Clinical trial NCT03969992
Conditions: Respiratory Distress Syndrome in Premature Infant
Keywords: Respiratory Distress Syndrome BPD surfactant Preterm Infant
Sponsor: Aerogen Pharma Limited
Start date: 2020-03-04; Completion date: 2024-08-05
Enrollment: 261 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this two-part Phase 2 study is to assess the safety, tolerability and efficacy of aerosolized SF-RI 1 (AeroFact) when delivered via nCPAP at two different doses.

Detailed description:
Part I Primary Objective To determine an optimal dose of AeroFact administered by nasal continuous positive airway pressure (nCPAP) versus stand of care in reducing the rate of intubation/cannulation and bolus surfactant instillation in the first 7 days after birth.

Part II Primary Objective To evaluate pulmonary outcomes and respiratory utilization at 3, 6, 9, and 12 months post-menstrual age (PMA)

Arms: arm 1: Standard of Care (nasal continuous positive airway pressure-nCPAP) with instilled bolus surfactant when medically necessary arm 2: AeroFact-low dose SF-RI 1 arm 3: AeroFact-high dose SF-RI 1
Interventions: intervention 1: AeroFact intervention 2: nCPAP
Intervention descriptions: intervention 1: Aerosolized SF-RI 1 intervention 2: nCPAP (nasal continuous positive airway pressure) alone

Protocol documents:
Prot_SAP_000.pdf: 
Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
Confidential: APC-AF-CLN-002 Amendment 8- 09 Mar2022 
1
   
 
PROTOCOL TITLE 
A Partially-Blind, Randomized, Controlled, Parallel-Group Dose Ranging Study to 
Determine the Efficacy, Safety and Tolerability of AeroFact
TM (SF-RI 1 surfactant 
for inhalation combined with a dedicated drug delivery system) in Preterm Infants at 
Risk of Worsening Respiratory Distress Syndrome 
 
PROTOCOL NUMBER 
 
AMENDMENT 
NUMBER 
APC-AF-CLN-002 
 
Amendment 8 
INVESTIGATIONAL 
PRODUCT 
 
Study IND 
AeroFactTM (SF-RI 1 surfactant for inhalation combined with a dedicated drug 
delivery system) 
 
132548 
INDICATION 
Respiratory Distress Syndrome 
PHASE 
Phase 2b 
SPONSOR 
Aerogen Pharma  
1660 S Amphlett Boulevard, Suite 360 
San Mateo, CA 94402 
United States 
APPROVAL DATE 
 09 March  2022 
 
GCP STATEMENT 
This study is to be performed in full compliance with International Conference on 
Harmonization (ICH) and all applicable local Good Clinical Practices (GCP) and 
regulations.  All required study documentation will be archived as required by 
regulatory authorities. 
CONFIDENTIALITY 
STATEMENT 
This document is confidential as it contains proprietary information of Aerogen 
Pharma.  Any viewing or disclosure of such information that is not authorized in 
writing by the Aerogen Pharma is strictly prohibited.  Such information may be used 
solely for the purpose of reviewing or performing this study. 


Aerogen Pharma 
Protocol Number  APC-AF-CLN-002 
Confidential: APC-AF-CLN-002 Amendment 8- 09 Mar2022 
2
PROTOCOL APPROVAL PAGE 
PROTOCOL TITLE 
A Partially-Blind, Randomized, Controlled, Parallel-Group Dose Ranging 
Study to Determine the Efficacy, Safety and Tolerability of AeroFact
TM (SF-
RI 1 surfactant for inhalation combined with a dedicated drug delivery 
system) in Preterm Infants at Risk of Worsening Respiratory Distress 
Syndrome 
PROTOCOL NUMBER 
AMENDMENT 
NUMBER 
APC-AF-CLN-002 
Amendment 8 
APPROVAL DATE 
09 March 2022 
___________________________________________________________________________ 
Judy Doto 
 
 
 
 
 
 
 
Date 
Head of Clinical Operations 
Aerogen Pharma 
___________________________________________________________________________ 
Jeanette Asselin  
Date 
Clinical Director, Neonatal Programs 
Aerogen Pharma 
___________________________________________________________________________ 
Plamena Entcheva-Dimitrov 
 
 
 
 
 
Date 
Head of Regulatory and Medical Affairs 
Aerogen Pharma 
__________________________________________________________________________ 
David Durand, MD 
 
 
 
 
 
              Date 
Chief Medical Officer 
Aerogen Pharma 
___________________________________________________________________________ 
Andy Clark 
 
 
 
 
 
 
 
Date 
Vice President and General Manager 
Aerogen Pharma 
10 Mar 2022
09MAR2022
10Mar2022
10 Mar 2022


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
Confidential: APC-AF-CLN-002 Amendment 8- 09 Mar2022 
3
INVESTIGATOR’S SIGNATURE PAGE 
PROTOCOL TITLE: 
A Partially-Blind, Randomized, Controlled, Parallel-Group Dose Ranging 
Study to Determine the Efficacy, Safety and Tolerability of AeroFact
TM (SF-
RI 1 surfactant for inhalation combined with a dedicated drug delivery 
system) in Preterm Infants at Risk of Worsening Respiratory Distress 
Syndrome 
 
 
PROTOCOL 
NUMBER: 
APC-AF-CLN-002 
 
 
AMENDMENT 
NUMBER  
Amendment 8-09 March 2022 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with ICH-GCPs and all applicable local guidelines. 
 
 
 
Principal Investigator (printed/typed) 
 
 
 ________________________________________________  
____________________ 
  Principal Investigator Signature  
 
 
 
 
Date 
 


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
Confidential: APC-AF-CLN-002 Amendment 8- 09 Mar2022 
4
1 
CLINICAL PROTOCOL SYNOPSIS 
Sponsor 
Aerogen Pharma 
Protocol 
Number 
 
APC-AF-CLN-002 
 
Title of Study 
A Partially-Blind, Randomized, Controlled, Parallel-Group Dose Ranging Study to 
Determine the Efficacy, Safety and Tolerability of AeroFact
TM (SF-RI 1 surfactant 
for inhalation combined with a dedicated drug delivery system) in Preterm Infants 
at Risk of Worsening Respiratory Distress Syndrome 
Study Centers 
Multicenter 
Phase of 
Development 
Phase 2b 
Objectives 
 
Part I 
Primary Objective 
To determine an optimal dose of AeroFact™ administered to preterm infants on nCPAP or 
nIMV vs. nCPAP or nIMV alone in reducing the incidence of intubation/cannulation and 
bolus surfactant instillation in the first 7 days after birth. 
Secondary Objectives 
• 
To compare the time to the first intubation/cannulation across groups for infants 
requiring intubation due to surfactant deficiency  
• 
To compare need for repeat surfactant dosing between groups within 7 days  
• 
To evaluate the safety and tolerability of AeroFact administered by inhalation 
 
Part II 
Additional  Objectives 
• 
To evaluate pulmonary outcomes and respiratory resource utilization at 3, 6, 9, 
and 12 months corrected age 
• 
To evaluate respiratory morbidity per quarter and compare pulmonary morbidity 
across groups 
• 
To evaluate early neurologic Gross Motor Function Score (modified GMFS) 
outcomes at 12 months corrected age 
 
Study Design 
 
This partially-blind, randomized, controlled, parallel-group, dose-ranging study is divided 
into 2 Parts.  Part I includes birth through 40 weeks PMA or  hospital discharge (treatment) 
and Part II discharge through 12 months corrected age  (Follow Up).   
Part I 
Part I is to determine the optimal dose of AeroFact administered to preterm infants on 
nCPAP or nIMV (Active) vs. nCPAP or nIMV alone (Control) in reducing the incidence 
of intubation/cannulation and bolus surfactant instillation in the first 7 days after birth.  261 
preterm infants who are at risk of worsening Respiratory Distress Syndrome (RDS) will be 
enrolled.  The AeroFact dose and dosing strategy determined in this study will be used in 


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
Confidential: APC-AF-CLN-002 Amendment 8- 09 Mar2022 
5
a Phase 3 definitive trial.  Preterm infants who require nCPAP (either by bubble CPAP or 
machine CPAP) or nIMV, and meet the inclusion and no exclusion criteria, will be enrolled 
into the study.  
In the delivery room, infants will be stabilized on nCPAP/nIMV per site clinical guidelines. 
Once the infant has been stabilized, determined as eligible, and parental consent obtained, 
the infant will be block randomized in a 1:1:1 partially-blind fashion to receive one of two 
doses of AeroFact or Control. The randomization will be stratified by site and two 
gestational age groups (26 0/7 to 28 6/7 and 29 0/7 to 31 6/7 weeks). Patients who meet all 
inclusion and no exclusion criteria and are randomized to receive an Active dose, will have 
the initial assigned treatment administered within the first twenty-four hours after birth.  
Patients who are assigned to the Control group will continue to receive nCPAP/nIMV.  If 
twins or triplets are enrolled, only the first sibling will be randomized and subsequent 
siblings will receive the same treatment assignment. 
Active treatment dose allocation will be unblinded to pharmacy and respiratory dosing staff 
or designees.  All other hospital personnel will be blinded.  Randomization will be a two-
step process.  Step 1: a designated member of the study staff will obtain a randomization 
envelope for the appropriate gestational age group, which will randomize the infant to 
either the Active or Control group.  Step 2: active envelopes will be forwarded to the 
unblinded pharmacist or designee, where the active envelope will be opened and allocation 
to the Low or High dose group (108 mg/kg or 216 mg/kg) will be determined.  Active drug 
dose will be calculated and dispensed  according to the pharmacy manual instructions.  
Active drug will be administered according to study protocol.   
For AeroFact dosing, oxygenation, ventilation parameters, and nasal congestion/aspiration 
will be monitored every 15 minutes for duration of dosing or a minimum of two hours by 
a blinded study/staff member.  Dosing tolerance will be evaluated at 4 and 24 hours after 
the start of each AeroFact dose.  Oxygenation, ventilation parameters, nasal 
congestion/aspiration and dosing tolerance will also be collected after each bolus surfactant 
instillation at similar timepoints.  AeroFact tubing/nebulizer and vial will remain in place 
for a minimum of 2 hours. The AeroFact delivery system will be removed from the patient’s 
bedside after dosing has been completed or a minimum of 2 hours.  The patient may be 
transitioned back to their standard nCPAP interface.  A new AeroFact drug delivery circuit 
must be used for each dose administered. 
Infants receiving active drug will continue on nCPAP/nIMV after dose completion.  If 
oxygenation and ventilation requirements increase within 96 hours of birth, AeroFact 
administration may be repeated up to three times for a total of 4 doses over the first 96 
hours after birth.  Re-dosing of AeroFact (same randomized group) will be allowed if the 
RSS is 1.5 to 2.39 and at least two hours have elapsed since the start of the previous dose:  
• 
If FiO2 > 0.23, re-dosing will occur.  
• 
If FiO2 ≤ 0.23, re-dosing is at the discretion of the investigator.   
 SpO2 between 90-95% must be used to meet study eligibility through 96 hours for all study 
groups (Active/Control).   Site-specific SpO2 clinical guidelines may be used after 96 
hours.  Each site must use these guidelines uniformly across treatment groups.  Infants 
randomized to the Control group will be clinically managed until the criteria for treatment 
escalation have been met.  If at any time the criteria for treatment escalation are met in any 
of the three treatment arms, intubation and/or bolus instillation of surfactant may be 
administered at the discretion of the clinical team.   
 
Criteria for treatment escalation for AeroFact or Control groups include any of the 


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
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following: 
• 
Respiratory Severity Score (RSS) ≥ 2.4  
• 
Partial Pressure of Carbon Dioxide (PCO2) > 65 mg Hg and/or pH < 7.20 
• 
Base deficit > 10 mEq/L, on two blood gases 4 hours apart 
• 
nCPAP > 8 cm 
• 
Three severe apneas with bradycardia within six hours requiring escalation of 
support 
• 
Infant’s work of breathing has increased warranting escalating therapy, but infant 
does not meet RSS or other criteria above.   
Study treatment will be discontinued if any of the following occur: 
1. Pneumothorax (requiring chest tube) 
2. Pulmonary hemorrhage (frank bleeding from the lungs that is not related to irritation 
due to suctioning or infection) 
3. Infant shows evidence of pulmonary hypertension requiring iNO  
Each infant will be clinically assessed and evaluated per protocol during their stay in the 
NICU, to 40 weeks PMA or discharge, whichever comes first. 
 
Part II 
Patients who survive to 40 weeks PMA or discharge will be eligible for Part II.  Part II will 
begin at discharge/40 weeks PMA and include telephone Questionnaires performed at 3, 6, 
9 and 12 months corrected age . Evaluation of home environment, respiratory support, 
medical history, modified GMFS and respiratory resource utilization after discharge will 
be collected. (See Appendices for Questionnaires) 
Number/Type of 
Subjects 
Approximately 261 (87 per study arm) subjects will be block randomized in a 1:1:1 
allocation.  This number will be reassessed at the interim analysis. 
Inclusion 
Criteria 
 
Preterm infants are eligible for this study if they meet all of the following criteria: 
1. Parental consent obtained prior to study procedures being performed (pre-natal 
consent is allowed) 
2. 26 0/7 to 31 6/7 weeks of gestational age 
3. Weight < 2000 grams 
4. Weight appropriate for gestational age (AGA 3% to 97%) 
5. Age ≤ twenty-four hours at the initiation of study treatment  
6. RSS (MAP x FiO2) 1.4  – 2.0 on nCPAP or nIMV 
7. Chest radiograph or lung ultrasound [13,14] consistent with a diagnosis of RDS 
Exclusion 
Criteria 
 
Preterm infants are NOT eligible for this study if they meet any of the following criteria: 
1. Apgar score ≤ 5 at five minutes after birth 
2. Need for chest compressions or administration of epinephrine or bicarbonate in the 
delivery room 
3. Premature rupture of membranes (PROM) > 14 days,  
4. Criterion Removed 
5. Base deficit > 10 mEq/L on clinically indicated blood gas at time of randomization 


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
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6. Need for intubation and/or mechanical ventilation prior to enrollment  
7. HFNC and RAM Cannula or are not allowed to determine eligibility 
8. Prior instillation of surfactant 
9. Enrollment in another treatment study with competing outcomes 
10. Active pneumothorax requiring chest tube 
11. Significant congenital anomaly 
12. Known or suspected chromosomal abnormality 
13. Other etiologies of respiratory distress  (e.g. meconium aspiration syndrome, hydrops 
fetalis, toxoplasmosis, rubella, cytomegalovirus, herpes simplex) 
14. Concomitant treatment with inhaled nitric oxide   
15. Suspected PPHN with sustained pre/post SpO2  ductal differences > 10% 
Study 
Treatment(s) 
Infants will be block randomized in a 1:1:1 fashion to Active or Control.  Stratification 
across all groups will be by site and gestational age (26 0/7 to 28 6/7 and 29 0/7 to 31 6/7 
weeks).  Patients randomized to Active drug will receive 1 of 2 nominal dose levels of 
AeroFact (108 mg/kg or 216 mg/kg).   
Up to three additional doses of AeroFact within 96 hours of birth will be allowed if RSS 
is 1.5 to 2.39 and at least two hours have elapsed since the start of the previous dose:  
• 
If FiO2 > 0.23, re-dosing will occur.  
• 
If FiO2 ≤ 0.23, re-dosing is at the discretion of the investigator.   
SpO2 between 90-95% must be used to meet study eligibility through 96 hours for all study 
groups (Active/Control).   Site-specific SpO2 clinical guidelines may be used after 96 
hours.  Each site must use these guidelines uniformly across treatment groups. 
All infants randomized will be clinically managed until the criteria for treatment escalation 
have been met.  
Concomitant 
Therapy 
 
The use of Vitamin A or corticosteroids for BPD prophylaxis must be consistent, 
and appropriate for age, for all enrolled infants within each study site. 
The routine use of corticosteroids for blood pressure (BP) or adrenal support should be 
avoided during the first 96 hours after birth. 
HFNC and RAM Cannula are not permitted in the first 96 hours of life. 
Duration of 
Treatment 
The duration of study participation for each infant is as follows:  
Part I: 
• 
Treatment Period:  96 hours 
• 
Study Period: Through 40 weeks PMA or Discharge from NICU (whichever 
comes first) 
Part II: 
• 
Follow-Up Period:   12 months corrected age   
Criteria for 
Evaluation 
 
Efficacy Assessments 
Part I: 
Primary Efficacy Endpoint 
• 
Proportion of infants requiring intubation/cannulation and bolus surfactant 
instillation in the first 7 days of life. 


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
Confidential: APC-AF-CLN-002 Amendment 8- 09 Mar2022 
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Secondary Efficacy Endpoints 
• 
Time to first intubation/cannulation and bolus surfactant instillation between 
study treatments for first 7 days of life 
• 
Compare the proportion of infants across groups receiving multiple doses of 
surfactant.  
• 
Number of days on mechanical ventilation from the day of birth to 40 weeks PMA 
or discharge.  
• 
Number of days on supplemental oxygen administration from the day of birth to 
40 weeks PMA or discharge 
• 
Survival without bronchopulmonary dysplasia (BPD) at 36 and 40 week PMA. 
(If an infant is discharged from the NICU prior to 36 and/or 40 weeks, a study 
member will call the family to verify the respiratory support status.)  
 
 
Safety and Tolerability Assessments 
Safety and tolerability will be assessed through the monitoring of oxygenation, 
bradycardia, nasal congestion/aspiration, and other adverse events of interest (AEs) to 40 
weeks PMA or discharge. Incidence of comorbidities of prematurity/AE’s will be assessed. 
Tolerance of the AeroFact dosing administration and all doses of bolus surfactant will be 
assessed during and up to 24 hours following dosing.  
Part II: 
Additional Efficacy Endpoints 
• 
Assessment of pulmonary outcomes at 3, 6, 9 and 12 months corrected age   
• 
Length of NICU Stay (LOS)  
• 
Proportion of subjects with any respiratory resource utilization at 3, 6, 9 and 12 
months corrected age  
• 
Respiratory morbidity per quarter till 12 months of corrected age  
• 
Assessment of modified GMFS (early neurologic) at 12 months of corrected age  
 
Criteria for 
Individual 
Patient 
Discontinuation 
Aerogen Pharma, the Investigator or parent (s) may discontinue pre-term infants from the 
study at any time for the following reasons:  
• 
Safety 
• 
Withdrawal of parental consent  
• 
At the discretion of the Investigator 
Statistical 
Considerations 
 
Randomization, Stratification and Sample Size:  
Two hundred and sixty-one (261) subjects (87 in each arm) will be randomized in a 1:1:1 
ratio in order to assure that 246 subjects (82 in each arm) complete the study. The 
randomization will be stratified by site and gestational age.  
Infants requiring treatment escalation in the AeroFact dose groups is estimated to be 20% 
and in the control group is estimated to be 40%, with an odds ratio of 0.375. 
Under the above assumptions, 82 subjects in each treatment group will be required, to meet 
the Type I error rate of 0.05 and 80% statistical power. To accommodate the potential 
dropouts, a 5% dropout rate is included in this sample size calculation. 
Analyses Populations: 


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
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Intent-to-Treat (ITT) population: The Intent-to-Treat (ITT) population is defined as all 
randomized subjects. The ITT population will be the primary population for the primary, 
secondary and additional efficacy analysis.  
Per Protocol (PP) population: The Per Protocol (PP) population is defined as all 
randomized subjects who were not associated with a major protocol violation. The PP 
analysis of primary, secondary and additional endpoints will be considered supportive.  
Safety population: The Safety population is defined as all randomized subjects . This 
population will be used for the analysis of safety parameters. 
 
 Interim 
Analysis 
 
 
 
 
A blinded interim analysis is planned and will be conducted when approximately 60% of 
subjects have been randomized and completed first 7 days of life or early terminated, 
whichever occurs first.  
The main purpose of this interim analysis will be: 
• 
sample size re-assessment to evaluate the final sample size needed to proceed with 
the study based on the control responder rate at interim analysis, and;to evaluate 
the safety of AeroFact on the frequency of adverse events, nasal 
congestion/aspiration, dosing tolerance events, and serious adverse events 
Efficacy 
Analyses 
The primary analyses of the primary, secondary, and additional efficacy endpoints will be 
conducted on the ITT population. The PP population analyses of primary, secondary, and 
additional endpoints will be considered supportive. 
For the efficacy endpoints the data will be summarized and compared according to the 
variable type:  
• 
Continuous data summaries will include:  
o 
Descriptive summary of number of observations, mean, standard 
deviation, median, and minimum and maximum values.   
o 
Analysis of Covariance (ANCOVA) or Mixed Model Repeated 
Measures (MMRM) adjusted for stratification factors for inferential 
statistics.  
• 
Categorical data summaries will include: 
o 
Frequency counts and percentages 
o 
Logit model or Generalized Estimating Equation (GEE) method adjusted 
for stratification factors and clustering of multiple births within a mother 
for inferential statistics 
• 
Time-dependent data: Cox proportional hazards model will be used to analyze 
time dependent data and to depict the time to event data.  
Safety Analyses 
 
Safety will be evaluated on the Safety Population.   
The number and percent of infants experiencing TEAEs, serious adverse events, and 
TEAEs leading to study discontinuation will be summarized for each treatment group by 
Medical Dictionary for Regulatory Affairs (MedDRA) system organ class and/or preferred 
term. Additional summaries will include TEAE severity and relationship to study drug. 
PK Sampling 
Not applicable 
 


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
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Table 1 – Schedule of Assessments and Procedures – Part I and Part II 
Part I 
Part 
II 
 
 
Day 1 
Day 2-4 
Day 5 – 
Day 28 
 
36 Weeks 
PMA 
 
40 Wks 
PMA 
 
Discharge  
3, 6, 9, 12 
Months 
Corrected 
Age 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
Maternal/Infant Medical History 
 
X 
 
 
 
 
 
 
Chest Radiograph or Lung 
Ultrasound 
 
X 
 
 
 
 
 
 
Medication History 
 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Clinical Blood Gas 
Assessments2 
 
X 
X 
 
 
 
 
 
Weight, Recumbent Length, 
Head Circumference3 
 
X 
 
 
 
 
X 
X 
Administer AeroFact or begin 
nCPAP/nIMV alone4-5,  
 
X 
X 
 
 
 
 
 
Oxygenation and Respiratory 
Parameters6-7 
 
X 
X 
X 
X8 
X8 
 
 
Nasal Congestion Assessment9 
 
X 
X 
 
 
 
 
 
Dosing Tolerance10  
 
X 
X 
 
 
 
 
 
AE/Co-Morbidities Monitoring 
 
X 
X 
X 
X 
 
X 
 
Concomitant Medications 
 
X 
X 
X 
X 
 
X 
 
Feeding Status/Pulmonary 
Questionnaire/Audiology/Opthal
mology Reports 
 
 
 
 
 
 
X 
 
Room Air Challenge (RAC) 11 
 
 
 
 
X 
X 
 
 
Follow-Up Telephone 
Questionnaire12 
 
 
 
 
 
 
 
X 
1 Informed consent may be obtained prenatally 
2  Blood gases (pH, PCO2, PO2, HCO3-, base deficit)  will be obtained prior to enrollment and intubation or in relationship to an 
SAE (if clinically obtained). 
3Recumbent Length and Head Circumference at birth and discharge from NICU only  
4AeroFact administered by nCPAP/nIMV or nCPAP/nIMV alone is to be initiated within 24 hours after birth. The anticipated 
duration of each AeroFact dosing is approximately approximately 2 hours. 
5 Re-dosing of AeroFact will be allowed if the RSS to maintain SpO2 between 90 and 95%  is 1.5 to 2.39 and at least two hrs. have 
elapsed since the start of the previous dose.  If RSS is in range and FiO2 >0.23, re-dosing will occur.  If RSS is in range and FiO2 is 
≤0.23, re-dosing may occur at the discretion of the investigator. Up to 3 additional doses of AeroFact within 96 hrs. will be allowed. 
6 Oxygenation and respiratory parameters (FiO2, SpO2 [%], Positive-End Expiratory Pressure [PEEP]/CPAP [cm H2O], Flow Rate 
[L/min], Mean Airway Pressure [Paw in cm H2O], and Respiratory Support Status) will be obtained prior to dosing with AeroFact 


Aerogen Pharma 
 
Protocol Number  APC-AF-CLN-002 
 
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delivery, every 15 minutes from the start of AeroFact dosing (T0 to end of dose or a minimum of 2 hours). These parameters will 
be collected after the start of AeroFact administration or bolus instillation of surfactant for all groups.  
7 Days 1-7 oxygen and resp. parameters will be obtained q 8 hrs., followed by daily from Days 8-28 and daily from 35 to 37 Wks. 
PMA and 39 through 40 Wks. PMA,  Monitoring of O2/resp parameters will occur at the same frequency for all groups.  
8 Respiratory Support Status at 36 & 40 weeks PMA will be assessed by telephone if patient was discharged prior to that timepoint. 
9Nasal congestion/nasal aspiration will be assessed prior to and during each AeroFact dose or bolus instillation of surfactant for all 
groups. 
10 Dosing tolerance completed at 4 and 24 hrs. after start of AeroFact administration or bolus instillation of surfactant for all groups.   
11 RAC will be performed if infant is on nasal cannula ≤ 2 L/min and oxygen or nasal cannula < 4 L/min in room air. 
12 Pulmonary outcomes will be assessed at 3, 6, 9 and 12 months corrected age and Neurologic Outcomes at 12 months corrected 
age. See Appendix II 


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Protocol Number APC-AF-CLN-002 
 
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TABLE OF CONTENTS 
INVESTIGATOR’S SIGNATURE PAGE ....................................................... 3 
1 
CLINICAL PROTOCOL SYNOPSIS............................................... 4 
TABLE OF CONTENTS ........................................................................ 12 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITION OF 
TERMS ................................................................................................... 16 
2 
BACKGROUND AND RATIONALE ............................................. 18 
2.1 
Introduction ................................................................................. 18 
2.2 
AeroFact ....................................................................................... 19 
2.2.1 
Nonclinical Experience .......................................................... 19 
2.2.2 
Clinical Experience ............................................................... 19 
2.2.3 
Summary of Clinical Results .................................................. 21 
2.2.4 
Summary of Pharmacokinetic Results ..................................... 22 
2.2.5 
Summary of Known and Potential Risks of Aerosolized 
Surfactant Administration ................................................................. 22 
2.2.6 
Dosing Rationale for AeroFact ............................................... 22 
2.2.7 
Risk Assessment ................................................................... 23 
3 
STUDY OBJECTIVES ................................................................... 24 
3.1 Part I – Study Objective ................................................................... 24 
3.1.1 
Part I-Primary Objective ........................................................ 24 
3.1.2 
Part I - Secondary Objectives ................................................. 24 
3.2 
Part II – Additional  Objectives ................................................... 24 
4 
OVERALL STUDY DESIGN AND PLAN .................................... 24 
4.1 
Part I ............................................................................................ 24 
4.2 
Part II – Follow-Up ...................................................................... 27 
4.3 
Screening ...................................................................................... 27 
4.4 
Treatment ..................................................................................... 28 
4.4.1 
Part I.................................................................................... 28 
4.4.2 
Part II .................................................................................. 28 
5 
SELECTION AND WITHDRAWAL OF PATIENTS .................... 28 
5.1 
Inclusion Criteria ......................................................................... 28 
5.2 
Exclusion Criteria ........................................................................ 28 
5.3 
Re-Screening of Patients ............................................................. 29 
5.4 
Removal of Patients from Therapy or from the Study ............... 29 
6 
STUDY TREATMENT ................................................................... 29 
6.1 
Identity of Investigational Product ............................................. 29 
6.2 
Storage Conditions ....................................................................... 30 


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Protocol Number APC-AF-CLN-002 
 
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6.3 
Treatments Administered ............................................................ 30 
6.3.1 
Part I.................................................................................... 30 
6.3.2 
Part II – Follow-Up ............................................................... 30 
6.4 
Study Medication Supply, Preparation, and Administration ..... 30 
6.4.1 
Study Medication Supply ....................................................... 30 
6.4.2 
Study Medication Preparation................................................. 31 
6.4.3 
Study Medication Administration ............................................ 31 
6.5 
Drug Delivery System.................................................................. 31 
6.5.1 
Identity of Device ................................................................. 31 
6.5.2 
Aerosol Delivery System Components .................................... 31 
6.5.3 
Device Supply ...................................................................... 33 
6.5.4 
Device Replacement .............................................................. 33 
6.6 
Blinding ........................................................................................ 34 
6.7 
Concomitant Medication/Therapies of Interest .......................... 34 
6.7.1 
Discouraged Concomitant Therapy ......................................... 34 
6.8 
Investigational Product (IP) Supplies and Accountability ......... 35 
7 
EFFICACY ENDPOINTS .............................................................. 36 
7.1 
Primary Efficacy Endpoint – Part I ............................................ 36 
7.2 
Secondary Efficacy Endpoints – Part I ....................................... 36 
7.3 
Additional  Efficacy Endpoints – Part II .................................... 36 
8 
SAFETY ASSESSMENTS ............................................................. 36 
8.1 
General Safety Procedures .......................................................... 37 
8.1.1 
Ventilator/Respiratory Measurements ...................................... 37 
8.1.2 
Weight Measurements ........................................................... 37 
8.1.3 
Nasal Congestion .................................................................. 37 
8.1.4 
Surfactant Dosing Tolerance ................................................... 37 
8.1.5 
Clinical Blood Gas Measurements .......................................... 37 
8.2 
Adverse Events/Co-Morbidities of Prematurity ......................... 37 
8.2.1 
Definitions ........................................................................... 38 
8.2.2 
Grading of Adverse Events ..................................................... 39 
8.2.3 
Relationship to Study Medication/Study Device/Study 
Procedure ........................................................................................ 39 
8.2.4 
AE/Co-Morbidities of Prematurity Action Taken ...................... 39 
8.2.5 
AE/Co-Morbidities of Prematurity Outcomes ........................... 40 
8.2.6 
Serious Adverse Events (SAEs), Treatment Emergent Adverse 
Events (TEAE), and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) ........................................................................ 40 
8.2.7 
Reporting for SAEs ............................................................... 41 
9 
PHARMACOKINETIC ASSESSMENTS ...................................... 41 
10 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ............ 42 
10.1 
Part I ............................................................................................ 42 
10.1.1 Consenting .......................................................................... 42 


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10.1.2 Screening (Assessment for Eligibility) ................................... 42 
10.1.3 Study Enrollment ................................................................. 43 
10.1.4 Study Conduct ..................................................................... 43 
10.1.5 Neonatal Intensive Care Unit (NICU) .................................... 44 
10.2 
Part II – Follow-Up ...................................................................... 46 
10.2.1 Follow-Up Questionnaires .................................................... 46 
11 
DATA QUALITY ASSURANCE..................................................... 46 
11.1 
Data Collection ............................................................................. 46 
11.2 
Clinical Data Management ......................................................... 46 
11.3 
Database Quality Assurance ....................................................... 46 
12 
STATISTICAL CONSIDERATIONS ............................................. 46 
12.1 
Treatment Groups ........................................................................ 47 
12.2 
Description of Study Endpoints .................................................. 47 
12.2.1 Primary Efficacy Endpoint – Part I ........................................ 47 
12.2.2 Secondary Efficacy Endpoints – Part I ................................... 47 
12.2.3 Additional Efficacy Endpoints – Part II .................................. 47 
12.2.4 Safety and Tolerability Assessments ...................................... 47 
12.3 
Sample Size Determination and Rationale................................. 48 
12.4 
Randomization ............................................................................. 48 
12.5 
Stratification ................................................................................ 49 
12.6 
Blinding and prevention of Bias .................................................. 49 
12.7 
Interim Analysis (IA) ................................................................... 49 
12.8 
General Statistical Considerations ............................................. 49 
12.9 
Analysis Populations ................................................................... 50 
12.9.1 Intent-to-Treat (ITT) population ............................................ 50 
12.9.2 Per Protocol (PP) Population ................................................. 50 
12.9.3 Safety Population ................................................................ 50 
12.10 
Covariates .......................................................................... 50 
12.11 
Adjustment due to Multiple Comparisons ....................... 50 
12.12 
Statistical Methods ........................................................... 50 
12.12.1 Subject Disposition ............................................................ 50 
12.12.2 Demographics and baseline characteristics analysis ............... 51 
12.12.3 Concomitant Medications/Therapies of Interest ..................... 51 
12.13 
Efficacy Analyses............................................................... 51 
12.14 
Safety Analyses ................................................................. 51 
12.14.1 Adverse Events .................................................................. 51 
12.14.2 Clinical Laboratory Data .................................................... 52 
12.14.3 Other Safety Data .............................................................. 52 
12.15 
Extent of Exposure ............................................................ 52 
12.15.1 Adverse Events .................................................................. 52 


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12.16 
The Procedure for Revising the Analysis Plan ................ 52 
12.17 
Data Safety Monitoring Board ......................................... 52 
13 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS ..... 53 
13.1 
Ethics ............................................................................................ 53 
13.1.1 Institutional Review Boards/Independent Ethics Committees ... 53 
13.1.2 Regulatory Notification ........................................................ 53 
13.1.3 Ethical Conduct of the Study................................................. 53 
13.1.4 Patient Information and Informed Consent ............................. 54 
13.2 
Administrative Procedures .......................................................... 54 
13.2.1 Changes to the Protocol ........................................................ 54 
13.2.2 Adherence to the Protocol ..................................................... 55 
13.2.3 Monitoring Procedures ......................................................... 55 
13.2.4 Recording of Data ................................................................ 56 
13.2.5 Quality Assurance and Quality Control .................................. 56 
13.2.6 Retention of Records ............................................................ 56 
13.2.7 Auditing Procedures and Inspection ....................................... 56 
13.2.8 Handling of Study Investigational Product ............................. 57 
13.2.9 Publication of Results .......................................................... 57 
13.2.10 Disclosure and Confidentiality ............................................ 57 
13.2.11 Discontinuation of Study .................................................... 57 
13.2.12 Patient Insurance and Indemnity .......................................... 58 
14 
REFERENCES ............................................................................... 59 
15 
APPENDIX I- PART I DISCHARGE BREATHING 
QUESTIONNAIRE ................................................................................ 61 
16 
APPENDIX II – PART II QUESTIONNAIRE .............................. 63 
 


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LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
AE 
Adverse Event 
AF 
AeroFact 
AGA 
Appropriate for Gestational Age 
APC 
Aerogen Pharma Corporation 
BiPAP 
Bilevel Positive Airway Pressure 
BP 
Blood Pressure 
BPD 
Bronchopulmonary Dysplasia 
CFR 
Code of Federal Regulations 
CLN 
Clinical 
CMV 
Corrected Age 
Continuous Mandatory Ventilation 
Chronological Age - Weeks Premature  
CPAP 
Continuous Positive Airway Pressure 
CRA 
Clinical Research Associate 
CRF 
Case Report Form  
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
Cystic PVL 
Cystic Periventricular Leukomalacia 
DSMB 
Data Safety Monitoring Board 
ETT 
Endotracheal Tube 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCP 
Good Clinical Practice 
GMFS 
Gross Motor Function Score (Modified) 
HFJV 
High Frequency Jet Ventilation 
HFNC 
High Flow Nasal Cannula 
HFOV 
High Frequency Oscillatory Ventilation 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
ITT 
Independent Ethics Committee 
Intention to Treat 
IRB 
Institutional Review Board 
IVH 
IP 
Intraventricular Hemorrhage 
Investigational Product 
kg 
Kilogram 
LOS 
Length of Stay 
MAP 
Mean airway pressure 


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Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
Minute 
MOP 
Manual of Procedures 
NC 
Nasal Cannula 
nCPAP 
Nasal Continuous Positive Airway Pressure 
NEC 
Necrotizing Enterocolitis 
NICU 
Neonatal Intensive Care Unit 
NIH 
National Institutes of Health 
nIMV 
Nasal Intermittent Mandatory Ventilation 
O2 
Oxygen 
OTC 
Over-the-Counter 
PCO2 
Partial Pressure of Carbon Dioxide 
PO2 
Partial Pressure of Oxygen 
Paw 
Mean Airway Pressure 
PDA 
Patent Ductus Arteriosus 
PEEP 
Positive-End Expiratory Pressure 
PHT 
Pulmonary Hypertension 
PIE 
Pulmonary Interstitial Emphysema 
PIP 
Peak Inspiratory Pressure 
PMA 
Postmenstrual Age  
PPP 
Per Protocol Population 
PPHN 
Persistent Pulmonary Hypertension in the Neonate 
PROM 
Premature Rupture of Membranes 
RAC 
Room Air Challenge 
RDS 
Respiration Sensor 
Respiratory Distress Syndrome 
aka Breath Sensor 
ROP 
Retinopathy of Prematurity 
RR 
Respiration Rate 
RSS 
Respiratory Severity Score = CPAP or MAP (cm H20) x Fi02  
SAE 
Serious Adverse Event 
SE 
Standard Error 
SOP 
Standard Operating Procedures 
SpO2 
Oxygen Saturation 
TEAE 
Treatment-Emergent Adverse Event 
TLD 
Target Lung Dose 
T0 
Start of AeroFact dose 
WHO 
World Health Organization 


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2 
BACKGROUND AND RATIONALE 
2.1 
Introduction 
Aerogen Pharma is developing AeroFact, an investigational drug/device combination product 
consisting of lyophilized bovine-origin surfactant SF-RI 1 (sold in Europe since 1989 under the 
proprietary name AlveoFact®) administered following reconstitution to a 45 mg/ml suspension with 
semi-isotonic saline buffer using a proprietary breath-actuated vibrating mesh nebulizer with a nasal 
cannula interface. 
Current surfactants used for prevention or treatment of Respiratory Distress Syndrome (RDS) in 
preterm infants are approved for delivery only as a liquid bolus instillation via an endotracheal tube 
(ETT) while intubated/cannulated.  Intubation and cannulation with a tube into the trachea for 
surfactant administration are associated with adverse events (AEs) [1,2,3].  Access to surfactant 
therapy without invasive procedures that further exacerbate the condition is therefore a major unmet 
medical need in this vulnerable population.  Reports suggest that AEs caused by intubation or 
cannulation can be avoided if there is a means of non-invasive delivery, i.e. aerosolized surfactant 
delivered through nasal continuous positive airway pressure (nCPAP) [5]. 
Current therapies for RDS in preterm infants are associated with the following challenges: 
• Endotracheal intubation of preterm infants is an invasive procedure associated with airway 
tissue trauma, vagal stimulation, hypoxia, and bradycardia [1,2,3].  Additionally, insertion 
of small catheters into the infant trachea and positioning above the bifurcation can be 
traumatic.  Both techniques require specialized skills, medical support, and training that 
must be kept current via frequent practice. 
• Liquid bolus surfactant instillation via ETT is associated with airway obstruction (due to the 
large volume of liquid relative to preterm infant lung volumes) and transient physiological 
events such as hypoventilation, hyperventilation, changes in systemic blood pressure, 
alterations of cerebral blood flow, and other pulmonary and neurological effects. 
• Respiratory 
support 
with 
nCPAP 
alone, 
albeit 
less 
traumatic 
compared 
to 
intubation/mechanical ventilation, results in delayed delivery of surfactant or absence of 
exogenous surfactant administration.  This can lead to: 
o Atelectasis 
o Stress within the lungs associated with pneumothoraxes and bronchopulmonary 
dysplasia (BPD) 
o Increased fraction of inspired oxygen (FiO2) requirements, which are associated 
with lung toxicity and ophthalmic vascular changes leading to Retinopathy of 
Prematurity (ROP) 
o Ventilation/perfusion mismatching resulting in intra-pulmonary and intra-cardiac 
shunts 
In summary, as practice has evolved, many clinicians avoid subjecting preterm infants to risk of 
intubation/cannulation and instillation of liquid bolus surfactant until RDS has progressed to 
moderate or severe levels.   


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2.2 
AeroFact 
2.2.1 Nonclinical Experience 
SF-RI 1 (the drug component of Aerofact) delivered as a bolus instillation has been assessed in a 
series of nonclinical studies in order to gain regulatory approval in several European countries and 
territories around the world.  (Please refer to the Investigator’s Brochure on non-clinical trials 
conducted with Alveofact). These nonclinical studies have been deemed acceptable to support the 
safety of SF-RI 1 for intratracheal bolus instillation in preterm neonates.   
Several studies comparing IT instillation of surfactant to nebulized surfactant indicate potential 
advantages to inhaled aerosol therapy.  Efficacy has been demonstrated by the Sponsor, using 
aerosolized SF-RI 1.  In these studies, using a breath synchronized vibrating mesh nebulizer, similar 
to the clinical delivery platform, rabbits with surfactant depleted lungs from repeated saline washes, 
showed improvement in the oxygenation index and ventilation efficiency index after intratracheal 
delivery of aerosolized SF-RI 1. These data support the safe use of aerosolized SF-RI 1 in  
preventing progression of infant respiratory distress syndrome (RDS) when delivered either as a 
bolus instillation or as an aerosol.  
Because SF-RI 1 administration with Aerofact is by a new route (nebulized aerosol passing through 
the neonate’s nose to be delivered to the lungs), the potential toxicity of SF-RI 1 to the nasal cavity, 
and general lung tolerability, were evaluated by the Sponsor in support of the proposed clinical 
development program.  Specifically, the toxicity and local tolerability of SF-RI 1 were assessed in 
two 14-day GLP studies, one in post-weanling Sprague Dawley rats and one in post-weanling New 
Zealand White rabbits.  For these studies, nose only inhalation was used as this is the intended 
clinical route. Additionally, the drug was administered daily for 14 consecutive days, which exceeds 
the frequency of dosing in the clinical situation.  The high dose in the 14-day animal studies was 
determined by using the maximum feasible concentration for SF-RI 1 in an attempt to obtain an 
acceptable margin over the anticipated clinical dose. In both studies standard parameters were 
assessed including, body weight, food consumption, clinical observations, clinical pathology 
(hematology, coagulation and clinical chemistry) and ophthalmology, as well as a complete 
necropsy and histopathology of over 50 tissues.   No adverse effects were observed in any standard 
assessment of toxicity, including the electrocardiogram.  Technical issues with the rabbit study 
resulted in lower-than-targeted aerosol exposure.  Inflammation and increased alveolar 
macrophages were present in all treatment groups including the control.  Therefore, a No-Observed-
Adverse-Effect-Level (NOAEL) was not determined. In rats, based on the absence of any adverse 
findings in any of the measured parameters, the NOAEL from 14 days of nose-only inhalation of 
SF-RI 1 was considered to be the maximal feasible dose of 1,223 mg/kg/day. 
2.2.2 Clinical Experience  
More detailed summaries of AeroFact clinical experience can be found in the Investigator Brochure. 
APC-AF-CLN-001, a Phase 2a study of AeroFact, was performed in three clinical centers in 
Australia.  Only two of the centers enrolled subjects.  The third site withdrew from the study prior 
to enrolling any subjects.  The enrollment period was 21 November 2017 to 1 August 2018.  The 
study was An Open-Label Study of the Safety and Tolerability of AeroFactTM (Aerosolized 
Alveofact®) in Preterm Infants on nCPAP at Risk of Worsening Respiratory Distress Syndrome.  


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The study was conducted in 2 parts, Part I, single dose and Part II, multiple dose. Each part was 
conducted in a separate group of preterm infants.   
Infants who were 26 0/7 to 30 6/7 weeks gestational age at birth, required CPAP or nIMV after the 
delivery room, and satisfied the inclusion and exclusion criteria were enrolled within two hours into 
this study.  For each enrolled infant, retrospective data was collected on 3 comparative infants of 
the same gestational age who were born within the two previous years. 
AeroFact treatment failure criteria for intubation and bolus instillation of surfactant were one or 
more of the following: 
1.  
RSS ≥ 2.4 
2. 
PCO2 > 65 mmHg and/or pH < 7.20 
3. 
nCPAP > 8 cm 
4. 
Three severe apneas with bradycardia within six hours requiring escalation of support 
Infants were followed for their need for AeroFact and/or bolus dosing of surfactant. Tolerance of 
Aerofact dosing  had the following data collected: changes in respiratory support over the first 28 
days of life, BPD status at 36 weeks PMA and co-morbidities of prematurity/AEs monitored until 
the time of discharge.  
2.2.2.1 APC-AF-CLN-001 Part I  
Part I of the study was designed to determine the safety and tolerability of administering a single 
nominal dose of 216 mg/kg of aerosolized AeroFact (SF-RI 1) by nCPAP.  Ten preterm infants 
who required nCPAP (machine CPAP) and satisfied the inclusion and exclusion criteria were 
enrolled into this part of the study. 
After successful completion of Part I and a proceed recommendation by an Independent Data Safety 
Monitoring Board (DSMB), sites were permitted to begin enrollment into Part II of the study. 
2.2.2.2 APC-AF-CLN-001 Part II  
Part II of the study was designed to determine the safety and tolerability of administering up to four 
doses of aerosolized AeroFact (SF-RI 1) by nCPAP. Twenty (21) preterm infants were enrolled 
into this part of the study.  
An initial nominal dose of 216 mg/kg of aerosolized SF-RI 1 was administered. Oxygenation and 
ventilation parameters were monitored as outlined in the protocol.  Infants continued on nCPAP. 
Re-dosing of AeroFact (nominal dose of 216 mg/kg) occurred if the RSS to maintain SpO2 between 
90% and 95% (as measured by pulse oximetry) ≥ 2.0 and at least (1) 2 hours elapsed since the end 
of the first dose and (2) 4 hours elapsed since the end of either the second or third dose. Up to 3 
additional doses of AeroFact within 96 hours were allowed. 


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2.2.3 Summary of Clinical Results 
2.2.3.1 APC-AF-CLN-001-Safety Analysis Conclusions:  
• The overall incidence of TEAEs was low among AeroFact patients; 3 patients (30%) had 1 
or more TEAE(s) in Part I, and 5 patients (23.8%) had 1 or more TEAE(s) in Part II. 
• There were no TEAEs which were assessed by the Investigator as related to the study drug, 
device, or procedure, and none led to premature discontinuation from the study drug or 
premature discontinuation from the study. 
• The most common TEAEs reported were patent ductus arteriosus occurring for 1 patient 
(10%) in Part 1 and for 3 patients (9.5%) in Part II, and pneumothorax occurring for 1 patient 
(10%) in Part 1 and 1 patient (4.8%) in Part II. 
• All TEAEs in Part I were mild and the majority of TEAEs in Part II were mild with a severe 
TEAE occurring in 1 patient (4.8%) (pulmonary hemorrhage identified after intubation). 
• During Day 1 to study Day 4, following AeroFact dosing, there was 1 occurrence (10%) of 
moderate nasal congestion in Part I, and 5 occurrences (23.8%) of moderate nasal 
congestion and 1 occurrence (4.8%) of severe nasal congestion in Part II of the study. Nasal 
aspiration occurred in 2 patients (9.5%) in Part II on Day 1 in the study.  Neither nasal 
congestion or nasal aspiration data were available from the historical control patients for 
comparison. 
• One patient in Part I and 1 patient in Part II of the study had an SAE. Both patients had the 
SAE of culture-proven sepsis, which was not related to the study drug, the device, or the 
procedure, did not emerge during the treatment period, and resulted in death. 
• Generally, the incidence of AEs associated with dosing tolerance in the first 24 hours was 
low; the incidence of AEs for AeroFact only vs. AeroFact plus bolus surfactant 
demonstrated comparability. 
• The incidence of post-dose comorbidities of prematurity and AEs was low and consistent 
between the patients treated with AeroFact vs. historical controls.  
2.2.3.2  APC-AF-CLN-001-Efficacy Analysis Conclusions: 
• At 36 Weeks PMA, a larger proportion of patients receiving AeroFact in Part I and Part II 
of the study survived without BPD (88.9% and 78.9%, respectively) compared with Part I 
and Part II historical control patients (73.3% and 66.7%, respectively).    
• The median (range) length of stay in the NICU for AeroFact patients in Part I and Part II 
was comparable to historical control patients. 
• For AeroFact patients in Part I and Part II, the median time-to-failure using AeroFact criteria 
was consistently numerically greater than for historical control patients.  
• For AeroFact patients in Part II, the median time-to-instilled surfactant was consistently 
numerically greater than for Part II historical control patients. 
• No patients in the AeroFact group or in the historical control group required instilled 
surfactant after 72 hours of life. 


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• For patients receiving AeroFact treatment in Part II, the proportion of patients requiring 
rescue with instilled surfactant was lower than for the matched historical controls (25% vs 
45%); this corresponded to a relative risk of 0.56, in favor of AeroFact treatment. 
 Study APC-AF-CLN-001 overall conclusions: 
• Administration of AeroFact, up to 4 doses within 96 hours of life, was shown to be safe and 
well tolerated in patients ranging from 26 2/7 weeks to 30 4/7 weeks of gestational age and 
with weights between 640 to 1,664 grams.  
• No AeroFact-treated patients in Part I or Part II of the study, or among the matched historical 
controls, received instilled surfactant beyond 72 hours of life.  
• The need for rescue therapy by instilled bolus surfactant was lower in Part II of the study 
compared with matching historical controls; 5 AeroFact patients (25%) in Part II required 
rescue with surfactant bolus instillations vs. 27 patients (45%) who required instillations in 
the matching historical control group; this corresponded to a relative risk of 0.56, in favor 
of AeroFact treatment. 
2.2.4 Summary of Pharmacokinetic Results  
Pharmacokinetic studies are not applicable. 
2.2.5  Summary of Known and Potential Risks of Aerosolized Surfactant Administration 
Experimental use  of  inhaled surfactant is reported in the clinical literature and this use is expanding 
(Pillow and Minocchieri 2012, Minocchieri, Knoch et al. 2013, Minocchieri, Berry et al. 2018). 
Current publications indicate feasibility and safety of inhaled surfactant for managing preterm 
infants at risk for worsening RDS. SF-RI 1 was shown to have a significant effect on oxygenation, 
and none reported treatment-related AEs (Jorch, et al, 1997).  As suggested, aerosolized surfactant 
is expected to augment current nCPAP therapy (Pillow and Minocchieri 2012, Soll, Edwards et al. 
2013, Carlo 2014, Polin, Carlo et al. 2014) by delivering an effective surfactant dose, while 
minimizing the negative impacts of the current treatments for RDS. 
 
The completed Phase 2a AeroFactTM study of inhaled SF-RI 1surfactant with nCPAP also showed 
no treatment-related AEs and appears safe and well tolerated.  
 
2.2.6 Dosing Rationale for AeroFact 
Marketed single doses of instilled Alveofact are 54 to 108 mg/kg.  AeroFact dose selection 
was based on 50% delivery device efficiency from a nominal dose of 108 mg/kg and 216 
mg/kg and additional approximetly 50% of the inhaled dose being delivered to lungs vs. the 
nasal passages.  The maximal feasible dose determined in toxicology studies was 1,223 
mg/kg/day.   
This supports clinical dosing of up to a nominal dose of 864 mg/kg/day or 432 mg/kg/day 
(i.e. up to 4 doses in 96 hours after birth). 


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2.2.7 Risk Assessment 
2.2.7.1 Risks to Subjects 
The Sponsor has conducted risk analysis and the following clinical harms with overall high 
unmitigated risk have been identified: 
• 
Hypoventilation, bradypnea, hypoxemia 
• 
Progression of RDS (in the event of under-dosing) 
• 
Skin irritation 
• 
Pneumothorax, volutrauma 
These clinical risks will be properly controlled and/or mitigated relative to the device design e.g. 
implementation of alarms, verification testing or labeling (instructions, warnings and cautions) 
prior to clinical trials on infants. 
Furthermore, the drug delivery system will be tested for its safety following ISO and IEC 
standards for materials, biological and electrical safety, and electromagnetic compatibility. 
The toxicology program in two species of newborn animals did not identify any risks with 
the dose or the route of administration. 
 
The most common side effects reported when premature infants are given surfactant through the 
ETT or cannula are:  
• decreases in oxygen saturation (SpO2) 
• plugging of breathing tube  
• decreases in heart rate, reflux of surfactant into the breathing tube  
• the need for extra mechanical breaths to be given from the breathing machine  
These events are generally brief and not associated with serious complications or death.  
Risks of aerosolized surfactant are unknown.  However, due to the small aerosol size and gradual 
nature of the liquid aerosol administration, they are expected to be less than those associated with 
administration through an ETT/or cannula.  The surfactant will be given by skilled caregivers in the 
NICU who can respond to all of these potential side effects should they occur.Risks of using the 
AeroFact drug delivery system are detailed in the  Investigator’s Brochure. 
2.2.7.2 Benefits to Subjects 
There is no guarantee that the infant will receive direct benefit from his/her participation in this 
study.  Infants will have a 66% chance of receiving study drug.  The benefits of being in this study 
may be the possibility that administering AeroFact may improve lung function and decrease the 
need for increases in respiratory support.   Participation may provide information that may benefit 
other premature babies by helping to determine the safety and efficacy of aerosolized surfactant.  


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3 
STUDY OBJECTIVES 
3.1 Part I – Study Objective 
3.1.1 Part I-Primary Objective 
• To determine an optimal dose of AeroFact™ administered to preterm infants on nCPAP or 
nIMV vs. nCPAP or nIMV alone in reducing the incidence of intubation/cannulation and 
bolus surfactant instillation in the first 7 days after birth 
3.1.2 Part I - Secondary Objectives 
• To compare the time to the first intubation/cannulation across groups for infants requiring 
intubation due to surfactant deficiency  
• To compare need for repeat surfactant dosing between groups within 7 days 
• To evaluate the safety and tolerability of AeroFact administered by inhalation  
3.2 
Part II – Additional  Objectives 
• To evaluate pulmonary outcomes and respiratory resource utilization at 3, 6, 9, and 12 
months corrected age.  
• To evaluate respiratory morbidity per quarter and compare pulmonary morbidity across 
groups 
• To evaluate early neurologic (modified GMFS) outcomes at 12 months corrected age  
4 
OVERALL STUDY DESIGN AND PLAN 
The partially-blind, randomized, parallel-group, dose-ranging study is divided into 2 Parts.  Part I 
includes birth through hospital discharge or 40 weeks PMA and Part II discharge through 12 months 
corrected age  (Follow Up).   
4.1 
Part I 
Part I is to determine the optimal dose of AeroFact compared to nCPAP or nIMV alone in reducing 
the incidence of intubation/cannulation and bolus surfactant instillation in the first 7 days after birth.  
261 preterm infants who are at risk of worsening Respiratory Distress Syndrome (RDS), will be 
enrolled.  The AeroFact dose and dosing strategy determined in this study will be used in a Phase 
3 definitive trial.  Preterm infants who require nCPAP (either by bubble CPAP or machine CPAP) 
or nIMV, and meet all inclusion and no exclusion criteria, will be enrolled into the study.  
In the delivery room, infants will be stabilized on nCPAP/nIMV per site clinical guidelines. Once 
the infant has been stabilized, eligibility determined, and parental consent obtained, the infant will 
be block randomized in a 1:1:1 partially-blind fashion to receive one of two doses of AeroFact 
(Active) or Control. The randomization will be stratified by site and two gestational age groups (26 
0/7 to 28 6/7 and 29 0/7 to 31 6/7 weeks). Patients who meet all inclusion, no exclusion criteria and 
are randomized to receive Active dose, will have the assigned treatment administered within first 
twenty-four hours after birth.  Patients who are assigned to the Control group will continue to 
receive nCPAP/nIMV.  If twins or triplets are enrolled, only the first sibling will be randomized 


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and subsequent siblings will receive the same treatment assignment.  The Neonatal Intensive Care 
Unit (NICU) staff, the Principal Investigator (PI), the infant’s family, and the sponsor will be 
blinded to AeroFact treatment allocation.   
The study treatment allocation will be designated as either Active or Control. The Neonatal 
Intensive Care Unit (NICU) staff, the Principal Investigator (PI), the infant’s family, and sponsor 
will be blinded to Active treatment dose allocation.  Randomization will be a two-step process.  
Step 1: a designated member of the study staff will obtain a randomization envelope for the 
appropriate gestational age group, which will randomize the infant to either the Active or Control 
group.  Step 2: active envelopes will be forwarded to the unblinded pharmacist or designee, where 
the active envelope will be opened and the Low or High dose group (108 mg/kg or 216 mg/kg) will 
be determined.  Active drug dose will be calculated and dispensed according to the pharmacy 
manual instructions.   
Active drug will be reconstituted according to the AeroFact package insert instructions or the  
pharmacy/respiratory therapy manual.  Active study drug doses distributed by the pharmacy or 
designee will be labelled with patient ID.  Parameters required to set up the AeroFact delivery 
system to administer the proper study treatment regimen (patient weight and mg/kg) will be 
programmed into the controller by the unblinded member of the study staff.  For active drug doses, 
an unblinded study member will set up the AeroFact delivery system. The AeroFact system will be 
primed and set to deliver the appropriate dose.  If the infant is randomized to Control, the infant 
will continue to receive nCPAP/nIMV.  
While preparing the set-up for the AeroFact system, a privacy screen will be placed around the 
delivery system to ensure the blind is maintained.  Once the system is set up, the privacy screen 
will be moved aside to allow access to the infant and controller.  Prior to aerosol administration, 
infant will be transitioned from their standard CPAP/nIMV to the AeroFact interface.  
Administration of AeroFact will be managed by the unblinded staff member.  When adjustment of 
the AeroFact system is required (drug vial change, alarms, etc.), a privacy screen should be utilized 
to mask the treatment allocation. 
Oxygenation, ventilation parameters, and nasal congestion/aspiration will be monitored every 15 
minutes for the duration of dosing or a minimum of two hours after the start of dosing by a blinded 
study or staff member. Dosing tolerance will be evaluated at 4 and 24 hours after the start of each 
AeroFact dose.  AeroFact aerosol delivery will be stopped at the time of dose completion, but 
AeroFact tubing/nebulizer and vial will remain in place for a minimum of 2 hours. The AeroFact 
delivery system will be removed from the patient’s bedside after dosing is completed or 2 hours 
have elapsed (whichever is longer) and patient may be transitioned back to their standard nCPAP 
circuit.  A new drug delivery circuit must be used for each subsequent dose administered. 
Infants receiving active drug will continue on nCPAP/nIMV after dose completion.  If 
oxygenation and ventilation requirements increase within 96 hours after birth, AeroFact 
administration may be repeated up to three times for a total of 4 doses over the first 96 hours after 
birth.  Re-dosing of AeroFact (same randomized group) will be allowed if the RSS to maintain 
SpO2 between 90 and 95%  is 1.5 to 2.39 and at least two hours have elapsed since the start of the 
previous dose:   
• If FiO2 > 0.23, re-dosing will occur.  
• 
If FiO2 ≤ 0.23, re-dosing is at the discretion of the investigator.   


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SpO2 between 90-95% must be used to meet study eligibility through 96 hours for all study groups 
(Active/Control).   Site-specific SpO2 clinical guidelines may be used after 96 hours.  Each site 
must use these guidelines uniformly across treatment groups. All infants randomized will be 
clinically managed until the criteria for treatment escalation have been met.  If at any time the 
criteria for treatment escalation are met in any of the three treatment arms, intubation and/or bolus 
instillation of surfactant may be administered per site’s standard of care.  Oxygenation, ventilation 
parameters, nasal congestion/aspiration and dosing tolerance will be collected for each bolus 
instillation of surfactant. 
Criteria for treatment escalation for AeroFact or nCPAP/nIMV only therapy includes any of the 
following: 
1. Respiratory Symptom Severity (RSS) ≥ 2.4 
2. Partial Pressure of Carbon Dioxide (PCO2) > 65 mg Hg and/or pH < 7.20 
3. Base deficit > 10 mEq/L, on two blood gases 4 hours apart 
4. nCPAP > 8 cm 
5. Three severe apneas with bradycardia within six hours requiring escalation of support 
6. Infant’s work of breathing has increased warranting escalating therapy, but infant does not meet 
RSS or other criteria above.   
Data on all enrolled infants will be assessed through 40 weeks PMA or discharge from the NICU.  
Information to include: maternal/infant delivery, resuscitation history, oxygenation/ventilation 
parameters, concomitant medications of interest, and safety.  Oxygenation and ventilation 
mode/parameters routinely monitored q 8 hours through Day 7, daily days 8 through 28, and daily 
at weeks 35 to 37  and 39 to 40 PMA/discharge. If an infant is discharged from the NICU prior to 
36 and/or 40 weeks, a study member will call the family to verify the respiratory support status. 
 Co-morbidities of prematurity (e.g.: pneumothorax, IVH, PDA, NEC, sepsis, etc.) and adverse 
events (treatment-related or otherwise) will be collected to 40 weeks PMA/Discharge.  
 
 
 


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4.2 
Part II – Follow-Up 
Part II will begin at discharge and be based on telephone questionnaires performed at 3, 6, 9 and 12 
months corrected age. Evaluation of home environment, asthma, respiratory support, medical and 
family history, and respiratory resource utilization after discharge will be collected.  A modified  
GMFS is included in the questionnaire collected at 12 months.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3 
Screening 
The purpose of Screening is to ensure that each infant meets all the specified inclusion and none of 
the exclusion criteria.  Screening is conducted for Part I only.  Any subject enrolled who participated 
in Part I will continue into Part II. 
Part 
II 
Follow 
Up 
Questions 
3 months 
6 months 
9 month 
12 months 
Respiratory symptoms 
X 
X 
X 
X 
Dr visit/ER/hospital visit 
X 
X 
X 
X 
Oxygen/ventilator use 
X 
X 
X 
X 
Respiratory Medications 
X 
X 
X 
X 
Home living situation 
X 
X 
X 
X 
Type and route of feedings 
 
X 
 
X 
Care outside home 
 
X 
 
X 
Smoking in home 
 
X 
 
X 
Family/social history 
 
 
 
X 
Medical 
history, 
vision 
hearing 
 
 
 
X 
Medications 
for 
chronic 
conditions 
 
 
 
X 
Allergies 
 
 
 
X 
Motor milestones 
 
 
 
X 
Growth parameters 
 
 
 
X 
Modified 
Gross 
Motor 
Function Score 
 
 
 
X 


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4.4 
Treatment 
4.4.1 
Part I 
In the two active arms of this study, nominal doses of 108 mg/kg or 216 mg/kg aerosolized SF-RI 
1 will be administered by a dedicated drug delivery system to infants who are receiving  
nCPAP/nIMV.  A maximum of four doses over 96 hours will be permitted.  Re-dosing will be 
allowed if the RSS to maintain SpO2 between 90% and 95% is 1.5 to 2.39 and at least 2 hours have 
elapsed since the start of the previous dose: 
• If FiO2 > 0.23, re-dosing will occur.  
• If FiO2 ≤ 0.23, re-dosing is at the discretion of the investigator.   
In the control arm, infants will receive nCPAP/nIMV alone as determined by their clinical team 
until criteria for escalation of treatment occurs.  SpO2 between 90-95% must be used to meet study 
eligibility through 96 hours for all study groups (Active/Control).   Site-specific SpO2 clinical 
guidelines may be used after 96 hours.  Each site must use these guidelines uniformly across 
treatment groups. 
4.4.2 
Part II 
No treatment is given during Part II of this study.    
5 
SELECTION AND WITHDRAWAL OF PATIENTS 
Two hundred and sixty-one (261) preterm infants will be enrolled at approximately 45 sites.   
Preterm infants who do not meet all the inclusion criteria or who meet any of the exclusion criteria 
will not be eligible for study participation.  
5.1 
Inclusion Criteria 
Preterm infants are eligible for this study if they meet all of the following criteria: 
1. Parental consent obtained prior to study procedures being performed (pre-natal consent is 
allowed) 
2. 26 0/7 to 31 6/7 weeks of gestational age 
3. Weight < 2000 grams 
4. Weight appropriate for gestational age (AGA 3% to 97%) 
5. Age ≤ twenty-four hours at the initiation of study treatment (active or nCPAP/nIMV alone)   
6. Current RSS (MAP x FiO2) 1.4 - 2.0 (nCPAP or nIMV)  
7. Chest radiograph or lung ultrasound [13,14] consistent with a diagnosis of RDS 
 
5.2 
Exclusion Criteria 
Preterm infants are NOT eligible for this study if they meet any of the following criteria: 
1. Apgar score ≤ 5 at five minutes after birth 
2. Need for chest compressions or administration of epinephrine or bicarbonate in the delivery 
room 
3. Premature rupture of membranes (PROM) > 14 days 


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4. Criterion Removed 
5. Base deficit > 10 mEq/L on clinically indicated blood gas at time of randomization 
6. Need for intubation and/or mechanical ventilation prior to enrollment  
7. HFNC and RAM Cannula are not allowed to determine eligibility 
8. Prior instillation of surfactant 
9. Enrollment in another treatment study with competing outcomes 
10. Active pneumothorax requiring chest tube 
11. Significant congenital anomaly 
12. Known or supected chromosomal abnormality 
13. Other etiologies of respiratory distress  (e.g. meconium aspiration syndrome, hydrops fetalis, 
toxoplasmosis, rubella, cytomegalovirus, herpes simplex) 
14. Concomitant treatment with inhaled nitric oxide   
15. Suspected PPHN with sustained pre/Post SpO2  ductal differences > 10% 
 
5.3 
Re-Screening of Patients 
Infants may not be enrolled more than once.   
 
5.4 
Removal of Patients from Therapy or from the Study 
Study treatment will be discontinued if any of the following occur:  
• pneumothorax (requiring chest tube) or  
• pulmonary hemorrhage (frank bleeding from the lungs that is not related to irritation due 
to suctioning or infection).   
• Infant shows evidence of pulmonary hypertension requiring treatment with iNO. 
Aerogen Pharma, the Investigator, or the parents of the preterm infant may discontinue study drug 
dosing or withdraw the infant early from the study at any time for safety or administrative reasons.  
Infants may be withdrawn from dosing per parent request, protocol violation, worsening clinical 
condition, investigator decision, study terminated by sponsor, or other.   Infants who discontinue 
study drug dosing will remain in the study for outcomes measurements, unless consent has been 
withdrawn. 
6 
STUDY TREATMENT 
6.1 
Identity of Investigational Product 
The drug in AeroFact is SF-RI 1 which is a lyophilized bovine-origin surfactant, marketed under 
the name Alveofact in Germany and 25 other European and non-European countries.  It is 
manufactured by Lyomark Pharma GmbH and has been analyzed and released according to the 
approved specifications.  The AeroFact drug delivery system consists of reusable and single-patient 
components and is manufactured by Aerogen Limited in Ireland. 


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The clinical label will identify both the study medication and drug delivery system components by 
protocol number, name, lot number, Sponsor, storage conditions, and indicate that it is limited to 
investigational use only. 
6.2 
 Storage Conditions 
Both the vials of lyophilized SF-RI 1 and pre-filled sterile syringe containing 0.45% saline should 
not be stored above 30oC (86oF) and should not be allowed to freeze.  If unavoidable, transient 
excursions up to 40oC are permissible as long as reconstitution has not occurred. Once the drug 
product has been reconstituted with the 0.45% saline, the resulting suspension can be stored up to 
4 hours at 2-8°C or room temperature.  In such cases, the vial should be inverted gently 5 times 
before use.  Study medication will be stored in a secure, controlled-access location at the study sites.    
The storage conditions of the re-usable controller and the single-patient, single use disposable, drug 
delivery circuit and respiration sensor are:  Temperature -20 to +60°C.  In addition, the reusable 
controller and stand with basket should be stored in an area so that they may be charged when not 
in use. 
6.3 
 Treatments Administered 
6.3.1 
Part I 
Enrolled infants randomized to one of the two active drug treatments will receive nominal doses of 
108 mg/kg or 216 mg/kg aerosolized SF-RI 1 by a dedicated drug delivery system while on 
nCPAP/nIMV.  A maximum of four doses over 96 hours will be permitted.  Re-dosing will be 
allowed if the RSS to maintain SpO2 between 90% and 95%  is 1.5 to 2.39 and at least 2 hours have 
elapsed since the start of the previous dose: 
• If FiO2 > 0.23, re-dosing will occur.  
• If FiO2 ≤ 0.23, re-dosing is at the discretion of the investigator.   
Infants enrolled into the control arm will receive either nCPAP or nIMV alone.  SpO2 between 90-
95% must be used to meet study eligibility through 96 hours for all study groups (Active/Control).   
Site-specific SpO2 clinical guidelines may be used after 96 hours.  Each site must use these 
guidelines uniformly across treatment groups. 
6.3.2 Part II – Follow-Up 
There is no active treatment in Part II of this study. Parents will be asked to complete a telephone 
questionnaire at 3, 6, 9, and 12 months corrected age.  This questionnaire will assess the home 
environment, respiratory support, medical history, modified GMFS and respiratory resource 
utilization at each time period. 
See Section 4.2 or Appendicesfor Questionnaires. 
6.4 
Study Medication Supply, Preparation, and Administration 
6.4.1 Study Medication Supply 
The pharmaceutical dosage form of AeroFact is lyophilized SF-RI 1 dry powder in a type 1 glass 
vial (nominal volume 5 mL).  The labelled vial size is 108 mg.  The closure is a gray butyl rubber, 
fluoropolymer-coated, 13 mm stopper with an aluminum/propylene, blue, 13 mm flip-off seal.  The 
current manufacturing facility is BAG Health Care (BAG) GmbH, Amtsgerichtstrasse 1-5, 35423 
Lich, Germany. 


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The pre-filled syringe is hydrolytic glass type 1, 3.0 mL.  It is aseptically filled to 2.4 mL with 
0.45% (semi-isotonic) saline buffer for reconstituting the 108 mg vials. There are two variants. 
The first, manufactured by IDT Biologika, Dessau-Rosslau, Germany, is a luer-slip format with a 
chlorobutyl rubber (4432/50) gray plunger stopper and a synthetic gray polyisoprene tip cap 
(7028/55). The second, manufactured by S.C. Rompharm Company S.R.L, Ilfov County, 
Romania, is a luer-lock format with a gray bromobutyl rubber (FM 257/2) plunger stopper, and a 
synthetic gray isoprene-bromobutyl blend tip cap (7025/65). 
6.4.2 Study Medication Preparation 
There are two ways to prepare the SF-RI 1 suspension, either with a vial-adapter or with a cannula.  
Please refer to the package insert, or the AeroFact Pharmacy/Respiratory Therapy Manual for 
reconstitution of the drug product. 
6.4.3 Study Medication Administration 
The study drug in the AeroFact, SF-RI 1, will be administered by a dedicated drug delivery system 
while infants are on nCPAP/nIMV.  Please refer to the Directions for Use (DFU) or the AeroFact 
Pharmacy/Respiratory Therapy Manuals for details on aerosol administration. 
6.5 
Drug Delivery System 
6.5.1 Identity of Device 
AeroFact™ is a drug /device combination product consisting of three basic components: (i) drug 
(SF-RI 1 bovine-origin surfactant); (ii) reusable device controller; and (iii) disposable single-
patient, single-use drug delivery circuit and breath sensor.  This is a stand-alone drug delivery 
system that integrates with a variety of nCPAP and nIMV devices and is not designed to be 
connected to the hospital network or the Internet.  The AeroFact™ drug delivery system is designed 
to administer aerosolized surfactant to the lungs of spontaneously breathing premature infants 
receiving nCPAP or nIMV. 
6.5.2 Aerosol Delivery System Components 
The AeroFact drug delivery system (Figure 1) consists of reusable and single-patient elements: 
6.5.2.1 Reusable Components 
The controller is a multi-patient, reusable component with flat panel touch-screen display, 
electronics, and software. The controller has three core functions: 
 
• To detect inspiration via a single-patient-use respiration sensor 
 
• To advance suspension to the nebulizer via an integrated feed mechanism 
 
• To generate aerosol during inspiration at the nCPAP interface 
 
These functions occur in synchrony with the infant’s inspiratory cycle. The flat panel touch-screen 
utilizes a graphical user interface (GUI) to allow the user to set and monitor delivery parameters, 
alarms, and system diagnostics. Visual and audible alarms are integrated into the controller. The 


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Pod communicates the signal from the disposable single patient use respiration sensor to the 
controller and breath synchronizes aerosol generation. 
 
6.5.2.2 Single-patient disposable items: 
Drug Reservoir (drug vial) is the reservoir, from which the drug product (lyophilized 
SF-RI 1) is reconstituted into a suspension and dispensed. 
Drug delivery circuit is a disposable, single-patient circuit consisting of: 
• Drug Feed Tubing which includes drug contacting components as follows: (i) luer connector 
(to VVAD) and (ii) tubing conveying drug suspension from the luer to the AF nebulizer. 
• Vented Vial Access Device (VVAD) facilitates access to the drug reservoir and is provided 
to the user in an individual package. 
• AF Nebulizer/nCPAP Interface uses a custom photo defined aperture plate (PDAP) vibrating 
mesh, which is unique in its ability to provide small droplet sizes and higher output rates. 
This is due to its innovative architecture, which provides up to 20-fold more apertures  with 
smaller  diameters  than  the conventional mesh.  This meets the stringent requirements for 
efficient surfactant delivery to infants and represents enabling technology for the AeroFact 
platform.  The AF nebulizer/nCPAP interface is designed to dispense aerosol proximal to 
the infant’s airway and connect to conventional nCPAP systems. 
Respiration Sensor is a separate sensor that is placed on the infant’s abdomen which synchronizes 
drug delivery with the infant’s breathing. 
 
Ancillary non-investigational clinical supplies include the following: 
• Nasal Prongs connect to the end of the drug delivery circuit and are provided in a variety of 
sizes to accommodate different size infants 
• Knit cap/bonnet (F&P™ not shown) to secure the nasal prongs and nebulizer to the infant 
• Cavilon™ no sting barrier film to protect the integrity of the skin prior to applying the breath 
sensor 
• Kind™ Removal silicone tape to be placed over the breath sensor which secures it to the 
abdomen without comprising the integrity of the skin 
• Study Medication Lock box 
• Bedsheet clip 
 
Refer to the AeroFact Drug Delivery System Directions for Use. 
 
 


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Figure1-AeroFact Drug Delivery System 
 
 
6.5.3 Device Supply 
Prior to AeroFact dosing, the drug delivery system will be brought to the bedside.  The serial 
numbers for the controller/Pod and disposable drug delivery circuit will be recorded in the study 
records.  A controller and Pod will be used by more than one patient and will be cleaned between 
each patient (see DFU).  A new drug delivery circuit is required for each dose of AeroFact given 
and will never be re-used. 
Used and unused disposable devices will be inventoried and returned to the Sponsor or Sponsor’s 
designee.  Drug Delivery Systems and their components will be returned to the Sponsor or 
Sponsor’s designee at the conclusion of Part I.  
6.5.4 Device Replacement 
One device (controller, drug delivery circuit and associated components) is expected to perform 
throughout the duration of dose.  If the controller or the drug delivery circuit are not functioning 
optimally for any reason, instructions for trouble-shooting provided in the device instruction 
manual should be followed by the trained unblinded staff.  If one or more devices need to be 
 


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replaced, the reason should be documented in the patient’s medical record and appropriate study 
records.  Additional devices are provided for this purpose.  The unique serial numbers of the new 
controller and drug delivery circuit will be recorded in the patient’s medical record and study 
records. 
Controllers and drug delivery circuits should be replaced at any time if there is a confirmed or 
suspected malfunction. 
• Device substitution, whether controller or circuit, should be recorded on the appropriate 
page of the study records. 
• Notation must be made if the investigator suspects the device is not performing optimally 
for any reason. 
If the Device fails, there is no way to restart a partial dose. 
• For any partial dose delivered, note the amount of dose remaining on the controller drug 
delivery screen (if available) and record on Unblinded dosing record.  Otherwise estimate 
the amount delivered and record on Unblinded dosing record.  This will count as a one of 
the 4 delivered doses.   Patient will be eligible for repeat dosing 2 hours after the start of the 
previous dose. 
• Only a maximum of four doses of AeroFact will be delivered. 
For device performance problems or complaints, the Sponsor or the Sponsor’s designee should be 
contacted within 48 hours.  Complaints should be submitted to: Complaints@aerogenpharma.com.  
Failed devices and drug delivery circuits will be inventoried and returned to the Sponsor or the 
Sponsor’s designee. 
6.6 
Blinding 
Clinical and research staff will remain blinded to dose level being administered with the exception 
of pharmacy staff or designee and respiratory therapy staff or designee.  AeroFact drug delivery 
circuit will remain in line for the duration of dosing or a minimum of 2 hours, regardless of dose 
volume being administered.   
6.7 
Concomitant Medication/Therapies of Interest 
Concomitant medications of interest will be collected for all enrolled infants.  Concomitant 
medications of interest include: corticosteroids, methylxanthines, continuous infusion vasopressors, 
vitamin A, bolus surfactant and medications for the prophylaxis or treatment of PDA administered 
to the patient during the course of the study (starting on Day 1) will be recorded on the Concomitant 
Medications CRF.  Blood products and surgeries will also be recorded.  The Investigator will record 
any AE on the AE CRF for which a concomitant medication/therapy was administered during Part 
I only. 
6.7.1 Discouraged Concomitant Therapy  
The use of Vitamin A or corticosteroids for BPD prophylaxis must be consistent, and appropriate 
for age, for all enrolled infants within each study site. 


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The routine use of hydrocortisone as first-line therapy for BP/adrenal support should be avoided 
during the first 96 hours of life.  Clinical guidelines for use of glucocorticoids can be found in the 
Manual of Procedures (MOP).  
Potential candidates for initiation of glucocorticoids for hypotension will include inadequate 
response to vasopressor therapy (dopamine ≥ 20 mcg/kg/min ± dobutamine or epinephrine) with 
either: 
• Persistent hypotension despite fluid resuscitation, or 
• Inability to wean medications for > 48h 
   
 
and  
• No contraindications to glucocorticoid therapy  
6.8 
Investigational Product (IP) Supplies and Accountability 
Investigational Product (IP) supplies will not be sent to the Investigator(s) until the following 
documentation has been received by the Sponsor: 
• Written proof of approval of the protocol and its informed consent forms (ICFs) by the 
Independent Review Board (IRB) for the institution where the study is to be conducted. 
• An Investigator-signed and dated FDA Form 1572. 
• A signed and dated curriculum vitae (CV) of the Principal Investigator including a copy of 
the Principal Investigator’s current medical license (required in the US). 
The Sponsor may send components of the IP in advance of the completion of the regulatory 
documents if those components are for training purposes only.  In these cases, the Sponsor should 
send documentation to the site instructing them that the IP components are for training purposes 
only and screening and enrolment may not begin until an SIV is completed and a favourable IRB 
approval has been granted  The Investigator and study staff will be responsible for the accountability 
of all investigational product study supplies (dispensing, inventory, and record keeping) following 
Aerogen Pharma instructions, adhering to Good Clinical Practice (GCP) guidelines and local and/or 
regional requirements. 
Under no circumstances will the Investigator allow the study investigational products or ancillary 
components to be used other than as directed by this protocol.  Study investigational product will 
not be administered to any individual who is not enrolled into the study. 
An accurate and timely record of the receipt of all study investigational product; dispensing of study 
investigational product to the patient; collection of unused study investigational product; and 
subsequent return of unused study investigational product to Aerogen Pharma (or designee) must 
be maintained.  This includes but may not be limited to: (a) documentation of receipt of study 
investigational product, (b) study investigational product dispensing/return reconciliation log, (c) 
study investigational product accountability log, (d) all shipping service receipts, and (e) 
documentation of returned study investigational product to the Sponsor.  All forms will be provided 
by Aerogen Pharma.  Any comparable forms that the investigational site wishes to use must be 
approved by Aerogen Pharma. 


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The supplies and inventory records must be made available, upon request, for inspection by the 
designated representative of Aerogen Pharma, a representative of the FDA, or a representative of a 
non-US health authority.  All unused study investigational product, including empty containers are 
to be returned to Aerogen Pharma at the conclusion of the study, unless provision is made by 
Aerogen Pharma for destruction of supplies and containers at the investigational site.  Upon 
completion of study investigational product accountability and reconciliation procedures by 
investigational site personnel and documentation procedures by Aerogen Pharma personnel, study 
investigational product that is to be returned to Aerogen Pharma, if necessary, must be boxed and 
sealed and shipped back to Aerogen Pharma following all local regulatory requirements.   
7 
EFFICACY ENDPOINTS  
7.1 
Primary Efficacy Endpoint – Part I 
• Proportion of infants requiring intubation/cannulation and bolus surfactant instillation in the 
first 7 days after birth 
7.2 
Secondary Efficacy Endpoints – Part I 
• Time to first intubation/cannulation and bolus surfactant instillation between study 
treatments for first 7 days of life 
• Compare the proportion of infants across groups receiving multiple doses of surfactant.  
• Number of days on mechanical ventilation from the day of birth to 40 weeks PMA or 
discharge.  
• Number of days on supplemental oxygen administration from the day of birth to 40 weeks 
PMA or discharge 
• Survival without bronchopulmonary dysplasia (BPD) at 36 and 40 weeks PMA 
7.3 
Additional  Efficacy Endpoints – Part II 
• 
Assessment of pulmonary outcomes at 3, 6, 9 and 12 months corrected age  
• Length of NICU Stay (LOS)  
• Proportion of subjects with any respiratory resource utilization at 3, 6, 9 and 12 months 
corrected age  
• Respiratory morbidity per quarter till 12 months corrected age 
• Assessment of modified GMFS at 12 months corrected age 
8 
SAFETY ASSESSMENTS 
Safety and tolerability will be assessed through the monitoring of oxygenation, bradycardia, nasal 
congestion/aspiration, and other adverse events (AEs) of interest to 40 weeks PMA or discharge. 
Tolerance of the AeroFact dosing administration and all doses of bolus surfactant will be assessed 
during and following dosing. Safety assessment frequency is shown in the Schedule of Assessments 
and Procedures. 


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8.1 
General Safety Procedures 
8.1.1 Ventilator/Respiratory Measurements 
Serial measurements of respiratory support will be collected from the time of birth through 28 days 
of life, 35 to 37 Weeks PMA, 39 through 40 Weeks PMA and at the time of discharge from the 
NICU for all groups.  If infants are discharged from the NICU prior to 36 and or 40 weeks, the 
study staff will collect applicable 36/40 week PMA information by telephone. Measurements 
include: Mode of support (CPAP, Continuous Mandatory Ventilation [CMV], High Frequency 
Oscillatory Ventilation [HFOV]/High Frequency Jet Ventilation [HFJV], NIMV/Bilevel Positive 
Airway Pressure [BiPAP], high flow nasal cannula (HFNC) or nasal cannula (NC) > 2 liters per 
min (L/min), NC ≤ 2 L/min, or room air (RA), CPAP/PEEP, mean airway pressure (Paw),  flow 
rate, FiO2, SpO2, and respiratory support status.  A room air challenge (RAC) will be performed on 
those infants on nasal cannula support at 36 and 40 Weeks PMA.  Duration of assisted ventilation 
and supplemental oxygen will also be collected.  See Manual of Operations (MOP) for detailed 
instructions regarding the process for performing a RAC. 
8.1.2 Weight Measurements 
Weight (grams) will be obtained at the time of birth, discharge from NICU and 12 month corrected 
age assessment (Part II- by parent/guardian report). Head circumference and recumbent length will 
be collected at birth and discharge from the NICU. 
8.1.3 Nasal Congestion 
Prior to and during the AeroFact dosing period and bolus instillation of surfactant, the patency of 
the nasal prongs and blockage of nostrils with surfactant and/or secretions will be closely monitored 
and the severity of nasal congestion will be assessed every 15 minutes for the duration of dosing or 
a minimum of 2 hours.    Document any suctioning done (none/oral/nasal/ETT) following  AeroFact 
or bolus instillation of surfactant. 
8.1.4 Surfactant Dosing Tolerance 
Tolerance of surfactant dosing by AeroFact or bolus instillation will be assessed at 4 hours and 24 
hours after the start of administration.   
8.1.5 Clinical Blood Gas Measurements 
Blood gas measurements drawn for clinical care only will be recorded if collected prior to dosing,  
and/or as verification for meeting escalation criteria or in relationship to an SAE. 
Supplemental oxygen and respiratory support will be adjusted to maintain SpO2 between 90% and 
95% during the first 96 hours after birth.  
8.2 
Adverse Events/Co-Morbidities of Prematurity 
Occurrence of any AEs of interest (Co-morbidities of prematurity) will be collected and recorded 
until discharge or 40 weeks PMA.  Only SAEs that result in an outcome of death will be recorded 
during Part II.  Death is not an SAE but the outcome of the SAE. 


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8.2.1 Definitions 
8.2.1.1 Co-Morbidities of Prematurity (AEs of interest) include: 
• Culture Proven Sepsis 
• Cystic Periventricular Leukomalacia (PVL) 
• Hearing Loss 
• Hydrocephalus requiring shunt 
• Intraventricular Hemorrhage (IVH) Grades 1, 2, 3, or 4 (Worst Grade) 
• Isolated Gastrointestinal Perforation without NEC 
• Necrotizing Enterocolitis (NEC) requiring treatment 
• Patent Ductus Arteriosus (PDA) requiring ligation 
• PDA requiring treatment with indomethacin, ibuprofen, or acetaminophen 
• Pneumothorax requiring chest tube 
• Pulmonary Hypertension 
• Pulmonary Interstitial Emphysema (PIE) 
• Retinopathy of Prematurity (ROP) Stages 1, 2, 3, 4, or 5 (Worst Grade) 
• Severe hypotension 
• Severe pulmonary hemorrhage 
• Tracheal Stenosis 
• Tracheomalacia 
• Vocal Cord Paralysis 
BPD is not recorded as an AE but is recorded as an outcome at 36 and 40 weeks PMA. 
8.2.1.2  Adverse events  
Adverse events (AE) for this study include the co-morbidities of prematurity listed above or any  
untoward medical occurrence deemed significant by the Principal Investigator.  An AE does not 
necessarily have to have a causal relationship with this treatment.  An AE may also occur which 
may be related to the medical device that is being tested. The Investigator will be asked to determine 
the causal relationship of each AE to the investigational device.  This includes any event that is the 
result of incomplete user manual information or of incorrect use of the medical device. 
8.2.1.3  Pre-existing Co-morbidities of Prematurity 
A pre-existing condition or symptom/co-morbidity of prematurity prior to dosing is one that is 
present at the start of the study and is reported as part of the patient’s medical history.  A pre-
existing condition or symptom should be reported as an AE only if its frequency, intensity or 
character worsens during study treatment. 


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All co-morbidities/AEs that occur from randomization through the discharge or 40 weeks PMA  
must be appropriately documented in the patient’s medical chart and on the CRFs.  When known, 
investigators should report syndromes rather than list symptoms associated with the syndrome.  
AEs occurring in Part I should be followed until: 
• resolution/stable sequelae; or 
• the Investigator determines that it is no longer clinically significant; or  
• the study patient is discharged.  
If no follow-up is provided, the Investigator must provide a written justification. 
8.2.2 Grading of Adverse Events 
The severity of each AE will be categorized using the following criteria: 
• Grade 1 (Mild):  usually transient; requires no special treatment 
• Grade 2 (Moderate):  usually ameliorated by simple therapeutic measures 
• Grade 3 (Severe):  may require systemic drug therapy or other medical treatment 
8.2.3 Relationship to Study Medication/Study Device/Study Procedure 
The Investigator must assess the relationship of each reported AE.  The Investigator must assess 
the relationship of the AE to the study medication using the following scale: 
• Unrelated: The AE is definitely not or unlikely to be associated with study 
medication/study device/study procedure and is judged due to causes other than the study 
medication/study device/study procedure. 
• Related:  The AE is possibly or probably related with study medication/study device/study 
procedure.  
8.2.4 AE/Co-Morbidities of Prematurity Action Taken 
Any action taken in response to AE/co-morbidities of prematurity will be recorded as follows: 
• Study Medication 
o Dose not changed 
o Drug interrupted  
o Dosing stopped 
• Study Device/Procedure 
o None 
o Remove/Replace Controller 
o Remove/Replace Circuit 


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8.2.5 AE/Co-Morbidities of Prematurity Outcomes 
The following terms and definitions are used in assessing the final outcome of an AE/Co-
Morbidities of Prematurity:  
• Recovered/Resolved - The participant has fully recovered, or by medical or surgical 
treatment, the condition has returned to the level observed at the first trial-related activity 
after the participant signed the informed consent. 
• Recovering/Resolving - The condition is improving, and the participant is expected to 
recover from the event. 
• Recovered/Resolved with sequelae - The participant has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequelae meets an 
SAE criterion, the AE must be reported as an SAE. 
• Not recovered/Not resolved - The condition of the participant has not improved, and the 
symptoms are unchanged, or the outcome is not known at the time of reporting. 
• Fatal - This term is only applicable if the participant died from a condition related to the 
reported AE. An AE with fatal outcome must be reported as an SAE. 
8.2.6 Serious Adverse Events (SAEs), Treatment Emergent Adverse Events (TEAE), and 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
8.2.6.1 SAEs 
The Investigator is required to determine if each AE is a Serious Adverse Event (SAE).  A SAE is 
any AE occurring after randomization through discharge from NICU or 40 weeks PMA and results 
in any of the following outcomes: 
• Death, or 
• Is life-threatening, or 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
The Investigator is required to determine the causal relationship of each SAE to the investigational 
device based on the outcomes listed above in the definition of a SAE.   
Important medical events that may not result in death, be life-threatening, or require prolongation 
of hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
In the event of death, the cause of death should be recorded as the SAE (death is an outcome, not 
the AE itself).   


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8.2.6.2 TEAEs 
Treatment-emergent adverse events (TEAEs) will be summarized up to 7 days after birth and are 
defined as one of the following occurring from the first dose of AeroFact for the active group or 
from the first bolus instillation of surfactant in the control group:  
• AEs that emerge during treatment, having been absent at pretreatment (Baseline), or  
• Reemerge during treatment, having been present at Baseline but stopped prior to treatment, 
or  
• Worsen in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
8.2.6.3 SUSARs 
A Suspected Unexpected Serious Adverse Reaction is an AE or suspected adverse reaction is 
considered "unexpected" if it is not listed in the investigator brochure or is not listed at the 
specificity or severity that has been observed; or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended.  
8.2.7 Reporting for SAEs   
Part I 
Regardless of causality, an SAE must be followed clinically until resolution or stabilization.   
All SAEs after randomization through discharge from the NICU or 40 weeks PMA must be reported 
to the Sponsor or the Sponsor’s representative within 24 hours of the investigational site’s 
knowledge of the occurrence.  The investigational site will either telephone the report to the Sponsor 
or the Sponsor’s representative or transmit by email a Serious Adverse Event Report (SAER) to the 
Sponsor or the Sponsor’s representative.  If the initial report is made via telephone, a completed 
SAER must be emailed within 24 hours of the site’s knowledge of the event.  Investigational sites 
will be provided with SAER forms. 
The SAER should be emailed within 24 hours with as much information as available at the time.  
At a minimum the initial report should include: patient number, event, treatment group (active or 
control), investigator assessment of causality, and event proximity to study drug dosing should be 
reported, if known.  Supplemental information may be transmitted using a follow-up report and 
should not delay the initial report. 
Part II 
Only SAE’s resulting in death will be recorded.  Information on death will be collected and reported 
to Sponsor within 1 week of  site notification. 
9 
PHARMACOKINETIC ASSESSMENTS 
Not applicable. 


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10 SCHEDULE OF ASSESSMENTS AND PROCEDURES 
The assessments and procedures for Part I and Part II of this study are described in detail below and 
presented in the Schedule of Assessments and Procedures located behind the Synopsis. 
10.1 Part I 
10.1.1 Consenting 
Potential study patient(s) will be recruited by the study staff from hospitalized preterm infants 26 
0/7 to 31 6/7 weeks of gestational age and who are at risk for worsening RDS.  Prior to performing 
any study procedures or assessments, the nature of the study and the potential risks associated with 
the trial will be explained to the infant’s parent(s) or legally authorized representative.  An 
opportunity to ask questions will be provided to the parent(s) or legally authorized representative.  
Once all questions and concerns have been addressed by the study staff, a written informed consent 
will be obtained.  A signed copy of the informed consent will be provided to the parent(s) or legally 
authorized representatives of the infant.  Prenatal consent is allowed. 
10.1.2 Screening (Assessment for Eligibility) 
Preterm infants will be assessed for eligibility on Day 1.  The following items will be assessed:  
• Chest radiograph or lung ultrasound  
• Gestational age and demographics (including date of birth, gender, race, and ethnicity)   
• Medical history for mother and infant (including current medications)  
• Birth weight, Recumbent Length, and Head Circumference 
• Apgar Scores 
• Respiratory support parameters (FiO2, SpO2, PEEP/CPAP pressure and flow rate, Paw, and 
Respiratory Support Status) (initial stabilization in delivery room, first stabilization in 
NICU, and one hour post nCPAP start) 
• Qualifying RSS based on FiO2 and CPAP calculated from parameters above 
• Inclusion and exclusion criteria  
 
The following items will be obtained prior to dosing: 
• If a blood gas has been obtained for clinical purposes only, record PO2, PCO2, pH, 
bicarbonate prior to randomization/dosing, and/or as verification for meeting intubation 
criteria or in relationship to an SAE. 
• Assess and document nasal congestion just prior to AeroFact dosing  
• Evaluate identified Co-Morbidities of Prematurity prior to AeroFact dosing 
 
If the baby has been assessed as eligible to participate in study and informed consent has been 
obtained, the baby may be enrolled into the study. 


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10.1.3 Study Enrollment  
10.1.3.1 Randomization 
• Infant will be randomized to one of three study arms Active-Low Dose (108 mg/kg), Active 
High Dose-216 mg/kg or Control-nCPAP/nIMV alone.  If twins or triplets are enrolled, only 
the first sibling will be randomized and subsequent siblings will receive the same treatment 
assignment. 
• Randomization is a two-step process: 
o Step 1: a designated member of the study staff will obtain a randomization envelope for 
the appropriate gestational age group, which will randomize the infant to either the 
Active or Control group.  The study staff will be made aware if the infant was 
randomized to the control group.  The randomization envelope will be stored in a secure 
location within the infant’s study file. 
o Step 2: active envelopes will be forwarded to the unblinded pharmacist or designee, 
where the active envelope will be opened and the Low or High dose group (108 mg/kg 
or 216 mg/kg) will be determined.  Active drug dose will be calculated and dispensed  
according to the pharmacy manual instructions.  Active drug will be administered 
according to study protocol. 
10.1.3.2 Drug Dispensing & Preparation 
• Pharmacy or designee will calculate AeroFact dose (depending on group assignment) and 
dispense the appropriate number of trays of AeroFact to the study drug lockbox provided 
• Study medication will be labeled according to the study pharmacy manual 
• Study drug will not be reconstituted in the pharmacy but prepared by the unblinded 
respiratory therapist or designee on a just in time basis, according to package insert. 
• Medication, drug calculations, additional study labels, and reconstitution instructions will 
be delivered to the NICU in the study drug lockbox 
10.1.3.3 AeroFact Delivery System Set-up (Unblinded Staff Member Only) 
• Re-usable and single patient use device components will be brought to the infant’s bedside. 
• See Directions for Use (DFU) Manual or the Manual of Procedures (MOP) for step by step 
instructions of device set-up.  
10.1.4 Study Conduct 
10.1.4.1 AeroFact Dosing 
Patients who meet inclusion and no exclusion criteria will receive initial assigned treatment 
administered via nCPAP or nIMV within first twenty-four hours after birth.  Up to three additional 
doses of AeroFact within 96 hours of birth will be allowed.  Re-dosing of AeroFact will be allowed 
if the RSS to maintain SpO2 between 90 and 95% is 1.5 to 2.39 and at least two hours have elapsed 
since the start of the previous dose: 
• If FiO2 > 0.23, re-dosing will occur.  
• If FiO2 ≤ 0.23, re-dosing is at the discretion of the investigator.   
 


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All infants randomized  will be clinically managed  until the criteria for treatment escalation have 
been met.  SpO2 between 90-95% must be used to meet study eligibility through 96 hours for all 
study groups (Active/Control).   Site-specific SpO2 clinical guidelines may be used after 96 hours.  
Each site must use these guidelines uniformly across treatment groups. 
Infants will be evaluated for tolerance of AeroFact administration: 
• Assess nasal congestion (none,mild, moderate, or severe) and document aspiration (nasal, 
oral, ETT or none) every 15 minutes during the administration of AeroFact or a minimum 
of 2 hours. 
• Monitor oxygenation and respiratory support parameters (FiO2, SpO2, PEEP/CPAP pressure 
and flow rate, Paw, and Respiratory Support Status) every 15 minutes from the start of 
AeroFact dosing (T0) until dose has been completed or a minimum of 2 hours post start of 
dosing. 
• Dosing Tolerance Adverse Events of interest will be assessed at 4 and 24 hours after the 
start of each AeroFact dose. 
10.1.5 Neonatal Intensive Care Unit (NICU) 
Data collection will occur at the same frequency regardless of treatment assignment. 
10.1.5.1 Birth to Day 28 
All study infants will undergo the following procedures and evaluations: 
• Monitor clinical blood gases as clinically warranted 
• Infants will have oxygenation and ventilation parameters routinely monitored q 8 hours 
through Day 7, daily days 8 through day 28.  Parameters to include: FiO2, SpO2, 
PEEP/CPAP pressure and flow rate, Paw, and Respiratory Support Status  
• Assess nasal congestion (none, mild, moderate, or severe) and document aspiration (nasal, 
oral, ETT or none) every 15 minutes during the administration of AeroFact and/or bolus 
surfactant  or a minimum of 2 hours. 
• Evaluate dosing tolerance of AeroFact administration and/or bolus surfactant instillation 
• Record AEs of interest /Co-Morbidities of Prematurity  
• Record concomitant medications of interest 
10.1.5.2 36 Weeks PMA 
Study infants will undergo the following procedures and evaluations: 
• Monitor oxygenation and respiratory support parameters (FiO2, SpO2, PEEP/CPAP pressure 
and flow rate, Paw, and Respiratory Support Status) +/- one week around 36 Weeks PMA 
date  (Daily the week before and the week after 36 week PMA date) 
• Record concomitant medications of interest 
• BPD outcomes will be assessed at 36 Weeks PMA.  A RAC will be performed if infant is 
eligible   
• Record AEs of interest/Co-Morbidities of Prematurity 


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If an infant is discharged from the NICU prior to 36 weeks, a study member will call the family to 
verify respiratory support status at 36 weeks. 
10.1.5.3 End of Study at 40 weeks PMA  
Study infants will undergo the following procedures and evaluations: 
• Monitor oxygenation and respiratory support parameters (FiO2, SpO2, PEEP/CPAP pressure 
and flow rate, Paw, and Respiratory Support Status) +/- one week around 40 Weeks PMA 
date  (Daily the week before and the week after 40 week PMA date) 
• Record concomitant medications of interest 
• Record AEs/Co-Morbidities of Prematurity 
• BPD outcomes will be assessed at 40 Weeks PMA.  A RAC will be performed if infant is 
eligible  
If an infant is discharged from the NICU prior to 40 weeks, a study member will call the family to 
verify respiratory support status at 40 weeks.  
10.1.5.4 Discharge from the NICU 
Study infants will undergo the following procedures and evaluations: 
• Date of discharge 
• Discharge disposition 
• Discharge weight (grams), Recumbent Length and Head Circumference 
• SpO2  
• Respiratory status 
• BPD medications 
• Feedings 
• Audiology evaluation 
• Assessment of Ophthalmology/ROP screening 
• Records surgeries performed 
• Record transfusions performed 
• Assessment of ventilation days 
• Last day on oxygen 
• Last day on respiratory support 
• Record concomitant medications of interest 
• Discharge/End of Part I Pulmonary Questionnaire 


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10.2 Part II – Follow-Up 
10.2.1 Follow-Up Questionnaires 
Follow-Up Questionnaires will be completed by telephone with parents at 3, 6, 9, and 12 months 
corrected age to assess current respiratory support, the home environment, interim medical history 
and respiratory medical resource utilization and neurological outcomes (12 months corrected  only). 
11 DATA QUALITY ASSURANCE 
11.1 Data Collection 
Investigator(s) will enter the information required by the protocol onto the CRFs in accordance with 
the CRF Completion Guidelines that are provided with the CRFs.  CRAs will visit each 
investigational site as frequently as documented in the monitoring plan to review the blinded CRFs 
for completeness and accuracy against the source documents.  CRAs will highlight any 
discrepancies found in the documentation of study conduct and ensure that appropriate site 
personnel address the discrepancies.  Only data that is blinded will be reviewed.  If necessary, an 
unblinded CRA may visit site to review unblinded data and perform drug accountability during the 
course of the study.  An unblinded CRA will perform drug accountability and return used and 
unused investigational product prior to close-out. 
11.2 Clinical Data Management 
Data from CRFs and other external data will be entered into a clinical database as specified in the 
data management plan.  Quality control and data validation procedures will be applied to ensure the 
validity and accuracy of the clinical database.  An unblinded data manager will be assigned to 
process the unblinded data. 
11.3 Database Quality Assurance 
All databases will be reviewed and checked for omissions, apparent errors, and values requiring 
further clarification using computerized and manual procedures.  Data queries requiring 
clarification will be documented and returned to the investigational site for resolution.  Only 
authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail. 
12  STATISTICAL CONSIDERATIONS 
This section presents general information about statistical considerations and concepts such as 
randomization, covariates, statistical power, sample size, and a brief discussion on analysis 
methodology, as well as some data conventions. Detailed descriptions of the statistical analysis 


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methods and data conventions will be included in a separate document; i.e., the Statistical Analysis 
Plan (SAP). 
12.1 Treatment Groups  
For this study the following treatment groups will be assessed:   
Group 
Description 
Active-Low Dose 
AeroFact 108 mg/kg (Aerosolized SF-RI 1)  
Active-High Dose 
AeroFact 216 mg/kg (Aerosolized SF-RI 1)  
Control 
nCPAP or nIMV alone 
 
12.2 Description of Study Endpoints  
12.2.1 Primary Efficacy Endpoint – Part I 
• Proportion of infants requiring intubation/cannulation and bolus surfactant instillation in the 
first 7 days after birth 
12.2.2 Secondary Efficacy Endpoints – Part I 
• Time to first intubation/cannulation and bolus surfactant instillation between study 
treatments for first 7 days of life 
• Compare the proportion of infants across  groups receiving multiple doses of surfactant  
• Number of days on mechanical ventilation from the day of birth to 40 weeks PMA or 
discharge.  
• Number of days on supplemental oxygen administration from the day of birth  to 40 weeks 
PMA or discharge 
• Survival without bronchopulmonary dysplasia (BPD) at 36 and 40 weeks PMA 
12.2.3 Additional Efficacy Endpoints – Part II 
• Length of Stay (LOS) in NICU 
• Assessment of pulmonary outcomes at 3, 6, 9 and 12 months corrected age  
• Proportion of subjects with any respiratory resource utilization at 3, 6, 9 and 12 months  
corrected age 
• Respiratory morbidity per quarter till 12 months of corrected age 
• Assessment of modified GMFS  at 12 months of corrected age 
12.2.4 Safety and Tolerability Assessments 
Safety and tolerability will be assessed through the monitoring of oxygenation, bradycardia, nasal 
congestion/aspiration (AeroFact dosing and bolus instillation of surfactant), and other adverse 
events (AEs) to 40 weeks PMA or discharge. Incidence of comorbidities of prematurity/AE’s will 
be assessed. Tolerance of the AeroFact dosing administration and all doses of bolus surfactant will 
be assessed during and up to 24 hours following each AeroFact dose or bolus instillation.  Tolerance 
monitoring will end and begin anew with any AeroFact dose or bolus surfactant dose administered 
within the 24 hour assessment period.  Only SAE’s resulting in death wil be recorded in Part II.  


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12.3 Sample Size Determination and Rationale 
Two hundred and sixty-one (261) subjects (87 in each arm) will be randomized in a 1:1:1 ratio in 
order to assure that 246 subjects (82 in each arm) complete the study. The randomization will be 
stratified by site, gestational age and dosing group.  
Infants requiring treatment escalation in the AeroFact dose groups is estimated to be 20% and in 
the control group is estimated to be 40%, with an odds ratio of 0.375. 
Under the above assumptions, 82 subjects in each treatment group will be required, to meet the 
Type I error rate of 0.05 and 80% statistical power. To accommodate the potential dropouts, a 5% 
dropout rate is included in this sample size calculation.  
The sample size is depicted in Figure 12.1. 
Figure 12-1: Sample Size 
 
12.4 Randomization 
Infants will be block randomized in a 1:1:1 partially-blind fashion to receive one of two doses of 
AeroFact (Active) or Control. The randomization will be stratified by site and gestational age. There 
will be two sets of randomization envelopes, one for each gestational age group and they will be 
color-coded.  If twins or triplets are enrolled, only the first sibling will be randomized and 
subsequent siblings will receive the same treatment assignment. 
Treatment group will be randomly assigned using a predetermined randomization schedule created 
by an independent individual who is not on the study team. The randomization schedule will be 
generated using an appropriate block size to help maintain treatment groups of equal size within 
each age strata. Subjects who do not complete the study will not be replaced.  
 


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12.5 Stratification 
The randomization will be stratified by site and gestational age (26 0/7 to 28 6/7; and 29 0/7 to 31 
6/7 weeks. 
 
12.6 Blinding and prevention of Bias 
For the active dose groups, clinical and research staff will remain blinded to dose level being 
administered.  AeroFact drug delivery circuit will remain in line for the duration of dosing or a 
minimum of 2 hours, regardless of dose volume being administered.   
 
Treatment unblinding for investigator site personnel  will occur after the completion of Part II and 
all clinical data have been received, data inconsistencies have been resolved, and the database is 
locked, except for emergency unblinding due to safety reasons.  For all other study personnel 
(sponsor, vendors, stats, data management, etc.),  active dose unblinding will occur after the 
completion of Part I and all clinical data for Part I have been received, data inconsistencies have 
been resolved, and the database of Part I is locked, except for emergency unblinding due to safety 
reasons. 
 
The control group for this study  are infants treated with nCPAP or nIMV alone.  
 
12.7 Interim Analysis (IA) 
A blinded interim analysis is planned and will be conducted when approximately 60% of subjects 
have been randomized and completed first 7 days of life or early termination, whichever occurs 
first.  
The main purpose of this interim analysis will be: 
• sample size re-assessment to evaluate the final sample size needed to proceed with the study 
based on the control responder rate at interim analysis, and; 
• to evaluate the safety of AeroFact primarily on the frequency of adverse events, nasal 
congestion/aspiration, dosing tolerance events, and serious adverse events 
The results of the interim analysis are to be reviewed by an independent DSMB who would assess 
the data for both safety and efficacy. The DSMB responsibilities are further elaborated in the DSMB 
charter. The DSMB will make recommendations to the sponsor  on the sample size adjustment and 
any safety concerns. The details of the interim analysis will be included in the statistical analysis 
plan. 
There will be no statistical penalty or statistical adjustment due to this interim analysis as this is a 
blinded interim analysis with no interim unblinding.  
 
12.8 General Statistical Considerations  
All collected study data will be presented in subject data listings. Statistical analyses will be 
performed using SAS® for Windows, version 9.4 or later. Descriptive statistics (n, mean, standard 
deviation, median, minimum and maximum) will be calculated by treatment group for continuous 
variables. Frequencies and percentages will be presented by treatment group for categorical 
variables. 


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12.9 Analysis Populations  
The details of the analysis population to be used for the study are described in the below sections. 
12.9.1 Intent-to-Treat (ITT) population 
The Intent-to-Treat (ITT) population is defined as all randomized subjects. The ITT population will 
be the primary population for the primary, secondary and additional efficacy analysis.  
12.9.2 Per Protocol (PP) Population  
The Per Protocol (PP) population is defined as all randomized subjects who were not associated 
with a major protocol violation that affects patient safety or the integrity of the data. The PP analysis 
of primary, secondary and additional endpoints will be considered supportive.  
12.9.3 Safety Population 
The Safety population is defined as all randomized subjects. This population will be used for the 
analysis of safety parameters. 
12.10 Covariates  
The covariates planned for this study will be detailed in the statistical analysis plan. 
 
12.11 Adjustment due to Multiple Comparisons  
There are two comparisons for the primary endpoint because of the two active dose groups 
compared with a control. Hence, a closed test procedure will be used to protect the type I error rate, 
the order of testing will be: 
1) AeroFact 216 mg/kg (Aerosolized SF-RI 1) vs. Control (nCPAP or nIMV alone)  
2) AeroFact 108 mg/kg (Aerosolized SF-RI 1) vs. Control (nCPAP or nIMV alone) 
 
Similarly, since there are multiple secondary endpoints a closed test procedure will be used to 
project the Type I error rate. The order of the secondary endpoints will be specified in the statistical 
analysis plan.   
12.12 Statistical Methods  
A Statistical Analysis Plan (SAP) will be developed and approved before the database is locked. 
The SAP will present the detailed statistical methodology to be used in analyzing the efficacy and 
safety data from this trial. All inferential statistical analysis will be based on a two-sided test with 
a Type I error rate of 0.05. 
 
All the efficacy analyses presented here will be conducted using both ITT and PP populations. All 
safety analyses will be conducted using the Safety population. All data collected will be 
summarized according to the variable type. 
12.12.1  Subject Disposition  
The disposition of all subjects who sign an ICF will be provided. The numbers of subjects screened, 
randomized, completed, and discontinued during the study, as well as the reasons for all post-
randomization discontinuations will be summarized by treatment group. Disposition and reason for 
study discontinuation will also be provided as a by-subject listing.   


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12.12.2 Demographics and baseline characteristics analysis  
Demographics and baseline characteristics will be summarized by treatment group using 
appropriate descriptive statistics. 
12.12.3  Concomitant Medications/Therapies of Interest 
Concomitant medications of interest/therapies will be summarized separately for the Safety 
population. All prior and concomitant medications of interest recorded in the case report form will 
be coded to all matching Anatomic Therapeutic Classification codes using the most recent version 
of WHO Drug. Descriptive summaries by treatment group will be prepared using the coded term. 
All concomitant medications of interest/therapies recorded in the case report form will be listed.   
12.13 Efficacy Analyses 
The primary analyses of the primary and secondary efficacy endpoints will be conducted on the 
ITT population. The PP population analyses of primary and secondary endpoints will be considered 
supportive. 
For the efficacy endpoints the data will be summarized and compared according to the variable type:  
• Continuous data summaries will include:  
o Descriptive summary of number of observations, mean, standard deviation, median, 
and minimum and maximum values.   
o Analysis of Covariance (ANCOVA) or Mixed Model Repeated Measures (MMRM) 
adjusted for stratification factors for inferential statistics.  
• Categorical data summaries will include: 
o Frequency counts and percentages 
o Logit model or Generalized Estimating Equation (GEE) method adjusted for 
stratification factors and clustering of multiple births within a mother for inferential 
statistics 
• Time-dependent data: Cox proportional hazards model will be used to analyze time 
dependent data and to depict the time to event data.  
 
12.14   Safety Analyses  
12.14.1  Adverse Events  
Adverse events will be coded using MedDRA. TEAEs will be summarized for subjects who 
received at least one dose of AeroFact for the active group or received bolus instillation for the 
control group. AEs and TEAEs will also be summarized for up to 7 days after birth. 
TEAEs will be summarized by treatment group, System Organ Class, and preferred term. The 
following TEAE summaries will be provided: 
• TEAEs by severity grade 
• TEAEs by relationship to study treatment. 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 


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12.14.2Clinical Laboratory Data 
There are no required laboratory tests for this study.  
12.14.3Other Safety Data  
All changes in safety data will be listed and summarized over time. 
12.15 Extent of Exposure 
Exposure data will be summarized by treatment group using frequencies and percentages. 
12.15.1Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA).  AEs will 
be presented by preferred term nested within System Organ Class.  Verbatim description and all 
MedDRA level terms, including the lower level terms, for all AEs will be contained in the data 
listings of the CSR.  
AEs will be summarized by presenting, for each treatment group, the incidence of AEs.  Although 
a MedDRA term may be reported more than once for a patient, that patient will be counted only 
one time in the incidence count for that MedDRA term. 
12.16 The Procedure for Revising the Analysis Plan 
Any changes to the statistical analysis plan will be formalized and dated in an amendment and 
documented in the CSR. 
12.17 Data Safety Monitoring Board 
Safety oversight will be provided by a physician Medical Monitor who will provide study 
supervision for any safety concerns. 
An independent DSMB will be comprised of at least three members consisting of at least two 
physician experts and one statistician who are not investigators in the study nor otherwise 
associated with the study. The DSMB will perform an evaluation of the data if requested by the 
Medical Monitor.  Safety parameters will be assessed. The DSMB will establish its own charter, 
procedures, and criteria for recommendations regarding sample size adjustments and safety. 
 
 


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13 ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS 
13.1 Ethics 
13.1.1 Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be reviewed 
and approved by an IRB or IEC constituted and functioning in accordance with International 
Conference on Harmonization (ICH) E6, Section 3, and any local regulations, i.e., Federal 
Regulations, Title 21 Code of Federal Regulations (CFR) Part 56.  Any protocol amendment and/or 
revision to the ICF will be resubmitted to the IRB/IEC for review and approval (except for changes 
involving only logistical or administrative aspects of the study (e.g., change in CRA[s], change of 
telephone number[s]).  Documentation of IRB/IEC compliance with the ICH and any local 
regulations regarding constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC Chairman must be sent to the Principal 
Investigator with a copy to the Sponsor prior to study start and the release of any study medication 
to the site by the Sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend 
or terminate the study, the Investigator will immediately send the notice of study suspension or 
termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator or 
Sponsor, depending on local regulatory obligations.  If the Investigator is required to report to the 
IRB/IEC, he/she will forward a copy to the Sponsor at the time of each periodic report.  The 
Investigator or the Sponsor will submit, depending on local regulations, periodic reports and inform 
the IRB/IEC of any reportable AEs per ICH guidelines and local IRB/IEC standards of practice.  
Upon completion of the study, the Investigator will provide the IRB/IEC with a brief report of the 
outcome of the study, if required. 
13.1.2 Regulatory Notification 
The requirements for the conduct of clinical trials in accordance with the applicable US FDA 
regulations under an Investigational New Drug application (21 CFR 312) will be met before 
commencement of this study. 
13.1.3 Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating practices of Aerogen Pharma 
(or designee), which are designed to ensure adherence to GCP guidelines as required by the 
following: 
• ICH - E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonization of Pharmaceuticals for Human Use. 
• US CFR dealing with clinical studies (21 CFR, including parts 50 and 56   concerning 
Informed Patient Consent and IRB regulations). 


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13.1.4 Patient Information and Informed Consent 
In some cases, a potential parent(s) will be approached and given information about the study prior 
to birth of the infant, and prenatal consent will be obtained.  In others, consent will be obtained 
postnatally. 
As part of administering the informed consent document, the Investigator must explain to the 
parent(s) the nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved, and any potential discomfort.  The parent(s) must be informed 
that participation in the study is voluntary and that they may withdraw their infant from the study 
at any time and that withdrawal of consent will not affect their infant’s subsequent medical 
treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language.  The parent(s) should understand the statement before signing and dating it and 
will be given a copy of the signed document.  The parent(s) will be asked to sign an informed 
consent prior to any study-specific procedures being performed.  No infant can enter the study 
before informed consent has been obtained. 
Due to the COVID-19 pandemic, informed consent may be conducted by phone or video-
conference, rather than in-person. Discussion of study and consent may be done remotely. Consents 
may be given to parent to sign or sent via email for electronic signature.  If remote process of 
consent and signatures are used, they must be witnessed using process approved by site IRB.  
An unsigned copy of an IRB/IEC and Sponsor-approved written informed consent must be prepared 
in accordance with ICH E 6, Section 4, and all applicable local regulations, i.e., Federal 
Regulations, Title 21, CFR Part 50, and provided to the Sponsor.  The parent(s) must sign an 
approved informed consent prior to study participation.  The form must be signed and dated by the 
appropriate parties.  The original signed ICF for each infant will be verified by the Sponsor and 
kept in the study center’s investigational site files. 
The parent(s) should be informed in a timely manner if new information becomes available that 
may be relevant to their willingness to continue participation of their child in the trial.  The 
communication of this information should be documented. 
13.2  Administrative Procedures 
13.2.1 Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  Protocols 
will be followed as written. 
Any change to the protocol requires a written protocol amendment or administrative change that 
must be approved by the Sponsor before implementation.  Amendments specifically affecting the 
safety of patients, the scope of the investigation, or the scientific quality of the study require 
additional approval by the applicable IRBs/IECs of all investigational sites and, by the FDA.  These 
requirements should in no way prevent any immediate action from being taken by the Investigator, 
or by the Sponsor, in the interest of preserving the safety of all patients included in the study.  If an 
immediate change to the protocol is felt to be necessary by the Investigator for safety reasons, the 


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Sponsor’s Medical Monitor must be notified promptly and the IRB/IEC for the site must be 
informed as soon as possible. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval, but the IRB/IEC must be kept informed of such changes.  In 
these cases, the Sponsor will send a letter to the site for forwarding on to the IRB/IEC detailing 
such changes. 
13.2.2 Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol (refer to ICH E6, 
Section 4.5).  Any requests for a planned deviation from the protocol must be discussed with 
Aerogen Pharma so that a protocol waiver may be generated. 
13.2.3 Monitoring Procedures 
The Sponsor or Sponsor’s representative will maintain contact with the Investigator and designated 
staff by telephone, letter, and/or email between study visits.  Monitoring visits (blinded and 
unblinded) may be done either remotely or by visits to each investigational site and conducted by a 
Sponsor representative or CRA.  The Investigator will allow the CRA to inspect the clinical and 
pharmacy facilities to assure compliance with GCPs and local regulatory requirements.  The CRFs 
and patient’s corresponding original medical records (source documents) are to be fully available 
for review by the Sponsor’s representatives at regular intervals.  These reviews verify adherence to 
study protocol and data accuracy in accordance with federal regulations and local regulations.  All 
records at the investigational site are subject to inspection by the FDA. 
In accordance with ICH E6, Section 6.10, source documents include, but are not limited to the 
following: 
• Clinic, office, hospital charts. 
• Copies or transcribed health care provider notes which have been certified for accuracy after 
production. 
• Recorded data from automated instruments such as x-rays, and other imaging reports, e.g., 
sonograms, computed tomography scans, magnetic resonance images, radioactive images, 
ECGs, rhythm strips, electroencephalographs, polysomnographs, pulmonary function tests 
(regardless of how these images are stored, including microfiche and photographic 
negatives). 
• Records of telephone contacts. 
• Diaries or evaluation checklists. 
• Study medication distribution and accountability logs maintained in pharmacies or by 
research personnel. 
• Laboratory results and other laboratory test outputs, e.g., serum pregnancy test result 
documentation. 
• Correspondence regarding a study patient’s treatment between physicians or memoranda 
sent to the IRBs/IECs. 


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• CRF components (e.g., questionnaires) that are completed directly by patients and serve as 
their own source. 
13.2.4 Recording of Data 
In order to provide the Sponsor with accurate, complete, and legible case reports, the following 
criteria are to be maintained.  The Investigator will enter the information required by the protocol 
onto the CRFs in accordance with the CRF Completion Guidelines provided by the Sponsor, report 
the CRFs to the Sponsor, and preserve the copy of the CRFs after the Investigator signs to the CRFs. 
13.2.5 Quality Assurance and Quality Control 
To ensure compliance with ICH GCP and all applicable regulatory requirements, the sponsor (or a 
designated third party), may conduct a quality assurance audit of the study site. Regulatory agencies 
may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any 
time during or after completion of the study. If an audit or inspection occurs, the Investigator and 
institution agree to notify the sponsor as soon as possible following awareness of an impending 
regulatory inspection. The Investigator and Institution agree to allow the auditor/inspector direct 
access to all relevant documents and allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues. 
The sponsor (or its designee) will perform the quality assurance and quality control activities of this 
study; however, responsibility for the accuracy, completeness, and reliability of the study data 
presented to the sponsor lies with the Investigator (and delegate(s)) generating the data.   
Prior to the study initiation, the sponsor (or its designee) will explain the protocol, Investigator’s 
Brochure, and CRF to the Investigator and clinical facility staff involved in this study. In addition, 
the assigned study monitor will be available to explain applicable regulations and to answer any 
questions regarding the conduct of the study. 
13.2.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the Investigator has 
the responsibility to retain all study documents, including but not limited to the protocol, copies of 
CRFs, Investigator's Brochure, regulatory agency registration documents, e.g., FDA 1572 form, 
ICFs, and IRB/IEC correspondence.  In addition, the Sponsor will send a list of treatment codes by 
study patient to the Investigator after the clinical database for this study has been secured after the 
completion of Part II.  The investigational site should retain the records and reports required by this 
part for 2 years after a marketing application is approved for the drug; or, if an application is not 
approved for the drug, until 2 years after shipment and delivery of the drug for investigational use 
is discontinued and FDA has been so notified, or as required by their site IRB. 
It is requested that at the completion of the required retention period, or should the Investigator 
retire or relocate, the Investigator contacts the Sponsor, allowing the Sponsor the option of 
permanently retaining the study records. 
13.2.7 Auditing Procedures and Inspection 
In addition to the routine monitoring procedures, the Sponsor’s Quality Assurance department or 
representative conducts audits of clinical research activities in accordance with the Sponsor’s or 
representative’s SOPs to evaluate compliance with the principles of ICH GCPs and all applicable 


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local regulations.  A government regulatory authority may also wish to conduct an inspection 
(during the study or after its completion).  If an inspection is requested by a regulatory authority, 
the Investigator must inform the Sponsor immediately that this request has been made. 
13.2.8 Handling of Study Investigational Product  
All study investigational product (IP) will be supplied to the Principal Investigator (or designated 
pharmacist) by the Sponsor or Sponsor representative.  Study investigational product supplies must 
be kept in an appropriate secure area (e.g., locked cabinet) and stored according to the conditions 
specified on the study investigational product labels.  The Investigator (or designated pharmacist) 
must maintain an accurate record of the shipment and dispensing of the study investigational 
product (s) in an IP accountability ledger, a copy of which must be given to the Sponsor at the end 
of the study.  An accurate record of the date and amount of study IP dispensed to each patient must 
be available for inspection at any time. 
All study IP supplies are to be used only for this protocol and not for any other purpose.  The 
Investigator (or designated pharmacist) must not destroy any study investigational product labels 
or any partly used or unused study supply.  At the conclusion of Part I of the study and as appropriate 
during the course of the study, the Investigator (or designated pharmacist) or a sponsor 
representative will return all used and unused study investigational product containers, study 
investigational product labels, and a copy of the completed study investigational product disposition 
form to the Sponsor or their designee. 
13.2.9 Publication of Results 
The detailed obligations regarding the publication of any data, material results, or other information, 
generated or created in relation to the study shall be set out in the agreement between each 
Investigator and Aerogen Pharma, as appropriate. 
13.2.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the course of this 
study will be kept confidential by the Investigator, the Investigator’s staff, and IRB/IEC and will 
not be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study without the written consent of the Sponsor.  No data collected as part of this 
study will be utilized in any written work, including publications, without the written consent of 
Sponsor.  These obligations of confidentiality and non-use shall in no way diminish such obligations 
as set forth in the Confidentiality Agreement between the Sponsor and the Investigator.  All persons 
assisting in the performance of this study must be bound by the obligations of confidentiality and 
non-use set forth in the Confidentiality Agreement between the Investigator and Sponsor (provided 
by the Sponsor). 
13.2.11 Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or any other reason at 
any time.  If a trial is prematurely terminated or suspended, the Sponsor should promptly inform 
the Investigator/Institution and the regulatory authority(ies) of the termination or suspension, and 
the reason(s) for the termination or suspension.  The IRB/IEC should also be informed promptly 
and provided the reason(s) for the termination or suspension by the Sponsor or by the 
Investigator/Institution, as specified by the applicable regulatory requirement(s). 


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The Investigator reserves the right to discontinue the study should his/her judgment so dictate.  If 
the Investigator terminates or suspends a trial without prior agreement of the Sponsor, the 
Investigator should inform the Institution where applicable, and the Investigator/Institution should 
promptly inform the Sponsor and the IRB/IEC and should provide the Sponsor and the IRB/IEC a 
detailed written explanation of the termination or suspension.  Study records must be retained as 
noted above. 
13.2.12Patient Insurance and Indemnity 
The Sponsor will provide the insurance in accordance with local guidelines and requirements as a 
minimum for the patients participating in this study. 
 
 
 
 


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14 REFERENCES 
1. 
Brookmeyer R and Crowley JJ.  A confidence interval for the median survival time.  
Biometrics 1982; 38:29-41. 
2. 
Gopel W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, Siegel J, Avenarius S, von der 
Wense A, Vochem M, Groneck P, Weller U, Moller J, Hartel C, Haller S, and Herting E.  
Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing 
preterm infants (AMV): an open-label, randomized, controlled trial.  Lancet 2011; 
378(9803):1627-1634. 
3. 
Herting E.  Less invasive surfactant administration (LISA) – ways to deliver surfactant in 
spontaneously breathing infants.  Early Hum Dev 2013; 89(11):875-880. 
4. 
Kanmaz HG, Erdeve O, Canpolat FE, Mutlu B, and Dilmen U.  Surfactant administration via 
thin catheter during spontaneous breathing; randomized controlled trial.  Pediatrics 2013; 
131(2): e502-509. 
5. 
Mazela J and Polin R.  Aerosol delivery to ventilated newborn infants: historical challenges 
and new directions.  Eur J Pediatr 2011; 170:433-444. 
6. 
Pillow JJ and Minocchieri S.  Innovation in surfactant therapy II: surfactant administration by 
aerosolization.  Neonatology 2012; 101(4):337-344.  
7. 
Jorch, G., H. Hartl, B. Roth, A. Kribs, L. Gortner, T. Schaible, K. H. Hennecke and C. Poets 
(1997). "Surfactant aerosol treatment of respiratory distress syndrome in spontaneously 
breathing premature infants." Pediatr Pulmonol 24(3): 222-224. 
8. 
Minocchieri, S., S. Knoch, W. M. Schoel, M. Ochs and M. Nelle (2013). "Nebulizing 
poractant alfa versus conventional instillation: Ultrastructural appearance and preservation of 
surface activity." Pediatr Pulmonol 49(4): 348-356. 
9. 
Minocchieri, S., C. A. Berry, J. J. Pillow and T. CureNeb Study (2018). "Nebulised surfactant 
to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial." 
Arch Dis Child Fetal Neonatal Ed. 
10. Soll, R. F., E. M. Edwards, G. J. Badger, M. J. Kenny, K. A. Morrow, J. S. Buzas and J. D. 
Horbar (2013). "Obstetric and neonatal care practices for infants 501 to 1500 g from 2000 to 
2009." Pediatrics 132(2): 222-228. 
11. Carlo, W. (2014). "Respiratory Support in Preterm Infants at Birth." Pediatrics 133(1): 171-
174. 
12. Polin, R. A., W. A. Carlo, F. Committee on, Newborn and P. American Academy of (2014). 
"Surfactant replacement therapy for preterm and term neonates with respiratory distress." 
Pediatrics 133(1): 156-163. 
13. Wu, J., Wang, Y., Zhao, A., Wang, Z. (2020). “Lung ultrasound for the diagnosis of neonatal 
respiratory distress syndrome.” Ultrasound Quarterly 36(2): 102-109. 


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14. Raimondi, F., Yousef, N., Migliaro, F., Capasso, L., DeLuca, D. (2021). “Point-of-care lung 
ultrasound in neonatology: classification into descriptive and functional applications.” 
Pediatric Research 90: 524-531. 


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15 APPENDIX I- PART I DISCHARGE BREATHING QUESTIONNAIRE 
 


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16 APPENDIX II – PART II QUESTIONNAIRE 
Part 
II 
Follow 
Up 
Questions  
3 
months 
Corrected 
Age 
6 
months 
Corrected 
Age 
9 months 
Corrected 
Age 
12 months 
Corrected 
Age 
Respiratory symptoms 
X 
X 
X 
X 
Dr visit/ER/hospital visit 
X 
X 
X 
X 
Oxygen/ventilator use 
X 
X 
X 
X 
Respiratory Medications 
X 
X 
X 
X 
Home living situation 
X 
X 
X 
X 
Type and route of feedings 
 
X 
 
X 
Care outside home 
 
X 
 
X 
Smoking in home 
 
X 
 
X 
Family/social history 
 
 
 
X 
Medical 
history, 
vision 
hearing 
 
 
 
X 
Medications 
for 
chronic 
conditions 
 
 
 
X 
Allergies 
 
 
 
X 
Motor milestones 
 
 
 
X 
Growth parameters 
 
 
 
X 
Modified 
Gross 
Motor 
Function Score  
 
 
 
X 
 
 
 
 
 


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