, all evaluable subjects will be analyzed for efficacy signals. 
Evaluable subjects are those in whom complications of prematurity (eg, PDA, IVH, sepsis,) do 
not preclude assessment of efficacy signals (eg, improvement in oxygenation, need for intubation 
and IMV). For all variables, summary statistics will be provided by dosing group, including 
frequency count and percentage for discrete or categorical variables, and mean, standard 
deviation, median, minimum, and maximum for continuous variables. In addition, time-to-event 
variables will be summarized using Kaplan-Meier methodology. Incidence and rates of death, 
BPD, survival without BPD, and worst-stage ROP at 36 weeks PMA will be summarized. 
If no values are recorded in a given eCRF data field, they will be treated as missing and will not 
be imputed. 
13.2 
Interim Analyses 
The SRC will evaluate the tolerability and safety data upon completion of 72 hours for active 
subjects, and all available safety endpoint data for control subjects (Section 6). An independent 
statistician, not a member of the committee, will be responsible for the statistical analysis of the 
data to be reviewed at each meeting. The committee will review the AEs related to dosing 
(Appendix 1) and all AEs and device effects. The SRC will have the authority to recommend 
suspending enrollment or not based on their independent review findings relevant to the safety of 
study subjects. At each review, the control subjects will be summarized in aggregate. 

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13.3 
Sample Size and Randomization 
Sample size is not based on statistical estimation for this phase 2 study. The number of subjects 
randomized (approximately 8 in each active group and approximately 8 in each control group) 
will be considered sufficient to establish safety and tolerability before proceeding to the next higher 
dose. The total of approximately 32 subjects assigned to the active arm and approximately 32 
subjects for the control arm for the entire study is considered sufficient to assess overall safety 
and tolerability. 

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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 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, except as necessary 
for monitoring by the FDA. The investigators must also comply with all applicable privacy 
regulations (eg, HIPPA, EU Data Protection Directive 95/46/EC). 
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement (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 treated with lucinactant for 
inhalation. 
Study personnel at each site will enter data from source documents into the protocol-specific 
eCRF within 5 days of the information becoming available. 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 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, (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.  
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 
scheduled basis throughout the study, in accordance with enrollment at the study site. At these 

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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, the following will be observed: 
• 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 review and approval of the study before study 
initiation at his/her clinical site, and ensure timely updates to the IRB/IEC as 
mandated by local and national regulatory requirements, and to ensure timely 

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communications to Discovery of all IRB/IEC 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. 
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. 
• 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 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 IRBs are 
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 (see Appendix 6), 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. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in 21 CFR 50 and 21 CFR 56. 
4. Report any AEs/SAEs that occur in the course of the study to Discovery or designee, in 
accordance with 21 CFR 312.64. 
5. Ensure that all associates, colleagues, and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments. 
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. 
8. Ensure the local IRB complies with the requirements of 21 CFR 56 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 and Discovery or designee all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
10. Seek IRB 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. 
 
 

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16 REFERENCES 
1. 
Soll RF, Hallman M, Merritt TA. Surfactant in the Prevention and Treatment of 
Respiratory Distress Syndrome. In Boynton B, Carlo W, Jobe A, editors. New Therapies 
for Neonatal Respiratory Failure. Cambridge: Cambridge University Press; 1994. p. 49-
80. 
2. 
Engle W. Surfactant-replacement therapy for respiratory distress in the preterm and term 
neonate. Pediatrics. 2008; 121. 
3. 
Vermont Oxford Network. Expanded database summary. ; 2003. 
4. 
AARC Clinical Practice Guidelines. Application of continuous positive airway pressure to 
neonates via nasal prongs, nasopharyngeal tube, or nasal mask. ; 2004. 
5. 
Lewis JF, Ikegami M, Jobe AH, Absolom D. Physiologic responses and distribution of 
aerosolized surfactant (Surfanta) in a nonuniform pattern of lung injury. Am Rev Respir 
Dis. 1993; 147: p. 1364-1370. 
6. 
Gaon P, Lee S, Hannan S, Ingram D, Milner AD. Assessment of effect of nasal 
continuous positive pressure on laryngeal opening using fibre optic laryngoscopy. Arch 
Dis Child Fetal Neonatal Ed. 1999; 80(3): p. F230-F232. 
7. 
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). 
8. 
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. 
9. 
Arroe M, Pedersen-Bjergaard L, Albertsen P, Bode S, Greisen G, Jonsbo F, et al. 
Inhalation of aerosolized surfactant (Exosurf) to neonates treated with nasal continuous 
positive airway pressure. Prenat Neonat Med. 1998; 3: p. 346-352. 
10. 
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 
Paediatrica. 2000; 89(4): p. 460-464. 
11. 
Finer N, Merritt T, Bernstein G, Job L, Mazela J, Liu G. A multicenter pilot study of 
Aerosurf delivered via nasal continuous positive airway pressure (nCPAP) to prevent 
respiratory distress syndrome in preterm neonates. Paper presented at: Pediatric Academic 
Societies' Annual Meeting. 2006. 
12. 
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 of care 
for treatment of meconium aspiration syndrome. Pediatrics. 2002; 109(6): p. 1081-1087. 

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13. 
Wiswell TE, Smith RM, Katz LB, Mastroianni L, Wong DY, Willms D, et al. 
Bronchopulmonary segmental lavage with Surfaxin (KL4-surfactant) for acute respiratory 
distress syndrome. Am J Respir Crit Care Med. 1999; 160(4): p. 1188-1195. 
14. 
Bide RS, Armour S, Yee E. Allometric respiration/body mass data for animals to be used 
for estimates of inhalation toxicity to young adult humans. J Appl Tox. 2000; 20: p. 273-
290. 
15. 
Bhutani VK, Sivieri EM. Pulmonary function and graphics. In Goldsmith JP, Karotkin 
EH, editors. Assisted Ventilation of the Neonate. 4th ed.: Saunders; 2003. 
16. 
Soll RF, Sinclair JC, Bracken MB. Meta-analysis of surfactant trials: the effect of 
prophylactic surfactant vs surfactant treatment of established RDS. Pediatr Res. 1993; 33: 
p. 276A. 
17. 
Charnon A, Taeusch HW, Fitzgibbon C, Smith GB, Treves ST, Phelps D. Factors 
associated with surfactant treatment response in infants with severe respiratory distress 
syndrome. Pediatrics. 1989; 83: p. 348-354. 
18. 
Fenton T. A new growth chart for preterm babies: Babson and Benda's chart updated with 
recent data and new format. BMC Pediatrics. 2003;: p. 13. 
19. 
Sun Pharmaceuticals Industries, Ltd. Caffeine Citrate for Injection.. 
 
 

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Appendix 1 
Protocol Definitions 
Definitions 
Aerosol, study 
Output of ADS device (eg, aerosolized lucinactant) 
Aerosol, time 
Length of time subject is exposed to aerosolized lucinactant 
AEs related to dosing 
1. Bradycardia: heart rate < 100 bpm for > 20 seconds 
2. Desaturation: SpO2 < 80% for > 20seconds 
3. Apnea: for purposes of this study a sustained apnea event 
is defined as lasting ≥ 20 seconds and is coincident with 
at least one of the following: (1) HR < 100 bpm, (2) 
desaturation (oxygen saturation < 80%), (3) requirement 
for intermittent positive pressure breaths using inflating 
pressures above the set CPAP pressure administered  
manually or mechanically through any patient interface  
4. Complications related to placement of bi-nasal prongs: 
a) bleeding 
b) apparent obstruction of the nares  
c) occlusion of the interface requiring removal and 
replacement 
d) nasal irritation (erythema of nares or septum, 
inflammation of nares or septum) 
 
Air leak, lung 
Chest radiographic evidence of air leak (pneumothorax, 
pulmonary interstitial emphysema, pneumomediastinum, 
pneumopericardium, subcutaneous emphysema) resulting 
from lung parenchymal disease. 
Arm, active 
The study subpopulation that is determined through 
randomization to be administered lucinactant for inhalation in 
addition to nCPAP 
Arm, control 
The study subpopulation that is determined through 
randomization to be administered nCPAP alone 
Capillary aerosol generator 
(CAG) 
A technology designed to produce high volume, low-velocity 
aerosolized lucinactant for intra-pulmonary delivery.  
Final Visit 
The concluding study visit to occur at 36 weeks PMA or at 
the time of discharge or withdrawal (whichever comes first).  
Gestational age 
Best obstetrical estimate or ultrasound. 

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Definitions 
Intraventricular hemorrhage 
(IVH) 
Detected by cranial ultrasound. See Appendix 3. 
Lucinactant for inhalation 
The active investigational agent, lyophilized lucinactant, in 
combination with the investigational delivery device, 
Aerosurf Delivery System  
nCPAP settings 
(recommended as initial 
settings) 
CPAP = 5-6 cm H2O to obtain appropriate SpO2, defined as: 
• SpO2 ≥ 88% and ≤ 95% 
•  FiO2 ≥ 0.30 (based on inclusion criteria met; refer to 
Section 4.2) and < 0.50 
Necrotizing enterocolitis 
(NEC) 
Using the grading scale of Bell, et al. (Appendix 4). 
NIPPV 
Nasal Intermittent Positive Pressure Ventilation includes all 
forms of nasal ventilation; bi-level, synchronized, or 
continuous.  NIPPV cannot be used to qualify the infant or be 
used during aerosol treatment.   
Oxygen, off supplemental 
Neonates who do not require any form of supplemental 
oxygen for > 24 hours. Neonates requiring oxygen only 
during feeding are considered off supplemental oxygen. 
Oxygen, other delivery modes 
Includes all modes of non-pressure support (nasal cannula, 
oxygen hood, etc.) 
Oxygen, supplemental  
Any requirement for additional oxygen (FiO2 > 0.21). 
Period, extended 
observational  
The study timeframe occurring > 48 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 ≤ 48 hours from 
randomization  
Periventricular leukomalacia 
(PVL) 
The presence of one or more echolucent cysts in and around 
the cerebral ventricles noted on cranial ultrasounds. This is 
not the early presence of bright echogenic areas (known as 
“flares” or periventricular “echodensities”). 
Physical exam 
Includes the following organ systems: cardiac, respiratory, 
abdomen, genitalia and perineum, skin, extremities, head, 
neck and mouth, and neurological. 
Pressure support 
Includes all modes of pressure support (IMV/SIMV, AC, 
HFV, CPAP, etc.) 

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Definitions 
Pulmonary hemorrhage 
The presence of bright red blood in a tracheal aspirate 
deemed not to be the result of tracheal trauma, associated 
with deterioration in the subject’s condition and a change in 
chest radiographs. 
Study dosing 
The randomized to receive 1 dose of lucinactant for 
inhalation through an investigational ADU device for either 
30 or 45 minutes in conjunction with the protocol required 
nCPAP support. 
Worsening of respiratory 
status  
A subject will be categorized as having worsening respiratory 
status if they meet at least 1 of the following criteria: (1) need 
for additional surfactant therapy following exposure to 
lucinactant for inhalation; (2) a sustained FiO2 > 0.50 for > 30 
minutes to maintain an oxygen saturation (SpO2) > 90%; (3) a 
PCO2 > 65 mm Hg on ≥ 2 consecutive observations; (4) 
persistent, arterial pH  < 7.20 (if blood gas values are available 
and obtained for non-study related clinical assessment); (5) 
any sustained apneic event, defined as ≥ 20 seconds and 
meeting at least one of the following: (a) 
HR < 100 beats per minute (bpm), (b) desaturation (oxygen 
saturation < 80%), (c) requirement for intermittent positive 
pressure breaths using inflating pressures above the set CPAP 
pressure administered  manually or mechanically through any 
patient interface; (6) intubation for any reason (except for 
elective surgical procedures); (7) nCPAP > 7 cm H2O; (8) 
initiation of intermittent positive pressure breaths using 
inflating pressures above the set CPAP pressure administered  
manually or mechanically through any patient interface; (9) 
death while on study; or (10) the study PI determines the 
subject to have worsening respiratory status based on their best 
clinical judgment. 
Worsening of respiratory 
status, early 
Worsening occurring ≤ 72 hours after birth 
Worsening of respiratory 
status, late 
Worsening occurring > 72 hours and ≤ 7 days after birth 
 
 

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Appendix 2 
Protocol Event Schedule Summarization  
 
Study Period 
Measurement/Procedure 
Screening 
Primary 
Observation 
Extended 
Observation 
Final Observation 
 
Days 1-2 
Days 3-7 
Day 8 to 
36w PMA 
Final Visit  
(36w PMA) 
Informed Consent/HIPAA 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Maternal/Birth History1 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
Chest Radiograph2 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
Lucinactant for inhalation 
 
X 
 
 
 
Body Weight 
 
X1 
 
 
 
Defecation3 
 
X 
 
 
 
Vital Signs  
 
X4 
X4 
 
 
Monitoring of SpO2 5 
 
X 
X 
 
 
Monitoring of PCO26 
 
X 
 
 
 
Respiratory support and O2 delivery  
X 
X 
X 
X7 
X7 
Serum Electrolytes 
 
X8 
 
 
 
Gastric Liquid Volume9 
 
X 
 
 
 
Peri-Dosing Events10 
 
X 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
Adverse device effects 
 
X 
 
 
 
Concomitant Medication 
 
X 
X 
X 
X 
Note: Day 1 for all subjects is the day of study randomization. 
1 
Birth weight will be captured with birth history and as the first body weight obtained after randomization (Section 7.1.2). 
2 
A chest radiograph prior to intubation (refer to Sections 7.1.8, 7.5), is required if such a procedure does not delay or 
compromise the emergent care of the subject. 
3 
The number of stools occurring within 24 hours from the time of randomization is to be recorded (Section 7.1.10). 
4 
Vital signs will be documented within 15 minutes ( 5 minutes) prior to randomization.  For the active arms, vital signs will be 
documented every 5 minutes ( 2 minutes) during dosing for Dosing Group I and II; every 15 minutes ( 5 minutes) during 
dosing for Dosing Group III and IV. For the control arms, vital signs will be documented at 15 minutes ( 5 minutes) post 
randomization (Section 7.1.1). In addition, record at 1, 3 ( 15 minutes), 6, 12 ( 1 hour), 18, 24, 36 and 48 hours ( 2 hours) 
post randomization and daily at 0800 ( 2 hours) on days 3 to 7 for all randomized subjects.  
5 
Continuous monitoring of oxygen saturations by pulse oximetry will be initiated at the time of randomization and continued 
until completion of Study Day 7 (Section 7.1.3).  
6 
Continuous trancutaneous PCO2 monitoring is to be initiated following randomization and at least 30 minutes prior to the start 
of ADS delivery, and continued for 72 hours post randomization (Section 7.1.5).  
7 
Only the date and time of the initiation and discontinuation of ventilator and pressure support is to be documented in the study 
eCRF from Study Day 8 to Final Study Visit (Section 7.6). 

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8 
Serum electrolytes are to be evaluated 24 hours from randomization ( 6 hours) (Section 7.1.7) 
9 
Gastric liquid volume will be assessed 30 minutes ( 15 minutes) following completion of lucinactant for inhalation 
administration. Enteral feedings are to be held during and ≥ 1 hour following completion of lucinactant for inhalation 
administration (Section 7.1.9). 
10 Peri-dosing events are defined as any adverse event with an onset time ≤ 2 hours from the time of initiating administration of 
lucinactant for inhalation 
 

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Appendix 3 
Papile Scoring System for Intraventricular Hemorrhage (IVH) 
Any method of classifying IVH must describe the location of the hemorrhage and the size of the 
ventricles. Numerous systems have been proposed, but the one developed by Papile is most often 
used. Although it was developed for CT scanning, it has also been applied to ultrasonography. 
Grade I. Subependymal, germinal matrix hemorrhage. 
Grade II. Intraventricular hemorrhage without ventricular dilatation. 
Grade III.  Intraventricular hemorrhage with ventricular dilatation. 
Grade IV.  Intraventricular hemorrhage with parenchymal extension. 
 
 
Gomella, TL et al. Neonatology: Management, Procedures, On-Call Problems, Diseases and 
Drugs, Appleton & Langes, 1994, p.386. 
 

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Appendix 4 
Scoring System of Bell for Necrotizing Enterocolitis (NEC) 
The presentation may vary from a benign gastrointestinal abnormality such as abdominal 
distention (the most frequent early sign, noted in 70% of cases), ileus, and increased volume of 
gastric aspirate or bilious aspirate (two-thirds of cases) to frank signs of shock, blood per rectum, 
peritonitis, and perforation. It can also present with nonspecific signs such as labile temperature, 
apnea, bradycardia, or other signs that would make one suspect sepsis. The clinical syndrome has 
been classified into stages by Bell et al (1978) and modified by Walsh and Kliegman (1986) to 
include systemic, intestinal, and radiographic findings. 
A. Stage I: Suspected NEC 
1. Systemic findings are nonspecific, including apnea, bradycardia, lethargy, and temperature 
instability. 
2. Intestinal findings include gastric residuals and guiac-positive stools. 
3. Radiographic findings are normal or nonspecific. 
 
B. Stage IIA: Mild NEC 
1. Systemic findings are similar to Stage 1. 
2. Intestinal findings include prominent-abdominal distention with or without tenderness, absent 
bowel sounds, and gross blood in the stools. 
3. Radiographic findings include ileus, with dilated loops with focal areas of pneumatosis 
intestinalis. 
 
C. Stage IIB: Moderate NEC 
1. Systemic findings include mild acidosis and thrombocytopenia. 
2. Intestinal findings include abdominal wall edema, tenderness with or without a palpable mass. 
3. Radiographic findings include extensive pneumatosis and early ascites.  Intrahepatic portal 
venous gas may be present. 
 
D. Stage IIIA: Advanced NEC 
1. Systemic findings include respiratory and metabolic acidosis, assisted ventilation for apnea, 
decreasing blood pressure and urine output, neutropenia, and disseminated intravascular 
coagulation (DIC). 
2. Intestinal findings include spreading edema, erythema, and induration of the abdomen. 

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3. Radiographic findings include prominent ascites and possibly persistent sentinel loops with no 
perforation. 
 
E. Stage IIIB: Advanced NEC 
1. Systemic findings reveal deteriorating vital signs and laboratory indices, shock syndrome, and 
electrolyte imbalance. 
2. Intestinal and radiographic findings reveal evidence of perforation. 
 
 
 
Gomella, TL, et al. Neonatology: Management, Procedures, On-Call Problems, Diseases and 
Drugs, Appleton & Langes, 1994, p.379. 
 

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Appendix 5 
International Classification of Retinopathy of Prematurity (ROP) 
The International Classification of ROP is a general agreement on staging of active disease. 
 
Stage I. 
A thin demarcation line develops between the vascularized region of the retina 
and the avascular zone. 
 
Stage II. 
This line develops into a ridge protruding into the vitreous, in which there is 
histologic evidence for an arteriovenous shunt. 
 
Stage III. 
Extraretinal fibrovascular proliferation occurs with the ridge.  Neovascular tufts 
may be found just posterior to the ridge.  
 
Stage IV. 
Fibrosis and scarring occur as the neovascularization extends into the vitreous. 
Traction occurs on the retina, resulting in retinal detachment. 
 
Plus disease 
Noted when vessels posterior to the ridge become dilated and tortuous (eg, stage 
III+) 
 
 
 
Gomella, TL, et al. Neonatology: Management, Procedures, On-Call Problems, Diseases and 
Drugs, Appleton & Langes, 1994, p.438. 
 

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Appendix 6 
Investigator Agreement Form 
Study Title: 
A Multicenter, Randomized, Open-Label, Controlled Trial to Assess the 
Safety and Tolerability of Lucinactant for Inhalation in Preterm Neonates 
26 to 28 Weeks PMA 
Study Number: 
03-CL-1401 
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 or 
Research Ethics Board and Discovery Laboratories, Inc. (Discovery) and will fulfill all 
responsibilities for submitting pertinent information to the IRB/REB. 
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: __________________