Clinical trial NCT02772081
Conditions: Respiratory Distress Syndrome (RDS)
Keywords: Less Invasive Surfactant administration LISPAP Neonates Newborns Respiratory Distress Syndrome (RDS) CUROSURF®
Sponsor: Chiesi Farmaceutici S.p.A.
Start date: 2021-05-18; Completion date: 2022-08-13
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compared the administration of porcine surfactant (poractant alfa, Curosurf®) through a less invasive method (LISA), using a thin catheter, CHF 6440 (LISACATH®), during non-invasive ventilation (CPAP, NIPPV, BiPAP) with an approved conventional surfactant administration during invasive ventilation followed by rapid extubation in terms of short term and mid-term safety and efficacy in spontaneously breathing preterm neonates who have clinical signs of respiratory distress syndrome (RDS).

Detailed description:
This study was an open-label, multicentre, randomized, controlled study of spontaneously breathing neonates with RDS. Neonates were evaluated according to the selection criteria and then randomized to surfactant treatment via LISA or standard administration procedure. The enrolment was staggered: the gestational age was restricted to 27+0 weeks up to 28+6 weeks for the first 15 neonates. Provided no safety concerns were raised, the enrolment was planned to be extended to the whole population (i.e. 25+0 weeks up to 28+6 weeks). Enrolled neonates were evaluated in a main phase of the trial until discharge or 40 weeks post-menstrual age (PMA), whichever came first. Their clinical status and neurodevelopment was to be assessed at 24-month corrected age as a separate stand-alone visit.

The Sponsor decided to terminate the study early, due to uncertain sufficient availability of the CHF 6440 catheter.

Arms: arm 1: Single dose of poractant alfa 200 mg/kg via brief insertion of a thin catheter (CHF 6440) into the trachea in neonates with RDS.

A second surfactant dose at 100 mg/kg will be administered with the same technique as the first dosage administration if needed.

After the first and second surfactant administration, neonates could receive a third surfactant dose at 100 mg/kg through a standard technique if needed. arm 2: Single dose of poractant alfa 200 mg/kg via the conventional intubation with endotracheal tube in neonates with RDS.

A second surfactant dose at 100 mg/kg will be administered with the same technique as the first dosage administration if needed.

After the first and second surfactant administration, neonates could receive a third surfactant dose at 100 mg/kg through a standard technique if needed.
Interventions: intervention 1: LISA combination product (Curosurf+catheter CHF6440) intervention 2: Curosurf through conventional administration (endotracheal tube)
Intervention descriptions: intervention 1: Curosurf administration through brief insertion of a thin catheter into the trachea intervention 2: Curosurf through conventional administration (endotracheal tube), followed by rapid extubation

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
STUDY CODE No.: CCD-050000-01
IND No: 127511
AN 
OPEN-LABEL, 
MULTICENTER, 
RANDOMIZED, 
CONTROLLED STUDY IN SPONTANEOUSLY BREATHING 
PRETERM 
NEONATES 
WITH 
RESPIRATORY 
DISTRESS 
SYNDROME TO COMPARE TWO PROCEDURES FOR PORCINE 
SURFACTANT 
(PORACTANT 
ALFA, 
CUROSURF®) 
ADMINISTRATION: A LESS INVASIVE METHOD (LISA) 
DURING NON-INVASIVE VENTILATION (NIV) AND THE 
CONVENTIONAL ADMINISTRATION DURING BRIEF INVASIVE 
VENTILATION.
Acronym: LISPAP (Less Invasive Surfactant administration combined with nCPAP)
Version No.: 4.0
Date: 08 SEPTEMBER 2020
The information contained in this document is confidential and will not be disclosed to others without written 
authorization from Chiesi Farmaceutici S.p.A., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered or for discussions with local regulatory authorities, Ethics 
Committee/Investigational Review Boards, or people participating in the conduct of the study.
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma, Italy
NCT02772081


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GENERAL INFORMATION
Sponsor:
Chiesi Farmaceutici S.p.A.*
Via Palermo 26/A
43122 Parma (Italy)
Tel.: +39 0521 2791
Fax: +39 0521 774468
E-mail:  info@chiesigroup.com
*Also reported as Chiesi throughout document
SPONSOR MEDICAL EXPERT
(Clinical Research Physician)
, MD
Clinical Research Physician
Tel.: 
Mobile: 
 (Readily available in case of urgent 
medical questions)
E-mail: 
Clinical Project Manager:
Clinical Project Manager
Tel.: 
, extension 
E-mail: 
Monitoring CRO:
 
Lead Investigator 
Rangasamy Ramanathan, MD
Professor of Pediatrics
Chief, Division of Neonatology, 
LAC+USC Medical Center & 
Good Samaritan Hospital
Director, NPM 
 
Program & NICU
Director, Neonatal Respiratory 
Therapy Services, 
LAC+USC Medical Center


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VERSION HISTORY
Versi
on
Date
Change History
1.0
04th May 2016
Original version
2.0
30th November 
2017
Non-substantial changes/clarifications 
requested by the FDA (USA) in the IND Full 
Clinical Hold letter, dated 07/28/2016
3.0
7th August 2019
Change of the sample size from 300 neonates 
to 100
4.0
8th September 
2020
Change sample size from 100 neonates to 
150; change from multinational study to US 
only; change start of adverse event reporting 
from point of signed informed consent to 
start of procedure; update based on revised 
protocol template; addition of 40 Weeks 
PMA visit
For detailed list of changes see Summary of 
Changes from Protocol v 3.0 to Protocol v 4.0


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PROTOCOL OUTLINE
Study Title
An Open-Label, Multicenter, Randomized, Controlled Study in 
Spontaneously Breathing Preterm Neonates with Respiratory Distress 
Syndrome to Compare Two Procedures for Porcine Surfactant 
(poractant alfa, Curosurf®) Administration: a Less Invasive Method 
(LISA) During Non-Invasive Ventilation (NIV) and the Conventional 
Administration During Brief Invasive Ventilation
Sponsor
Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43122 Parma, Italy
Name of the Product
Poractant alfa (porcine derived surfactant, Curosurf®) administered 
through a specific thin catheter, CHF 6440 (LISACATH®), for less 
invasive surfactant administration (LISA)
Centers
Approximately 25 investigational sites will be involved in US
Indication
Treatment of Respiratory Distress Syndrome (RDS)
Study design
Open-label, multicenter, randomized, controlled study
Study phase
III B
Objectives
The main objective of this study is to evaluate the safety profile of the 
administration of porcine surfactant (poractant alfa, Curosurf®) through 
a less invasive method (LISA) using a thin catheter (CHF 6440) during 
non-invasive ventilation (NIV), compared to conventional surfactant 
administration during invasive ventilation and rapid extubation, in 
spontaneously breathing preterm neonates with clinical signs of 
respiratory distress syndrome (RDS). The short-term and mid-term 
safety will be assessed: adverse events and adverse drug reactions 
occurring during overall procedure for surfactant administration, 
neonatal pain assessment pre- and during surfactant administration, 
duration of surfactant administration, incidence of bronchopulmonary 
dysplasia (BPD) at 36 weeks post menstrual age (PMA) , major 
neonatal morbidities and vital signs.
Moreover, short-term and mid-term efficacy profile will also be 
assessed mainly in terms of: reduced oxygen requirement and 
ventilatory support, need for invasive mechanical ventilation in the first 
72 hours of life and throughout the study period, duration of invasive 
and non-invasive ventilation and need for additional surfactant doses.


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Treatment duration
Spontaneously breathing subjects, stabilized with NIV, will be 
randomized starting from age 30 minutes up to 24 hours after birth to 
receive a single dose of poractant alfa 200 mg/kg either via brief 
insertion of a thin catheter (CHF 6440) into the trachea (LISA group) 
while NIV is maintained, or conventional intubation with endotracheal 
tube (ETT) during brief positive pressure ventilation. Randomization 
will occur as soon as a FiO2 ≥0.30 is needed to maintain preductal 
oxygen saturation, determined by pulse oximetry (SpO2), in the target 
range of 88–95%. 
A second surfactant dose (poractant alfa 100 mg/kg) will be 
administered using the same technique as the first dose administration, 
in cases of lack of efficacy, or clinical deterioration, as per 
randomization criteria (FiO2 ≥0.30 to maintain SpO2 in the target range 
of 88–95%) within approximately 12 hours from the previous dose.
After the first and the second surfactant administration, neonates could 
receive a third surfactant dose (poractant alfa 100 mg/kg).  If a third 
dose is administered, it will be provided through a standard technique. 
Neonates could be intubated (LISA group) or re-intubated (control 
group) for mechanical ventilation (MV) at neonatologist’s discretion, 
if one or more of the below detailed conditions for MV are satisfied.
Criteria for intubation and mechanical ventilation:
Intubation for mechanical ventilation and further surfactant doses 
could happen if one or more of the following criteria are satisfied:

FiO2 ≥0.45 to maintain preductal SpO2 in the target range of 88-
95% for at least 30 minutes, unless rapid clinical deterioration 
occurs;

Significant apnea (more than four episodes of apnea/hour or more 
than two episodes of apnea/hour if ventilation with bag and mask 
was required);

Respiratory acidosis (pCO2 >65 mmHg/8.5 kPa and pH <7.20 
identified by either arterial or capillary blood gas monitoring).
These criteria will be applied during the first 3 days of life (72 hours).
Criteria for termination of mechanical ventilation and extubation:
The decision to terminate mechanical ventilation will depend on the 
following criteria:

Clinical signs of respiratory improvement, e.g. presence of a 
good respiratory drive;

Ability to wean FiO2, e.g. FiO2 <0.30 to maintain SpO2 in the 


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target range of 88 and 95%;

Ability to wean ventilatory pressures, e.g. MAP 7 in 
conventional ventilation or MAP 8 in HFOV;

Normalization of blood gases’ values, e.g. pCO2 <65 mmHg and 
pH ≥7.20.
Test product 
dose/route/regimen
Poractant alfa 200 mg/kg or 100 mg/kg (for additional doses, if 
needed) is a sterile suspension in 3.0 mL glass vials with a total 
concentration of 80 mg/mL for intratracheal administration. This is a 
standard natural surfactant prepared from porcine lungs and containing 
almost exclusively polar lipids, in particular phosphatidylcholine 
(about 70% of the total phospholipid content), and about 1% of specific 
low molecular weight hydrophobic proteins SP-B and SP-C.
LISA-delivery of poractant alfa to the lung will be done via brief 
insertion of a thin catheter (CHF 6440) through the mouth into the 
trachea while the subject is being supported with NIV (CPAP, NIPPV, 
BiPAP). The thin catheter will be provided by the Sponsor. CHF 6440 
is a sterile, single-use catheter. It has a working length of 130.0 mm, 
presents a 1.7 mm Outer Diameter (corresponding to a 5 French OD), 
with a 1.1 mm Internal Diameter (corresponding to 3.5 French ID) 
through which the surfactant is delivered. The hole at the distal edge 
has a diameter of 0.8 mm.
Printed depth markings on the outer surface of the shaft provide visual 
guide to the depth of device insertion during clinical procedure.
The neonate will be placed supine with the head in the neutral position 
prior to the onset of the LISA procedure. Following direct 
laryngoscopy, the catheter will be introduced orally and inserted 
though the vocal cords into the trachea, the laryngoscope will be 
carefully removed while the position of the catheter is secured by the 
fingers of the neonatologist/investigator who will finally close the 
neonate’s mouth. Surfactant will be slowly administered over 0.5-3 
minutes with careful observation of the neonate’s continuous 
spontaneous breathing. Before removing the LISA catheter, it should 
be fully cleared of surfactant with some additional air. After 
completion of surfactant administration, the ventilatory support may 
require transient   adjustments.   Airways   suction   should   not   be 
performed for 1 hour after surfactant instillation, unless signs of 
significant airway obstruction occur.
Reference product 
dose/route/regimen
As standard control treatment, neonates spontaneously breathing and 
stabilized on NIV will be intubated with an endotracheal tube to receive 
poractant alfa 200 mg/kg under invasive ventilation.


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Poractant alfa will be instilled according to the approved endotracheal 
method of administration, connecting the syringe filled with poractant 
alfa suspension to either:

a 5-French end-hole catheter inserted into the ETT
or

the proximal end of the secondary lumen of a dual lumen ETT.
After administration, manual ventilation could be continued, or the 
neonate could be connected to the ventilator, or the neonate could be 
immediately extubated and placed again on NIV. If connected to the 
ventilator, extubation should be performed within one hour after 
surfactant administration and then the neonate placed again on NIV.
Number of subjects
One hundred (100) randomized neonates to LISA treatment group, fifty 
(50) randomized neonates to conventional surfactant administration 
group (150 neonates in total)
Study population
Preterm neonates with early clinical signs of RDS
Inclusion/exclusion 
criteria
Inclusion Criteria
Subjects must meet all the following inclusion criteria to be eligible for 
enrollment into the study:
1. Written 
informed 
consent 
obtained 
by 
parents/legal 
representative (according to local regulation) prior to or after 
birth;
2. Preterm neonates of either sex aged ≥30 minutes and <24 hours, 
spontaneously breathing and stabilized on NIV;
3. Gestational age of 25+0 weeks up to 28+6 completed weeks; 
enrollment will be restricted to subjects aged 27+0 weeks up to 28+6 
GA weeks until safety evaluation of first 15 subjects is completed;
4. Clinical course consistent with RDS;
5. FiO2 ≥0.30 to maintain preductal SpO2 in the target range of 88–
95%.
Inclusion/exclusion 
criteria
Exclusion Criteria
The presence of any of the following will exclude a subject from the study 
enrollment:
1. Need 
for 
immediate 
endotracheal 
intubation 
for 
cardiopulmonary resuscitation or insufficient respiratory drive;
2. Use of nasal high frequency oscillatory ventilation (nHFOV) 


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prior to study entry;
3. Use of surfactant prior to study entry and need for intratracheal 
administration of any other treatment (e.g. nitric oxide);
4. Known genetic or chromosomal disorders, major congenital 
anomalies (congenital heart diseases, myelomeningocele, etc);
5. Mothers with prolonged premature rupture of the membranes 
(>21 days duration) which could cause complications (in 
particular 
severe 
pulmonary 
hypoplasia 
due 
to 
oligohydramnios);
6. Presence of air leaks if identified and known prior to study entry;
7. Evidence of severe birth asphyxia (e.g. continued need for 
resuscitation at 10 minutes after birth, altered neurological state or 
neonatal encephalopathy);
8. Neonatal seizures prior to study entry;
9. Any condition that, in the opinion of the Investigator, would place 
the neonate at undue risk;
10. Participation in another clinical trial of any medicinal product, 
placebo, experimental medical device or biological substance 
conducted under the provisions of a protocol on the same 
therapeutic target; the participation in studies involving diagnostic 
devices or studies with treatments for different conditions than lung 
and respiratory function impairments may be permitted following 
an agreement with the sponsor. Non-interventional observational 
studies are allowed.
Most relevant 
allowed concomitant 
treatments
Any concomitant medication required for the normal care of preterm 
neonates will be permitted during the study.
The use of sedative/analgesic medication, as well as the use of 
atropine, before/during surfactant administration, will be at 
investigator’s discretion, according to each neonatal intensive care unit 
(NICU) standard practice. If premedication is used, the Investigator 
should define a protocol (with specification of drugs and dosages) 
before starting enrollment, which allows for a step-by-step 
management of pain and sedation for the endotracheal administration 
of surfactant. Each neonate will be managed according to the pre-
defined protocol, and decision on which step of the protocol to apply 
should be based on neonate’s needs.  The same step-by-step protocol 
should be applied to both treatment arms.  The protocol will be 
provided to the Sponsor.
If caffeine is administered, it should be used in both treatment arms.


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Most relevant 
forbidden 
concomitant 
treatments

Surfactant treatment prior to randomization and study treatment 
administration

Intratracheal administration of any other treatment (e.g. nitric 
oxide) prior to randomization and study treatment administration

Other investigational drugs or investigational devices under the 
provisions of a protocol on the same therapeutic target. See 
exclusion criteria #10.
Safety variables
During procedures for surfactant administration

Number and percentage of neonates with adverse events (AEs) 
starting during overall procedure for surfactant administration 

Number and percentage of neonates with AEs starting during 
overall procedure for surfactant administration and judged 
related to the procedure

Number of AEs starting during overall procedure for surfactant 
administration requiring either oxygen alone or an increase in 
FiO2 without the need for escalation of invasive or non-invasive 
ventilator support

Number of AEs starting during overall procedure for surfactant 
administration requiring administration of manual (bag and 
mask) pressure positive ventilation and related duration of 
ventilation (non-invasive ventilation)

Number of AEs starting during overall procedure for surfactant 
administration requiring endotracheal intubation and related 
duration of intubation (invasive ventilation)

Number of AEs starting during overall procedures for surfactant 
administration 
requiring 
circulatory 
support 
including 
administration of crystalloids

Number of AEs starting during overall procedures for surfactant 
administration requiring cardiopulmonary resuscitation including 
administration of cardiac massage or adrenaline
After first administration

Number and percentage of neonates with failed 1st attempt to 
insert the CHF 6440/ETT

Number of attempts to the first successful insertion

Number of device misallocation (i.e., esophageal insertion)

Number of maneuvers discontinued due to neonate’s severe 
destabilization


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
Duration of surfactant administration (min)

Duration of the overall surfactant administration procedure 
(from the insertion of laryngoscope up to the removal of the 
catheter or ETT)
Safety variables

Heart rate and respiratory rate (0, 5, 15, 30 min, 1 hour, 6 hours, 
and 12 hours after administration)

Systolic, diastolic and mean blood pressure (15 min, 30 min, 1 
hour, 6 hours, and 12 hours after administration)

Premature Infant Pain Profile (PIPP) score (end of surfactant 
administration)
During the study

AEs, including incidence of major neonatal complications of 
prematurity (listed in APPENDIX III), and adverse drug 
reactions (ADRs)

Blood pressure (SBP, DBP, MBP), at 24, 48, 72, 120 hours post-
administration 

Heart Rate (HR) and Respiratory Rate (RR) at 24, 48, 72, 120 
hours post-administration, 28 Post-Natal Age (PNA), 36 weeks 
Post-Menstrual Age (PMA) and at discharge or 40 weeks PMA 
whichever comes first

Incidence of major neonatal morbidities at discharge home or 
40 weeks PMA, whichever comes first 

Incidence of BPD at 36 weeks PMA

Death/BPD incidence at 36 weeks PMA

Mortality at Day 28 PNA and 36 weeks PMA

Oxygen use (alone and / or during invasive and non-invasive 
ventilation) at Day 28 PNA and 36 weeks PMA

Feeding and hearing status at discharge home or 40 weeks PMA, 
whichever comes first

Weight, occipital-frontal circumference (OFC) and length at 
discharge home or 40 weeks PMA

Neonates needing invasive or non-invasive respiratory support at 
discharge home or 40 weeks PMA

Neonates needing respiratory medications at discharge home or 
40 weeks PMA 
24 months (±3 months) corrected age (This stand-alone assessment 
will be analyzed and reported separately from the main phase)


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Health status questionnaire, including:
•
Bayley Scales of Infant Development (cognitive and 
language scores)
•
Feeding method: spoon, nasogastric tube or gastrostomy
•
Cerebral palsy evaluation
•
Seizure evaluation
•
Vision, hearing and communication evaluation
•
Clinical assessment of respiratory conditions and 
morbidity.
•
Vital signs (SBP, DPB, MBP, HR, RR) 
•
Growth assessment (Weight, OFC and length).
Efficacy variables

Percentage of neonates needing invasive mechanical ventilation 
in the first 72 hours of life, at 28 days PNA and within 36 weeks 
PMA

Duration of invasive ventilation (hours) in the first 72 hours of 
life, 28 days PNA and within 36 weeks PMA

Percentage of neonates needing any intubation procedure, 
outside of the initial surfactant administration period, in the first 
72 hours of life, 28 days PNA and 36 weeks PMA

SpO2 at time 0 (study treatment administration), 5, 15, 30 
minutes, at 1, 6, 12, 24, 48, 72, and 120 hours post treatment; 
additionally, at 28 days PNA and at 36 weeks PMA for neonates 
still receiving any form of respiratory support

FiO2 at time 0 (study treatment administration), 5, 15, 30 
minutes, at 1, 6, 12, 24, 48, 72, and 120 hours post treatment; 
additionally, at 28 days PNA and 36 weeks PMA for neonates 
still receiving any form of respiratory support

SpO2/FiO2 at time 0 (study treatment administration), 5, 15, 30 
minutes, at 1, 6, 12, 24, 48, 72, and 120 hours post treatment; 
additionally, at 28 days PNA and 36 weeks PMA for neonates 
still receiving any form of respiratory support

Percentage 
of 
neonates 
needing 
additional 
surfactant 
(Curosurf®) doses and number of surfactant doses

Duration of oxygen supplementation (days), any non-invasive 
ventilation during the study (days)

Blood gas analysis, specifically acid-base balance parameters 
(i.e. pH, pCO2, pO2, HCO3, BE, lactate) pre-surfactant 
administration (when applicable), at 1 hour, 6 hours, 24, 48, 72 
hours after study treatment


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Safety Monitoring
An Independent Safety Monitoring Board (ISMB) will provide 
ongoing trial review for the monitoring of subjects’ safety. An ISMB 
meeting will be scheduled after the first 15 neonates have been enrolled. 
If no safety concerns are raised, enrollment will continue and will be 
extended to newborns with GA at birth between 25+0 weeks up to 28+6. 
Before obtaining a favorable opinion from the ISMB, only newborns with 
GA from 27+0 to 28+6 weeks will be enrolled. Further ISMB meetings will 
be scheduled after the first 60, 105 and 150 subjects, respectively. Ad-hoc 
ISMB meetings can be scheduled, if needed, in case of unexpected safety 
issues.
Sample size 
calculation
No primary efficacy endpoint was defined in this study since the main 
objective is to describe the overall safety and efficacy profile of 
administering poractant alfa with two different procedures: LISA 
technique or conventional administration with endotracheal tube and 
brief invasive ventilation. A total number of one hundred-fifty (150) 
neonates is deemed appropriate for the study aim. Neonates will be 
randomized with a ratio 2:1 to the LISA technique arm (i.e. 100 
neonates) and to the conventional technique (i.e. 50 neonates).
Statistical methods
Safety variables

Number and percent of neonates reporting AEs started during 
procedure for surfactant administration as well as AEs started 
during the procedure and judged related to the procedure will be 
summarized by treatment group.
For LISA group, any AE assessed as related to CHF 6440 
medical device will be considered procedure-related.
These events will be also summarized by treatment group based 
on action required, if any (i.e. supplementary oxygen or 
transient increase in FiO2, manual positive pressure ventilation, 
endotracheal intubation, administration of crystalloids, cardiac 
massage or administration of adrenaline). The duration of 
endotracheal intubation (invasive ventilation) and manual 
positive pressure ventilation will be summarized as well.
A subgroup analysis of surfactant- and procedure- related AEs 
will be performed based on the use of sedation and/or analgesia 
(Yes/No).

Incidence of all the AEs (including neonatal complications of 
prematurity), related AEs (ADRs), serious AEs (SAEs) and AEs 
leading to death will be summarized by treatment group both in 
terms of frequency of neonates with at least one AE and in terms 
of frequency of AEs (number of events). All the aforementioned 


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categories of AEs will be summarized by System Organ Class 
(SOC) and Preferred Term (PT).

Vital signs parameters (SBP, DBP, MBP, RR and HR) will be 
summarized by treatment group using descriptive statistics. 
Change from baseline (pre-procedure) will be also presented.

PIPP score will be summarized by treatment group by means of 
descriptive statistics.

Number of 1st failed attempt to insert CHF 6440/ETT will be 
summarized by treatment group. Percentage of neonates with 1st 
failed attempt will be compared between group using the 
Cochran-Mantel-Haenszel test (CMH) test adjusted for 
gestational age group. The CMH adjusted difference with its 
95% CI will be presented.
Statistical methods

Number of attempts to the first successful insertion will be 
summarized by treatment group by means of descriptive 
statistics.

Number of device misallocation (i.e., esophageal intubation) 
will be summarized by treatment group by means of descriptive 
statistics.

Number of maneuvers discontinued due to neonate’s   severe 
destabilization will be summarized by treatment group by 
means of descriptive statistics.

Duration of surfactant administration (min) and overall 
procedure for surfactant administration will be compared 
between treatment groups by using the Mann-Whitney U-test.

Death/BPD incidence at 36 weeks PMA will be compared by 
treatment by means of CMH test adjusted for GA group and 
related 95% CI will be provided.

The incidence of BPD at 36 weeks PMA will be compared by 
treatment as for Death/BPD incidence.

The incidence of oxygen use (alone and / or during any kind of 
MV) at Day 28 PNA will be compared by treatment as for 
Death/BPD incidence.

The mortality at 36 weeks PMA and at Day 28 PNA will be 
compared by treatment as for Death/BPD incidence.

Frequency of neonates with major neonatal morbidities at 
discharge/40 weeks PMA (whichever comes first) will be 
summarized by treatment group.

Feeding and hearing status at discharge or 40 weeks PMA 
(whichever comes first) will be summarized by treatment group by 
frequency distributions.


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
Weight, OFC and length at discharge home or 40 weeks PMA will 
be summarized by treatment group by descriptive statistics.

Percentage of neonates needing invasive or non-invasive 
respiratory support at discharge home or 40 weeks PMA will be 
summarized by treatment group by frequency distribution 

Neonates needing respiratory medications at discharge home or 40 
weeks PMA will be summarized by treatment group by frequency 
distribution 

Bayley Scales of Infant Development (BSID) (cognitive and 
language scores) will be summarized using descriptive statistics 
by treatment group and BSID version (III or IV).

Vital signs and all other variables collected through the 
questionnaire (i.e., anthropometric measures, cerebral palsy, 
seizures, feeding method, functional disability and respiratory 
morbidity) will be summarized by treatment group by 
frequency distribution or descriptive statistics as appropriate.
Statistical methods
Efficacy variables

Percentage of neonates needing invasive mechanical ventilation 
in the first 72 hours of life, in the first 28 days PNA and within 
36 weeks PMA will be compared between groups using the 
Cochran-Mantel-Haenszel (CMH) test adjusted for gestational 
age group. The CMH adjusted difference with its 95% 
confidence interval (CI) will be presented. Additional analysis 
will be performed to explore the impact of use of sedation 
and/or analgesia. 

Duration of invasive mechanical ventilation in the first 72 hours 
of life, in the first 28 days PNA and within 36 weeks PMA will 
be compared between treatment groups by using the Mann-
Whitney U-test.

Percentage of neonates needing any intubation procedure, 
outside the initial surfactant administration period, in the first 72 
hours, in the first 28 days PNA and within 36 weeks PMA will 
be compared between treatment as need for invasive 
mechanical ventilation.

SpO2 will be analysed using a linear mixed model for repeated 
measures (MMRM) including treatment, time point, treatment 
by time point interaction, and gestational age group as fixed 
effects and pre-procedure SpO2 as covariate. The adjusted 
means in each treatment group, the adjusted mean difference 
between treatments and their 95% CIs at each time point and 
averaged over the first 120 hours post treatment will be estimated 
by the model. Time profile plot of mean SpO2 in the first 120 


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hours post-administration will be presented by treatment group.

SpO2 will be summarized by treatments on neonates still receiving 
respiratory support at 28±2 PNA, and at 36 weeks PMA using 
descriptive statistics. 

FiO2 will be analyzed as SpO2.

SpO2/FiO2 will be analyzed as SpO2.

Percentage of subjects requiring at least one additional 
surfactant dose will be compared by treatment group by means 
of a Fisher’s exact test at 5% significance interval. Odds ratio 
(OR) and related exact 95% CI will be also provided. Subjects 
with pulmonary hemorrhage will be excluded from this 
summary.
Statistical methods
Number of additional surfactant doses will be summarized by 
treatment group by means of descriptive statistics.
Duration of stand-alone oxygen supplementation (days) and non-
invasive ventilation (days) will be compared between treatment 
groups by using the Mann- Whitney U-test.
Acid-base balance parameters (i.e. pH, pCO2, pO2, HCO3, BE, 
lactate) will be summarized by treatments group as absolute and 
change from pre-treatment values by means of descriptive statistics.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ADE
Adverse Device Effect
ADR
Adverse Drug Reaction
AE
Adverse Event
APGAR
Appearance, Pulse, Grimace, Activity, Respiration
ATC
Anatomical Therapeutic Chemical classification
BiPAP
Bi-level Positive Airway Pressure
BPD
Bronchopulmonary Dysplasia
BSID
Bayley Scales of Infant Development
BE
Base Excess
BW
Birth Weight
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical 
CMH
Cochran-Mantel-Haenszel test
CPAP
Continuous Positive Airway Pressure
CRA
Clinical Research Associate
CRO
Clinical Research Organization
CTS
Clinical Trial Supply
DBP
Diastolic Blood Pressure
DPPC
Dipalmitoylphosphatidylcholine
eCRF
electronic Case Report Form
EC
Ethics Committee
ETT
Endotracheal Tube
FiO2
Fraction of inspired Oxygen
FIP
Focal Intestinal Perforation
GA
Gestational Age
GCP
Good Clinical Practice
HCO3-
Bicarbonates
HFOV
High Frequency Oscillatory Ventilation
HR
Heart Rate
ICH
International Conference on Harmonization
IFU
Instructions For Use
IIT
Investigator Initiated Trial
IRB
Institutional Review Board
IND
Investigational New Drug Application
IRT
Interactive Response Technology
ISMB
Independent Safety Monitoring Board
ITT
Intention to Treat
IVH
Intraventricular Hemorrhage
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LISA
Less Invasive Surfactant Administration
LSMs
Least Square Means
MAP
Mean Airway Pressure
MBP
Mean Blood Pressure
MDI
Mental Development Index


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MDR
Medical Device Report
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model for Repeated Measures
MV
Mechanical Ventilation
nCPAP
Nasal Continuous Positive Airway Pressure
NDA
New Drug Application
nHFOV
Nasal High Frequency Oscillatory Ventilation
NICHD
National Institute of Child Health and Human 
NICU
Neonatal Intensive Care Unit
NIPPV
Nasal Intermittent Positive Pressure Ventilation
NIV
Non-Invasive Ventilation
OFC
Occipital-Frontal Circumference
OR
Odds ratio
pO2
Partial Pressure of Oxygen
pCO2
Partial Pressure of Carbon Dioxide
PDA
Patent Ductus Arteriosus
PEEP
Positive End-Expiratory Pressure
PIE
Pulmonary Interstitial Emphysema
PIP
Peak Inspiratory Pressure
PIPP
Premature Infant Pain Profile
PMA
Post-Menstrual Age
PNA
Post-Natal Age
PPV
Positive Pressure Ventilation
PVL
Periventricular Leukomalacia
RCT
Randomized Clinical Trial
RDS
Respiratory Distress Syndrome
ROP
Retinopathy of Prematurity
RR
Respiratory rate
RSS
Respiratory Severity Score
SAE
Serious Adverse Event
SaO2
Oxygen Saturation
SAP
Statistical Analysis Plan
SP-B
Surfactant Protein B
SP-C
Surfactant Protein C
SBP
Systolic Blood Pressure
SOP
Standard Operating Procedure
SpO2
Preductal Oxygen Saturation
SUSAR
Suspected Unexpected Serious Adverse Reaction
UADE
Unanticipated Adverse Device Effect
WHO
World Health Organization


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CONTENT
GENERAL INFORMATION........................................................................................................................2
PROTOCOL OUTLINE................................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS...........................................................16
CONTENT..................................................................................................................................................18
1.
INTRODUCTION ...............................................................................................................................23
1.1
Background Information and Study Rationale ............................................................................23
1.2
Risk/benefit assessment ...............................................................................................................24
2.
STUDY OBJECTIVES........................................................................................................................25
2.1 
Primary Objective(s)....................................................................................................................25
2.2
Secondary Objective(s)................................................................................................................25
3.
STUDY DESIGN.................................................................................................................................26
4.
SUBJECT SELECTION CRITERIA ..................................................................................................27
4.1
Subject Recruitment ....................................................................................................................27
4.2
Inclusion Criteria .........................................................................................................................27
4.3
Exclusion Criteria ........................................................................................................................27
4.4
Subject Withdrawals....................................................................................................................28
5.
CONCOMITANT MEDICATIONS ...................................................................................................29
5.1
Permitted concomitant Medications ............................................................................................29
5.2
Non-permitted previous and concomitant Medications...............................................................30
6.
TREATMENT(S) ................................................................................................................................30
6.1
Appearance and Content..............................................................................................................30
6.2
Dosage and Administration..........................................................................................................30
6.2.1
Selection of doses in the study............................................................................................30
6.2.2
Dosage.................................................................................................................................30
6.2.3
Administration....................................................................................................................30
6.2.4
Subject Training .................................................................................................................36
6.3
Packaging.....................................................................................................................................36
6.3.1
Primary packaging..............................................................................................................37
6.3.2
Secondary packaging .........................................................................................................37
6.3.3
Tertiary packaging..............................................................................................................37
6.4
Labeling .......................................................................................................................................37


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6.5
Treatment allocation ....................................................................................................................37
6.6
Treatment Code............................................................................................................................38
6.7
Treatment compliance..................................................................................................................38
6.8
Drug and Device Storage.............................................................................................................38
6.9
Drug Accountability.....................................................................................................................39
6.10
Provision of additional care .........................................................................................................39
7.
STUDY PLAN.....................................................................................................................................39
7.1
Study Schedule.............................................................................................................................39
7.1.1
Pre-randomization Period - On admission prior to study treatment administration......42
7.1.2
Day 1 - From study treatment administration to 24 hours post-treatment .....................43
7.1.3
48 hrs after study treatment administration......................................................................44
7.1.4
72 hrs after study treatment administration......................................................................44
7.1.5
120 hrs after study treatment administration....................................................................45
7.1.6
28 days PNA .......................................................................................................................45
7.1.7
36 weeks PMA....................................................................................................................45
7.1.8
Discharge home or 40 weeks PMA (whichever comes first) ..............................................46
7.1.9
Clinical assessment at 24 months (±3 months) corrected age.........................................47
7.2
Investigations...............................................................................................................................47
7.2.1
Neonatal pain assessment by Premature Infant Pain Profile (PIPP) score [26].............47
7.2.2
Vital signs and Blood tests ................................................................................................48
7.2.3
Assessment of Bronchopulmonary Dysplasia..................................................................48
7.2.4
Clinical assessment of growth and development and respiratory morbidity, using a 
health status questionnaire.................................................................................................................48
8.
EFFICACY ASSESSMENTS .............................................................................................................49
9.
SAFETY ASSESSMENTS..................................................................................................................50
10.
ADVERSE EVENTS REPORTING ...............................................................................................52
10.1.
Definitions................................................................................................................................52
10.2.
Expectedness............................................................................................................................54
10.3.
Intensity of Adverse Event.......................................................................................................54
10.4.
Causality Assessment...............................................................................................................55
10.5.
Action taken with study drug due to AE..................................................................................56
10.6.
Other actions taken ..................................................................................................................56
10.7.
Outcome...................................................................................................................................56
10.8.
Recording Adverse Events.......................................................................................................56


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10.9.
Reporting Serious Adverse Events to the Sponsor ..................................................................58
10.10.
Reporting Serious Adverse Events/Unanticipated Adverse Device Effects to Regulatory 
Authorities/ IRB.......................................................................................................................................59
10.11.
General Notes...........................................................................................................................59
10.12.
Independent Safety Monitoring Board.....................................................................................60
11.
DATA MANAGEMENT.................................................................................................................61
12.
STATISTICAL METHODS............................................................................................................61
12.1.
Sample Size..............................................................................................................................61
12.2.
Populations for analysis...........................................................................................................62
12.3.
Statistical analysis....................................................................................................................62
12.3.1.
Descriptive Statistics..........................................................................................................62
12.3.2.
Missing data........................................................................................................................62
12.3.3.
Description of the population-description of baseline characteristics............................62
12.3.4.
Efficacy variables...............................................................................................................63
12.3.5.
Safety variables...................................................................................................................64
12.3.6.
Interim Analysis .................................................................................................................66
13.
INSTITUTIONAL REVIEW BOARD APPROVAL .....................................................................66
14.
REGULATORY REQUIREMENTS...............................................................................................67
15.
INFORMED CONSENT .................................................................................................................67
16.
SOURCE DOCUMENTS/DATA....................................................................................................67
16.1.
Recording of source data .........................................................................................................67
16.2.
Direct access to source document/data ....................................................................................67
17.
STUDY MONITORING .................................................................................................................68
18.
QUALITY ASSURANCE...............................................................................................................68
19.
INSURANCE AND INDEMNITY .................................................................................................68
20.
CONFIDENTIALITY......................................................................................................................69
21.
PREMATURE TERMINATION OF THE STUDY .......................................................................69
22.
CLINICAL STUDY REPORT ........................................................................................................69
23.
RECORD RETENTION..................................................................................................................69
24.
PUBLICATION OF RESULTS ......................................................................................................70
25.
REFERENCES ................................................................................................................................71
APPENDIX I ...............................................................................................................................................75
APPENDIX II..............................................................................................................................................76
APPENDIX III.............................................................................................................................................77


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APPENDIX IV.............................................................................................................................................78


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APPENDICES
APPENDIX I
Approval of Clinical Study Protocol by the Investigator 
APPENDIX II
Minimum list of Source Data Required 
APPENDIX III
Complications of Prematurity
APPENDIX IV
PIPP Score Assessment Tool


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1.
INTRODUCTION
1.1
Background Information and Study Rationale
Respiratory distress syndrome (RDS) is the most common respiratory disease of premature 
neonates and its incidence is directly proportional to the degree of prematurity. The National 
Institute of Child Health and Human Development (NICHD) Neonatal Research Network 
showed a 93% incidence of RDS in a cohort of 9575 extreme premature neonates with 
gestational age (GA) of 28 weeks or below, born between 2003 and 2007 [1]. In fact, despite 
a constant improvement of neonatal care, RDS still represents one of the major causes of 
mortality in preterm neonates, as confirmed in a recent US review (64 deaths per 1000 live 
births) [2].
The clinical features of RDS start appearing soon after birth. RDS is characterized by 
tachypnea (rapid breathing), expiratory grunting, subcostal and intercostal retractions, 
cyanosis, nasal flaring, apnea and/or hypothermia in extremely immature neonates. In the pre-
surfactant era, the disease led rapidly to progressive respiratory failure in the first 2-3 days of 
life [3] and, in the most severe cases, to the death of premature babies. Moreover, RDS can be 
followed by respiratory complications, such as bronchopulmonary dysplasia (BPD), most 
commonly in those neonates who required ventilatory support and/or oxygen therapy for RDS 
treatment [4].
The pathophysiology of RDS has been correlated to lung immaturity and surfactant 
deficiency. Surfactant, a macro-aggregate composed of highly organized lipids and specific 
proteins, is produced by type 2 cells in the alveoli and placed in the air liquid interface. It 
mainly reduces surface tension and prevents alveolar collapse, particularly at end-expiration, 
so that adequate gas exchange is maintained throughout the ventilatory cycle [5].
Surfactant therapy has become the standard of care in management of preterm neonates with 
RDS since it was able to reduce mortality and the incidence of pulmonary air leaks such as 
pneumothorax by about 50% [6,7].
The current American [8] and European [3] approach for treatment of neonatal RDS 
recommends a policy of early initiation of non-invasive ventilation, like Continuous Positive 
Airway Pressure (CPAP), immediately after birth and early selective surfactant 
administration. This strong recommendation derives from different studies that demonstrated 
the role of CPAP as first-step stabilization of preterm neonates with RDS in combination with 
early rescue surfactant therapy [9,10]. A new technique to deliver surfactant intratracheally in 
spontaneously-breathing neonates by using a thin catheter in combination with CPAP has been 
described in the literature in the last years [11].The development of this technique, most 
frequently called Less Invasive Surfactant Administration (LISA), has been based on the 
evidence from several studies that avoiding endotracheal MV and stabilizing very premature 
neonates on early CPAP in the delivery room may be one way of reducing BPD [12]. Indeed, 
even a short period of positive pressure ventilation could be harmful for the immature lung of 


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preterm neonates. Furthermore, LISA could allow administration of surfactant without the 
disadvantage of withholding non-invasive respiratory support [11].
A meta-analysis of seven randomized clinical trials (RCTs) comprising 3289 subjects 
confirmed that avoiding endotracheal MV reduces the combined outcome of death or BPD in 
preterm neonates <30 weeks’ GA [12]. The early studies analyzed in the meta-analysis 
compared non- invasive respiratory support (e.g., CPAP) with standard intubation and 
rapid extubation after surfactant instillation, while more recent studies compared the LISA 
method with standard endotracheal intubation and surfactant administration. In spite of the 
differences of the study protocols and designs, the overall strategy of avoiding MV consistently 
led to a reduction in the incidence of death or BPD in all trials.
In Germany a first LISA technique with a soft, small diameter tube (gastric catheter) inserted 
through the nose into the pharynx with the use of Magill forceps has been described [13,14]. A 
second procedure, the Hobart method [15,16], has been proposed by an Australian group who 
uses a slightly stiffer vascular catheter, introduced through the mouth into the pharynx without 
the use of Magill forceps. In both procedures, the catheter is secured by the fingers of the 
neonatologist and surfactant slowly administered without withholding CPAP support. After 
surfactant instillation, the catheter is immediately removed. Maintaining the neonates on 
CPAP throughout the whole procedure seems helpful in reducing the incidence of 
desaturations.
The LISA method has only been evaluated in Investigator Initiated Trials (IITs) that showed 
promising results in terms of neonatal respiratory morbidity and seem to represent a 
significant improvement in the management of RDS [17,18].
The LISA method for porcine surfactant administration (poractant alfa, Curosurf®, Chiesi 
Farmaceutici S.p.A.) has been approved and added to the current authorized 
methods/techniques by European Authorities and other countries outside of Europe; 
moreover, the specific thin catheter (CHF 6440), developed by Chiesi Farmaceutici S.p.A. 
(Parma, Italy) for poractant alfa delivery through LISA technique and used in the present 
study, has been approved (CE mark) in Europe as well as other countries.
This Phase IIIb explorative study is mainly aimed at investigating the safety and efficacy 
profiles of porcine surfactant (poractant alfa, Curosurf®, Chiesi Farmaceutici S.p.A.) 
administered through LISA technique during a non-invasive respiratory support or 
conventional intubation with brief ventilation.
This trial will be conducted in compliance with the Declaration of Helsinki (1964 and 
amendments), the current ICH E6 Good Clinical Practices and all other applicable laws and 
regulations.
1.2
Risk/benefit assessment
The application of LISA technique allows administration of surfactant without interrupting the 
non-invasive respiratory support, so avoiding the need for intubation and administration of 


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invasive positive pressure ventilation even for a short period.
The LISA technique, as well as other methods for less invasive surfactant administration through 
thin catheter, have been evaluated in several IIT and compared with conventional surfactant 
administration through endotracheal tube (including application of an intubation, surfactant 
administration and rapid extubation procedure). Even with limitations related to the heterogeneity 
and quality of the studies, recent meta-analysis showed that benefits associated with less invasive 
surfactant methods include reduced need for MV and reduced rate of mortality and BPD [17,18].
Moreover, some recent studies have also suggested a reduction in the incidence of Retinopathy of 
prematurity (ROP) and Intraventricular hemorrhage (IVH) in neonates receiving surfactant 
through LISA technique [19,20].
Some transient adverse events, including oxygen desaturation, apnea, bradycardia, coughing, 
chocking, sneezing, and surfactant reflux, have been observed more frequently during LISA 
procedure compared to conventional administration [17,21,22]. These events are usually mild and 
easily managed. In a recent large cohort study, an increased risk of focal intestinal perforation 
(FIP) (10% vs 7.4%) was observed in the subgroups of neonates <26 weeks GA [19]. The authors 
suggest that other factors, beside LISA, could contribute to the pathogenesis of FIP in this 
population of highly vulnerable neonates, including: early exposure to maximum CPAP levels, 
modulators of mucosal integrity (devices, bacterial colonization, nutrition, drugs), delayed 
meconium passage, and frequency of episodes of relevant desaturation (leading to temporary 
hypoxia of the gut).
Considering the above reported information, the safety profile of the treatment, the measures in 
place to ensure the patients’ safety and the expected scientific value, the overall risk/benefit 
assessment can be considered acceptable for the proposed trial.
2.
STUDY OBJECTIVES
2.1 
Primary Objective(s)
The main objective of this study is to evaluate the safety profile of the administration of 
porcine surfactant (poractant alfa, Curosurf®) through a less invasive method (LISA) using a 
thin catheter (CHF 6440) during non-invasive ventilation (NIV) (CPAP, NIPPV, BiPAP), 
compared to an approved conventional surfactant administration during invasive ventilation 
and rapid extubation, in spontaneously breathing preterm neonates with clinical signs of 
respiratory distress syndrome (RDS).  The short-term and mid-term safety will be assessed: 
adverse events and adverse drug reactions occurring during overall procedure for surfactant 
administration, neonatal pain assessment pre- and during surfactant administration, duration 
of surfactant administration, incidence of BPD at 36 weeks post menstrual age (PMA), major 
neonatal morbidities and vital signs.
2.2
Secondary Objective(s)
Moreover, short-term and mid-term efficacy profile will also be assessed mainly in terms of: 
reduced oxygen requirement and ventilatory support, need for invasive mechanical ventilation 
in the first 72 hours of life and throughout the study period, duration of invasive and non-


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invasive ventilation and need for additional surfactant doses.
3.
STUDY DESIGN
This is an open-label, multicenter, randomized and controlled study. Approximately 25 
investigational sites will be involved in US. Neonates will be evaluated according to the 
selection criteria and then randomized to surfactant treatment via LISA or standard 
administration procedure (Table 1). The enrollment will be staggered: the gestational age will 
be restricted to 27+0 weeks up to 28+6 completed weeks until safety evaluation by ISMB is 
performed for the first 15 neonates. Provided no safety concerns are raised, the enrollment 
will then be extended to the whole population (i.e. 25+0 weeks up to 28+6 completed weeks). 
Enrolled neonates will be evaluated: 
until discharge,  
until 40 weeks PMA (if still in hospital), 
if discharge occurs before 36 weeks, the last evaluation will be at 36 weeks PMA.
This period represents the main phase of the trial. 
Their final assessment of development will be at 24-month corrected age as a separate stand-
alone visit. This 24-month clinical assessment will be analyzed and evaluated separately from 
the initial part of the study and will be object of an addendum to the initial core clinical study 
report.
Table 1: TIMETABLE
PROCEDURE A
poractant alfa 200 mg/kg LISA (thin catheter CHF 6440) (re-dosing if 
needed with poractant alfa 100 mg/kg)
Prior to study treatment 
from 30 min to 24 
hours of life
PROCEDURE B
poractant alfa 200 mg/kg ETT with brief 
ventilation (re-dosing if needed with poractant alfa 
100 mg/kg)
Time
0
5’
15’
30’
1h
6h
12h
24h
48h
72h
120h 28 days 
PNA
36 wks 
PMA
Discharge / 40 
wks PMA
24 -month 
clinical 
assessment
Surfactant 
administration


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End of the trial
The end of the trial will correspond to the last evaluation of the last neonate from the recruiting 
site or from the continuing care site in case the treated baby was transferred from the original 
recruiting site. The last evaluation could be:
-
the date of the assessment for BPD diagnosis (i.e. 36 weeks PMA) if the patient is 
discharged home before 36 weeks PMA, 
-
discharge home (if discharged between 36 weeks and 40 weeks PMA), or
-
40 weeks PMA (if still in hospital). 
4.
SUBJECT SELECTION CRITERIA
4.1
Subject Recruitment
The study population consists of premature neonates with early clinical signs of RDS, 
spontaneously breathing and stabilized with NIV (CPAP, NIPPV, BiPAP). One hundred and 
fifty (150) subjects who meet all the inclusion and none of the exclusion criteria are expected 
to be randomized in the study. No limitation by ethnic origin or social status will be used. 
RDS is defined in this study population by the presence of respiratory symptoms and signs, 
associated to an increased inspired oxygen requirement, from 30 minutes up to the first 24 
hours of life.
4.2
Inclusion Criteria
Subjects must meet all the following inclusion criteria to be eligible for enrolment into the 
study:
1.
Written informed consent obtained by parents/legal representative (according to 
local regulation) prior to or after birth;
2.
Preterm neonates of either sex aged ≥30 minutes and <24 hours, spontaneously 
breathing and stabilized on NIV;
3.
Gestational age of 25+0 weeks up to 28+6 completed weeks; enrollment will be restricted 
to subjects aged 27+0 weeks up to 28+6 GA weeks until safety evaluation of first 15 
subjects is completed;
4.
Clinical course consistent with RDS;
5.
Fraction of inspired Oxygen (FiO2) ≥0.30 to maintain preductal SpO2 in the target 
range of 88–95%.
4.3
Exclusion Criteria
The presence of any of the following criteria will exclude a subject from study enrollment:
1.
Need for immediate endotracheal intubation for cardiopulmonary resuscitation or 
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2.
Use of nasal high frequency oscillatory ventilation (nHFOV) prior to study entry;
3.
Use of surfactant prior to study entry and need for intratracheal administration of 
any other treatment (e.g. nitric oxide);
4.
Known genetic or chromosomal disorders, major congenital anomalies (congenital 
heart diseases, myelomeningocele, etc.);
5.
Mothers with prolonged premature rupture of the membranes (> 21 days duration) 
which could cause complications (in particular, severe pulmonary hypoplasia due 
to oligohydramnios);
6.
Presence of air leaks if identified and known prior to study entry;
7.
Evidence of severe birth asphyxia (e.g. continued need for resuscitation at 10 
minutes after birth, altered neurological state or neonatal encephalopathy);
8.
Neonatal seizures prior to study entry;
9.
Any condition that, in the opinion of the Investigator, would place the neonate at 
undue risk;
10.
Participation in another clinical trial of any medicinal product, placebo, 
experimental medical device or biological substance conducted under the 
provisions of a protocol on the same therapeutic target; the participation in studies 
involving diagnostic devices or studies with treatments for different conditions 
than lung and respiratory function impairments may be permitted following an 
agreement with the sponsor. Non-interventional observational studies are allowed.
4.4
Subject Withdrawals
Parents/legal representative have the right to withdraw the subject from the study at any time 
for any reason.
The Investigator also has the right to withdraw the subjects from the study in the event of:

An adverse event which is considered intolerable by the Investigator prior to 
surfactant administration.

An abnormal laboratory test result that the Investigator considers clinically 
significant and warranting the withdrawal of the subject prior to surfactant 
administration.

A 
concomitant 
clinical 
condition/disorder/anomaly 
that 
necessitates 
pharmacological treatment with a drug which interacts in any way with the study 
treatment prior to surfactant administration.

Hypersensitivity to the active substance or to any of the excipients with regards to 
the second and third possible treatments with poractant alfa (if needed).

The development of any exclusion criterion prior to surfactant administration.
Detection of COVID-19 infection at the enrollment or during the study does not automatically 
lead to withdrawal of the subject.  It will be up to the investigator’s judgement to withdraw 


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the subject from the study if he/she deems that remaining in the study will place the subject 
and/or the clinical site at undue risk by continuing their participation. The investigator/site 
staff must take all necessary precautions to minimize and avoid the risk of transmission and 
exposure to study subjects and site staff, according to local guidelines.
The Investigator is responsible for the optimal individual treatment for the subject. The 
Investigator must complete the “Study Termination” page of the electronic case report form 
(eCRF) explaining the main reason for withdrawal.
5.
CONCOMITANT MEDICATIONS    
Subjects may be treated with other medications as needed in the critical care situation. The 
treating physician will manage neonates as he/she deems to be in their best interest.
Investigators are required to record all these medications in the eCRF with the only exception of 
the following drugs, when they are administered for prophylaxis only and not relative to any 
adverse event:  

Multivitamin or single vitamins (except for vitamin K and vitamin A which must be 
recorded);

Probiotics and lactoferrin;

Nystatin;

Iron supplements;

Folic acid;

Calcium and phosphorus;

Symeticon;

Glycerine suppository. 
5.1
Permitted concomitant Medications
Any concomitant medication required for the normal care of preterm neonates will be 
permitted during the study and recorded in the eCRF.
The use of sedative/analgesic medication, as well as the use of atropine, before / during 
surfactant administration, will be at investigator’s discretion and according to each neonatal 
intensive care unit (NICU) internal standard practice. If premedication is used, the 
Investigator should define a protocol (with specification of drugs and dosages) before starting 
enrollment, which allows for a step-by-step management of pain and sedation for the 
endotracheal administration of surfactant. Each neonate will be managed according to the pre-
defined protocol, and decision on which step of the protocol to apply should be based on 
neonate’s needs.  The same step-by-step protocol should be applied to both treatment arms. 
The protocol will be provided to the Sponsor.
If caffeine is administered, it should be used in both treatment arms.


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5.2
Non-permitted previous and concomitant Medications
1.
Surfactant treatment prior to randomization and study treatment administration;
2.
Intratracheal administration of any other treatment (e.g. nitric oxide) prior to 
randomization and study treatment administration;
3.
Other investigational drugs or investigational devices under the provisions of a 
protocol on the same therapeutic target. See exclusion criteria #10.
6.
TREATMENT(S)
6.1
Appearance and Content
Poractant alfa (Curosurf®) is a standard natural surfactant treatment prepared from porcine 
lungs for intratracheal administration and containing almost exclusively polar lipids, in 
particular phosphatidylcholine (about 70% of the total phospholipid content), and about 1% 
of specific low molecular weight hydrophobic proteins SP-B and SP-C with a total 
concentration of 80 mg/ml. The drug product is filled in sealed 3.0 ml glass vials
Chiesi Farmaceutici S.p.A. will supply the study medication and also provide the 
Pharmacist/Investigator with appropriate certificates of analytical conformity.
6.2
Dosage and Administration
6.2.1
Selection of doses in the study
Poractant alfa (Curosurf®) will be administered as 200 mg/kg for the first dose and 100 mg/kg 
for additional doses.
6.2.2
Dosage
Poractant alfa (Curosurf®) 2.5 ml/kg (200 mg/kg) sterile suspension in one single intratracheal 
administration from 30 minutes after birth up to 24 hours after birth.
Poractant alfa 1.25 ml/kg (100 mg/kg) will be used for further re-dosing in both arms (see 
section 6.2.3.6) up to two repeated doses.
6.2.3
Administration
6.2.3.1 Preparation for surfactant administration
Poractant alfa should be administered by, or under the supervision of, clinicians experienced 
in intubation, ventilator management, and general care of premature neonates. The neonate 
should be stabilized before surfactant administration.
Since poractant alfa suspension is refrigerated, before use each vial must be warmed up slowly 
to room temperature e.g. by placing it in an incubator for about 1 hour or keeping it in hands 
for 5-10 minutes and gently turned upside down, without shaking, avoiding the formation of 
foam. Artificial warming methods should not be used.


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The entire contents of the vial of poractant alfa suspension should be slowly withdrawn into a 
3 or 5mL plastic syringe through a large-gauge needle and the excess poractant alfa discarded. 
The syringe filled with poractant alfa suspension will be connected directly to LISA thin 
catheter (CHF 6440) in LISA cohort or attached to a 5-French catheter end-hole inserted into 
the endotracheal tube (ETT) or to the proximal end of the secondary lumen of a dual lumen 
ETT in the standard cohort, according to the approved delivery method.
Preparation should also include appropriate equipment such as an oxygen source, 
appropriately sized bags, face masks, stylet, laryngoscope and suction.
Neonatal team should include at least two people present during the maneuver: one performing 
the procedure and one additional person who can assist.
Before starting the procedure and throughout it, neonates must have cardiorespiratory 
monitoring: oxygen saturation and heart rate continuously through pulse oximetry, blood 
pressure measurement either continuously in presence of an arterial catheter or intermittently 
if no arterial line is in place.
6.2.3.2 Sedation and analgesia
The use of sedative/analgesic medication, as well as the use of atropine, before/during 
surfactant administration, will be at investigator’s discretion and according to each neonatal 
intensive care unit (NICU) internal standard. 
If premedication is used, the Investigator should define a protocol (with specification of drugs 
and dosages) before starting enrollment, which allows for a step-by-step management of pain 
and sedation for the endotracheal administration of surfactant. Each neonate will be managed 
according to the pre-defined protocol, and decision on which step of the protocol to apply 
should be based on neonate’s needs. The same step-by-step protocol should be applied to both 
treatment arms. The protocol will be provided to the Sponsor.
A first step could be attempted with a non-pharmacological analgesic technique (sucrose, glucose, 
holding, swaddling and methods of sensorial saturation).
A pharmacological intervention could be given following a progression in the use of 
sedatives/analgesics, based on neonate’s need. As a guidance, examples of pharmacological 
interventions which can be used (either alone or in combination) are the following:

Vagolytic agents (e.g. atropine).

Sedative/analgesics medications with rapid onset and short duration of action (e.g. 
fentanyl).
The use of sedation/analgesia and other medications will be carefully recorded along with 
related information (e.g. date and time of administration, dosage and route) in the relevant 
section of the eCRF.
6.2.3.3 LISA procedure
LISA-delivery of poractant alfa to the lung will be done via brief insertion of the thin catheter 


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(CHF 6440) through the mouth into the trachea, while the subject is being supported with 
NIV. The thin catheter will be provided by the Sponsor (Figure 1: CHF 6440).
CHF 6440 is a sterile, single-use catheter. It has a working length of 130.0 mm, presents a 1.7 
mm Outer Diameter (corresponding to a 5 French OD), with a 1.1 mm Internal Diameter 
(corresponding to 3.5 French ID) through which the surfactant is delivered. The hole at the 
distal edge has a diameter of 0.8 mm. It includes a standard polycarbonate mono Luer 
connection at the proximal end. The Luer is bonded to a reinforced shaft, with the shaft 
consisting of composite assembly of an overcoat / jacket, a braided woven stainless steel, and 
a Pebax liner. The Pebax leading tip of the device presents a rounded and soft distal edge to 
provide an atraumatic lead for the catheter during insertion via mouth. Printed depth markings 
on the outer surface of the shaft provide visual guide to the depth of device insertion during 
clinical procedure. Do not manipulate, kink and bend the catheter prior to its insertion. Check 
the presence of the ring markings prior to the insertion of this catheter.
The neonate will be placed supine with the head in neutral position before the onset of the 
procedure. The procedure should be performed with the NIV remaining in situ during 
surfactant administration. Poractant alfa should be administered by, or under the supervision 
of clinicians experienced in intubation of premature neonates. The investigators’ site staff will 
be trained during the Investigators’ meeting and site initiation visits in performing the LISA 
technique through a specific informative video as well as the provision of a specific 
mannequinError! Hyperlink reference not valid. designed to facilitate the training of healthcare 
professionals in the initiation of proper care and resuscitation of preterm infants.
Following direct laryngoscopy, the catheter will be introduced orally and inserted though the 
vocal cords into the trachea to the desired depth of 1-2 cm, the laryngoscope will be carefully 
removed while the catheter is secured by the fingers of the neonatologist/investigator, who 
will finally close the neonate’s mouth. The correct position of the catheter into the trachea will 
be confirmed by the visualization of tip depth markings and by the tip- to-lip measurement. The 
thin catheter presents three different ring markings close to the tip, equal to 1, 2 and 3 cm 
(Figure 1C) and helpful to address the depth of insertion beyond the vocal cords. Moreover, 
the catheter presents markings going from 5 to 9 cm for the tip-to-lip measurement, which 
represents the standard method to estimate the correct position also of the ETT [23]. 
After having confirmed the correct position of the catheter into the trachea, the syringe filled 
with poractant alfa suspension will be connected to the Luer of the catheter and poractant alfa 
will be instilled over 0.5-3 minutes with careful observation of the neonate’s continuous 
spontaneous breathing. Once the surfactant is administered, the catheter will be removed. 
Before removing the LISA catheter, it should be fully cleared of surfactant with some 
additional air. After completion of surfactant administration, ventilatory support may require 
transient adjustments. Airways suction should not be performed for 1 hour after surfactant 
instillation, unless signs of significant airway obstruction occur.
If on the first attempt the catheterization of the trachea is not possible within 30 seconds, the 
laryngoscope should be removed and if required neonate’s recovery allowed. Then a second 


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attempt should be performed for a total number of 3 attempts.
Details of the procedure as well as neonate’s vital signs and any occurring adverse event will 
be recorded according to the time points of the protocol by the team member assisting or 
observing the procedure.
Figure 1: CHF 6440
Figure 1A
CHF 6440 Full View
Figure 1B
Close-up on CHF 6440 Components 
a) Standard Luer
b) Rounded and Soft Tip


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Figure 1C
Close-up of Markings Present on CHF 6440 Shaft


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6.2.3.4 Conventional Intubation, surfactant administration and brief ventilation
As standard control treatment, neonates spontaneously breathing and stabilized on NIV will 
receive surfactant via ETT using an approved method of administration, connecting the 
syringe filled with poractant alfa suspension to:

a 5-French end-hole catheter inserted into the ETT 
or

the proximal end of the secondary lumen of a dual lumen ETT.
The standard ETT has markings along the side to help identifying the correct distance from the 
tip of the tube.
Following direct laryngoscopy, the ETT will be inserted through the vocal cords into the 
trachea to the desired depth. The laryngoscope will be then carefully removed. The correct ETT 
position into the trachea will be confirmed by the visualization of tip depth markings and by 
the tip-to-lip measurement. The tube position could be checked by auscultation of the chest to 
ensure equal aeration of both lungs, observation of chest movement synchronous with positive 
pressure inflation, enhancement of vital signs, absence of stomach distension while 
ventilation, and where possible, with the measurement of end tidal CO2 by colorimetric system 
on the ETT. Once the tube position is confirmed, the ETT will be secured with adhesive tape or 
other ways according to the NICU policy.
After administration, manual ventilation can be continued, or the neonate can be connected to 
the ventilator, or the neonate can be immediately extubated and placed again on NIV. Do not 
suction airways for 1 hour after surfactant instillation unless signs of significant airway obstruction 
occur. 
If connected to the ventilator, extubation should be performed within one hour after surfactant 
administration and then the neonate placed again on NIV.
Details of the procedure as well as neonate’s vital signs and any occurring adverse event will 
be recorded according to the time points of the protocol by the team member assisting or 
observing the procedure.
6.2.3.5Need for resuscitation during surfactant administration
In both arms of the study, if a life-threatening event requiring resuscitation occurs during 
poractant alfa administration, the procedure of surfactant administration will be stopped and 
resuscitation provided starting from supplying Positive Pressure Ventilation (PPV) and 
following step-by-step the American Guidelines for Neonatal Resuscitation [24,25].
6.2.3.6 Additional surfactant treatment
Up to two repeated doses could be administered at 100 mg/kg.
A second surfactant dose (poractant alfa 100 mg/kg) will be administered using the same 
technique as the first dose administration in case of lack of efficacy, or clinical deterioration, 


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as per randomization criteria (FiO2 ≥0.30 to maintain preductal oxygen saturation (SpO2) in 
the target range 88–95%), within approximately 12 hours from the initial dose.
After the first and the second surfactant administration, neonates could receive a third 
surfactant dose (poractant alfa 100 mg/kg).  If a third dose is administered, it will be provided 
through a standard technique. Neonates could be intubated (LISA group) or re-intubated 
(control group) for MV at neonatologist’s discretion, if one or more of the below detailed 
conditions for MV in section 6.2.3.7 are satisfied.
6.2.3.7Intubation and extubation criteria
Intubation for mechanical ventilation and further surfactant doses could happen if one or more 
of the following criteria are satisfied:

FiO2 ≥0.45 to maintain preductal SpO2 of 88-95% for at least 30 minutes, unless 
rapid clinical deterioration occurs;

Significant apnea (more than four episodes of apnea/hour or more than two 
episodes of apnea/hour if ventilation with bag and mask was required);

Respiratory acidosis (pCO2 >65 mmHg/8.5 kPa and pH <7.20 identified by either 
arterial or capillary blood gas monitoring).
These criteria will be applied during the first 3 days of life (72 hours).
After the first 3 days of life, intubation and mechanical ventilation can happen as per Investigator’s 
clinical judgement.
FiO2 and SpO2 values should be collected at time of decision for intubation and recorded in eCRF 
as well as the criterion for intubation.
Criteria for termination of Mechanical Ventilation and Extubation are defined as follows:

Clinical improvement, e.g. presence of a good respiratory drive;

Ability to wean FiO2, e.g. FiO2 <0.30 to maintain SpO2 between 88 and 95%.

Ability to wean ventilatory pressures, e.g. MAP <7 in conventional ventilation or 
MAP <8 in HFOV;

Normalization of blood gases’ values, e.g. pCO2 < 65 mmHg and pH ≥7.20.
6.2.4
Subject Training
Not Applicable.
6.3
Packaging
Chiesi Farmaceutici S.p.A. will supply the study medication for both groups as well as the 
thin catheter (CHF 6440) for the administration in the relevant LISA treatment group.
The study medication kit is composed of a single glass vials of 3 ml of Poractant alfa for initial 
dosing or possible re-dosing; the vial will be packed in an outer box and will be provided to 


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the investigational sites. Each vial is for single use only. Any need for dosing and re-dosing 
will require a vial to be issued via IRT (see Section 6.6).
CHF 6440 catheters will be packed and provided separately. 
6.3.1
Primary packaging
Poractant alfa:
Labeled glass vial containing 3 ml of Poractant alfa at a concentration of 80 mg/ml for 
respectively initial dosing and possible re-dosing.
CHF 6440 catheters:
A sterile labeled tyvek pouch containing CHF 6440 catheter.
6.3.2
Secondary packaging
Poractant alfa:
A holder containing one labelled glass vial containing 3 ml of Poractant alfa.
CHF 6440 catheter:
A labeled carton containing a tyvek pouch .
6.3.3
Tertiary packaging
Not applicable.
6.4
Labeling
The supplies (Poractant alfa and CHF 6440 catheters, in primary and secondary packaging) 
will be labeled in English and according to US law and FDA regulatory requirements in 
compliance with Annex 13 of Volume 4 of the GMPs and in compliance with 21 CFR 312.6 
“Labelling of an Investigational New Drug”, for US Trials.
The tear-off sticker from the vial box and the tear off sticker from the catheter carton will be 
applied in the appropriate section of the surfactant accountability log.
6.5
Treatment allocation
A balanced block randomization scheme stratified by investigational site and gestational age 
group (i.e. from 25+0 to 26+6 weeks and from 27+0 to 28+6 weeks) will be prepared via a 
computerized system. Once the neonate’s eligibility to take part in the study is confirmed, 
neonates will be centrally assigned to one of the two treatment arms (LISA/Poractant alfa or 
ETT/Poractant alfa) through an IRT system (Interactive Response Technology, combination 
of voice and web response system and also referred as IVRS/IWRS). Enrollment will be 
staggered: the gestational age will be restricted to 27+0 to 28+6 weeks for at least the first 15 
randomized neonates. After ISMB evaluation of safety data from the first 15 neonates, provided 
no safety concerns are raised, the enrolment will be extended to the whole population (25+0 to 26+6 
weeks and from 27+0 to 28+6 weeks).


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The IRT will allocate the subject to a certain treatment group using a list-based randomization 
algorithm and assign the unique screening number of eight digits: the country will be the first 
three digits (according to ISO 3166 Numeric Country Code), the investigational site number 
will be the second two digits and the following three digits will be the progressive numbering 
of the subject within each site (e.g. for the first USA site the screening numbers will be 
84001001, 84001002 etc.). The IRT will also generate a confirmation after every IRT 
transaction is performed.
The Investigator will call the IRT on admission to receive the subject screening number and 
randomize the subject and obtain the medication (Poractant alfa) kit numbers. Detailed 
instructions for use of IRT will be provided to the site.
In the LISA group, the relevant catheter provided by the Sponsor (CHF 6440) will be dispensed 
and used for administration. In the control group, the endotracheal tubes available at the 
investigational sites for clinical practice will be used for administration.
The LISA catheter (CHF 6440) will be dispensed by the IRT system.
6.6
Treatment Code
The study medication (Poractant alfa) will be packaged and uniquely numbered. The IRT will 
be used to assign both initial and subsequent kits in order to have an inventory control and 
subject dosing tracking. The IRT will also maintain quantities, kit numbers, drug types, 
batch/code numbers, expiration dates and do not dispense after these dates. The IRT will 
monitor inventory levels at all sites and manage the study drug re-supply.
6.7
Treatment compliance
The actual volume of poractant alfa administered will be entered in eCRF. The evaluation of 
compliance will be done based on the actual volume administered in relation to the neonates’ 
weight using the following formula:
Volume administered / Volume scheduled * 100% = % of administered volume
The volume scheduled will be calculated on the basis of neonates’ weight as 2.5ml x birth 
weight (kg) for the first dose and as 1.25 ml x birth weight (kg) for following doses.
6.8
Drug and Device Storage
The Pharmacist/Investigator will be responsible for the safe storage of all medications and 
catheters assigned to this study, in a secure place with restricted access, and maintained within 
the appropriate ranges of temperature.
Poractant alfa will have to be stored between 2° and 8°C (36° to 46°F), protected from light, 
until the moment of use. 
CHF 6440 catheter does not require any special storage condition. Keep in a cool dry place.


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Please refer to CTS Instructions for Use.
6.9
Drug Accountability
The Investigator or pharmacist is responsible for the management of all the study treatments 
and thin catheters CHF 6440 to be used for the study. Study treatments should be stored in a 
locked, secure storage facility with access limited to those individuals authorized to dispense 
the study drugs.
An inventory will be maintained by the Investigator or pharmacist (or other nominated 
individual), to include a signed account of all the study treatment(s) and LISA catheters 
received and used for each subject. The actual volume of instilled study treatment will be 
reported in the relevant section of the eCRF.
At the conclusion or termination of the study, the Investigator or the pharmacist shall conduct 
and document a final drug supply (used and unused) inventory. An explanation should be 
given for any discrepancies.
No surfactant material or catheters for this trial are to be used for any other purpose.
In addition, a signed account shall be kept of all study treatments administered to each subject.
All the study treatments supplied, used or unused, will be returned for destruction to the 
designated Clinical Trial Supply (CTS) vendor/depot under Sponsor’s responsibility or 
destroyed directly by the Pharmacy of the involved investigational site upon provision of 
destruction certificate and documentation assuring the occurred destruction according to 
standard procedures and filed both at investigator’s site file and at Sponsor/CRO trial master 
file.
6.10
Provision of additional care
At study completion, it is the Investigator’s responsibility to prescribe the more appropriate 
treatment for the subject.
7.
STUDY PLAN
7.1
Study Schedule
This study will include the following periods and visits:
Periods:

Pre-randomization period: on admission to the study prior to study treatment;

Day 1: randomization, before start of study procedure, treatment administration up 
to end of surfactant administration (T0); up to 24 hours after receiving study 
treatment (5, 15, 30 min, 1, 6, 12, 24 hours);

Day 2: from 24 hours to 48 hours post treatment;

Day 3: from 48 hours to 72 hours post treatment;


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
Day 5: from 96 hours to 120 hours post treatment.
Follow-up visits:

28 days Post-Natal Age (PNA);

36 weeks Post-Menstrual Age (PMA);

Discharge home or 40 weeks PMA, whichever comes first; 

24 months (±3 months) corrected age visit.
Details are reported in the following sections and summarized in the following flowchart 
(Table 2):


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Table 2: FLOWCHART
ASSESSMENT
On admission prior 
to study treatment
from 30 minutes up 
to 24 hours of life
Before starting 
procedure(1)
T0 (2)
5’
15’
30’
1-h
6-h
12-h
24-h
48-h
72-h
120-h
DAY 28 
PNA
36 wk 
PMA
Disch. 
Home/40 
wk(3)PMA
24-m 
Clin. 
Ass.
Randomization/ Access IRT
X
Study Treatment (Surfactant administration)
X
Informed Consent (Parental/ Maternal) (4)
X
Inclusion/ Exclusion Criteria
X
Pregnancy complications and prenatal 
corticosteroids use
X
Demographic data (including weight, OFC, 
length)
X
X(5)
X 
X
Apgar Score
X
Medical History (conditions diagnosed before 
treatment)
X
X
Vital signs (HR, RR, BP)
X
X
X (6)
X (6)
X
X
X
X
X
X
X
X
X
X (6)
X (6)
X (6)
X
Preductal Oxygen Saturation (SpO2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fraction of Inspired Oxygen (FiO2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Evaluation of respiratory support and oxygen 
alone use
X
  
NIV parameters
X
X
X
X
X
X
X
X
Pain Score Assessment
X
X
Concomitant Medications
X
Blood gas analysis 
X
X
X
X
X
X
X
Record information for BPD assessment
X
Adverse Events (7)
Flow rate evaluation
X
X
Bayley Scales
X
Health status questionnaire
X
X
(1)
Parameters and Pain score assessment to be collected within 15 minutes before starting procedure (laryngoscope insertion)
(2)
End of surfactant administration
(3)
Health status visit will be performed at discharge home or 40 weeks PMA, whichever comes first
(4)
Signature of Parental/ Maternal Informed Consent can be obtained prior to birth or after birth
(5)
Only weight to be assessed 
(6)
Only heart rate and respiratory rate
(7)
AEs to be assessed and recorded starting from the beginning of the procedure


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The following time deviations from theoretical post-dose times will be allowed:
Table 3: ALLOWED TIME DEVIATIONS
Post-dose time assessments
Allowed deviations
5, 15 minutes
+ 1 minute
30 minutes
+ 5 minutes
1 hour
+ 10 minutes
6, 12 and 24 hours
+ 30 minutes
48, 72, and 120 hours
+ 2 hours
28 days PNA
+ 2 days
36 wks PMA
+ 4 days
40 wks PMA (if still in hospital)
+ 2 days
24 months clinical assessment
+ 3 months
7.1.1
Pre-randomization Period - On admission prior to study treatment 
administration
The study will be explained to the parents of a potentially eligible neonate prior to birth, if 
possible, giving the parents the maximum time to make an informed choice. Once parental/ 
maternal written informed consent has been obtained either prior to or after birth, the neonate’s 
eligibility to take part in the study will be assessed according to the post-birth inclusion and 
exclusion criteria. If the neonate becomes eligible, then the medical history of the mother, the 
complications during pregnancy and the prenatal use of corticosteroids will be collected.
If the neonate becomes eligible, then the following information will be collected:

Birth weight, occipital-frontal circumference (OFC), length;

Apgar score at 1 and 5 min from birth;

All medical conditions diagnosed before treatment drug administration, to be 
reported as “Medical History”. To this group should be added thereafter those 
congenital conditions that, even if already present at birth, could be diagnosed after 
study treatment administration (including: major organ malformations, genetic 
diseases and/or chromosomal abnormalities); 

Concomitant medications;

Clinical signs of RDS, such as tachypnea, retractions, nasal flaring, expiratory grunt;

SpO2 along with vital signs (systolic, diastolic and mean blood pressure, heart rate, 
respiratory rate);


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
Fraction of inspired oxygen (FiO2);

Type of respiratory support (CPAP, BiPAP, NIPPV);

Blood gas analysis (values of pH, pCO2, pO2, HCO3, BE, lactate), when feasible.
7.1.2
Day 1 - From study treatment administration to 24 hours post-treatment
Once the neonate’s eligibility to take part in the study is confirmed, the Investigator will have 
to call/check the IRT to randomize the neonate to the treatment group (LISA or ETT).
Before starting the procedure:
Within 15 minutes before starting the procedure (before laryngoscope insertion), the 
following information will be collected:

SpO2 along with vital signs (systolic, diastolic and mean blood pressure, heart rate, 
respiratory rate);

Fraction of inspired oxygen (FiO2);

Type of respiratory support (CPAP, BiPAP, NIPPV);

Non-invasive ventilation parameters (CPAP pressure, BiPAP pressures, NIPPV peak 
pressure, PEEP, mean airway pressure);

Pain score assessment (PIPP score) [26] by observing the subject for 15 seconds 
(see APPENDIX IV);

Blood gas analysis (values of pH, pCO2, pO2, HCO3, BE, lactate), unless the time 
from the blood gas analysis at screening is less than 1 hour. In this case only one blood 
gas analysis is acceptable;

All medical conditions diagnosed before treatment drug administration, to be 
reported as “Medical History”, including congenital conditions that could be 
diagnosed after study treatment administration;

Concomitant Medications.
After Starting the Procedure:
From the start of the procedure (laryngoscope insertion) through the first 24 hours from 
administration, the following information will be collected:

SpO2 and FiO2 at time 0 (end of surfactant administration), and at 5, 15, 30 min, 
1 hour, 6, 12 and 24 hours after the end of study treatment administration;

Vital signs (SDB, DBP, MBP, HR, RR):  15, 30 min, 1 hour, 6, 12 and 24 hours 
after the end of study treatment administration; HR and RR to be reported also at 
time 0 and 5 min (as showed in flow chart Table 2);

Evaluation of respiratory support: any change in non-invasive ventilation, need 
for intubation and invasive mechanical ventilation with the relevant dates and 
times;

If applicable, NIV parameters (as specified above) at 30 minutes, 1 hour, 6, 12 and 24 


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hours after the end of treatment administration; 

Evaluation of oxygen alone use: duration of needing supplementary oxygen with 
the relevant dates and times;

PIPP score immediately following surfactant administration after observing the 
neonates for 30 seconds (see APPENDIX IV);

Capillary or arterial blood gas analysis (values of pH, pCO2, pO2, HCO3, BE, 
lactate) at 1 hour, 6 hours and 24 hours after the end of study treatment 
administration;

Surfactant- and procedure-related adverse events will be strictly monitored during 
the whole procedure for surfactant administration (see section 10.8);

Adverse events diagnosed after treatment administration (including worsening of 
conditions pre-existing to treatment); major complications of prematurity (listed in 
APPENDIX III) to be recorded among adverse events; 

Further neonatal concomitant medications.
7.1.3
48 hrs after study treatment administration
The following information will be collected:

FiO2, SpO2, vital signs (SBP, DBP, MBP, HR and RR) and, if applicable, NIV 
parameters (as specified above) at the same time;

Evaluation of respiratory support: any change in non-invasive ventilation, need 
for intubation and invasive mechanical ventilation with the relevant dates and 
times;

Evaluation of oxygen alone use: duration of needing supplementary oxygen with 
the relevant dates and times;

Blood gas analysis (values of pH, pCO2, pO2, HCO3, BE, lactate);

Further neonatal concomitant medications and adverse events (including 
worsening of conditions pre-existing to treatment), as well as changes in those 
already reported; major complications of prematurity (listed in APPENDIX III) to be 
recorded among adverse events.
7.1.4
72 hrs after study treatment administration
The following information will be collected:

FiO2, SpO2, vital signs (SBP, DBP, MBP, HR and RR) and, if applicable, NIV 
parameters (as specified above) at the same time;

Evaluation of respiratory support: any change in non-invasive ventilation, need for 
intubation and invasive mechanical ventilation with the relevant dates and times;

Evaluation of oxygen alone use: duration of needing supplementary oxygen with 
the relevant dates and times;

Blood gas analysis (values of pH, pCO2, pO2, HCO3, BE, lactate);


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
Further neonatal concomitant medications and adverse events (including 
worsening of conditions pre-existing to treatment) as well as changes in those 
already reported; major complications of prematurity (listed in APPENDIX III) to be 
recorded among adverse events.
7.1.5
120 hrs after study treatment administration
The following information will be collected:

FiO2, SpO2 and vital signs (SBP, DBP, MBP, HR and RR) at the same time;

Evaluation of respiratory support: any change in non-invasive ventilation, need for 
intubation and invasive mechanical ventilation with the relevant dates and times;

Evaluation of oxygen alone use: duration of needing supplementary oxygen with 
the relevant dates and times;

Further neonatal concomitant medications and adverse events (including 
worsening of conditions pre-existing to treatment) as well as changes in those 
already reported; major complications of prematurity (listed in APPENDIX III) to be 
recorded among adverse events.
7.1.6
28 days PNA
The following information will be collected:

FiO2 (highest recorded value), SpO2, HR and RR at the same time;

Evaluation of respiratory support: any change in non-invasive ventilation, need for 
intubation and invasive mechanical ventilation with the relevant dates and times;

Evaluation of oxygen alone use: duration of needing supplementary oxygen with the 
relevant dates and times;

Further neonatal concomitant medications and adverse events (including worsening 
of conditions pre-existing to treatment) as well as changes in those already reported; 
major complications of prematurity (listed in APPENDIX III) to be recorded among 
adverse events.
In case the neonate was discharged home (either by the recruiting site or by a continuing care 
site) prior to 28 days of life, the neonate should be recalled for an on-site clinic visit at the 
recruiting site. If not feasible, any effort should be made to collect information about the 
occurrence of any adverse events as well as about any change in concomitant medications. The 
Investigator should contact the family pediatrician to collect the relevant information.
In case the treated neonate was transferred to a continuing care site prior to 28 days PNA and 
the neonate is still hospitalized there, the neonate should be recalled at the recruiting site for the 
visit. If this is not feasible, the visit can be replaced by a contact/phone call by the Investigator 
to the physician of the continuing care site to collect relevant information and check the 
occurrence of any other adverse event as well as of any change in concomitant medications.
7.1.7
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The following information will be collected:

Weight

FiO2 (highest recorded value) SpO2, HR and RR at the same time;

Evaluation of respiratory support: any change in non-invasive respiratory support, 
need for intubation and invasive mechanical ventilation with the relevant dates and 
times;

Evaluation of oxygen use alone: duration of needing supplementary oxygen with 
the relevant dates and times;

If receiving respiratory support via nasal cannulae: evaluation if flow rate ≤2 l/min 
or >2 l/min

BPD assessment: breathing room air or on oxygen, if neonate has received oxygen 
for at least 28 days, need of positive-pressure respiratory support (see Section 
7.2.3);

Further neonatal concomitant medications and adverse events (including 
worsening of conditions pre-existing to treatment) as well as changes in those 
already reported; major complications of prematurity (listed in APPENDIX III) to be 
recorded among adverse events.
In case the subject is discharged home or transferred to a continuing care site prior to this 
visit, the subject should be recalled as soon as possible for an on-site clinic visit at the 
recruiting site. If not feasible, any effort should be made to collect relevant information for BPD 
assessment, adverse events as well as any change in concomitant medications. The investigator 
should therefore contact the physician of the continuing care site or the family pediatrician to 
collect the relevant information. In case study visits or procedures are modified or missed due to 
COVID-19, the relevant information will be recorded in the eCRF. If the subject was discharged 
without any supplemental oxygen or respiratory support, an on-site visit is not mandatory, but the 
Investigator should contact the family pediatrician to collect the relevant information to complete 
BPD evaluation.
7.1.8
Discharge home or 40 weeks PMA (whichever comes first)
The below assessments will be performed at discharge, or at 40 weeks PMA if the infant is 
still in hospital. The following information will be collected:

SpO2, HR and RR at the same time;

Weight, OFC and length;

Evaluation of respiratory support (if present): non-invasive respiratory support, or 
invasive mechanical ventilation and related FiO2;

If receiving respiratory support via nasal cannulae: evaluation if flow rate ≤2 l/min 
or >2 l/min

Evaluation of feeding status, hearing screen status, medications for respiratory 
problems;


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
Assessment of relevant neonatal co-morbidities, their severity and treatment;

Further neonatal concomitant medications and adverse events (including 
worsening of conditions pre-existing to treatment) as well as changes in those 
already reported.
In case the infant had been transferred to a continuing care site, the recruiting site is 
responsible for the proper continuation of data collection and documentation of the primary 
and secondary outcomes. The investigator of the recruiting site should keep contacts and 
provide the continuing care site with written instruction about management of the above as 
well as for the reporting of serious AE, if any. The recruiting site should receive a discharge 
letter clarifying as much detailed information as possible the progress in subject’s 
conditions.
Routine clinical safety data included in the discharge home summary letter should be 
sought to complete data collection.
If the discharge home coincides with the 36 weeks PMA visit, both assessments should be 
completed and recorded in the eCRF.
7.1.9
Clinical assessment at 24 months (±3 months) corrected age
A further clinical assessment will be performed at 24 months (±3 months) corrected age at the 
participating study centers. In this occasion, age and age corrected for prematurity will be 
collected. This clinical assessment will be based on:

Bayley Scales of Infant Development Edition III or IV (see Section 7.2.4);

Health status questionnaire (additional evaluation of growth and development, 
respiratory assessment);

Vital signs (SBP, DBP, MBP, HR and RR);

Body weight, length and OFC.
7.2
Investigations
7.2.1
Neonatal pain assessment by Premature Infant Pain Profile (PIPP) score [26]
This is a composite score system based on the following indicators:

Gestational age;

Behavioral state before painful stimulus;

Change in heart rate during painful stimulus;

Change in oxygen saturation during painful stimulus;

Brow bulge during painful stimulus;

Eye squeeze during painful stimulus;

Nasolabial furrow during painful stimulus.
The interpretation can vary from a minimum score of 0 to a maximum score of 21. The higher 
the score the greater the pain behavior (APPENDIX IV).


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-
7.2.2
Vital signs and Blood tests

Heart rate and pre-ductal SpO2 are measured by pulse oximetry;

Respiratory rate is shown on the cardiorespiratory monitor and can be measured by 
bioimpedance electrode sensors or chest wall motion sensors;

Systolic, diastolic and/or mean blood pressures are measured either in a non-
invasive or in invasive way, depending on the availability of an arterial catheter;

Blood gas analysis (values of pH, pCO2, pO2, HCO3, BE, lactate) will be 
performed either with arterial or capillary samples. Small volumes of blood (e.g. 
some droplets) will be collected in pre-heparinized tubes or syringes. When 
collected through an arterial line, at least 1.6 ml of blood should be withdrawn 
before collection of the blood gas sample to avoid contamination errors.
7.2.3
Assessment of Bronchopulmonary Dysplasia
To define presence and severity of BPD, the definition from the National Institute of Child Health 
and Human Development (NICHD) will be used, with some adaptation [4] (Table 4). According 
to this definition, BPD is diagnosed if treatment with >21% oxygen is required for at least 28 days; 
for subjects with GA at birth <32 weeks (including our study population); severity of BPD is 
assessed at discharge or at 36 weeks PMA, whichever comes first, and is based on requirement of 
oxygen and/or positive pressure ventilation (Table 4). It is classified as mild, if at the time point 
of assessment the subject is breathing room air, moderate if still needs for supplemental oxygen 
less than 30%, severe if needs oxygen greater than or equal to 30% and/or positive pressure (PPV 
or nCPAP). 
In this clinical study, BPD assessment will be performed at 36 weeks PMA for all treated subjects. 
If the discharge home is before the 36 weeks PMA and the subject is discharged with supplemental 
oxygen and/or positive pressure, a further visit will be required at 36 weeks PMA. If the discharge 
home is before 36 weeks PMA and the subject is discharged without supplemental oxygen or any 
respiratory support, an on-site visit is not mandatory, but the Investigator should contact the caring 
pediatrician to collect the relevant information and complete the evaluation. 
Table 4
Definition of bronchopulmonary dysplasia for infants with GA at birth < 32 weeks: 
Diagnostic criteria adapted from 2001 NICHD consensus workshop [4]
Gestational Age
< 32 wks
Time point of assessment*
36 wks PMA 
Treatment with oxygen >21% for at least 28 days plus
Mild BPD
Breathing room air
Moderate BPD
Need for <30% oxygen
Severe BPD
Need for ≥30% oxygen and/or positive pressure (PPV or NCPAP)
* Assessed at 36 weeks timepoint for all the study subjects when possible
7.2.4
Clinical assessment of growth and development and respiratory morbidity, 
using a health status questionnaire 


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The Clinical assessment of growth and development and respiratory morbidity will be done 
through a questionnaire to record weight, length and head circumference, result of the last 
cardiological evaluation and timing, the feeding method, the cerebral palsy, seizures, functional 
disability (vision, hearing, and communication), respiratory conditions and morbidity. This latter 
is mainly addressed to test the BPD severity (if any) at two-year corrected age.
To measure cognitive and language development, the score from the related sections of the Bayley 
Scales III and IV (i.e. cognitive and language domains) will be reported in the questionnaire. 
Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, aged 0-3. This measure consists of a series of 
developmental play tasks and takes between 45 - 60 minutes to administer. Raw scores of 
successfully completed items are converted to scale scores and to composite scores. These scores 
(recorded in the eCRF) are used to determine the child's neurodevelopmental performance 
compared with norms taken from typically developing children of their age (in months).
8.
EFFICACY ASSESSMENTS
The following variables will be used to describe the efficacy of the two procedures:

Percentage of neonates needing invasive mechanical ventilation (MV) in the first 
72 hours of life, 28 days PNA and within 36 weeks PMA defined as follows:
ETT group

neonates not extubated within 1 hour from initial surfactant administration and 
receiving MV for more than 1 hour;

neonates extubated and re-intubated to receive MV of any duration.
LISA group

neonates intubated to receive MV of any duration, 
o
Duration of invasive ventilation (hours) in the first 72 hours of life, 28 days 
PNA and within 36 weeks PMA;
o
Percentage of neonates needing any intubation procedure, outside the 
initial surfactant administration period, in the first 72 hours of life, in the 
first 28 days PNA and within 36 weeks PMA;
o
SpO2 at time 0 (study treatment administration), 5, 15, 30 minutes, at 1, 6, 
12, 24, 48, 72 and 120 hours post treatment; additionally, at 28 days PNA 
and at 36 weeks PMA for neonates still receiving any form of respiratory 
support;
o
FiO2 at time 0 (study treatment administration), 5, 15, 30 minutes, at 1, 6, 
12, 24, 48, 72 and 120 hours post treatment; additionally, at 28 days PNA 
and at 36 weeks PMA for neonates still receiving any form of respiratory 


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support;
o
SpO2/FiO2 at time 0 (study treatment administration), 5, 15, 30 minutes, at 
1, 6, 12,24, 48, 72 and 120 hours post treatment; additionally, at 28 days 
PNA and at 36 weeks PMA for neonates still receiving any form of 
respiratory support;
o
Percentage of neonates needing additional surfactant doses and number of 
surfactant doses;
o
Duration of oxygen alone supplementation (days) and any non-invasive 
ventilation during the study (days);
o
Blood gas analysis, specifically acid-base balance parameters (i.e. pH, 
pCO2, pO2, HCO3, BE, lactate) pre-surfactant administration (when 
applicable), at 1 hour, 6 hours, 24, 48 and 72 hours after study treatment.
9.
SAFETY ASSESSMENTS
The following variables will be used to describe the safety of the two procedures:
During procedure for surfactant administration

Number and percentage of neonates with AEs starting during overall procedure 
for surfactant administration; 

Number and percentage of neonates with AEs starting during overall procedure 
for surfactant administration judged related to the procedure;

Number of AEs occurring during overall procedure for surfactant administration 
requiring either oxygen alone or an increase in FiO2 without the need for 
escalation of invasive or non-invasive ventilator support;

Number of AEs starting during overall procedure for surfactant administration 
requiring administration of manual (bag and mask) pressure positive ventilation 
and related duration of ventilation (non- invasive ventilation);

Number of AEs starting during overall procedures for surfactant administration 
requiring endotracheal intubation and related duration of intubation (invasive 
ventilation);

Number of AEs starting during overall procedures for surfactant administration 
requiring circulatory support including administration of crystalloids;

Number of AEs starting during overall procedures for surfactant administration 
requiring cardiopulmonary resuscitation including administration of cardiac 
massage or adrenaline.
After first administration


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
Number and percentage of neonates with failed 1st attempt to insert the 
CHF6440/ETT;

Number of attempts to the first successful insertion;

Number of device misallocation (esophageal insertion);

Number of maneuvers discontinued due to neonate’s severe destabilization;

Duration of the whole procedure (starting from the insertion of laryngoscope up 
to the removal of the catheter or ETT);

Duration of surfactant administration (min);

Heart rate (HR) and respiratory rate (RR) (0, 5, 15 and 30 min, 1 hour, 6 and 12 
hours after administration);

Systolic, diastolic, and mean blood pressure (SBP/DBP/ MBP) (15 and 30 min, 1 
hour, 6 and 12 hours after administration);

Premature Infant Pain Profile (PIPP) score [26] (end of surfactant administration).
During the study

AEs, including incidence of major neonatal complications of prematurity (listed 
in APPENDIX III) and adverse drug reactions (ADRs);

Blood pressure (SBP, DBP, MBP) at 24, 48, 72, 120 hours post-administration;

Heart Rate (HR) and respiratory rate (RR), at 24, 48, 72, 120 hours post-
administration and 28 PNA, 36 weeks PMA, discharge home or 40 weeks PMA 
whichever comes first;

Incidence of BPD at 36 weeks PMA;

Death/BPD incidence at 36 weeks PMA, defined as the incidence of the neonates 
who are dead or alive but with a diagnosis of BPD at the time of assessment (i.e. 
36 weeks PMA);

Mortality at Day 28 PNA and 36 weeks PMA;

Oxygen use (alone and/or during invasive and non-invasive ventilation) at Day 28 
PNA and 36 weeks PMA;

Weight, OFC and length at discharge home or 40 weeks PMA;

Feeding and hearing status at discharge home or 40 weeks PMA, whichever comes 
first;

Incidence of major neonatal morbidities at discharge home or 40 weeks PMA, 
whichever comes first; 

Neonates needing invasive ventilation or non-invasive respiratory support at 
discharge home or 40 weeks PMA;

Neonates needing respiratory medications at discharge home or 40 weeks PMA.


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24 months (±3 months) corrected age
(This stand-alone assessment will be analyzed and reported separately from the main phase)

Health status questionnaire, including:

Bayley Scales of Infant Development (cognitive and language scores);

Feeding method: spoon, nasogastric tube or gastrostomy;

Cerebral palsy evaluation;

Seizure evaluation;

Vision, hearing and communication evaluation;

Clinical assessment of respiratory conditions and morbidity;

Vital signs (SBP/DBP/MBP, HR, RR);

Growth assessment (Weight, OFC and length).
10.
ADVERSE EVENTS REPORTING
10.1.
Definitions
An Adverse Event is “any untoward medical occurrence in a subject or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment”.
An adverse event can therefore be any unfavorable and unintended sign (including abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product.
An Adverse Drug Reaction is an “untoward and unintended responses to an investigational 
medicinal product related to any dose administered”.
All adverse events judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to an investigational product qualify as adverse reactions. The 
expression “reasonable causal relationship” means to convey in general that there are facts 
(evidence) or arguments meant to suggest a causal relationship.
The definition covers also medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product.
A Serious Adverse Event (SAE)/Serious Adverse Drug Reaction is any untoward 
medical occurrence or effect that at any dose falls in one or more of the following 
categories:

Results in death
Death is not an adverse event but an outcome. It is the cause of death that should be 
regarded as the adverse event. The only exception to this rule is “sudden death” where 
no cause has been established; in this latter instance, “sudden death” should be 
regarded as the adverse event and “fatal” as its reason for being serious.


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
Is life-threatening
Life-threatening refers to an event in which the subject was at risk of death at the time 
of the event (e.g., aplastic anemia, acute renal failure and anaphylaxis). The term does 
not refer to an event which hypothetically might have caused death if it were more 
severe.

Requires hospitalization or prolongation of existing hospitalization
Hospitalization refers to a situation whereby an AE is associated with unplanned 
overnight admission into hospital, usually for purpose of investigating and/or treating 
the AE. Hospitalization for the treatment of a medical condition that occurs on an 
“elective” or “scheduled” basis or for a pre-existing condition that did not worsen 
during the study should not necessarily be regarded as an AE. Complications that 
occur during the hospitalization are AEs. If a complication prolongs hospitalization, 
the event is an SAE.
Emergency room visits that do not result in a formal admission into hospital should 
be evaluated for one of the other seriousness criteria (e.g., life-threatening; persistent 
or significant disability or incapacity; medically significant).

Results in persistent or significant disability or incapacity
The term significant disability should be viewed as any situation whereby an AE has 
a clinically important effect on the subject’s physical or psychological well-being to 
the extent that the subject is unable to function normally.

Is a congenital anomaly or birth defect (not applicable for this study)

Is a medically significant adverse event
This criterion allows for any situations in which important adverse events/reactions 
that are not immediately life-threatening or do not result in death or hospitalization 
may jeopardize the subject’s health or may require intervention to prevent one of the 
above outcomes.
Examples of such events are: intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.
Medical and scientific judgment should be exercised in deciding whether an event is 
serious because medically significant.
Any suspected transmission via a medicinal product of an infectious agent is also considered 
a serious adverse reaction.
A Non-Serious Adverse Event/Non-Serious Adverse Drug Reaction is an adverse event 
or adverse drug reaction that does not meet the criteria listed above for a serious adverse 
event/serious adverse drug reaction.


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A Device Deficiency, for the purpose of this trial, is any inadequacy of a medical device 
related to its identity, quality, durability, reliability, safety or performance, such as 
malfunction.
An Unanticipated Adverse Device Effect (UADE) is defined as any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.
10.2.
Expectedness
An expected adverse reaction is an adverse reaction, the nature or severity of which is 
consistent with the applicable reference safety information (included in the Poractant 
alfa/CHF 6440 catheter Investigator’s Brochure), otherwise it is considered unexpected.
Reports which add significant information on specificity or severity of a known, already 
documented serious adverse drug reaction constitute unexpected events. For example, an 
event more specific or more severe than described in the above relevant documentations 
would be considered as “unexpected”. General examples of such events are: (a) acute renal 
failure as a labeled ADR with a subsequent new report of interstitial nephritis and (b) 
hepatitis with a first report of fulminant hepatitis.
10.3.
Intensity of Adverse Event
The investigator is asked to assess the intensity of all the adverse events and to report them 
in the eCRF.
Each Adverse Event must be rated on a 3-point scale of increasing intensity:

Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations only; 
no change in baseline age-appropriate behavior (e.g. oral feeding behavior, 
voluntary movements and activity). The event does not lead to establishment of a 
correcting treatment.

Moderate: resulting in minor changes of baseline age appropriate behavior; 
requiring minor changes in baseline care or monitoring (e.g. oxygenation, 
ventilation, tissue perfusion, metabolic stability and organ functioning). The event 
leads to establishment of a correcting treatment.

Severe: resulting in severe discomfort with major changes of baseline age-
appropriate behavior; requiring major change in baseline care or monitoring (e.g. 
brief, local, non-invasive or symptomatic treatments). 
For the classification of AEs intensity, the ‘INC Neonatal Adverse Event Severity Scale 
(NAESS) v1.0’’[27] may be used as a guidance.
Since the above-mentioned guidance is based on a 5-grade table, the following conversion 
will be performed:


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
AEs grade 1: Mild

AEs grade 2: Moderate

AEs grade 3, 4 and 5: Severe
In order to guarantee objectivity and consistency in the evaluation of AEs (including 
classification of intensity), the proposed guidance should be followed in alignment with best 
medical practice. Moreover, clinical abnormalities and other abnormal assessments will be 
reported as AEs if are judged by the Investigator as being clinically significant.
10.4.
Causality Assessment
The following “binary” decision choice will be used by the Investigator to describe the 
causality assessment with the study medication/device/procedure:

Reasonable possibility of a relatedness with study medication/device/procedure

No reasonable possibility of relatedness with study medication/device/procedure
Each AE will be evaluated for its relationship with the study drug (Poractant alfa), and also 
with the specific procedure for surfactant administration in both treatment groups. Moreover, 
for baby randomized to the LISA group, causal relationship to CHF 6440 medical device 
will be also assessed.
An AE will be assessed as related to the medical device (i.e. CHF 6440 catheter) if associated 
with its technical features or with any defect/malfunction.
An AE will be assessed as related to the procedure (i.e. LISA or intubation, surfactant 
administration and brief ventilation) if connected with the technique, including user 
difficulties in applying it.
An AE can be assessed as related to multiple choices. 
The expression “reasonable possibility of relatedness” is meant to convey, in general, that there 
are facts (evidence) or arguments meant to suggest a causal relationship.
The Investigator will be asked to consider the following before reaching a decision on 
causality assessment:

Time relationship between study drug intake/device use/procedure for 
administration and event’s onset;

Medical history;

Lack of efficacy/worsening of existing condition;

Study treatment(s);

Mechanism of action of the study drug/device;

Class effects of the study drug;

Other treatments-concomitant or previous;

Erroneous treatment with study medication (or concomitant)/device/procedure for 


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administration;

Protocol related process.
10.5.
Action taken with study drug due to AE
Since subjects will receive a single dose of study drug, “action taken with study drug” will 
be not applicable.
10.6.
Other actions taken

Specific therapy/medication;

Concomitant procedure;

Supplementary oxygen alone;

FiO2 increase;

Manual Positive Pressure Ventilation;

Endotracheal intubation and invasive ventilation;

Administration of adrenaline, crystalloids or colloids;

Not applicable.
10.7.
Outcome
Each Adverse Event outcome must be described by choosing among:

Recovered/resolved;

Recovering/resolving;

Not recovered/not resolved;

Recovered with sequelae/resolved with sequelae;

Fatal;

Unknown.
10.8.
Recording Adverse Events
All AEs occurring during the course of the study must be documented in the Adverse Event 
page of the eCRF. Moreover, if the Adverse Event is serious, the Serious Adverse Event Form 
must also be completed.
It is responsibility of the Investigator to collect all adverse events (both serious and non-
serious).
The recording period for Adverse Events is the period starting from the beginning of the 
procedure until the subject’s study participation ends.
Given the significant amount of possible comorbidities in the study population, any condition 
diagnosed before the start of the procedure will be considered a baseline condition and will 
be recorded in the Medical History page of the eCRF. The occurrence or worsening of these 
conditions during and after the study procedure must be recorded as an AE in the eCRF. 


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The only exception to this rule is represented by congenital anomalies including major organ 
malformations, genetic diseases and/or chromosomal abnormalities, that should be reported 
as baseline conditions even if diagnosed after treatment. 
If a clinically significant abnormal laboratory finding or other abnormal assessment detected 
during the study period meets the definition of an AE and is not assessed as pre-existing, 
then the AE eCRF page must be completed, as appropriate. A diagnosis, if known, or clinical 
signs and symptoms if diagnosis is unknown, rather than the clinically significant abnormal 
laboratory finding, should be reported on the AE eCRF page. If no diagnosis is known and 
clinical signs and symptoms are not present, then the abnormal finding should be recorded as 
adverse event.
Occurrence of COVID-19 infection during the study will be reported in the Adverse Events 
section of the eCRF if symptoms judged related to the infection are present. Every effort should 
be made by the site to confirm all suspected incidences of COVID-19 in accordance with local 
diagnostic guidelines. Tests for detecting SARS-CoV-2 infection, as well as their results, will be 
reported in the eCRF. Documentation of testing and results obtained outside the clinical site, 
should be collected within 14 days of confirmed diagnosis (or whenever possible) and recorded 
in the eCRF. For all confirmed cases of COVID-19/SARS-CoV-2 the investigator must follow 
the standard of care in accordance with local treatment guidelines. All concomitant treatments 
must be recorded in the eCRF as well.
For pharmacovigilance purposes, all SAEs should be followed-up in order to elucidate as 
completely and practically as possible their nature and/or causality until resolution of all 
queries, clinical recovery is complete, laboratory results have returned to normal, stable 
condition is reached or until the subject is lost to follow-up. Follow-up may therefore 
continue after the subject has left the study. In this case, the follow-up will continue with no 
timelines for related SAEs, while for unrelated SAEs the type and extent of follow-up 
undertaken will be determined for each individual case and will depend upon the nature (e.g. 
events with poor prognosis or which do not resolve), severity and medical significance of the 
event.
AEs related to the procedure for surfactant administration
The procedure for surfactant administration will last from the application of the laryngoscope 
up to the removal of the CHF 6440 catheter in the LISA treatment group or the ETT in the 
comparator arm within one hour after the instillation of poractant alfa.
All AEs during procedures for surfactant administration will be carefully monitored and 
recorded in both arms. Specific focus will have to be paid on the following AEs:

Obstruction of the CHF 6440 catheter or ETT;

Bradycardia;

Neonatal oxygen desaturation;


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
Apnoea;

Hypotension requiring treatment;

Any episodes of cough, sneezing, choking, laryngospasm, surfactant reflux, 
vomiting.
A complete qualitative risk assessment has been conducted to identify and mitigate potential 
safety risks associated with use of CHF 6440 medical device. The results provide evidence 
that the benefits of using the device outweigh the residual risks and do not highlight any 
specific additional risk or safety issue than the ones listed above.
10.9.
Reporting Serious Adverse Events to the Sponsor
The Investigator (or delegate) must report all Serious Adverse Events and any UADE to the 
 Safety Contact listed below within 24 hours of awareness.
Information on SAE (including UADE) must be sent by providing the completed, dated and 
signed paper Serious Adverse Event form. At a later date, the 
 Safety Contact will 
report all information to Chiesi Global Pharmacovigilance, the Clinical Project Manager and 
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
Reporting of SAEs from the investigator site is from the start of the procedure 
until the subject’s study participation ends. After this date, even if no active 
monitoring of subjects is required, related SAEs occurring to a subject should be 
reported if the investigator becomes aware of them.

Up to the closure of the site, SAEs/UADEs reports should be reported to the 
 Safety Contact. New related serious adverse events occurring after the 
site is closed should be reported directly to the Chiesi Safety Contact.
10.10. Reporting Serious Adverse Events/Unanticipated Adverse Device Effects to 
Regulatory Authorities/ IRB
The Sponsor or designated CRO will report adverse events to the regulatory authorities in 
compliance with the timelines and standards of reporting according to local regulations 
(Guidance for industry and Investigators-Safety Reporting Requirements for INDs and 
BA/BE studies, December 2012) as well as to the Investigators and Central IRB, if applicable, 
by MedWatch/CIOMS form. The Investigator (or Sponsor/CRO where required) must inform 
the IRB per Sponsor instruction upon receipt of the SUSAR notification. An IND and/or NDA 
Safety Report will be submitted to regulatory authorities unblinded. Participating 
Investigators and IRB will receive a blinded IND Safety Report, unless otherwise specified. 
All UADEs which occur with the medical device will be reported by the sponsor or designated 
CRO to regulatory authorities, as required, as well as to the Investigators and Central IRB, if 
applicable, as IND Safety Reports.
The Investigator (or Sponsor/ 
 where required) must ensure that the IRB receives a 
copy of the report and that a copy is also filed within their study files.
10.11. General Notes

In case of death, a comprehensive narrative report of the case should be prepared 
by the Investigator and provided to the 
 Safety Contact together with the 
Serious Adverse Event form, retaining a copy on site;

If an autopsy is performed, copy of autopsy report should be actively sought by 
the Investigator and provided to the 
 Safety Contact as soon as available, 
Name and Title
Telephone no.
E-mail
 Safety 
Toll free numbers
provided separately
 
Global Pharmacovigilance Chiesi 
Farmaceutici S.p.A., Parma 
(Italy)
Phone: 
Fax: 
 
ct_cds@chiesi.com


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retaining a copy on site;

All source documents provided by the Investigator or site staff to the 
 
Safety Contact must be carefully checked for respect of confidentiality. All 
personal subject’s data must be redacted.

Any Adverse Drug Reaction (ADR) occurring with any marketed non-
investigational medicinal product and/or concomitant medication during the study 
must be reported by the Investigator to his/her concerned Health Authority 
according to the applicable laws. The Investigator is also recommended to report 
all adverse drug reactions to the relevant Marketing Authorization Holders of the 
involved medicinal products. Additionally, also conditions of use outside the 
marketing authorization of the medicinal products (i.e. off-label, overdose, misuse, 
abuse and medication errors) or from occupational exposure, as well as cases of 
suspected drug interaction and lack of efficacy should be reported.

If a neonate is transferred to a continuing care site prior to end of the main phase 
of the trial, the investigator should ensure that the receiving hospital site is aware 
that the neonate is participating to the present study and communication should be 
maintained in order to record any adverse event. Moreover, the investigator of the 
recruiting site will have to provide the continuing care site with written instruction 
about management and reporting of SERIOUS AE. After discharge home from the 
continuing care site a copy of the discharge summary letter should be requested in 
order to cross reference any adverse events and to contribute to BPD assessment.
10.12. Independent Safety Monitoring Board
An Independent Safety Monitoring Board (ISMB) will be established to ensure the safety of 
study subjects on an on-going basis. The involvement of independent expert advisors will 
provide an unbiased evaluation of the overall safety in the study, with particular regard to 
the incidence of major adverse outcomes (i.e. Serious Adverse Events) following study 
treatment administration.
The ISMB will be composed by independent Clinicians and one independent Biostatistician.
The ISMB will have periodical face-to face or telephone meetings, as appropriate, and a 
Safety Assessment Report will be issued after each meeting. 
An ISMB meeting will be scheduled after the first 15 neonates will have been enrolled. If no 
safety concerns will be raised, enrollment will continue and will be extended to newborns with 
GA at birth between 25+0 weeks up to 28+6. Before obtaining a favorable opinion from the 
ISMB, only newborns with GA from 27+0 to 28+6 weeks will be enrolled. Further ISMB 
meetings will be scheduled after the first 60, 105 and 150 subjects, respectively. Ad-hoc ISMB 
meetings can be scheduled, if needed, in case of unexpected safety issues.
The Sponsor (and other study personnel) may be involved in some parts of the ISMB 
meetings.
All ISMB members will keep as confidential all information and data deriving from the 


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ISMB activity, without disclosing them to others.
The complete ISMB guidelines including details regarding the members, duties and 
responsibilities, work and communication processes, frequency of meetings will be 
established by the ISMB members during the first meeting and reported in a separate charter.
11.
DATA MANAGEMENT
An electronic case report form (eCRF) to be filled in by the investigator and/or his/her 
designee will be used. Access to electronic systems used for data collection will be granted to 
the study personnel only after appropriate training.
Front-end edit checks will run at the time of data collection and back-end edit checks will be 
run by the CRO Data Manager to check for discrepancies and to ensure consistency and 
completeness of the data.
Conditions pre-existing to the start of the procedure, concomitant procedures (even if 
recorded in a different form) and adverse events will be coded using the MedDRA dictionary 
while medications will be coded using the WHO Drug dictionary and Anatomical 
Therapeutic Chemical classification (ATC). The same dictionaries will be used to code 
mother’s medical history, complications during pregnancy and mother’s prenatal medications.
After cleaning of the data, a review meeting will be held to determine the occurrence of any 
protocol violation and to define the subject populations for the analysis.
Once the database of the main phase study has been declared to be complete and accurate, the 
eCRF forms will be locked and the planned statistical analysis will be performed. Only 
authorized and well-documented updates to the study data are possible after eCRF forms 
lock.
The Investigators will receive electronic copies of the subject data for retention at the 
investigational sites.
The 24-month clinical assessment data will be collected and recorded in a separate visit of the 
database: once all the data of the 24-month clinical assessment has been declared to be 
complete and accurate, the complete database will be locked and the planned statistical 
analysis for this assessment will be performed. 
The complete database, including the main phase data, will be newly transferred. Comparing 
procedures documenting anything hasn’t been changed in the main phase study data, will be 
prepared and archived in the TMF.
12.
STATISTICAL METHODS
12.1.
Sample Size
No primary efficacy endpoint was defined in this study since the main objective is to describe 
the overall safety and efficacy profile of administering poractant alfa with two different 


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procedures: LISA technique or conventional administration with endotracheal tubes and 
brief invasive ventilation. A total of 150 neonates will be randomized in the study with a 
ratio 2:1 to LISA arm (i.e. 100) and conventional administration arm (i.e. 50).
12.2.
Populations for analysis
The following populations will be considered for the analysis:

Intention-to-Treat population (ITT): all randomized subjects who will receive 
at least one dose of study medication.

Safety population: all randomized subjects who will take at least one dose of 
study medication.
The efficacy analyses population will be performed in the ITT population. The Safety 
population will be used in the analysis of all safety variables.
In case of deviation between as-randomized treatment and treatment actually received, the 
treatment actually received will be used in the safety analyses (i.e. an as-treated analysis 
will be performed).
12.3.
Statistical analysis
A detailed statistical analysis plan (SAP) will be described in a separate document. The plan 
might be reviewed and updated as result of the review of the data before database locking.
12.3.1.Descriptive Statistics
General descriptive statistics for numeric variables will include the n (number of observed 
values), the mean, the standard deviation, 95% CI, the median, the minimum, and the 
maximum values. For categorical variables, the number and percent of subjects with a specific 
level of the variable will be presented.
12.3.2.Missing data
Details on dealing with missing data, along with the handling of possible outliers, will be 
described in the SAP. Critical missing data, if any, will be discussed during the review of the 
data before database locking. Decisions will be fully documented in the Data Review Report.
12.3.3.Description of the population-description of baseline characteristics
Demographics and baseline variables will be summarized by treatment group using 
descriptive statistics for the ITT population.
The following variables will be summarized by treatment group and overall in order to 
describe the study population: neonate baseline characteristics and demographics (birth 
weight, gestational age, sex, race, APGAR score), maternal history including the mother’s 
age, race, medical and pregnancy history, current and pre-birth medications and delivery 
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The sex, GA, weight, age and age corrected for prematurity will be summarized at 24 months 
corrected age.
12.3.4.Efficacy variables
Need for mechanical ventilation/intubation

Percentage of neonates needing invasive mechanical ventilation in the first 72 
hours of life, in the first 28 days PNA and within 36 weeks PMA will be 
compared between group using the Cochran-Mantel-Haenszel (CMH) test 
adjusted for gestational age group. The CMH adjusted difference with its 95% CI 
will be presented. Additional analysis will be performed to explore the impact of 
use of sedation and/or analgesia. 

Percentage of neonates needing any intubation procedure, outside the initial 
surfactant administration period, in the first 72 hours of life, 28 days PNA and 
within 36 weeks PMA will be compared between treatments as need for IMV.
SpO2

SpO2 will be analyzed using a linear mixed model for repeated measures 
(MMRM) including treatment, time point, treatment by time point interaction, and 
gestational age group as fixed effects and pre-procedure SpO2 as covariate. The 
adjusted means in each treatment group, the adjusted mean difference between 
treatments and their 95% CIs at each time point and averaged over the first 120 
hours post-treatment will be estimated by the model. Time profile plot of mean 
SpO2 in the first 120 hours post-administration will be presented by treatment 
group.

SpO2 will be summarized by treatments on neonates still receiving respiratory 
support at 28±2 PNA and 36 weeks PMA by means of descriptive statistics.
FiO2

FiO2 will be analyzed using a linear MMRM including treatment, time point, 
treatment by time point interaction, and gestational age group as fixed effects and 
pre-procedure FiO2 as covariate. The adjusted means in each treatment group, 
the adjusted mean difference between treatments and their 95% confidence 
intervals (CIs) at each time point and averaged over the first 120 hours post-
treatment will be estimated by the model. Time profile plot of mean FiO2 in the 
120 hours post-treatment will be presented by treatment group.

FiO2 will be summarized by treatments on neonates still receiving respiratory 
support at 28±2 PNA and 36 weeks PMA by means of descriptive statistics.
SpO2/FiO2 ratio

SpO2/FiO2 will be analyzed using a linear MMRM including treatment, time 
point, treatment by time point interaction, and   gestational age group as fixed 


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-
effects and pre-procedure SpO2/FiO2 as covariate. The adjusted means in each 
treatment group, the adjusted mean difference between treatments and their 95% 
CIs at each time point and averaged over the first 120 hours post-treatment will 
be estimated by the model. Time profile plot of mean SpO2/FiO2 in the first 120 
hours post-treatment will be presented by treatment group.

SpO2/FiO2 will be summarized between treatments at 28±2 Days PNA and at 36 
weeks PMA by means of descriptive statistics.
Blood gas analysis

Acid-base balance parameters (i.e. pH, pCO2, pO2, HCO3, BE, lactate) will be 
summarized by treatments group as absolute and change from pre-treatment 
values by means of descriptive statistics.
Use of additional surfactant doses

The percentage of subjects requiring at least one additional surfactant dose will 
be compared by treatment group by means of a Fisher’s exact test at 5% 
significance interval. Odds ratio (OR) and related exact 95% CI will be also 
provided. Subjects with pulmonary hemorrhage will be excluded from this 
summary.

The number of additional surfactant doses will be summarized by treatment 
group by means of descriptive statistics.
Duration of ventilation/oxygen supplementation (alone)

The median duration time of invasive mechanical ventilation in the first 72 hours 
of life (hours), in the first 28 days PNA and within 36 weeks PMA (days), stand- 
alone oxygen supplementation (days), non-invasive ventilation (days) will be 
compared between treatment groups by using the Mann-Whitney U-test.
12.3.5.Safety variables
Adverse Events and Neonatal Morbidities

Number and percent of neonates reporting AEs started during procedure for 
surfactant administration as well as AEs started during the procedure and judged 
related to the procedure will be summarized by treatment group.
For LISA group, any AE assessed as related to CHF 6440 catheter will be 
considered procedure-related.
These events will be also summarized by treatment group based on action 
required, if any (i.e. supplementary oxygen or transient increase in FiO2, manual 
positive pressure ventilation, endotracheal intubation, administration of, 
crystalloids, or cardiopulmonary resuscitation or administration of adrenaline). 
The duration of endotracheal intubation and positive pressure ventilation will be 


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summarized as well.
A subgroup analysis of AEs during procedure for surfactant administration will 
be performed based on the use of sedation and/or analgesia (Yes/No).

Incidence of AEs including neonatal complications of prematurity (see 
APPENDIX III for complete list), related AEs (ADRs), serious AEs (SAEs) and 
AEs leading to death will be summarized by treatment group both in term of 
frequency of neonates with at least one AE and in term of frequency of AEs 
(number of events). All the aforementioned categories of AEs will be summarized 
by System organ Class (SOC) and Preferred Term (PT).

Frequency of neonates with major neonatal morbidities at discharge or 40 weeks 
PMA (whichever comes first) will be summarized by treatment group.
Vital Sign

Vital signs parameters (SBP, DBP MBP, HR and RR) will be summarized as 
absolute and the change from baseline (pre-procedure) by treatment group using 
descriptive statistics.
Pain assessment

PIPP score will be summarized by treatment group by means of descriptive 
statistics.
First administration

Number of 1st failed attempt to insert the catheter/ETT will be summarized by 
treatment group. Percentage of neonates with 1st failed attempt will be compared 
between group using the Cochran-Mantel-Haenszel adjusted for gestational age 
group. The CMH adjusted difference with its 95% CI will be presented.

Number of attempts to the first successful insertion will be summarized by 
treatment group by means of descriptive statistics.

Number of device misallocation (i.e., esophageal intubation) will be summarized by 
treatment group by means of descriptive statistics.

Number of maneuvers discontinued due to neonate’s severe destabilization will be 
summarized by treatment group by means of descriptive statistics.

Duration of surfactant administration (min) and overall procedure for surfactant 
administration will be compared between treatment groups by using the Mann-
Whitney U- test.
Mortality and BPD

Death/BPD incidence at 36 weeks PMA will be compared by treatment by means 
of CMH test, adjusting for GA group and related 95% confidence interval will be 
provided.


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
The incidence of BPD at 36 weeks PMA will be compared by treatment as for 
Death/BPD incidence.

The mortality at 36 weeks PMA and at Day 28 will be compared by treatment as 
for Death/BPD incidence.

Oxygen use at Day 28 (alone and / or during any kind of MV) will be compared by 
treatment as for Death/BPD incidence.
Other safety variables

Feeding and hearing status at discharge or 40 weeks PMA (whichever comes first) 
will be summarized by treatment group by frequency distributions.

Weight, OFC and length at discharge home or 40 weeks PMA will be summarized 
by treatment group by descriptive statistics.

Neonates needing invasive or non-invasive respiratory support at discharge home 
or 40 weeks PMA will be summarized by treatment group by frequency distribution 

Neonates needing respiratory medications at discharge home or 40 weeks PMA 
will be summarized by treatment group by frequency distribution 
Health status questionnaire at 24 months (±3 months) corrected age
(This stand-alone assessment will be analyzed and reported separately from the main phase)

Bayley Scales of Infant Development (cognitive and language scores) will be 
summarized using descriptive statistics by treatment group and BSID version (III or 
IV).

Vital signs and all other variables collected through the questionnaire (i.e., 
anthropometric measures, cerebral palsy, seizures, feeding method, functional 
disability and respiratory morbidity) will be summarized by treatment group by 
frequency distribution or descriptive statistics, as appropriate.
12.3.6.Interim Analysis
No interim analysis is planned in this study.
13.
INSTITUTIONAL REVIEW BOARD APPROVAL
The study proposal will be submitted to the Institutional Review Board (IRB) in accordance 
with US requirements.
The IRB shall give its opinion in writing -clearly identifying the study number, study title and 
informed consent form approved-, before the clinical trial commences.
A copy of all communications with the IRB will be provided to the Sponsor.
The Investigator should provide written reports to the IRB annually or more frequently if 
requested on any changes significantly affecting the conduct of the trial and/or increasing risk 
to the subjects (according to the requirements of each country).


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14.
REGULATORY REQUIREMENTS
The study will be notified to the Health Authorities (or authorized by) according to the legal 
requirements in the US. In the case of a substantial amendment, approval from the Health 
Authority will be sought before implementation.
Selection of the subjects will not start before the approval of the IRB has been obtained and 
the study notified to Health Authorities (or authorized by).
The study will be conducted in accordance with the Declaration of Helsinki, with the Good 
Clinical Practices guidelines and following all other requirements of local laws.
15.
INFORMED CONSENT
It is the responsibility of the Investigator to obtain written consent from each subject’s parent 
or the parents’ legal representative prior to any study related procedures taking place, by using 
the latest IRB approved version of the Informed Consent document.
If the subject’s parents or the parents’ legal representative are unable to read, the informed 
consent will be obtained in the presence of an impartial witness, e.g. a person independent of 
the study who will read the informed consent form and the written information for the parents.
Adequate time shall be given to the subjects’ parents or legal representative to ask the PI 
about any clarifications needed and to consider parents’ decision to enroll the subject in the 
study.
Consent must be documented by the dated signature. The signature confirms that the consent 
is based on information that has been understood. Moreover, the Investigator must sign and 
date the informed consent form.
Each signed informed consent must be kept on file by the Investigator. One copy must be 
given to the subject.
16.
SOURCE DOCUMENTS/DATA
16.1.
Recording of source data
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data.
Data recorded in the eCRF derived from source documents should be consistent with the data 
recorded on the source documents (APPENDIX II).
16.2.
Direct access to source document/data
The Investigators or designated must permit trial-related monitoring, audits, IRB review or 
regulatory inspection, providing direct access to source data/documents.


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17.
STUDY MONITORING
Monitoring will be performed by the CRO, 
, who has been designated by Chiesi 
Farmaceutici S.p.A.
It is understood that the monitor(s) will contact and visit the Investigator/center before the 
study, regularly throughout the study and after the study had been completed, and that they 
will be permitted to inspect the various study records: case reports form, Investigator study 
file and source data, provided that subject confidentiality is respected.
The purposes of these visits are:

to assess the progress of the study;

to review the compliance with the study protocol;

to discuss any emergent problem;

to check the eCRFs for accuracy and completeness;

to validate the contents of the CRFs against the source documents;

to assess the status of drug storage, dispensing and retrieval.
Prior to each monitoring visit, the Investigator or staff will record all data generated since 
the last visit on the eCRF. The Investigator and/or study staff will be expected to be available 
for at least a portion of the monitoring visit to answer questions and to provide any missing 
information.
It is possible that the Investigator site may be audited by Sponsor personnel or regulatory 
national and/or international regulatory agencies during and after the study has been 
completed.
18.
QUALITY ASSURANCE
The R&D Quality Assurance Department of Chiesi Farmaceutici S.p.A may perform an audit 
at any time according to the Sponsor’s Standard Operating Procedures, in order to verify 
whether the study is being conducted in agreement with Good Clinical Practices and 
protocol.
19.
INSURANCE AND INDEMNITY
Chiesi Farmaceutici S.p.A. holds and will maintain an adequate insurance policy covering 
damages arising out of Chiesi’s sponsored clinical research studies.
Chiesi Farmaceutici S.p.A. will indemnify the Investigator and hold him/her harmless for 
claims for damages arising out of the investigation, in excess of those covered by his/her own 
professional liability insurance, providing that the drug was administered under his/her or 
deputy’s supervision and in strict accordance with accepted medical practice and with the 
study protocol.


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The Investigator must notify Chiesi Farmaceutici S.p.A. immediately upon notice of any 
claims or lawsuits.
20.
CONFIDENTIALITY
All study documents are provided by the Sponsor in confidence to the Investigator and 
his/her appointed staff. None of this material may be disclosed to any party not directly 
involved in the study without written permission from Chiesi Farmaceutici S.p.A.
The Investigator must assure the subject’s anonymity will be maintained. The Investigator will 
keep a separate list with at least the initials, the subject’s study numbers, names, addresses and 
telephone numbers. The Investigator will maintain this for the longest period of time allowed 
by his/her own institution and, in any case, until further communication from Chiesi 
Farmaceutici S.p.A.
21.
PREMATURE TERMINATION OF THE STUDY
The Sponsor, Competent Authorities and the Investigator reserve the right to terminate the 
study at any time. Should this be necessary, the procedures for an early termination or 
temporary halt will be arranged after consultation by all involved parties.
The Sponsor should submit a written notification to the Regulatory Authority concerned and 
the IRB providing the justification of premature ending or of the temporary halt.
22.
CLINICAL STUDY REPORT
The clinical study report, including the statistical and clinical evaluations, shall be prepared 
and sent to the Lead Investigator for agreement and signature.
At the end of the trial a summary of the clinical study report will be provided to all IRBs, to 
the Competent Authority of the US and to the Investigators.
23.
RECORD RETENTION
After completion of the study, all documents and data relating to the study will be kept in an 
orderly manner by the Investigator in a secure study file.
Regulations require that essential documents must be retained for at least two years after the 
final marketing approval in an ICH region or until two years have elapsed since the formal 
interruption of the clinical development of the product under study.
It is the responsibility of the Sponsor to inform the Investigator of when these documents can 
be destroyed. The Investigator must contact Chiesi Farmaceutici S.p.A. before destroying 
any trial- related documentation. In addition, all subjects’ medical records and other source 
documentation will be kept for the maximum time permitted by the institution.


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24.
PUBLICATION OF RESULTS
Chiesi Farmaceutici S.p.A. is entitled to publish and/or present any results of this study at 
scientific meetings, and to submit the clinical trial data to national and international 
Regulatory Authorities, and if they fall under the Chiesi commitments on Clinical Trial 
Transparency, to make them available on www.chiesi.com website. Furthermore, Chiesi 
Farmaceutici S.p.A. reserves the right to use such data for industrial purposes.
In the absence of a Study Steering Committee, Investigators will inform Chiesi Farmaceutici 
S.p.A. before using the results of the study for publication or presentation and agree to 
provide the Sponsor with a copy of the proposed presentation. Data from individual study 
sites must not be published separately.
Negative as well as positive results should be published or otherwise made publicly available.


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25.
REFERENCES
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Roth B, Herting E, German Neonatal Network. Avoidance of mechanical 
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J, Stöhr A, Herting E, Bernhard R, NINSAPP Trial Investigators. Nonintubated 
surfactant application vs conventional therapy in extremely preterm infants: a 
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Dargaville PA, Aiyappan A, Cornelius A, Williams C, De Paoli AG. Preliminary 
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Dargaville PA, Aiyappan A, De Paoli AG, Kuschel CA, Kamlin CO, Carlin JB, 
Davis PG. Minimally-invasive surfactant therapy in preterm infants on continuous 
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17.
Aldana-Aguirre JC, Pinto M, Featherstone RM, Kumar M. Less invasive surfactant 
administration versus intubation for surfactant delivery in preterm infants with 
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310299. Epub 2016 Nov 15.
18.
Rigo V, Lefebvre C, Broux I. Surfactant instillation in spontaneously breathing 
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19.
Härtel C, Paul P, Hanke K, Humberg A, Kribs A, Mehler K, Vochem M, Wieg C, Roll 
C, Herting E, Göpel W. Less invasive surfactant administration and complications of 
preterm birth. Sci Rep. 2018;8:8333. doi: 10.1038/s41598-018-26437-x.
20.
Cao ZL, Pan JJ, Shen X, Zhou XY, Cheng R, Zhou XG, Yang, Y. Less invasive 
surfactant administration in preterm infants with respiratory distress syndrome-an 
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Kribs A, Roll C, Göpel W, Wieg C, Groneck P, Laux R, Teig N, Hoehn T, Böhm W, 
Welzing L, Vochem M, Hoppenz M, Bührer C, Mehler K, Stützer H, Franklin J, Stöhr 
A, Herting E, Roth B, NINSAPP Trial Investigators. Nonintubated surfactant 
application vs conventional therapy in extremely preterm infants: a randomized 
clinical 
trial. 
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Pediatr. 
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Aug;169(8):723-30. 
doi: 
10.1001/jamapediatrics.2015.0504.
22.
Dargaville PA, Aiyappan A, Cornelius A, Williams C, De Paoli AG. Preliminary 
evaluation of a new technique of minimally invasive surfactant therapy. Arch Dis 
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2010 Oct 21.
23.
American Academy of Pediatrics and American Heart Association. NRP Neonatal 
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Wyckoff MH, Aziz K, Escobedo MB, Kapadia VS, Kattwinkel J, Perlman JM, 
Simon WM, Wiener GM, Zaichkin JG. Part 13: neonatal resuscitation: 2015 
American Heart Association guidelines update for cardiopulmonary resuscitation 
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Weiner GM, Wyckoff MH, Yamada NK, Zaichkin JG. 2019 American Heart 
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14;140(24):e922-e930. 
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Salaets T, Turner MA, Short M, Ward RM, Hokuto I, Ariagno RL, Klein A, 
Beauman S, Wade K, Thomson M, Roberts E, Harrison J, Quinn T, Baer G, Davis 
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Arch Dis Child. 2019 Sep;0:1-7.  doi:10.1136/ archdischild-2019-317399.
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Papile L, Burstein J, Burstein R, Koffler H. Incidence and evolution of 
subependymal and intraventricular hemorrhage: a study of neonates with 
birthweights less than 1500 gm. J Pediatr 1978 Apr;92(4):529-34. doi: 
10.1016/s0022-3476(78)80282-0.
29.
Inder 
TE, 
Perlman 
JM, 
Volpe 
JJ. 
Preterm 
Intraventricular 
Hemorrhage/Posthemorrhagic hydrocephalus. In: Volpe's Neurology of the Newborn, 
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30.
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marchall R, Barton L, Brotherton 
T. Neonatal necrotizing enterocolitis. Therapeutic decision based upon clinical 
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Neu J. Necrotizing enterocolitis: the search for a unifying pathogenic theory leading 
to prevention. Pediatr Clin North Am 1996 Apr;43(2):409-32. doi: 10.1016/s0031-
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32.
International Committee for the Classification of Retinopathy of Prematurity. The 
International Classification of Retinopathy of Prematurity Revisited. Arch 
Ophthalmol 2005 Jul;123(7):991-999. doi: 10.1001/archopht.123.7.991.
33.
Fierson WM; American Academy of Pediatrics Section on Ophthalmology; American 
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10.1542/peds. 2018-3061.


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APPENDIX I
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APPENDIX I
AN OPEN-LABEL, MULTICENTER, RANDOMIZED, CONTROLLED STUDY IN 
SPONTANEOUSLY BREATHING PRETERM NEONATES WITH RESPIRATORY 
DISTRESS SYNDROME TO COMPARE TWO PROCEDURES FOR PORCINE 
SURFACTANT (PORACTANT ALFA, CUROSURF®) ADMINISTRATION: A LESS 
INVASIVE METHOD (LISA) DURING NON-INVASIVE VENTILATION (NIV) AND THE 
CONVENTIONAL ADMINISTRATION DURING BRIEF INVASIVE VENTILATION.
Acronym: LISPAP (Less Invasive Surfactant administration combined with nCPAP)
Product: Poractant alfa (porcine derived surfactant, Curosurf®, Chiesi Farmaceutici S.p.A.)
Pharmaceutical Form: Sterile suspension
Test device: Thin catheter (CHF 6440, Chiesi Farmaceutici S.p.A.), specific for delivery 
of poractant alfa through LISA technique
Approval of Clinical Study Protocol by the Investigator:
I have carefully read this protocol and I agree that it contains all the necessary information 
required to conduct the study and I agree to conduct it as described.
I understand that this trial will not be initiated without Ethics Committee/Institutional 
Review Board approvals and that the administrative requirements of the governing body 
of the institution will be fully complied with.
Informed written consent will be obtained from the parents/legal representative of all 
participating subjects and appropriately documented, prior to the enrolment in the study.
The undersigned agrees that the trial will be carried out in conformity with the Declaration 
of Helsinki (as applicable, with attention being drawn to Section concerning freely given 
consent),  ICH E6 Good Clinical Practices and with all the other local laws and regulations 
relevant to the use of new and approved therapeutic agents in subjects.
Investigator’s Name: ______________________________________, MD
Center No.: 
Signature
Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A, 43122 Parma, Italy


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APPENDIX II
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APPENDIX II
MINIMUM LIST OF SOURCE DATA REQUIRED

Date of informed consent signature

Demographic data

Study number

Subject identity/number

Randomization number

Complications during  pregnancy

Neonatal comorbidities

Neonatal Concomitant Medications

Date of specific study visits

Labels of study drugs

Examination or assessments carried out during the study (please refer to Table 2)

Laboratory reports (blood gas analysis)

Adverse events / serious adverse events

24-month clinical assessment (Bayley scales, health status questionnaire)

If subject is withdrawn, reason for withdrawal


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APPENDIX III
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APPENDIX III
COMPLICATIONS OF PREMATURITY

Air leaks (pneumothorax, pneumomediastinum, pneumopericardium, 
pneumoperitoneum)   

Apnea of prematurity 

Focal intestinal perforation (Neonatal spontaneous intestinal perforation)

Germinal matrix hemorrhage/Intraventricular hemorrhage: to be classified 
according to the following [28,29]:
o
Grade I - Germinal matrix hemorrhage only or germinal matrix hemorrhage 
plus intraventricular hemorrhage less than 10% of ventricular area. 
o
Grade II – Germinal matrix hemorrhage and intraventricular hemorrhage; 
10 to 50% of ventricular area. 
o
Grade III - Germinal matrix hemorrhage and intraventricular hemorrhage 
involving more than 50% of ventricular area; lateral ventricles are usually 
distended. 
o
Grade IV: Hemorrhagic infarction in periventricular white matter ipsilateral 
to intraventricular hemorrhage (also called periventricular hemorrhagic 
infarction).  

Necrotizing enterocolitis, to be classified according to modified Bell staging 
criteria [30,31]

Patent ductus arteriosus 

Periventricular leukomalacia 

Pulmonary hemorrhage 

Pulmonary interstitial emphysema 

Retinopathy of prematurity – classification related to stage, localization and 
extent according to “The International Classification of Retinopathy of Prematurity 
Revisited” [32,33]


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APPENDIX IV
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APPENDIX IV
PIPP SCORE ASSESSMENT TOOL

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
STUDY CODE No.: CCD-050000-01 
AN OPEN-LABEL, MULTICENTER, RANDOMIZED, CONTROLLED STUDY IN 
SPONTANEOUSLY BREATHING PRETERM NEONATES WITH RESPIRATORY 
DISTRESS SYNDROME TO COMPARE TWO PROCEDURES FOR PORCINE 
SURFACTANT (PORACTANT ALFA, CUROSURF®) ADMINISTRATION: A LESS 
INVASIVE METHOD (LISA) DURING NON-INVASIVE VENTILATION (NIV) AND 
THE CONVENTIONAL ADMINISTRATION DURING BRIEF INVASIVE 
VENTILATION
Version No.: 1.0
Date: 18 November 2022
Author(s):
, 
Statistician , 
, 
Biostatistician , 
The information contained in this document is confidential and will not be disclosed to others without written 
authorization from Chiesi Farmaceutici S.p.A, with the exception of appropriate Institutional Review Board and 
Ethics Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential.
NCT02772081


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Contents
LIST OF ABBREVIATIONS..................................................................................................4
1
INTRODUCTION............................................................................................................6
2
STUDY DESIGN..............................................................................................................6
3
STUDY OBJECTIVES....................................................................................................9
3.1
PRIMARY OBJECTIVE...................................................................................................9
3.2
SECONDARY OBJECTIVES............................................................................................9
4
STUDY VARIABLES......................................................................................................9
4.1
EFFICACY VARIABLES.................................................................................................9
4.2
SAFETY VARIABLES ..................................................................................................10
4.3
OTHER VARIABLES ...................................................................................................12
5
SAMPLE SIZE...............................................................................................................12
6
ANALYSIS SETS...........................................................................................................12
6.1
SAFETY SET ..............................................................................................................12
6.2
INTENTION-TO-TREAT (ITT) SET ..............................................................................13
6.3
OTHER SETS DEFINED FOR TABLES AND LISTINGS....................................................13
7
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS......................13
7.1
STATISTICAL SIGNIFICANCE......................................................................................13
7.2
MULTIPLICITY...........................................................................................................13
7.3
HANDLING OF MISSING DATA...................................................................................13
7.3.1
Missing/Incomplete Dates:...................................................................................14
7.4
COVARIATES .............................................................................................................14
7.5
INTERIM ANALYSES ..................................................................................................14
7.6
EXAMINATIONS OF SUBGROUPS ................................................................................15
7.7
DESCRIPTIVE STATISTICS..........................................................................................15
7.8
DEFINITIONS .............................................................................................................15
7.8.1
Baseline and Change from Baseline ....................................................................15
7.8.2
Date of First Randomized Treatment...................................................................15
7.8.3
Study Day .............................................................................................................15
7.8.4
Duration ...............................................................................................................15
7.9
DIARY DATA.............................................................................................................16
7.10
DATA RE-ALLOCATION .............................................................................................16
7.11
EXCLUSION OF DATA FROM THE STATISTICAL ANALYSES ........................................16
7.12
LISTINGS ...................................................................................................................16
7.13
CODING.....................................................................................................................16
8
STUDY POPULATION.................................................................................................16
8.1
DISPOSITION OF SUBJECTS AND DISCONTINUATIONS ................................................16
8.1.1
Disposition of Subjects.........................................................................................16
8.1.2
Discontinuation from the Study............................................................................16
8.1.3
Protocol Deviations and Analysis Sets ................................................................17
8.2
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................................................17
8.2.1
Demographic Characteristics ..............................................................................17
8.2.2
Pregnancy History and Maternal Medical History .............................................17


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8.3
NEONATE MEDICAL HISTORY ...................................................................................19
8.4
MEDICATIONS ...........................................................................................................20
8.5
PROCEDURES.............................................................................................................20
8.6
COMPLIANCE.............................................................................................................20
9
EFFICACY ANALYSES...............................................................................................21
10
SAFETY ANALYSES....................................................................................................28
10.1
EXTENT OF EXPOSURE ..............................................................................................28
10.1.1
First Administration.........................................................................................28
10.1.1
First and Second Administration .....................................................................28
10.2
ADVERSE EVENTS .....................................................................................................28
10.3
VITAL SIGNS .............................................................................................................31
10.4
PAIN ASSESSMENT ....................................................................................................31
10.5
MORTALITY AND BPD ..............................................................................................31
10.6
OTHER SAFETY VARIABLES ......................................................................................32
11
OTHER ANALYSES.....................................................................................................32
12
CHANGES IN THE PLANNED ANALYSES FROM STUDY PROTOCOL.........32
13
OUTPUT .........................................................................................................................33
13.1
SOFTWARE ................................................................................................................33
13.2
REPORTING CONVENTIONS........................................................................................34
13.2.1
Treatment, Visit and Subgroup Descriptors.....................................................34
13.2.2
Decimal places.................................................................................................34
13.2.3
Other reporting conventions ............................................................................35
13.3
FORMAT ....................................................................................................................35
13.4
QUALITY CONTROL...................................................................................................37
14
SAS CODE......................................................................................................................37
14.1
MIXED MODEL FOR REPEATED MEASURES FOR SPO2, FIO2, AND SPO2/FIO2 RATIO:..37
14.2
COMPARISON OF TWO GROUPS USING FISHER’S EXACT TEST.....................................39
14.3
COMPARISON OF TWO GROUPS USING MANN-WHITNEY U-TEST..............................39
14.4
ESTIMATES OF MEDIAN DIFFERENCE AND CORRESPONDING 95% CI..........................39
14.5
TABLES THAT NEED 95% CIS WITHIN GROUP FOR CONTINUOUS VARIABLES: ............40
14.6
COMPARISON OF TWO GROUPS USING COCHRAN-MANTEL-HAENSZEL TEST ...........40
15
REFERENCES...............................................................................................................41
16
LIST OF TABLES, LISTINGS AND FIGURES........................................................42
16.1
TABLES .....................................................................................................................42
16.2
LISTINGS ...................................................................................................................72
16.3
FIGURES ..................................................................................................................101
APPENDIX I.........................................................................................................................102
APPENDIX II.......................................................................................................................103


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List of Abbreviations
ADaM
Analysis Dataset Model
ADR
Adverse Drug Reaction
AE
Adverse Event
APGAR
Appearance, Pulse, Grimace, Activity, Respiration
ATC
Anatomical Therapeutic Chemical
BE
Base Excess
BPD
Bronchopulmonary Dysplasia
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
CSR
Clinical Study Report
DBL
Database Lock
DBP
Diastolic Blood Pressure
DRM
Data Review Meeting
DRR
Data Review Report
eCRF
Electronic Case Report Form
ETT
Endotracheal Tube
FiO2
Fraction of inspired Oxygen
GCP
Good Clinical Practice
HCO3
Bicarbonates
HR
Heart Rate
IMV
Invasive Mechanical Ventilation
ITT
Intention-To-Treat
LISA
Less Invasive Surfactant Administration
MBP
Mean Blood Pressure
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model for Repeated Measures
MV
Mechanical Ventilation
NAESS
INC Neonatal Adverse Event Severity Scale
NIV
Non-invasive Ventilation
OFC
Occipital-Frontal Circumference
OR
Odd Ratio
pCO2
Partial Pressure of Carbon Dioxide
PIPP
Premature Infant Pain Profile
PMA
Post-menstrual Age
PNA
Post-natal age
pO2
Partial Pressure of Oxygen
RDS
Respiratory Distress Syndrome
RR
Respiratory Rate
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SOC
System Organ Class
SpO2
Preductal Oxygen Saturation


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TEAE
Treatment Emergent Adverse Event
WHO-DD
World Health Organization Drug Dictionary
VERSION HISTORY
Version 
Date 
Change History
1.0
18 November 2022
First version


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1 Introduction
This document presents the Statistical Analysis Plan (SAP) for Chiesi Farmaceutici S.p.A. 
protocol CCD-050000-01: An open-label, multicenter, randomized, controlled study in 
spontaneously breathing preterm neonates with respiratory distress syndrome to compare two 
procedures for porcine surfactant (poractant alfa, Curosurf®) administration: a less invasive 
method (LISA) during non-invasive ventilation (NIV) and the conventional administration 
during brief invasive ventilation.
This analysis plan is based on the final protocol (version 4.0, 8 September 2020) and the final 
electronic case report form (eCRF) (Final 4.0, 23 September 2021). 
The SAP provides the description of the final analyses. In case of deviations from the SAP, 
explanations will be provided in the Clinical Study Report (CSR).
 will perform the statistical analyses and is responsible for the production and quality 
control of all outputs described in this document.
Note: results from the 24-months (± 3 months) corrected age, will be analyzed and reported 
separately from the main phase and will not be part of this SAP.
2 Study Design
This is a phase III B, open-label, multicenter, randomized, controlled study in 150 randomized 
preterm neonates with early clinical signs of respiratory distress syndrome (RDS) in 
approximately 25 US sites.
Neonates will be evaluated according to the selection criteria and then randomized to surfactant 
treatment via less invasive surfactant administration (LISA) or standard administration 
procedure.
The enrollment will be staggered: the gestational age will be restricted to 27+0 weeks up to 28+6 
completed weeks until safety evaluation by an independent safety monitoring board (ISMB) is 
performed for the first 15 neonates. Provided no safety concerns are raised, the enrolment will 
then be extended to the whole population (i.e. 25+0 weeks up to 28+6 completed weeks). 
Enrolled neonates will be evaluated:
o
until discharge,
o
until 40 weeks post-menstrual age (PMA, if still in hospital), 
o
if discharge occurs before 36 weeks, the last evaluation will be at 36 weeks 
PMA. 
This period represents the main phase of the trial. 
Their final assessment of development will be at 24-month corrected age as a separate 
standalone visit. This 24-month clinical assessment will be analyzed and evaluated separately 
from the initial part of the study and will be object of an addendum to the initial core clinical 
study report.


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Table 1: Timetable
The end of the trial will correspond to the last evaluation of the last neonate from the recruiting 
site or from the continuing care site in case the treated baby was transferred from the original 
recruiting site. The last evaluation could be:
-the date of the assessment for bronchopulmonary dysplasia (BPD) diagnosis (i.e. 36 weeks 
PMA) if the patient is discharged home before 36 weeks PMA, 
-discharge home (if discharged between 36 weeks and 40 weeks PMA), or
-40 weeks PMA (if still in hospital)
There are 9 visits planned among three study periods, as below:

Pre-randomization period: on admission to the study prior to study treatment;

Treatment period:
o
Day 1: randomization, before start of study procedure, treatment administration 
up to end of surfactant administration (T0); up to 24 hours after receiving 
treatment (assessment at 5, 15, 30 min, 1, 6, 12, 24 hours)
o
Day 2: from 24 hours to 48 hours post treatment;
o
Day 3: from 48 hours to 72 hours post-treatment;
o
Day 5: from 96 hours to 120 hours post-treatment

Follow-up visits:
o
28 days post-natal age (PNA);
o
36-weeks PMA;
o
Discharge home or 40 weeks PMA, whichever comes first;
o
24 months (±3 months) corrected age visit
The study plan and scheduled tests are summarized in the following flow-chart:


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Figure 1: Study Flowchart


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3 Study Objectives
3.1 Primary Objective 
The primary objective of this study is to evaluate the safety profile of the administration of the 
porcine surfactant (poractant alfa, Curosurf®) through LISA using a thin catheter (CHF6440), 
compared to an approved conventional surfactant administration during invasive ventilation 
and rapid extubation, in spontaneously breathing preterm neonates with clinical signs of 
respiratory distress syndrome (RDS).
3.2
Secondary Objectives
The secondary objectives of this study are to assess short-term and mid-term efficacy profiles 
of the administration of the porcine surfactant (poractant alfa, Curosurf®) through LISA using 
CHF6440.
4 Study Variables
4.1 Efficacy Variables
The following variables will be used to describe the efficacy of the two procedures:

Percentage of neonates needing invasive mechanical ventilation (MV) in the first 72 
hours of life, 28 days PNA and within 36 weeks PMA defined as follows:
Endotracheal Tube (ETT) Group:

Neonates not extubated within 1 hour from initial surfactant administration and 
receiving MV for more than 1 hour; 

Neonates extubated and re-intubated to receive MV of any duration
LISA Group:

Neonates intubated to receive MV of any duration, 
o
Duration of invasive ventilation (hours) in the first 72 hours of life, 28 days 
PNA and within 36 weeks PMA;
o
Percentage of neonates needing any intubation procedure, outside the initial 
surfactant administration period, in the first 72 hours of life, in the first 28 days 
PNA and within 36 weeks PMA;
o
SpO2 at time 0 (study treatment administration), 5, 15, 30 minutes, at 1, 6, 12, 
24, 48, 72 and 120 hours post treatment; additionally, at 28 days PNA and at 36 
weeks PMA for neonates still receiving any form of respiratory support; 
o
FiO2 at time 0 (study treatment administration), 5, 15, 30 minutes, at 1, 6, 12, 
24, 48, 72 and 120 hours post treatment; additionally, at 28 days PNA and at 36 
weeks PMA for neonates still receiving any form of respiratory support;
o
SpO2/FiO2 at time 0 (study treatment administration), 5, 15, 30 minutes, at 1, 6, 
12,24, 48, 72 and 120 hours post treatment; additionally, at 28 days PNA and at 
36 weeks PMA for neonates still receiving any form of respiratory support; 


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o
Percentage of neonates needing additional surfactant doses and number of 
surfactant doses; 
o
Duration of oxygen alone supplementation (days) and any non-invasive 
ventilation during the study (days); 
o
Blood gas analysis, specifically acid-base balance parameters (i.e. pH, partial 
pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), HCO3, BE, 
lactate) pre-surfactant administration (when applicable), at 1 hour, 6 hours, 24, 
48 and 72 hours after study treatment
4.2
Safety Variables
Following safety variables are defined for this study in order to describe safety of the two 
procedures:
During procedure for surfactant administration:

Number and percentage of neonates with adverse events (AEs) starting during overall 
procedure for surfactant administration;

Number and percentage of neonates with AEs starting during overall procedure for 
surfactant administration judged related to the procedure;

Number of AEs occurring during overall procedure for surfactant administration 
requiring either oxygen alone or an increase in FiO2 without the need for escalation of 
invasive or non-invasive ventilator support;

Number of AEs starting during overall procedure for surfactant administration 
requiring administration of manual (bag and mask) pressure positive ventilation and 
related duration of ventilation (non- invasive ventilation);

Number of AEs starting during overall procedures for surfactant administration 
requiring endotracheal intubation and related duration of intubation (invasive 
ventilation);

Number of AEs starting during overall procedures for surfactant administration 
requiring circulatory support including administration of crystalloids;

Number of AEs starting during overall procedures for surfactant administration 
requiring cardiopulmonary resuscitation including administration of cardiac massage 
or adrenaline
After first administration:

Number and percentage of neonates with failed 1st attempt to insert the CHF6440/ETT;

Number of maneuvers discontinued due to neonate’s severe destabilization;

Heart rate (HR) and respiratory rate (RR) (0, 5, 15 and 30 min, 1 hour, 6 and 12 hours 
after administration);

Systolic, diastolic, and mean blood pressure (SBP/DBP/ MBP) (15 and 30 min, 1 hour, 
6 and 12 hours after administration);

Premature Infant Pain Profile (PIPP) score (end of surfactant administration)


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After first and second administration:

Number of device misallocation for LISA Group (esophageal intubation);

Number of attempts to the first successful insertion;

Duration of surfactant administration (min);

Duration of the whole procedure (starting from the insertion of laryngoscope up to the 
removal of the catheter or ETT);
During the study:

AEs, including incidence of major neonatal complications of prematurity (listed in 
APPENDIX I) and adverse drug reactions (ADRs);

Blood pressure (SBP, DBP, MBP) at 24, 48, 72, 120 hours post-administration;

HR and RR, at 24, 48, 72, 120 hours post-administration and 28 days PNA, 36 weeks 
PMA, discharge home or 40 weeks PMA whichever comes first;

Incidence of BPD at 36 weeks PMA;

Death/BPD incidence at 36 weeks PMA, defined as the incidence of the neonates who 
are dead or alive but with a diagnosis of BPD at the time of assessment (i.e. 36 weeks 
PMA);

Mortality at Day 28 PNA and 36 weeks PMA;

Oxygen use (alone and/or during invasive and non-invasive ventilation) at Day 28 PNA 
and 36 weeks PMA;

Weight, occipital-frontal circumference (OFC) and length at discharge home or 40 
weeks PMA;

Feeding and hearing status at discharge home or 40 weeks PMA, whichever comes first;

Incidence of major neonatal morbidities at discharge home or 40 weeks PMA, 
whichever comes first;

Neonates needing invasive ventilation or non-invasive respiratory support at discharge 
home or 40 weeks PMA;

Neonates needing respiratory medications at discharge home or 40 weeks PMA
24 months (±3 months) corrected age:

Health status questionnaire, including:
o
Bayley Scales of Infant Development (cognitive and language scores); 
o
Feeding method: spoon, nasogastric tube or gastrostomy; 
o
Cerebral palsy evaluation; 
o
Seizure evaluation; 
o
Vision, hearing and communication evaluation; 


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o
Clinical assessment of respiratory conditions and morbidity; 
o
Vital signs (SBP/DBP/MBP, HR, RR); 
o
Growth assessment (Weight, OFC and length)
This stand-alone assessment will be analyzed and reported separately from the main phase.
4.3
Other Variables
No other variables defined.
5 Sample Size
No primary efficacy endpoint was defined in this study since the main objective is to describe 
the overall safety and efficacy profile of administering poractant alfa with two different 
procedures: LISA technique or conventional administration with endotracheal tubes and brief 
invasive ventilation. A total of 150 neonates will be randomized in the study with a ratio 2:1 to 
LISA arm (i.e. 100) and conventional administration arm (i.e. 50).
6 Analysis Sets
The definitions of the analysis sets are summarized below. A final agreement on the subjects 
to be included in or excluded from each analysis set will be reached before the database lock 
(DBL) during Data Review Meeting (DRM). Inclusions and exclusions from analysis sets will 
be fully documented in the Data Review Report (DRR). 
6.1 Safety Set
All randomized subjects who will take at least one dose of study medication.
The Safety population will be used in the analysis of all safety variables. In case of deviation 
between as-randomized treatment and treatment actually received, the treatment actually 
received will be used in the safety analyses (i.e. an as-treated analysis will be performed).
The AEs will be analyzed based on whether the AE started during the first dose or second dose. 
An AE will be marked to have started during LISA or ETT by using a flag as follows:

First administration
AE by Dose flag = LISA; if (‘Did the AE start during 1st procedure or 2nd procedure?’ = ‘Yes’ 
and ‘If Yes, Clarify which one’ = ‘First’) and [(‘Was procedure for surfactant administration 
performed according to the randomization group? = Yes’ and ‘Patient group = LISA’) or (“Was 
procedure for surfactant administration performed according to the randomization group”=No 
and method used was ‘LISA’)];
AE by Dose flag = ETT, if (‘Did the AE start during 1st procedure or 2nd procedure?’ = ‘Yes’ 
and ‘If Yes, Clarify which one’ = ‘First) and [(‘Was procedure for surfactant administration 
performed according to the randomization group?= ‘Yes’ and ‘Patient group = ETT’) or (“Was 
procedure for surfactant administration performed according to the randomization group”=No 
and method used was ‘ET tube: Intubation, surfactant administration and rapid extubation 
(within 1 hour) / ET tube: subject receiving MV > 1 hour)];


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
Second administration
AE by Dose flag = LISA; if (‘Did the AE start during 1st procedure or 2nd procedure?’ = ‘Yes’ 
and ‘If Yes, Clarify which one’ = ‘Second’) and (‘If yes, please specify the method of 
administration’? =‘LISA’);
AE by Dose flag = ETT; if (‘Did the AE start during 1st procedure or 2nd procedure?’ = ‘Yes’ 
and ‘If Yes, Clarify which one’ = ‘Second) and (‘If yes, please specify the method of 
administration?”= ‘ET Tube: Intubation, surfactant administration and rapid extubation (within 
1 hour)’ or ‘ET Tube: subject receiving MV > 1 hour);
For all other safety assessments, analysis will be performed on Safety population based on the 
technique used for first treatment dose only, as treated analysis.
6.2
Intention-to-Treat (ITT) Set
All randomized subjects who will receive at least one dose of study medication.
The efficacy analyses will be performed in the ITT population (i.e. an as-randomized analysis 
will be performed).
6.3
Other Sets Defined for Tables and Listings
For the purposes of tables and listings the following sets are defined:

Enrolled Set: all subjects who have a signed  informed consent to participate in  the 
study;

Randomized Set: all patients randomized to study medication.
7 General Considerations for Statistical Analysis
7.1 Statistical Significance
All tests of hypotheses will be two-sided and conducted at the 0.05 significance level, and all 
confidence intervals will be two-sided at the 95% confidence level.
7.2
Multiplicity
No multiplicity adjustment will be performed.
7.3
Handling of Missing Data
The number of subjects with missing data will be presented under a “Missing” category. Unless 
otherwise stated, missing values will not be included in the denominator count when 
calculating percentages.
When quantitative variables are being summarized, only the non-missing values will be 
evaluated for calculating summary statistics.


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7.3.1
Missing/Incomplete Dates:
Medications:
In case of missing or incomplete dates not directly allowing allocation to any category of 
medications, a worst-case allocation will be done according to the available parts of the start 
and the stop dates. The medications will be allocated to the first category allowed by the 
available data, according to the following order:

Concomitant medication;

Maintained medication;

Prior medication.
Procedures:
In case of missing or incomplete dates not directly allowing allocation to any category of 
procedure, a worst-case allocation will be done according to the available parts of the start and 
the stop dates. The procedure will be allocated to the first category allowed by the available 
data, according to the following order:

Concomitant procedure;

Maintained procedure;

Prior procedure.
Adverse events:
In case of missing or incomplete date/time not directly allowing allocation to any of the 
category of AEs, a worst-case allocation will be done according to the available parts of the 
start and the stop dates/times. The AE will be allocated to the first category allowed by the 
available data, according to the following order:

Treatment emergent; 

Pre-treatment.
Missing severity of adverse events:
In case of missing severity, the severity will not be imputed and will be reported as “Missing”. 
Other critical missing data, if any, will be discussed during the review of the data. Decisions 
will be fully documented in the DRR.
7.4
Covariates
All repeated measures models will include the pre-procedure value of the variable as covariate 
and treatment, time point, treatment by time point interaction, and gestational age group as 
fixed effects.
7.5
Interim Analyses
No interim analysis will be performed.


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7.6
Examinations of Subgroups
A subgroup analysis of surfactant related and procedure related AEs and TEAEs will be 
performed based on the use of neonate sedation and/or analgesia (Yes/No). 
Only subjects with sedation and/or analgesia (selected as per Appendix II)  taken within ±150 
min from treatment (any dose intake) will be considered.
7.7
Descriptive Statistics
Descriptive statistics for quantitative variables will include n (the number of observed values), 
mean, standard deviation (SD), 95% confidence interval (CI), median, minimum and maximum 
values. 
Categorical variables will be summarized by using frequency count and percent distributions. 
The number of missing values will be displayed as a “Missing” category, where appropriate. 
Unless otherwise specified, the denominator for each percentage will be the number of non-
missing observations within the analysis set and procedure group.
7.8
Definitions
7.8.1
Baseline and Change from Baseline
Baseline will be pre-procedure assessment. If pre-procedure value is not available, baseline 
will be defined as the last non-missing value available before procedure.
Change from baseline will be derived as follows:
Assessment value at the time point - Assessment value at baseline
7.8.2
Date of First Randomized Treatment 
The date of first randomized treatment is the earliest date of randomized treatment considering 
the eCRF data, corresponding to the date part of the variable RFSTDTC in the SDTM dataset 
DM.
7.8.3
Study Day
The study day relative to the first randomized treatment procedure will be calculated as:

Date of event – date of first randomized treatment + 1 (if date of event ≥ date of first 
randomized treatment);
or

Date of event – date of first randomized treatment intake (if date of event < date of first 
randomized treatment).
7.8.4
Duration
Duration in days of any event/procedure will be calculated as:


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
End date of event/procedure – start date of the event/procedure +1
Duration in minutes of a procedure will be calculated as:

End time of the procedure – start time of the procedure
Duration in hours of any event/procedure will be calculated as:

(end time of the event/procedure – start time of the event/procedure)/60
7.9 Diary Data
Diary data is not collected in this study.
7.10 Data Re-allocation
Not applicable.
7.11 Exclusion of Data from the Statistical Analyses
All data collected in the database except for the data collected for 24 months evaluation, will 
be used for all statistical analyses for this SAP. 
7.12 Listings
All data collected in the eCRF except for the data collected for 24 months evaluation, will be 
presented in the listings. All the listings will be presented in Randomized Set.
7.13 Coding
Medical and surgical history, concomitant diseases, procedures and adverse events will be 
coded according to Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 
(March 2021 version).
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
version WHODrug Global B3 -format March 1, 2021.
8 Study Population
8.1 Disposition of Subjects and Discontinuations
8.1.1
Disposition of Subjects
The number of subjects screened, the number of screen failures and the number of subjects 
with each reason for screen failure will be presented (overall). All enrolled subjects will be 
included.
The number of subjects screened, randomized and completed the study will be also presented 
by country and by site.
8.1.2
Discontinuation from the Study
The number and percentage of subjects who completed the study, withdrew from the study, 
and the reason for withdrawal from the study will be presented by treatment group and overall 


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for Randomized Set.
An individual subject listing will be provided for the disposition data.
8.1.3
Protocol Deviations and Analysis Sets
Important protocol deviations will be classified according but not limited to the following 
categories:

Inclusion/Exclusion Criteria

Informed Consent

Safety Reporting

Study Intervention

Trial Procedures
These categories may be amended or other categories may be added, but any changes will be 
made prior to DBL and will be discussed during the DRM and documented in the DRR.
Important deviations will be summarized by procedure group and overall on ITT Set.
All significant deviations, including GCP deviations, will be listed.
The number of subjects included in the ITT Set and Safety Set will be summarized for each 
treatment group and overall using the Enrolled Set.
8.2
Demographic and Baseline Characteristics
No formal comparison between treatment groups on demographic and baseline characteristics 
will be performed.
All demographic and baseline characteristics will use ITT set for reporting.
8.2.1
Demographic Characteristics
Demographic characteristics will be summarized by treatment group and overall. These will 
include age (hours), gestational age (weeks), sex, race, ethnicity, birth weight, and Appearance, 
Pulse, Grimace, Activity, Respiration (APGAR) total scores at 1 min and 5 min post-birth.
Subject’s age (hours) will be calculated as:

Age (hours) = (Time of randomization – time of birth)/60
Gestational age in weeks will be calculated as:

Gestations age (weeks) = gestational age (weeks) +gestational age (days)/7
8.2.2
Pregnancy History and Maternal Medical History
Mother’s age, race and ethnicity will be summarized by treatment group and overall. Number 
and percentage of mothers who took any antibiotics during the pregnancy, number and 
percentage of mothers who took any corticosteroids during the pregnancy and total number of 
doses will be included in the summary table. In addition, number of days since last intake of 


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corticosteroid before delivery will be calculated and categorically summarized for categories 
0-1, 2-7, >7 as follow:

Number of days since last intake of corticosteroid before delivery = Date/time of 
neonate’s birth – date/time of last dose of corticosteroid before delivery.
Details of maternal COVID-19 infection will be presented in a listing.
Additionally, following pregnancy and medical history will be summarized.
Table 2: Pregnancy History and Maternal Medical History
Pregnancy/medical history of the mother
Categories/subcategories
Type of delivery
Spontaneous, C-section with labor, C-section 
without labor, Emergency C-section
If Spontaneous
Operative, Not operative
Pregnancy 
complication, 
relevant 
risk 
factors
Yes/No
Complications/relevant risk factors
Gestational diabetes, Chronic Diabetes 
mellitus, Pregnancy-induced hypertension, 
Pre-eclampsia, 
Eclampsia, 
HELLP 
syndrome, Chronic hypertension, Chronic 
epilepsy, Depression, Asthma, Thyroid 
disease, Anemia, Isoimmunization, Previous 
fetal or neonatal death, Bleeding in second or 
third 
trimester, 
Maternal 
infection 
(subcategories: 
Toxoplasma, 
Rubella, 
Cytomegalovirus, Herpes virus, Hepatitis 
B/C, HIV, Syphilis, Gonorrhea), Other 
maternal 
infections, 
Polyhydramnios, 
Oligohydramnios, Premature rupture of 
membranes >21 days, Multiple gestation, 
Size-dates 
discrepancy 
or 
Intrauterine 
Growth Restriction, Drug Therapy (Lithium 
carbonate, Magnesium, Adrenergic blocking 
drugs, Selective serotonin reuptake inhibitor 
antidepressants), Maternal substance abuse, 
Fetal 
malformation, 
Decreased 
fetal 
movements, Absent/insufficient  prenatal 
care, 
Age 
<16 
or 
>35 
years, 
Overweight/increased BMI, Obesity, Uterine 
fibroids, Other
Any treatment given or in progress for 
Pregnancy complication(s)
Yes/No
Were there any intrapartum complications?
Yes/No


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Intrapartum complications
Emergency cesarean section, Forceps or 
vacuum-assisted delivery, Breech or other 
abnormal presentation, Premature labor, 
Precipitous 
labor, 
Chorioamnionitis, 
Prolonged rupture of membranes (>18 hours 
before delivery), Prolonged labor (>24 
hours), Prolonged second stage of labor (>3 
hours), Fetal bradycardia, Non-reassuring 
fetal heart rate patterns, Use of general 
anesthesia, Uterine tetany, Narcotics given to 
mother, 
Meconium-stained 
amniotic, 
Prolapsed cord, Abruptio placentae, Placenta 
previa, Other
Treatment 
given 
or 
in 
progress 
for 
intrapartum complication
Yes/No
Maternal medical history
Medical 
diagnosis 
summarized 
using 
MedDRA system organ class (SOC) and 
preferred term (PT)
Medical condition ongoing?
Yes/No
Is 
the 
subject’s 
mother 
taking 
any 
medications for ongoing diagnosis
Yes/No
Medication
Please refer to section 8.4 below.
Notes:

Number and percentage of women with at least one pregnancy history/maternal medical 
history will be presented. For the categorical summary, the categories will only be 
presented if at least one mother reports a particular category i.e. a category with zero 
count will not be presented.

A mother can report one or more categories of complication/risk factor/medication and 
will be counted in all the categories that she reports i.e. the N count may not be equal 
to sum of n counts.
8.3
Neonate Medical History
Neonates’ medical history will be summarized for the following variables:

Whether any complication of prematurity have been identified before treatment 
administration (Yes/No)

Whether the baby experienced any other condition before treatment administration 
(Yes/No)

Any major organ malformation, genetic disease or chromosomal abnormalities 
diagnosed (including conditions diagnosed after treatment; Yes/No)
Additionally, neonate medical history will be summarized by MedDRA SOC and PT and 
treatment group.


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8.4
Medications
Prior medications and concomitant medications will be summarized by treatment group, using 
Safety Set through frequency distributions and percentages by Anatomical Main Group [1st 
level of the Anatomical Therapeutic Chemical (ATC) classification], Therapeutic Subgroup 
(2nd level of the ATC classification), Chemical Subgroup (4th level of the ATC classification) 
and Preferred Name. Prior medications will also be summarized on Overall.
The medications will be classified according to the following rules:

Prior medication: start date/time< date/time  of first randomized treatment 
administration and stop date/time  ≤ date/time  of first study medication administration;

Medication maintained during the randomized treatment period: start date/time  < 
date/time  of first randomized treatment administration and stop date/time  > date/time  
of first randomized treatment administration or ongoing;

Concomitant medication: date/time of first study medication administration ≤ start 
date/time < maximum (date of home discharge / date of BPD diagnosis assessment / 
date of 40 weeks PMA). 
Separate summaries will be presented for maternal prior medications during pregnancy or 
delivery, neonate prior medications, neonate maintained and neonate concomitant medications.
Further, for maternal prior medications, medications used during pregnancy and medications 
used during delivery will be reported separately.
8.5
Procedures
Previous procedures and concomitant procedures will be summarized by treatment group for 
the Safety Set through frequency distributions and percentages by SOC and PT. 
Prior procedures will also be summarized on Overall.
The procedures will be classified according to the following rules:

Previous procedures: start date/time  < date/time  of first randomized treatment 
administration ≤ date/time  of first randomized treatment administration;

Procedure maintained during the randomized treatment period: start date/time  < 
date/time  of first randomized treatment administration and stop date/time  >  date/time  
of first randomized treatment administration or ongoing;

Concomitant procedures: date/time  of first randomized treatment administration ≤ start 
date/time  < maximum (date of discharge/date of BPD diagnosis assessment/date of 40 
weeks PMA);
8.6
Compliance
Treatment Compliance
Actual volume of poractant alfa administered will be entered on the eCRF. Compliance to 
treatment will be evaluated based on the actual volume administered in relation to neonate’s 
weight using the following formula:

Volume administered/Volume scheduled*100 = % of administered volume


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where the volume scheduled will be calculated on the basis of neonates’ weight as 2.5ml x birth 
weight (kg) for the first dose and as 1.25 ml x birth weight (kg) for the following doses.
Treatment compliance will be summarized on the ITT Set by treatment group. An additional 
summary displaying the number and percentage of patients in the following categories will also 
be presented by treatment group:

<80%

[80%-120%]

>120%
9 Efficacy Analyses
All efficacy analyses (see Table 3) will be performed on ITT Set. Following table describes 
analyses of efficacy variables. Subjects will be flagged in the listings for COVID-19 infection 
of mothers as well as neonates as follow:

COVID-19 infection during pregnancy will be identified in the maternal infection 
form (specification for “Others”).

COVID-19 infection for neonates will be identified in AE form (AEDECOD 
containing ‘COVID-19’ or ‘COVID’).
Percentage of neonates needing invasive mechanical ventilation (IMV):
For ETT group, the neonates needing IMV will include those cases:
If the procedure for surfactant administration was performed according to the randomization 
group:
If the first administration=’ETT’ and if the duration of the procedure was less than 1 
hour (Date/Time of removal of ETT – Date/Time of the Laryngoscope <1 Hour)  and 
if any of the invasive ventilation method is ticked (HFOV, SIMV, PTV, SIPPV, IMV, 
A/C, PSV or other) on the Respiratory Support Form) for any duration.
AND
If the first administration=’ETT’ and if the duration of the procedure was more than 1 
hour (Date/Time of removal of ETT – Date/Time of the Laryngoscope ≥1 Hour) and if 
any of the invasive ventilation method is ticked (HFOV, SIMV, PTV, SIPPV, IMV, 
A/C, PSV or other) on the Respiratory Support Form) and if end date/time of the 
invasive ventilation – start date/time of the invasive ventilation>1 hour.
If the procedure for surfactant administration was not performed according to the 
randomization group:
If the first administration=’ENDOTRACHEAL TUBE: Intubation, surfactant 
administration and rapid extubation (within 1 hour)’ and if any of the invasive 
ventilation method is ticked (HFOV, SIMV, PTV, SIPPV, IMV, A/C, PSV or other) on 
the Respiratory Support Form) for any duration.
AND


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If the first administration=’ENDOTRACHEAL TUBE: subject receiving MV > 1 hour’ 
and if any of the invasive ventilation method is ticked (HFOV, SIMV, PTV, SIPPV, 
IMV, A/C, PSV or other) on the Respiratory Support Form) and if end date/time of the 
invasive ventilation – start date/time of the invasive ventilation>1 hour.
For LISA group: if any of the invasive ventilation method is ticked (HFOV, SIMV, PTV, 
SIPPV, IMV, A/C, PSV or other) on the Respiratory Support Form) for any duration.
Percentage of neonates needing any intubation procedure, outside the initial surfactant 
administration period during the first 72 Hours of live, in the first 28 days PNA or within 
36 weeks PMA
For both groups (ETT and LISA): if any procedure containing ‘Endotracheal intubation’ or 
‘Intubation’ is filled in the procedure form and if the start date of the procedure is after the end 
date of surfactant administration for the first administration the subject will be flagged.
Then if the start date of the procedure is ≤ the 72 hours of live, the neonates will be considered 
as needing intubation. 
Then if the start date of the procedure is ≤ 28 days PNA visit date, the neonates will be 
considered as needing intubation. 
Then if the start date of the procedure is ≤ 36 weeks PMA visit date, the neonates will be 
considered as needing intubation. 
SpO2 or FiO2 for neonates still receiving respiratory support at 28±2 days PNA or at 36 
weeks PMA
Flags will be created to identify subjects still receiving respiratory support if the start date of 
respiratory support is <28 days PNA (respectively 36Weeks PMA)  using: 

Flag for 28 days PNA = Y if ‘Any Respiratory support provided to the patient?’ from 
respiratory support form = yes and end date of ventilatory support is ≥ 28 days PNA 
visit date.

Flag for 36 weeks PMA = Y if ‘Any Respiratory support provided to the patient?’ from 
respiratory support form = yes and end date of ventilatory support is ≥ 36 weeks PMA 
visit date. 
SpO2 or FiO2 values collected at the 28 Days PNA visit (respectively 36 weeks PMA visit) 
will be used for the summary statistics.


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Duration of ventilation/oxygen supplementation (alone):
Median duration time of IMV in the first 72 hours of life (hours)
If any of the invasive ventilation method is ticked (HFOV, SIMV, PTV, SIPPV, IMV, A/C, 
PSV or other) on the Respiratory Support Form) and if IMV end date is ≤ 72 hours of life for 
the neonates the duration (hours) will be calculated as:
IMV end date/time – IMV start date/time
if IMV end date is ≥72 hours of life for the neonates or still ongoing the duration (hours) will 
be calculated as:
72 hours – (start date/time of IMV- birth date/time)
Median duration time of IMV in the first 28 days PNA
If any of the invasive ventilation method is ticked (HFOV, SIMV, PTV, SIPPV, IMV, A/C, 
PSV or other) on the Respiratory Support Form) and if end date is ≤ 28 days PNA visit date 
the duration (in days) will be calculated as:
(IMV end date – IMV start date)+1
if IMV end date is >28 days or still ongoing PNA date the duration (days) will be calculated 
as:
28 days – (start date of IMV- birth date) 
Median duration time of IMV within the 36 weeks PMA
If any of the invasive ventilation method is ticked (HFOV, SIMV, PTV, SIPPV, IMV, A/C, 
PSV or other) on the Respiratory Support Form) and if end date is ≤ 36 weeks PMA visit date 
the duration (in days) will be calculated as:
(IMV end date – IMV start date)+1
if IMV end date is >36 weeks PMA date the duration (days) will be calculated as:
[(date of 36 weeks PMA – date of birth) – (start date of IMV- birth date) +1]
All the duration will be calculated individually and then summarized and compared between 
procedure groups.
In case of multiple IMV for a same neonate the IMV duration considered for the analyses will 
be the sum of all IMV durations.
If a subject discontinue the study for any reason before the analysis timepoint (i.e 36Weeks 
PMA visit date) the discontinuation date will be use instead of the visit date.
Stand- alone oxygen supplementation (days)
If any of the oxygen supplementation without positive pressure method is ticked (Low flow 
nasal cannula, oxygen in incubator or other) on the Respiratory Support Form) the duration (in 
days) will be calculated as:


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(Oxygen supplementation end date – oxygen supplementation start date)+1
In case of multiple oxygen supplementation for a same neonate the duration considered for the 
analyses will be the sum of all oxygen supplementation durations.
Non-invasive ventilation (days)
If any of the non-invasive ventilation method is ticked (CPAP, BiPAP, NIPPV, HFNC, 
nSIPPV, nSIMV, nIMV, nHFV, nPSV or other) on the Respiratory Support Form) the duration 
(in days) will be calculated as:
(Non-invasive ventilation end date – non-invasive ventilation start date) +1
In case of multiple non-invasive ventilation for a same neonate the duration considered for the 
analyses will be the sum of all non-invasive ventilation durations.
Table 3: Analyses of Efficacy Variables
Efficacy Variable
Endpoint
Analysis Method
Need for mechanical 
ventilation/intubation
Percentage 
of 
neonates 
needing 
invasive 
mechanical 
ventilation 
(IMV) in the first 72 hours 
of life
Percentage 
of 
neonates 
needing IMV in the first 28 
days PNA
Percentage 
of 
neonates 
needing IMV within 36 
weeks PMA
Cochran-Mantel-Haenszel (CMH) test 
adjusted for gestational age group will 
be used to compare the percentage of 
neonates between treatment groups. The 
CMH adjusted difference with its 95% 
CI will be presented.
Additional analysis will be performed to 
explore the impact of use of sedation 
and/or analgesia. The CMH test will be 
repeated stratified for the use of 
sedation/analgesia (Yes/No), adjusted 
difference and corresponding 95% CI 
will be presented.
Percentage 
of 
neonates 
needing 
any 
intubation 
procedure, outside the initial 
surfactant 
administration 
period in the first 72 hours of 
life
Percentage 
of 
neonates 
needing 
any 
intubation 
procedure, outside the initial 
surfactant 
administration 
period in the first 28 days 
PNA
The similar comparisons will be made as 
need of IMV.


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Percentage 
of 
neonates 
needing 
any 
intubation 
procedure, outside the initial 
surfactant 
administration 
period within 36 weeks 
PMA
SpO2
SpO2

A linear mixed model for 
repeated measures (MMRM) 
including treatment, time point, 
treatment 
by 
time 
point 
interaction, and gestational age 
group as fixed effects and pre-
procedure SpO2 as covariate will 
be used to analyze SpO2 values. 
The adjusted means in each 
treatment group, the adjusted 
mean 
difference 
between 
treatments and their 95% CIs at 
each time point and averaged 
over the first 120 hours post-
treatment will be estimated by 
the model. 

Time profile plot of mean SpO2 
in the first 120 hours post-
administration will be presented 
by treatment group.

A forest plot will also be 
presented.
SpO2 for neonates still 
receiving 
respiratory 
support at 28±2 days PNA 
SpO2 values will be summarized 
descriptively by treatment group.
SpO2 for neonates still 
receiving 
respiratory 
support at 36 weeks PMA
SpO2 values will be summarized 
descriptively by treatment group.


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FiO2
FiO2

A linear mixed model for 
repeated measures (MMRM) 
including treatment, time point, 
treatment 
by 
time 
point 
interaction, and gestational age 
group as fixed effects and pre-
procedure FiO2 as covariate will 
be used to analyze FiO2 values. 
The adjusted means in each 
treatment group, the adjusted 
mean 
difference 
between 
treatments and their 95% CIs at 
each time point and averaged 
over the first 120 hours post-
treatment will be estimated by 
the model. 

Time profile plot of mean FiO2 in 
the 
first 
120 
hours 
post-
administration will be presented 
by treatment group.

A forest plot will also be 
presented.
FiO2 
for 
neonates 
still 
receiving 
respiratory 
support at 28±2 days PNA 
FiO2 
values 
will 
be 
summarized 
descriptively by treatment group.
FiO2 
for 
neonates 
still 
receiving 
respiratory 
support at 36 weeks PMA
FiO2 
values 
will 
be 
summarized 
descriptively by treatment group.
SpO2/FiO2 ratio
SpO2/FiO2 ratio

SpO2/FiO2 ratio will be analyzed 
using a linear MMRM including 
treatment, time point, treatment 
by time point interaction, and 
gestational age group as fixed 
effects 
and 
pre-procedure 
SpO2/FiO2 ratio as covariate. 
The adjusted means in each 
treatment group, the adjusted 
mean 
difference 
between 
treatments and their 95% CIs at 
each time point and averaged 
over the first 120 hours post-
treatment will be estimated by 
the model.


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
Time profile plot of mean 
SpO2/FiO2 ratio in the first 120 
hours post-treatment will be 
presented by treatment group.

SpO2/FiO2 
ratio 
will 
be 
summarized between treatments 
at 28±2 Days PNA and at 36 
weeks PMA by means of 
descriptive statistics.

A forest plot will also be 
presented.
Blood gas analysis
pH, pCO2, pO2, HCO3, BE, 
lactate
Descriptive statistics by treatment group 
for absolute values and change from pre-
procedure values will be reported.
Use 
of 
additional 
surfactant doses
% of subjects requiring at 
least 
one 
additional 
surfactant dose
The percentage of subjects requiring at 
least one additional surfactant dose will 
be compared by treatment group by 
means of a Fisher’s exact test. Odds ratio 
(OR) and related exact 95% CI will be 
also provided.
Subjects with pulmonary hemorrhage 
(from AE form, occurred during the first 
procedure) will not be included in this 
analysis.
Number 
of 
additional 
surfactant doses
Descriptive statistics will be reported by 
treatment group.
Duration 
of 
ventilation/oxygen 
supplementation 
(alone)
Median duration time of 
IMV in the first 72 hours of 
life (hours)
Median duration time of 
IMV in the first 28 days 
PNA
Median duration time of 
IMV within the 36 weeks 
PMA
Stand- 
alone 
oxygen 
supplementation (days)
Non-invasive 
ventilation 
(days)
Duration of IMV will be presented in 
hours for the first 72 hours of neonate’s 
life. For the rest of the study, the 
duration will be presented in days.
Comparison between treatment groups 
will be performed using Mann-Whitney 
U-test. Estimates of median difference 
and corresponding 95% CI will be 
presented.


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10Safety Analyses
The safety variables will be analyzed on the Safety Set.
10.1 Extent of Exposure
The number of poractant alfa drug administrations (1, 2 or 3) will be presented using 
frequencies for the treatment groups. Actual volume administered (ml) will be summarized 
using summary statistics.
10.1.1 First Administration
Following analyses will be presented for parameters related to first administration of poractant 
alfa:

Number of 1st failed attempt to insert the catheter/ETT will be summarized by treatment 
group. Percentage of neonates with 1st failed attempt will be compared between groups 
using the CMH adjusted for gestational age group. The CMH adjusted difference with 
its 95% CI will be presented.

Number of maneuvers discontinued due to neonate’s severe destabilization will be 
summarized by treatment group by means of descriptive statistics.
10.1.1 First and Second Administration
Following analyses will be presented for parameters related to first and second administration 
of poractant alfa, based on actual treatment received for first administration.
If the second amistration actually received is not compliant with the first administration, the 
data will not be analysed.

Number of device misallocation (i.e., esophageal intubation) will be summarized, only 
for LISA group, by means of descriptive statistics.

Number of attempts to the first successful insertion will be summarized by treatment 
group by means of descriptive statistics

Duration of surfactant administration (min) and overall procedure (hours and min) for 
surfactant administration will be compared between treatment groups by using the 
Mann-Whitney U-test. Procedure start is defined as date/time of laryngoscope insertion 
and end date/time is defined as the date/time of removal of the catheter/ETT.
10.2 Adverse Events
An adverse event (AE) will be classified as pre-treatment AE if it starts before the first 
randomized study medication administration (AE onset date/time < date/time of first 
randomized treatment administration).
An AE will be classified as a TEAE if it starts on or after the date of first randomized treatment 
administration up to date of discharge (date/time of first randomized treatment administration 
≤ AE onset date/time ≤ maximum (date of discharge/date of BPD diagnosis assessment/date of 
40 weeks PMA)).


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An Adverse Drug Reaction (ADR) is an AE judged as related to the study medication.
A serious ADR is a serious AE (SAE) judged as related to the study medication.
A severe AE is an AE with severe intensity. AEs will be graded using INC Neonatal Adverse 
Event Severity Scale (NAESS) v1.0. This is a 5-grade table hence the grades will be converted 
as below for reporting:

AEs grade 1: Mild

AEs grade 2: Moderate

AEs grade 3, 4 and 5: Severe
Refer to section 7.3 for missing severity.
An AE leading to death is an AE with outcome equal to “Fatal”.
Pre-treatment AEs and TEAEs will be presented separately. Pre-treatment AEs will be 
presented in the listings only.
Following AEs will be summarized by treatment group and overall:

Number and percentage of neonates with AEs starting during overall procedure for 
surfactant administration by dose (1st or 2nd; please refer to section 6.1);

Number and percentage of neonates with AEs starting during overall procedure for 
surfactant administration judged related to the procedure by dose (1st or 2nd; please refer 
to section 6.1);

Number of AEs occurring during overall procedure for surfactant administration 
requiring either oxygen alone or an increase in FiO2 without the need for escalation of 
invasive or non-invasive ventilator support;

Number of AEs starting during overall procedure for surfactant administration 
requiring administration of manual (bag and mask) pressure positive ventilation and 
related duration of ventilation (non-invasive ventilation);

Number of AEs starting during overall procedure for surfactant administration 
requiring endotracheal intubation and related duration of intubation (invasive 
ventilation);

Number of AEs starting during overall procedure for surfactant administration 
requiring circulatory support including administration of crystalloids; 

Number of AEs starting during overall procedure for surfactant administration 
requiring cardiopulmonary resuscitation including administration of cardiac massage 
or adrenaline
Incidence of related AEs (ADRs), serious AEs (SAEs) and AEs leading to death will be 
summarized by treatment group both in term of frequency of neonates with at least one AE and 
in term of frequency of AEs (number of events). All the aforementioned categories of AEs will 
be summarized by SOC and PT. 
Incidence of AEs indicating neonatal complications of prematurity (see APPENDIX I for 
complete list) will be summarized using frequency and percentage of neonates experiencing an 


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AE for each complication along with the grades. A neonate can experience more than one 
complication of prematurity and will be counted in all the categories experienced.
If a complication is reported more than once (with the same AEDECOD) for the same neonate, 
the complication will be counted only one time and the maximum grade will be considered.
To identify the complications of prematurity from other AEs, AE terms from appendix I will 
be flagged from AE form.
Complication of prematurity flag = Y if events (AETERM) in (“terms identified in appendix 
I”).
Only for AE starting during the procedure, the related duration of invasive ventilation and 
positive pressure ventilation will be summarized as well.
The duration in minutes is calculated as 

End time of invasive ventilation/ positive pressure ventilation – start time of invasive 
ventilation / positive pressure ventilation
The duration in hours will be calculated as

Duration in minutes / 60
The duration of invasive ventilation/PPV will be only calculated for AE starting during the 
procedure and for invasive ventilation/PPV used as ‘Other action taken’ = ‘Manual positive 
pressure ventilation’ or ‘Other action taken’ = ‘Endotracheal intubation and invasive 
ventilation’ as recorded on the eCRF page of ‘Adverse event with timing’ and the start and end 
time of the procedure will be used from the eCRF page of ‘Respiratory support’ where 
‘Indication’ = ‘Adverse event’.
A subgroup analysis of AEs during procedure for surfactant administration and TEAEs will be 
performed based on the use of sedation and/or analgesia (Yes/No). The above summaries will 
be repeated by use of sedation/analgesia if enough subjects.
Additionally, incidence of COVID-19 will be summarized separately. Related listing will also 
be presented. 
The relative day of AE onset will be calculated as follows:

for pre-treatment AEs:
o
AE onset date - date of first randomized treatment administration (if AE onset 
date is completely known);
o
Missing (if AE onset date is incomplete or unknown).

For TEAEs:
o
AE onset date - date of first randomized treatment administration +1 (if AE 
onset date is completely known);
o
Missing (if AE onset date is incomplete or unknown).
The duration of an AE (days) will be calculated as follows:

AE end date – AE onset date + 1 (when both dates are completely known);


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
Date of completion/discontinuation – AE onset date + 1 (when the AE onset date is 
fully known but the AE is not resolved at the end of the trial): in this case the duration 
will be presented as “>x days” in the listing rather than “x days”;

Missing (when the AE onset date is incomplete or unknown, or when the AE has 
resolved but with an incomplete or unknown end date, or when the AE onset date is > 
date of completion/discontinuation and the AE is not resolved).
10.3 Vital Signs
Vital signs parameters (SBP, DBP, MBP, HR and RR) will be summarized as absolute and the 
change from pre-procedure by treatment group using descriptive statistics at each scheduled 
visit. Changes from pre-procedure will not be calculated at 28 Days PNA, 36 Weeks PMA and 
Week 40 (Discharge).
10.4 Pain Assessment
Pain will be assessed using PIPP score. PIPP consists of 7 parameters to assess pain: gestational 
age, behavioral state, maximum HR, minimum O2 saturation, brow bulge, eye squeeze, 
nasolabial furrow and which are graded from 0 to 3. Total score will be calculated for each 
subject by summing up the individual scores. The interpretation can vary from a minimum 
score of 0 to a maximum score of 21. The higher the score the greater the pain.
PIPP total score on Day 1, calculated as sum of pre-procedure total PIPP score and total PIPP 
score recorded at T0; will be summarized using descriptive statistics by treatment group. 
10.5 Mortality and BPD

Number of deaths/BPD incidence at 36 weeks PMA will be compared by CMH test . 
Relative risk and related 95% CI will be presented. Frequency and percentages under 
each gestational group (25 to 26+6 weeks and 27 to 28+6 weeks) will also be displayed.

The incidence of BPD at 36 weeks PMA will be compared by treatment as for the 
Death/BPD incidence. Severity of BPD will also be summarized, defined as: 
o
Mild BPD (breathing room air), if (‘Is there a requirement for supplemental 
oxygen?’ = ‘No’)  AND  if (‘Is the patient receiving respiratory support via 
nasal cannula?’ = ‘No’ OR (‘Is the patient receiving respiratory support via 
nasal cannula?’ = ‘Yes’ and Flow rate is <=2 l/min in BPD form))
o
Moderate BPD (need for <30% oxygen), if oxygen level value (FiO2) collected 
in BPD form <30%;
o
Severe BPD (need for ≥30% oxygen and/or positive pressure (PPV or NCPAP)) 
if:

FiO2 ≥30% and/or

‘Is the subject receiving positive pressure for respiratory 
support’ = ‘Yes’ or

‘Is the patient receiving respiratory support via nasal cannula?’ 
= ‘Yes’ and Flow rate is > 2 l/min in BPD form.


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In case of missing BPD assessment the neonate will not be included in the analysis.

The mortality at 36 weeks PMA and at Day 28 will be compared by treatment as for 
Death/BPD incidence.

Oxygen use at Day 28 and at Week 36 (alone and/or during any kind of MV) will be 
compared by treatment as for Death/BPD incidence. In case of missing BPD assessment 
the neonate will not be included in the analysis.
If a subject discontinue the study for any reason before the analysis timepoint (i.e 36Weeks 
PMA visit date) the discontinuation date will be use instead of the visit date.
10.6 Other Safety Variables

Feeding and hearing status at discharge or 40 weeks PMA (whichever comes first) will 
be summarized by treatment group by frequency distributions. 

Frequency of neonates with major neonatal morbidities at discharge or 40 weeks PMA 
(whichever comes first) will be summarized by treatment group.

For hearing status, percentage of subjects with at least one “failed-referred” or abnormal 
result and percentage of monolateral (if either right or left ear is indicated) or bilateral 
(if both right and left ear are indicated) status will be summarized.

Weight (kg), OFC (cm) and length (cm) at discharge home or 40 weeks PMA will be 
summarized by treatment group by descriptive statistics. 

Neonates needing invasive or non-invasive respiratory support at discharge home or 40 
weeks PMA will be summarized by treatment group by frequency distribution.
Neonates needing invasive respiratory support are defined as subject with ‘Is the patient 
receiving mechanical ventilation via endotracheal tube’ = ‘Yes’ in respiratory evaluation 
form.
Neonates needing non-invasive respiratory support are defined as subjects with ‘Is the 
patient receiving non-invasive ventilation?’ = ‘Yes’ or ‘Is the patient receiving respiratory 
support via nasal cannula?’= ‘Yes’ or ‘Is the patient receiving any supplementary oxygen? 
= ‘Yes’ in respiratory evaluation form.

Neonates needing respiratory medications at discharge home or 40 weeks PMA will be 
summarized by treatment group by frequency distribution
11Other Analyses
No other analyses planned.
12Changes in the Planned Analyses from Study 
Protocol
The following Safety variables:


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
Number of device misallocation for LISA Group (esophageal intubation);

Number of attempts to the first successful insertion;

Duration of surfactant administration (min);

Duration of the whole procedure (starting from the insertion of laryngoscope up to the 
removal of the catheter or ETT);
will be analysed for first AND second administration.
Adjusted Differences and 95%CI using CMH test adjusted for gestational age groups has been 
deleted for Death/BPD and BPD analyses due to low number of subjects.
Percentage of neonates needing Invasive Mechanical Ventilation (IMV) by use of 
sedation/analgesia (Intention-To-Treat Set) will not include treatment comparison due to low 
number of subjects.
13Output
13.1 Software
SAS version 9.4 will be used to perform all the statistical analyses.


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13.2 Reporting Conventions
13.2.1 Treatment, Visit and Subgroup Descriptors
In the tables, listings and figures, the treatments and the visits will be identified as described 
below.
Treatment group
Descriptor for treatment
Poractant alfa Administered through LISA 
LISA Administration 
Poractant alfa Administered through Conventional 
Intubation with ETT 
Conventional 
Administration 
For listing purpose, the treatment descriptor will be shortened to “LISA” and “Conventional” 
according to actual treatment.
Output
Descriptor for timepoints/visits
Tables
Pre-procedure, T0, 5 Min Post-procedure, …, 24 Hours Post-
procedure, …, Day 28 PNA, 36 Weeks PMA, Discharge or 40 Weeks 
PMA 
Listings
Same as above.
Figures
Same as ‘Tables’ above.
13.2.2 Decimal places
Quantitative variables will be listed with the same number of decimal places as in the actual 
data.
The following rules on decimal places will be considered in the listings for the derived variables 
(in the analyses rounding will not be performed):

Duration time of IMV (hours for the first 72 hours and then in days), duration of 
ventilation (hours/days), duration of an AE (days), duration of endotracheal 
intubation/PPV (hours), duration of surfactant administration (min), neonate age 
(hours), maternal age (years), medication duration (days) and duration of whole 
procedure (min): integer numbers;

Gestational age (weeks), compliance (%): 1 decimal 

Duration of whole procedure (Hours): 2 decimals

SpO2/FiO2 ratio: 2 decimals

Birth weigth (Kg): 2 decimals

Change from baseline/pre-dose: same as the variable considered.
The following rules on decimal places will be considered for the results of the analyses (if the 
analyses are performed on derived variables, the level of precision of the actual data is derived 
from the previous list):

Min, max: same as actual data;

Mean and its confidence limits (unadjusted and adjusted), adjusted difference between 
means and its confidence limits, SD, median, first and third quartiles: actual data + 1 


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decimal place (with the exception of health economic data: actual data + 2 decimal 
places);

Percentage: 1 decimal place;

Odds ratio and its confidence limits: 3 decimal places;

p-values will be presented to 3 decimal places. If the p-value is less than 0.001, it will 
be presented as <0.001
13.2.3 Other reporting conventions
Treatments will be presented with the following order in the tables: poractant alfa through 
LISA, poractant alfa through ETT.
Unless otherwise stated, listings will be sorted by Subject ID.
In a listing, in the case that a subject’s record has been continued to the next page, an 
appropriate identification (e.g., the subject ID number) must be presented at the beginning of 
that page.
In general, dates will be presented on listings in the format ddmmmyyyy (date9.) and time in 
the format hh:mm (time5.). In case of partial dates or times, missing information will be 
replaced by dashes.
13.3 Format
The following information should always be presented:

‘Clinical Study Code No.: <Study Code No.>’ followed by Chiesi denomination in the 
top portion of each page. Chiesi denomination is ‘Chiesi Farmaceutici S.p.A’.

The table/listing/figure number followed by the title, the analysis set used and the 
output page number in the format of ‘Page x of Y’ in the top portion of each page of 
any table/listing/figure.

The SAS program name followed by the date time of the output production and the 
analysis type (e.g. Dry Run; Draft Version; Final Version) in the bottom portion of each 
page of any table/listing/figure. The source listing/table/dataset will appear bottom left 
for every table/figure/listing. 

Tables and listings will be produced in rich text format (i.e., they will be tabular in 
format). Individual outputs must be provided in both portable format document (.pdf) 
and rich text format (.rtf). 

Combined PDF and RTF documents must also be provided, including a table of 
contents with hyperlinks. The combined documents should be divided by document 
type (tables, figures, listings). 

SAS outputs will be provided to the Sponsor in a similar manner (PDF and RTF; 
combined and with hyperlinked table of contents). The SAS outputs will be a separate 
deliverable to the Sponsor and are not intended for inclusion within the CSR.

The combined documents page number in the format of ‘Page n of N’ will be presented 
bottom right corner.


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The following should be followed for the tables:

A landscape layout and Letter size will be used.

A 9-point font size will be used using Courier New font. 

Horizontal lines will appear before and after the column heading of the output.

Additional footnotes may be included if strictly necessary for clarification. Footnotes 
will be put under the main body of text at the bottom left of the page and will be 
displayed on each page of the output and not only on the last one.

The left and right margins will be a minimum of 2.1 cm from the left and 1.9 cm from 
the right. The top and bottom margins will be a minimum 2.92 cm. Header and footer 
will be both 1.27 cm. 
The following should be followed for the listings:

A landscape layout and Letter size will be used.

An 8-point font size will be used using Courier New font.

Horizontal lines will appear before and after the column heading of the output.

Additional footnotes may be included if strictly necessary for clarification. Footnotes 
will be put under the main body of text at the bottom left of the page and will be 
displayed on each page of the output and not only on the last one.

The left and right margins will be a minimum of 2.1 cm from the left and 1.9 cm from 
the right. The top and bottom margins will be a minimum 2.92 cm. Header and footer 
will be both 1.27 cm. 
The following should be followed for the figures:

A portrait layout and Letter size will be used.

A 9-point font size will be used using Courier New font. 

Figures will be produced in RTF and PDF formats (as described above), including 
relevant titles and footnotes as separate elements on the page (not within the body of 
the figure). 

Additional footnotes may be included if strictly necessary for clarification. Footnotes 
will be put under the main body of text at the bottom left of the page and will be 
displayed on each page of the output and not only on the last one.

The size of the figures will be: width=16.3 cm, height=12.2 cm. The resolution will be 
set using the option IMAGE_DPI=400. Figures will have a footer specifying the source 
table or listing. Figures should clearly identify each treatment arm and require care of 
colors/symbols. 

The left margin will be a minimum of 2.5 cm, the right margin will be a minimum of 
2 cm. The top and bottom margins will be a minimum 0.8 cm. 


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13.4 Quality Control
The Quality Control steps are defined in the Datasets, Tables, Listings, Figures QC Plan.
14SAS Code
14.1 Mixed model for repeated measures for SpO2, FiO2, and SpO2/FiO2 
ratio:
PROC MIXED DATA = dataset;
CLASS tmt timepoint gest_age subject;
MODEL aval = tmt timepoint tmt*timepoint gest_age pre_proc_val/ DDFM=KR;
REPEATED timepoint / SUBJECT=subject TYPE=UN;
LSMEANS tmt tmt*timepoint / OM AT MEANS CL; 
LSMESTIMATE tmt*timepoint
'LISA vs. ETT: Day 1 T0' 
1 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0 0 0 0 0 0, 
'LISA vs. ETT: Day 1 5M' 
0 1 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0 0 0 0 0,
'LISA vs. ETT: Day 1 15M'  0 0 1 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0 0 0 0,
‘LISA vs. ETT: Day 1 30M’
0 0 0 1 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0 0 0,
‘LISA vs. ETT: Day 1 1H’ 
0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0 0 ,
‘LISA vs. ETT: Day 1 6H’ 
0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0,
‘LISA vs. ETT: Day 1 12H’ 
 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0,
‘LISA vs. ETT: Day 1 24H’ 
 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 -1 0 0 0,
‘LISA vs. ETT: Day 2’ 
 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 -1 0 0,
‘LISA vs. ETT: Day 3’ 
 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 -1 0,
‘LISA vs. ETT: Day 5’ 
 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 -1/ CL;
LSMESTIMATE tmt
'LISA vs. ETT: Overall (120 first hours)'
1 -1 / CL;
RUN;
Notes: 

“Aval”: value  at each time point of the variable;

“Tmt”: treatment group (treatment order: 1 = LISA Administration, 2 = Conventional 
Administration);

“Timepoint”: scheduled time point during main phase of the study;

“Gest_age: gestational age group of neonate

 “Pre_proc_val”: pre-procedure value of the variable;

“Subject”: subject number;

Calculation of adjusted means (least squares means):
The approach described above will ensure that the least squares means calculated by SAS 
will be based on:
–
coefficients for classification effects (i.e., the effects of categorical covariates) 
proportional to the margins observed in the group of patients analyzed;
–
effects of quantitative covariates set equal to their mean values in the group of 
patients analyzed.
The analysis is based on the following steps:
1. generate a dataset by selecting:


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–
For repeated post-randomization measurements (e.g., parameters at each 
visit, analyzed using a linear MMRM): all the post-randomization records 
for patients with at least one available and valid post-randomization 
measurement and no missing covariates;
2. in case of repeated post-randomization measurements, add to the dataset generated 
in step 1 the records for missing post-randomization visits of the patients included 
in the dataset. In the added records the value of the response variable will be 
missing, but the full information on covariates has to be included;
3. use the dataset obtained as the input dataset for the MIXED or the GENMOD 
procedure, specifying the following options in the LSMEANS statement:
–
in case of repeated post-randomization measurements: OM AT MEANS;
Example: analysis of value at all-time point based on a mixed model for repeated measures 
including the effects of treatment, time point (categorical variable), treatment by time point 
interaction, pre-procedure (V2) and another covariate. Visit 1 represents the screening visit.
Original dataset (X = available value, ‘.’ = missing or invalid value):
Patient
Treatment
Covariate
Baseline
Visit
Value
1
A
X
X
1
X
1
A
X
X
2
X
1
A
X
X
3
X
1
A
X
X
4
X
1
A
X
X
5
X
2
B
X
X
1
X
2
B
X
X
2
X
2
B
X
X
3
X
3
A
X
X
1
X
3
A
X
X
2
X
3
A
X
X
3
X
3
A
X
X
4
.
3
A
X
X
5
.
4
B
X
X
1
X
4
B
X
X
2
X
5
A
.
X
1
X
5
A
.
X
2
X
5
A
.
X
3
X
Step 1 (visits 1 and 2 not selected since pre-randomization, patient 4 not selected due to missing 
post-randomization measurements, patient 5 not selected due to missing covariate):
Patient
Treatment
Covariate
Baseline
Visit
Value
1
A
X
X
3
X
1
A
X
X
4
X
1
A
X
X
5
X
2
B
X
X
3
X
3
A
X
X
3
X
3
A
X
X
4
.
3
A
X
X
5
.


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Step 2 (added records in italic):
Patient
Treatment
Covariate
Baseline
Visit
Value
1
A
X
X
3
X
1
A
X
X
4
X
1
A
X
X
5
X
2
B
X
X
3
X
2
B
X
X
4
.
2
B
X
X
5
.
3
A
X
X
3
X
3
A
X
X
4
.
3
A
X
X
5
X
14.2 Comparison of two groups using Fisher’s exact test
PROC FREQ DATA = dataset;
TABLES Tmt * Variable / FISHER OR (CL=Exact);
EXACT OR;
ODS output OddsRatioCLs =OR1 fishersexact=pval;
run;
Notes: 
–
“TMT”: the treatment group, (treatment order: 1=LISA Administration, and 
2=Conventional Administration);
–
“Variable”: the categorical variable value.
14.3 Comparison of Two Groups using Mann-Whitney U-Test
PROC NPAR1WAY DATA = dataset WILCOXON; 
CLASS Tmt;
VAR Variable;
RUN;
Notes: 
–
“TMT”: the treatment group, (treatment order: 1=LISA Administration, and 
2=Conventional Administration)
–
“Variable”: the variable that need to be analyzed.
–
The normal approximation results will be displayed.
14.4 Estimates of median difference and corresponding 95% CI


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PROC QUANTREG DATA= dataset;
 CLASS Tmt;
   MODEL Variable = Tmt / quantile=0.5;
   ESTIMATE 'Difference in Medians' Tmt 1 -1 / CL;
   ODS output ParameterEstimates=Param Estimates=Est;
run;
Notes: 
–
“TMT”: the treatment group, (treatment order: 1=LISA Administration, and 
2=Conventional Administration)
–
“Variable”: the variable that need to be analyzed.
14.5 Tables that need 95% CIs within group for continuous variables:
DATA outdata; 
SET outname;
  
LCL=mean-(TINV(0.975,n-1)*(std/SQRT(n)));
  
UCL=mean+(TINV(0.975,n-1)*(std/SQRT(n)));
RUN;
14.6 Comparison of Two Groups using Cochran-Mantel-Haenszel Test 
PROC FREQ DATA=dataset;
TABLES GEST_AGE*TMT* Variable /cmh;
RUN;
Note for Death/BPD and BPD gestational age group will be omitted.
Notes: 
–
“TMT”: the treatment group, (treatment order: 1=LISA Administration, and 
2=Conventional Administration)
–
“Variable”: the variable that need to be analyzed.
–
“Gest_age”: gestational age of neonate
For adjusted mean difference and corresponding 95% for stratified please refer to the macro 
used in “Adjusted proportion difference and confidence interval in stratified randomized 
trials” published in PharmaSUG 2013 – Paper SP04 [2].
Use WALD CI Options


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15References
1. Stevens B Johnston C et al. Premature Infant Pain Profile: Development and initial 
validation. Clinical Journal of Pain. 1996; 12: 13-22.
2.  Yeonhee K et al. Adjusted proportion difference and confidence interval in stratified 
randomized trials. PharmaSUG 2013 - Paper SP04.


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16List of Tables, Listings and Figures
16.1 Tables
The SAS output for the analyses included in the flagged (***) tables below will be provided for internal use only and not for inclusion into the 
CSR.
Table Number
Table Title
Template 
Code
Notes
Footnotes/Source 
Listing Number
Table 14.1.1.1
Screen Failures (Enrolled Set) 
DST001
- Only Overall column should be 
displayed
Source: Listing 16.2.1.1
Table 14.1.1.2
Disposition by Treatment (Randomized Set) 
DST002
- Treatment groups and Overall 
columns should be displayed.
Source: Listing 16.2.1.2
Table 14.1.1.3
Disposition by Country and Site (Enrolled Set)
DST004
- Treatment groups and Overall 
columns should be displayed.
- Replace Country with Country 
or Site
- Present first Country (overall) 
then Site within each Country in 
the first column (Country sorted 
by Alphabetic order, Site sorted 
by ascending value).
- Number of subjects Enrolled, 
Randomized Completed and 
Discontinued should be 
displayed.
Source: Listing 16.2.1.2
Table 14.1.1.4
Important Protocol Deviations Leading to the 
Exclusion of the Whole Subject from Analysis 
(Intention-To-Treat Set)
DVT001
- Overall column should be 
displayed.
- Only Important deviation to be 
display.
Source: Listing 16.2.2.1


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Table Number
Table Title
Template 
Code
Notes
Footnotes/Source 
Listing Number
Table 14.1.1.5
Important Protocol Deviations not Leading to 
the Exclusion of the Whole Subject from 
Analysis (Intention-To-Treat Set) 
DVT001
Same as Table 14.1.1.4
Source: Listing 16.2.2.1
Table 14.1.1.6
Analysis Sets (Intention-To-Treat Set)
DST005
- Overall column should be 
displayed.
- Safety Set and ITT set to be 
displayed.
Source: Listing 16.2.3.1
Table 14.1.2
Demographic Characteristics (Intention-To-
Treat Set)
DMT001
- Overall column should be 
displayed.
- Variables to be summarized: 
Gestational Age Categories (25+0 
weeks to 26+6 weeks / 27+0 
weeks to 28+6 weeks), 
Gestational Age (Weeks), 
Gender, Race (categories as per 
CRF to be displayed), Ethnicity 
(categories as per the CRF to be 
displayed), Birth Weight (kg), 
APGAR Total Score at 1 minute 
post-birth and APGAR Total 
Score at 5 minutes post-birth.
- All categories should be 
displayed even if empty.
Source: Listing 16.2.4.1
Add footnote:
[1] APGAR: Appearance, 
Pulse, Grimace, Activity, 
Respiration)


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Table Number
Table Title
Template 
Code
Notes
Footnotes/Source 
Listing Number
Table 14.1.3.1 (Table 
split in 2 parts)
Pregnancy History and Maternal Medical 
History (Intention-To-Treat Set)
BLT001
- Overall column should be 
displayed.
- Variables to display: 
- Mother’s Age (Years)
- Mother’s Race
- Mother’s Ethnicity
- Any Antibiotics during the 
Pregnancy
- Any Corticosteroids during the 
Pregnancy
- Total Number of 
Corticosteroids Doses
- Number of Days from Last 
Corticosteroid Dose up to Birth 
(Categories to be presented are 
1, 2-7 and >7)
- Type of Delivery
    C-section with Labor
    C-section without Labor
    Emergency C-section
    Spontaneous
         Operative
         Not Operative
- 
Pregnancy/Complication/Releva
nt Risk Factor 
- Pregnancy 
Complication/Relevant Risk 
Factor (Categories to be 
presented as recorded in the 
CRF)
- Any Treatment Given or in 
Progress for Pregnancy 
Complication (Yes/No) [1/2]
Add footnotes: 
[1] A mother can report 
one or more categories of 
complication/risk 
factor/medication/intrapar
tum complication and will 
be counted in all the 
categories that she 
reports. 
[2] Number of days since 
last intake of 
corticosteroid before 
delivery = Date/time of 
neonate’s birth – 
date/time of last dose of 
corticosteroid before 
delivery
[3] Operative/Not 
Operative Frequencies are 
based on Spontaneous 
type number
Source: Listings 
16.2.4.2.1, 16.2.4.2.2, 
16.2.4.2.3.


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Table Number
Table Title
Template 
Code
Notes
Footnotes/Source 
Listing Number
Table 14.1.3.1 (Table 
split in 2 parts)
Pregnancy History and Maternal Medical 
History (Intention-To-Treat Set)
BLT001
[2/2]
- Any Intrapartum 
Complications? (Yes/No)
- Intrapartum Complications 
(Categories to be presented as 
recorded in the CRF)
- Treatment Given or in Progress 
for Intrapartum Complication 
(Yes/No)
- Maternal Medical Condition 
Ongoing (Yes/No)
- Any Medication for Ongoing 
Diagnosis (Yes/No)
Note: Categories will be 
presented only if at least one 
mother reports a particular 
category.
Add footnotes: 
[1] A mother can report 
one or more categories of 
complication/risk 
factor/medication/intrapar
tum complication and will 
be counted in all the 
categories that she 
reports. 
[2] Number of days since 
last intake of 
corticosteroid before 
delivery = Date/time of 
neonate’s birth – 
date/time of last dose of 
corticosteroid before 
delivery
[3] Operative/Not 
Operative Frequencies are 
based on Spontaneous 
type number
Source: Listings 
16.2.4.2.1, 16.2.4.2.2, 
16.2.4.2.3.
Table 14.1.3.2
Maternal Medical History (Intention-To-Treat 
Set)
MHT001
- Replace 
<Condition/Procedure> by 
Maternal Medical History.
Add footnotes: 
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
Source: Listing 16.2.4.2.5


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Table Number
Table Title
Template 
Code
Notes
Footnotes/Source 
Listing Number
Table 14.1.3.3
Neonate Medical History (Intention-To-Treat 
Set)
MHT001
- Replace 
<Condition/Procedure> by 
Neonate Medical History.
 
Add the footnote 
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
 
Source: Listing 16.2.4.2.4
Table 14.1.3.4
Prior Neonate Procedures (Safety Set)
MHT001
- Replace 
<Condition/Procedure> by Prior 
Neonate Procedure. 
Add the footnote
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
 
Source: Listing 16.2.4.5
Table 14.1.3.5
Maintained Neonate Procedures (Safety Set)
MHT002
- Please display as first row 
‘Number of Subjects  with at 
Least One Maintained Neonate 
Procedure’
Same as Table 14.1.3.4
Table 14.1.3.6
Concomitant Neonate Procedures (Safety Set)
MHT002
- Please display as first row 
‘Number of Subjects  with at 
Least One Concomitant 
NeonateProcedure’
Same as Table 14.1.3.4
Table 14.1.4.1
Prior Neonate Medications (Safety Set)
CMT001
- Overall column should be 
displayed
- Please display as first row 
‘Number of Subjects  with at 
Least One Prior Neonate 
Medication’
Add the footnote
[1] ATCs and Preferred 
Name are coded using 
WHO-DD <month year>.
Source: Listing 16.2.4.9
Table 14.1.4.2-a
Prior Maternal Medications used During 
Pregnancy (Safety Set)
CMT002
- Please display as first row 
‘Number of Subjects  with at 
Least One Prior Maternal 
Medication used During 
Pregnancy’ 
Source: Listing 16.2.4.8


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Table Number
Table Title
Template 
Code
Notes
Footnotes/Source 
Listing Number
Table 14.1.4.2-b
Prior Maternal Medications used During 
Delivery (Safety Set)
CMT002
- Please display as first row 
‘Number of Subjects  with at 
Least One Prior Maternal 
Medication used During 
Delivery’
Source: Listing 16.2.4.8
Table 14.1.4.3
Maintained Neonate Medications (Safety Set)
CMT002
- Please display as first row 
‘Number of Subjects  with at 
Least One Maintained Neonate 
Medication’
Source: Listing 16.2.4.9
Table 14.1.4.4
Concomitant Neonate Medications (Safety Set)
CMT002
- Please display as first row 
‘Number of Subjects  with at 
Least One Concomitant Neonate 
Medication’
Source: Listing 16.2.4.9
Table 14.1.5
Compliance to Study Treatment (Intention-To-
Treat Set)
EXT002
- For categorical summary 
present categories as: <80%, 
80%-120%, > 120%.
- Do not display overall column
Add footnotes:
[1] Compliance to 
Treatment (%) = Volume 
administered/Volume 
scheduled x 100.
[2] Volume Scheduled 
(ml) = 2.5 x birth weight 
(kg) for the first dose and 
1.25 x birth weight (kg) 
for following doses. 
Source: Listing 16.2.5.5


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Table 14.2.1.1
Statistical Analysis of Percentage of Neonates 
Needing Mechanical Ventilation/Intubation 
(Intention-To-Treat Set)
TPT005
- Change Visit by Parameter, 
Visit X by the list of parameters 
below: 
Percentage of Neonates Needing 
IMV in First 72 Hours of Life
Neonates Needing IMV in the 
First 28 Days PNA 
Neonates Needing IMV within 
36 Weeks PMA
Percentage of Neonates Needing 
any Intubation Procedure outside 
the Initial Surfactant 
Administration Period in first 72 
Hours of Life
Neonates Needing any 
Intubation Procedure outside 
Initial Surfactant Administration 
Period in First 28 Days PNA
Neonates Needing any 
Intubation Procedure outside 
Initial Surfactant Administration 
Period within 36 Weeks PMA. 
Add a column Treatment 
Comparison and display below it 
3 columns Adjusted Difference, 
95% CI and p-value.
Add footnotes:
[1] IMV = Invasive 
Mechanical Ventilation; 
PMA = Post-menstrual 
Age; PNA = Post-natal 
Age.
[2] Adjusted difference, 
its 95% CI and p-value 
are estimated using 
Cochran-Mantel-Haenszel 
test 
Source: Listing 16.2.6.1
Table 14.2.1.1_so
SAS Output: Statistical Analysis of Neonates 
Needing Invasive Mechanical Ventilation 
(IMV) (Intention-To-Treat Set)
 
Raw SAS output
 


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Table 14.2.1.2
Subgroup Analysis:  Summary of Percentage of 
Neonates Needing Invasive Mechanical 
Ventilation (IMV) by Use of 
Sedation/Analgesia (Intention-To-Treat Set) 
TPT005
- Repeat Table 14.2.1.1 without 
Treatment comparison columns 
(only summary statistics)
- Add header row above the 
table for Use of 
Sedation/Analgesia: <Yes/No>
Table 14.2.2.1-a
Summary of SpO2 – Absolute Values and 
Change from Pre-procedure Values (Intention-
To-Treat Set)
TPT001
- Include timepoints Pre-
procedure, T0, 5 Min, 15 Min, 
30 Min, 1 Hour, 6 Hours, 12 
Hours, 24 Hours, 48 Hours (Day 
2), 72 Hours (Day 3), 120 Hours 
(Day 5).
- Replace Baseline with Pre-
procedure.
- Replace Visit by Timepoint
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Add footnote:
[1] SpO2 = Preductal 
Oxygen Saturation 
Source: Listing 16.2.6.2
Table 14.2.2.1-b
Summary of SpO2 Values for Neonates still 
Receiving Respiratory Support at 28±2 days 
PNA and 36 Weeks PMA (Intention-To-Treat 
Set)
TPT002
- Only present statistics for 28±2 
days PNA and 36 Weeks PMA
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Add footnote:
[1] PMA = Post-
menstrual Age; PNA = 
Post-natal Age; SpO2 = 
Preductal Oxygen 
Saturation 
Source: Listing 16.2.6.2


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Table 14.2.2.2
Statistical Analysis of SpO2 Values in the first 
120 hours (Intention-To-Treat Set)
ANT001
Add footnotes:
[1] n corresponds to the 
number of subjects 
included in the analysis. 
[2] SpO2 = Preductal 
Oxygen Saturation. 
[3] The analysis is based 
on a mixed model for 
repeated measure 
(MMRM) model with 
treatment, timepoint, 
treatment by timepoint 
interaction, gestational 
age group as fixed effects 
and pre-procedure SpO2 
as covariate. 
 
Source: Listing 16.2.6.2
Table 14.2.3.1-a
Summary of FiO2 – Absolute Values and 
Change from Pre-procedure Values (Intention-
To-Treat Set)
TPT001
- Include timepoints Pre-
procedure, T0, 5 Min, 15 Min, 
30 Min, 1 Hour, 6 Hours, 12 
Hours, 24 Hours, 48 Hours (Day 
2), 72 Hours (Day 3), 120 Hours 
(Day 5).
- Replace Baseline with Pre-
procedure.
- Replace Visit by Timepoints
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Add footnote:
[1] FiO2 = Fraction of 
inspired Oxygen 
Source: Listing 16.2.6.2


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Table 14.2.3.1-b
Summary of FiO2 Values for Neonates still 
Receiving Respiratory Support at 28±2 days 
PNA and 36 Weeks PMA (Intention-To-Treat 
Set)
TPT002
- Only present statistics for 28±2 
days PNA and 36 Weeks PMA
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Add footnote:
[1] PMA = Post-
menstrual Age; PNA = 
Post-natal Age; FiO2 = 
Fraction of inspired 
Oxygen 
Source: Listing 16.2.6.2
Table 14.2.3.2
Statistical Analysis of FiO2 Values in the first 
120 hours (Intention-To-Treat Set)
ANT001
Add footnotes:
[1] n corresponds to the 
number of subjects 
included in the analysis. 
[2] FiO2 = Fraction of 
inspired Oxygen
[3] The analysis is based 
on a mixed model for 
repeated measures 
(MMRM) model with 
treatment, timepoint, 
treatment by timepoint 
interaction, gestational 
age group as fixed effects 
and pre-procedure FiO2 as 
covariate. 
 
Source: Listing 16.2.6.2


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Table 14.2.4.1-a
Summary of SpO2/FiO2 Ratio – Absolute 
Values and Change from Pre-procedure Values 
(Intention-To-Treat Set)
TPT001
- Include timepoints Pre-
procedure, T0, 5 Min, 15 Min, 
30 Min, 1 Hour, 6 Hours, 12 
Hours, 24 Hours, 48 Hours (Day 
2), 72 Hours (Day 3), 120 Hours 
(Day 5),
- Replace Baseline with Pre-
procedure.
- Replace Visit by Timepoints.
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Add footnote:
[1] FiO2 = Fraction of 
inspired Oxygen; SpO2 = 
Preductal Oxygen 
Saturation 
Source: Listing 16.2.6.2
Table 14.2.4.1-b
Summary of SpO2/FiO2 Ratio for Neonates still 
Receiving Respiratory Support at 28±2 days 
PNA and 36 Weeks PMA (Intention-To-Treat 
Set)
TPT002
- Only present statistics for 28±2 
days PNA and 36 Weeks PMA
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Add footnote:
[1] FiO2 = Fraction of 
inspired Oxygen; PMA = 
Post-menstrual Age; PNA 
= Post-natal Age; SpO2 = 
Preductal Oxygen 
Saturation 
Source: Listing 16.2.6.2


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Table 14.2.4.2
Statistical Analysis of SpO2/FiO2 Ratio in the 
first 120 hours (Intention-To-Treat Set)
ANT001
Add footnotes:
[1] n corresponds to the 
number of subjects 
included in the analysis. 
[2] FiO2 = Fraction of 
inspired Oxygen; SpO2 = 
Preductal Oxygen 
Saturation
[3] The analysis is based 
on a mixed model for 
repeated measured. 
MMRM model with 
treatment, timepoint, 
treatment by timepoint 
interaction, gestational 
age group as fixed effects 
and pre-procedure 
SpO2/FiO2 as covariate. 
 
Source: Listing 16.2.6.2
Table 14.2.5
Summary of Blood Gas Analysis Parameters – 
Absolute Values and Change from Pre-
Procedure (Intention-To-Treat Set)
LBT001
- Include timepoints Pre-
procedure, 1 Hour, 6 Hours, 24 
Hours, 48 Hours (Day 2), and 72 
Hours (Day 3).
- Replace Baseline with Pre-
procedure.
- Label first column as 
Timepoint instead of Visit – 
Timepoint.
- Include parameters pH, pCO2, 
pO2, HCO3, BE, lactate
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum. 
Add footnotes:
[1] HCO3 = Bicarbonates; 
pCO2 = Partial Pressure of 
Carbon Dioxide; pO2 = 
Partial Pressure of 
Oxygen.
Source: Listing 16.2.6.3


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Table 14.2.6.1
Summary of Percentage of Subjects Requiring 
at least one Additional Dose of Surfactant 
(Intention-To-Treat Set)
TPT005
- There is no Visit column to be 
presented.
- Display number and percentage 
of subjects requiring at least one 
additional dose of surfactant At 
Least one Additional Dose of 
Surfactant (Yes/No).
- Display number and percentage 
of subjects receiving additional 
surfactant dose under Number of 
Doses Received (2 and 3).
- Display number and percentage 
of subjects under Method of 
Administration for the second 
dose.
- Display number and percentage 
of subjects under Method of 
Administration for the third 
dose.
Add footnote:
[1] Subjects with 
pulmonary hemorrhage 
occurred during the first 
procedure are not 
included in the analysis.
Source: Listings 16.2.5.2-
a, 16.2.5.2-b and 16.2.5.3
Table 14.2.6.2
Statistical Analysis of Percentage of Subjects 
Requiring at least one Additional Surfactant 
Dose (Intention-To-Treat Set)
ANT004
- There is no Timepoint to be 
presented.
- Display on the table body only: 
<ARM A> (N=XXX), <ARM 
B> (N=XXX) lines and ARM A 
vs. ARM B line. 
- Display text in the first column 
‘Subjects Requiring at least one 
Additional Surfactant Dose’.
- Display all the column as per 
template (‘n’, ‘ODDs RATIO 
(95% CI)’, ‘ P-VALUE’).
Add footnotes:
[1] Odds ratio, its 95% CI 
and p-value are obtained 
using Fisher’s exact test.
[2] Subjects with 
pulmonary hemorrhage 
occurred during the first 
procedure are not 
included in the analysis.
Source: Listings 16.2.5.2-
a, 16.2.5.2-b and 16.2.5.3


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Table 14.2.7
Statistical Analysis of Duration of Ventilation 
and Oxygen Supplementation Alone (Intention-
To-Treat Set)
TPT002
- Change Visit by Parameter, 
Visit X by the list of parameters 
below: 
Duration Time of IMV in the 
First 72 Hours of Life
Duration time of IMV in the 
First 28 Days PNA
Duration time of IMV within 36 
Weeks PMA
Stand-alone Oxygen 
Supplementation (Days)
Non-invasive Ventilation (Days)
- Add 2 additional columns: 
First with median difference and 
CI95% and second one 
presenting the Mann-Whitney U-
test p-value.
Add footnotes:
[1] IMV = Invasive 
Mechanical Ventilation; 
PMA = Post-menstrual 
Age; PNA = Post-natal 
Age
[2] Median difference, its 
95% CI and p-value are 
obtained using Mann-
Whitney U-test. 
Source: Listing 16.2.6.1
Table 14.3.1.1
Extent of Exposure (Safety Set)
EXT001
- Display number and percentage 
of subjects for Number of 
Poractant Alfa Doses with 
categories 1, 2 and 3.
- Display summary statistics for 
Actual Volume (mL); present n, 
Mean, SD, 95% CI for the Mean, 
Median, Minimum and 
Maximum.
Source: Listing 16.2.5.5


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Table 14.3.1.2.1
Statistical Analysis of Number and Percentage 
of Neonates with Failed First Attempt to Insert 
Catheter/Endotracheal Tube (Safety Set)
TPT005
- Change Visit by Parameter and 
baseline, Visit X by the list of 
parameters below: 
Number and Percentage of 
Neonates with Failed First 
Attempt to Insert 
Catheter/Endotracheal Tube in 
the Parameter column. 
Display the results for the First 
and the Second Administration 
in 2 distincts blocks.
- Add a column Treatment 
Comparison and display below 3 
columns with Adjusted 
Difference,95% CI and p-value
Add footnote:
[1] Adjusted difference, 
its 95% and p-value CI 
are estimated using 
Cochran-Mantel-Haenszel 
test 
[2] Treatment groups are 
based on the first actual 
treatment received. In 
case of a second 
administration that did not 
match the first dose, data 
were discarded.
Source: Listings 16.2.5.1-
a, 16.2.5.1-b, 16.2.5.2-a 
and 16.2.5.2-b


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Table 14.3.1.2.2
Number of Attempts Description and Statistical 
Analysis of Duration of Surfactant 
Administration and Overall Procedure (Safety 
Set)
TPT002
- There is no visit to display.
- Number of Attempts to First 
Successful Insertion
Then display the variable below 
for the First and Second 
administration with the 
following subtitles: ‘First 
Admistration’ and then ‘Second 
Administration’
- Number of Device 
Misallocations
- Number of Maneuvers 
Discontinued due to Neonate’s 
Severe Destabilization
- Duration of Surfactant 
Administration (Minutes) 
- Duration of Overall Procedure 
(Hours)
 - Duration of Overall Procedure 
(Minutes)
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum
- Add a p-value column 
presenting the Mann-Whitney U 
test p-value for the last two 
parameters (Duration of 
Surfactant Administration and of 
Overall procedure)
Add fottnote:
[1] P-value is obtained 
using Mann-Whitney U-
test. 
[2] Treatment groups are 
based on the first actual 
treatment received. In 
case of a second 
administration that did not 
match the first dose, data 
were discarded.
Source: Listings 16.2.5.1-
a, 16.2.5.1-b, 16.2.5.2-a 
and 16.2.5.2-b


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Table 14.3.1.3.1-a
Summary of Treatment Emergent Adverse 
Events (Safety Set)
AET001
- Display Number of Subject 
with at least One:
    -TEAEs
    - Serious TEAEs
    - ADRs
    - TEAEs Leading to Death
Source: Listing 16.2.7.2


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Table 14.3.1.3.1-b 
(Table splited – first 
part)
Summary of Adverse Events Starting during 
Overall Procedure (Safety Set)
AET001
Data to display:
- Number of Subjects with AEs 
Starting during Overall 
Procedure for Surfactant 
Administration
- Number of Subjects with AEs 
Starting During Overall 
Procedure for Surfactant 
Administration Judged Related 
to the Procedure
- Number of Subjects with AEs 
Occurring During Overall 
Procedure for Surfactant 
Administration Requiring Either 
Oxygen Alone or an Increase in 
FiO2 without the Need for 
Escalation of Invasive or Non-
invasive Ventilator Support
- Number of Subjects with AEs 
Starting During Overall 
Procedure of Surfactant 
Administration Requiring 
Administration of Manual (Bag 
and Mask) Pressure Positive 
Ventilation
- Number of Subjects with AEs 
Starting During Overall 
Procedure for Surfactant 
Administration Requiring 
Endotracheal Intubation
 [1/2]
Add the footnote:
[1] Adverse events 
starting between the 
procedure start and 
medication and adverse 
events occurred during 
the medication 
administration are also 
considered here.
Source: Listings 16.2.7.1 
16.2.7.2


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Table 14.3.1.3.1-b 
Table splited – last 
part)
Summary of Adverse Events Starting during 
Overall Procedure (Safety Set)
AET001
[2/2]
-Number of Subjects with AEs 
Starting During Overall 
Procedures for Surfactant 
Administration Requiring 
Circulatory Support including 
Administration of Crystalloids
- Number of Subjects with AEs 
Starting During Overall 
Procedures for Surfactant 
Administration Requiring 
Cardiopulmonary Resuscitation 
including Administration of 
Cardiac Massage or Adrenaline
- Number of Subjects with at 
Least One SAE
Present AE during the first 2 
administrations following the 
dose flags described in section 
6.1 of SAP.
Add the footnote: 
[1] Adverse events 
starting between the 
procedure start and 
medication and adverse 
events occurred during 
the medication 
administration are also 
considered here.
Source: Listings 16.2.7.1 
16.2.7.2


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Table 14.3.1.3.2.a
Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Set)
AET003
For actual treatment column, 
please refer to section 6.1.
Add the footnotes
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
[2] Adverse events 
starting before the first 
randomized study 
medication administration 
are defined as pre-
treatment AEs including 
adverse events starting 
between the procedure 
start and medication start 
and are not considered.
Source: Listing 16.2.7.2
Table 14.3.1.3.2.b
Subgroup Analysis: Treatment Emergent 
Adverse Events by System Organ Class and 
Preferred Term by Use of Sedation/Analgesia 
(Safety Set)
AET003
Repeat Table 14.3.1.3.2 and 
present by Use of 
Sedation/Analgesia = Yes and 
Use of Sedation/Analgesia = No


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Table 14.3.1.3.3
Treatment Emergent Adverse Drug Reactions 
by System Organ Class and Preferred Term 
(Safety Set) 
AET003
 For actual treatment column, 
please refer to section 6.1.
Add the footnotes
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
[2] Adverse events 
starting before the first 
randomized study 
medication administration 
are defined as pre-
treatment AEs including 
adverse events starting 
between the procedure 
start and medication start 
and are not considered.
Source: Listing 16.2.7.4
Table 14.3.1.3.4
Serious Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (Safety 
Set)
AET003
 For actual treatment column, 
please refer to section 6.1.
Add the footnotes:
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
[2] Adverse events 
starting before the first 
randomized study 
medication administration 
are defined as pre-
treatment AEs including 
adverse events starting 
between the procedure 
start and medication start 
and are not considered.
Source: Listing 16.2.7.3


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Table 14.3.1.3.5
Treatment Emergent Adverse Events Leading 
to Death by System Organ Class and Preferred 
Term (Safety Set)
AET003
 For actual treatment column, 
please refer to section 6.1.
Add the footnotes:
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
[2] Adverse events 
starting before the first 
randomized study 
medication administration 
are defined as pre-
treatment AEs including 
adverse events starting 
between the procedure 
start and medication start 
and are not considered.
Source: Listing 16.2.7.5
Table 14.3.1.3.6
Incidence of Adverse Events Indicating 
Neonatal Complications of Prematurity (Safety 
Set)
TPT006
- Display number and percentage 
of subjects with At least one 
Complication and below the 
number and percentage of each 
Complication (by decreasing 
overall frequency) as listed in 
Appendix I along with the 
grades for each complication.
- If a neonate experiences more 
than 1 complications, he/she will 
be counted under all categories.
Add footnote:
[1] A neonate can 
experience more than one 
complication of 
prematurity and will be 
counted in all the 
categories experienced. 
Source: Listing 16.2.7.6


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Table 14.3.1.3.7
Summary of Duration of Endotracheal 
Intubation and Positive Pressure Ventilation 
(Safety Set)
TPT002
- Change Visit by Parameter and 
baseline, Visit X by the list of 
parameters below:
 Duration of Endotracheal 
Intubation (Min) and Duration of 
Positive Pressure Ventilation 
(Min).
- Present n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Display results only for AE 
occurring during the overall 
procedure (see section 10.2 of 
SAP)
Add footnotes:
[1] Duration of 
Endotracheal Intubation = 
End Time of Intubation – 
Start Time of Intubation.
[2] Duration of Positive 
Pressure Ventilation = 
End Time of Positive 
Pressure Ventilation – 
Start Time of Positive 
Pressure Ventilation
[3] Duration of 
endotracheal intubation 
and PPV is calculated 
only for the procedure 
required for an AE 
starting during the 
treatment procedure.
Source: Listing 16.2.4.7


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Table 14.3.4.1
Vital Signs: Actual Values and Change from 
Pre-procedure (Safety Set)
VST001
- Include Timepoints Pre-
procedure, T0, 5 Min, 15 Min, 
30 Min, 1 Hours, 6 Hours, 12 
Hours, 24 Hours, 48 Hours (Day 
2), 72 Hours (Day 3), 120 Hours 
(Day 5), 28 Days PNA, 36 
Weeks PMA and Week 40 
(Discharge)
- Include parameters Systolic 
Blood Pressure (mmHg), 
Diastolic Blood Pressure 
(mmHg), Mean Blood Pressure 
(mmHg), Heart Rate (beats/min), 
Respiratory Rate 
(breaths/minute)
- Replace Baseline with Pre-
procedure
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Changes from pre-procedure 
will not be displayed at 28 Days 
PNA, 36 Weeks PMA and Week 
40 (Discharge).
Add footnote:
[1] PMA = Post-
menstrual Age; PNA = 
Post-natal Age.
Source: Listing 16.2.8.1


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Table 14.3.4.2
Premature Infant Pain Profile (PIPP) Score: 
Actual Values (Safety Set)
VST002
- Include Timepoint T0 (For T0, 
score is calculated as sum of 
pre-procedure total PIPP score 
and total PIPP score recorded at 
T0).
- Present summary statistics for 
PIPP total score.
- Replace Baseline with Pre-
procedure.
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Add footnote:
[1] T0 score is calculated 
as sum of pre-procedure 
total PIPP score and total 
PIPP score recorded at 
T0.
Source: Listing 16.2.8.2
Table 14.3.5.1
Bronchopulmonary Dysplasia and Oxygen Use 
at 36 Weeks PMA (Safety Set)
TPT006
Do not display At Any 
Timepoint lines.
Present variables as follow:
-Subject Treated with Oxygen 
>21% for at least 28 Days 
<Yes/No>
- Requirement for Supplemental 
Oxygen <Yes/No>
- Positive Pressure for 
Respiratory Support <Yes/No>.
- Respiratory Support via Nasal 
Cannula <Yes/No>
Non-Invasive Ventilation 
<Yes/No>
- Mechanical Ventilation via an 
Endotracheal Tube <Yes/No>
- BPD Severity 
<Mild/Moderate/Severe>
Source: Listing 16.2.7.7


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Notes
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Listing Number
Table 14.3.5.2
Statistical Analysis of Deaths/ 
Bronchopulmonary Dysplasia Incidence at 36 
Weeks PMA (Safety Set)
TPT005
- Replace Visit by Parameter in 
the header
Present in the Parameter column:
   -  Number of Deaths/BPD at 
36 Weeks PMA
   -  BPD at 36 Weeks PMA [3]
         Mild
         Moderate
         Severe
   -  Mortality at Day 28 PNA
   -  Mortality at 36 Weeks PMA 
   -  Oxygen Use at Day 28 PNA 
[3]
   -  Oxygen Use at 36 Weeks 
PMA [3]
- For Oxygen use, please use 
“"Is there a requirement for 
supplemental oxygen?" in BPD 
form.
- Treatment Arm (<ARM A> 
will be replaced by 
‘Treatment/Gestational Age 
Category’. Display in this 
column first Treatment (N=XX)’ 
then the ‘Gestational Age 
Category (N=XX)’ within 
treatment group.
- Replace <ARM B> by Number 
of subject for each category.
-Add 3 columns at the end: 
‘Relative Risk (95%CI)’ and ‘p-
value’.
Add footnotes:
[1] PMA = Post-
menstrual Age.
 
[2] Relative Risk, its 95% 
CI  and p-value are 
estimated using Cochran-
Mantel-Haenszel test.
[3] Neonates with BPD 
assessment done.
Source: Listing 16.2.7.7


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Notes
Footnotes/Source 
Listing Number
Table 14.3.6.1
Incidence of Neonatal Morbidities at Week 40 
or Discharge (Safety Set)
TPT006
- Present number and percentage 
of Subjects with at least one 
Morbidity and then display 
number and percentage of 
subjects in each morbidity: 
Gastroesophageal Reflux, 
Retinopathy of Prematurity 
<Impacted Eye>, 
Laser/Cryotherapy/Anti-VEGF, 
Vitrectomy, Apnea of 
Prematurity, Pulmonary 
Hypertension <Medication for 
Pulmonary Hypertension , 
Ductus Arteriosus, Medication 
to Treat Seizure, Ventricular 
Stunt, Ileostomy/Ostomy.
Display all morbidities even if 0 
subject concerned. Display the 
morbidities by decreasing total 
frequency.
Add footnote:
[1] A neonate can 
experience more than one 
morbidity and will be 
counted in all the 
categories experienced. 
Source: Listing 16.2.7.8


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Code
Notes
Footnotes/Source 
Listing Number
Table 14.3.6.2
Summary of Feeding Status at Discharge/40 
Weeks (Safety Set)
TPT006
- There is no visit and Timepoint 
to display.
- Present frequency and 
percentage for:
Receiving Feedings via a 
Nasogastric Tube
Receiving Feedings via a 
Nasojejunal Tube
Gastrostomy 
Receiving Overnight Enteral 
Feeding, Require an Enteral 
Feeding Pump at Discharge
- Present categories as recorded 
in the eCRF.
Source: Listing 16.2.8.3
Table 14.3.6.3
Summary of Hearing Status at Discharge/40 
Weeks (Safety Set)
TPT006
- There is no visit and Timepoint 
to display.
- Present frequency and 
percentage for:
Otoacoustic Emission Test
Failure (%)
Bilateral (%)
Monolateral (%)
Auditory Brainstem Response 
Test
Abnormal (%)
Bilateral (%) 
Monolateral (%)
Source: Listing 16.2.8.3


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Notes
Footnotes/Source 
Listing Number
Table 14.3.6.4
Summary of Neonates Needing Respiratory 
Support at Discharge/40 Weeks (Safety Set)
TPT005
- There is no Visit column to be 
presented.
- Display following variables 
collected at discharge or 40 
weeks PMA:
Treated with Oxygen > 
21% for at Least 28 
Days
- Supplementary 
Oxygen
      - FiO2 (Fraction)
- Supplementary 
Oxygen Delivered in 
the Last 24 Hours
- Respiratory Support 
via Nasal Cannula
- Non-Invasive 
Ventilation
- Receiving Mechanical 
Ventilation via ETT
- Tracheostomy
- Additional Aid at 
Discharge
- Present categories as recorded 
on the eCRF. 
Source: Listing 16.2.8.5


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Table 14.3.6.5
Summary of Neonates Needing Respiratory 
Medications at Discharge /40 Weeks (Safety 
Set)
TPT005
- There is no visit and Timepoint 
to display.
- Present frequency and 
percentage for:
Diuretics for BPD
Inhaled Steroids for BPD
Systemic Steroids for BPD 
Inhaled Bronchodilators
- Present categories as recorded 
on the eCRF.
Source: Listing 16.2.5.4
Table 14.3.6.6
Summary of Growth Assessment: Actual 
Values and Change form Baseline. (Safety Set)
VST002
-Visit to be displayed: Baseline, 
36 weeks (PMA) only for weight 
and Discharge Home/40 Weeks 
PMA.
- Present summary for 
parameters Weight (kg), 
Occipital-Frontal Circumference 
(cm), Length (cm).
- Display n, Mean, SD, 95% CI 
for the Mean, Median, Minimum 
and Maximum.
Source: Listing 16.2.8.4


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16.2 Listings
Listing Number
Listing Title
Template Code
Notes
Footnotes
Listing 16.1.7
Randomization Schedule (Randomized Set)
DSL001
Note: Date of randomization to include both Date 
and Time
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.1.1
Screening Failures (Enrolled Set)
DSL002
-Do not present ‘Date of Visit’ columns
-Replace Age (Unit) by Gestational Age (Weeks)
- Add last column for ‘Death Date’.
-Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
-Date of Informed consent for both parents/ Legal 
representative to be reported; 
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.1.2
Subjects Disposition (Randomized Set)
DSL004
-Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
-Date of Informed consent for both parents/ Legal 
representative to be reported; 
-Do not present columns Period of Last Intake of 
Study Treatment, Last Treatment Received and 
DAY [3]
-Add last column for Death Date.
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.


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Listing Number
Listing Title
Template Code
Notes
Footnotes
Listing 16.2.1.3
Study Visits (Randomized Set)
SVL001
- Remove the words Retest and Unscheduled in 
header.
- Study Day in Period not to be presented.
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
-Remove column Reason for Early Termination 
Visit
- Add column for On-Site Visit to be reported for 
visit 36 Weeks PMA
-Add column for Contacted People to be reported 
for visit 36 Weeks PMA in case On-Site Visit is 
‘No’
-Add a flag to specify when visit ‘Discharge 
Home or 40 Weeks PMA’ was performed: add # 
for ‘Discharge Home’ or § for’40 Weeks PMA’
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.[3] # Discharge 
home
[4] § 40 Weeks PMA
Listing 16.2.2.1
Protocol Deviation (Randomized Set)
DVL002
- Include all deviations from DV.
- Add the following columns if any data to be 
displayed
    - Visit
    - Start Date/Time of Deviation
     - End Date/Time of Deviation
     - Timepoint 
- Remove Randomized sequence, Period, and 
Reference analysis set columns.
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.2.2
Violation of Inclusion/Exclusion Criteria 
(Randomized Set) 
DVL001
- Only deviations from DV in relation to 
inclusion/exclusion criteria.
- There is no Visit to display
- Remove Reference analysis set column.
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.


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Listing Number
Listing Title
Template Code
Notes
Footnotes
Listing 16.2.3.1
Analysis Sets Disposition (Randomized 
Set)
DSL006
- Remove Period and Randomized sequence
- Include Safety Set and ITT Set
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.3.2
Exclusion from Safety and Intention-To-
Treat Sets (Randomized set)
DSL007
- Remove Period and Randomized sequence
- Include reason for exclusion from safety set and 
from ITT sets
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.4.1
Neonate’s Demographic Characteristics 
(Randomized Set)
DML001
-In Column Date of birth include Date and Time
-Age to be reported in hours
Include parameters: Gestational Age (Weeks) 
concatenated with Gestational Age (Days), 
Gestational Age Categories, Sex - Race [Race 
‘Other’ specification in the same column, 
concatenated with ‘Others’], Ethnicity, Birth 
Weight (kg), APGAR Total Score at 1 min Post-
birth and APGAR Total Score at 5 min Post-birth, 
Clinical Diagnosis of RDS
- Do not present Age Category, Height, BMI and 
Childbearing Potential columns.
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.[3] APGAR 
:Appearance, Pulse, 
Grimace, Activity, 
Respiration)
Listing 16.2.4.2.1
Maternal Demographic Characteristics 
(Randomized Set)
SCL001 
Variables to display: 
- Mother’s Age (Years), 
- Mother’s Race [Race ‘Other’ specification in the 
same column, concatenated with ‘Others’]
- Mother’s Ethnicity
- Mothers Taking any Antibiotics during the 
Pregnancy
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.


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Listing Number
Listing Title
Template Code
Notes
Footnotes
- Mothers taking any Corticosteroids during the 
Pregnancy
- Total Number of Corticosteroids Doses
- Date of last Corticosteroids Administration prior 
to Birth/Number of Days since Last Corticosteroid 
Administration up to Birth
- Type of Delivery (add detail for Spontaneous: 
Operative / Not Operative in the same column)
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Listing 16.2.4.2.2
Pregnancy Complications (Randomized 
Set)
SCL001 
Variables to display: 
- If a Mother had any Pregnancy - 
Complication/Relevant Risk Factor (Yes/No)
- Pregnancy Complication/Relevant Risk Factor 
(Categories to be presented as recorded in the CRF 
including ‘Other, specify’)
- Any Treatment Given or in Progress for 
Pregnancy Complication (Yes/No)
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.4.2.3
Intrapartum Complications (Randomized 
Set)
SCL001 
Variables to display: 
- Were there any Intrapartum Complications? 
(Yes/No)
- Intrapartum Complications (Categories to be 
presented as recorded in the CRF including 
‘Other, specify’)
- Treatment Given or in Progress for Intrapartum 
Complication (Yes/No)
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.


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Listing Number
Listing Title
Template Code
Notes
Footnotes
Listing 16.2.4.2.4
Neonate Medical History (Randomized Set)
MHL001
Add a column after Randomized Treatment 
‘Medical History Category’ with following 
categories populated in 3 sub-columns:
        - Complication of Prematurity
        - Other Condition 
        - Major Organ Malformation/Genetic Disease 
/Chromosomal Abnormalities
Then display the columns as per template for the 
description of the disease.
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add the footnotes 
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
 [2] *Maternal COVID-
19 Infection during 
Pregnancy.
[3] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.4.2.5
Maternal Medical History (Randomized 
Set)
MHL001
Variables to display: 
- Additional Maternal Medical Condition 
- If  Yes, then add columns for Medical History, 
Start /End Date or Ongoing for the Medical 
Condition
 - Mother taking any Medication for Ongoing 
Diagnosis 
  If Yes, then add columns for the Medication 
from Maternal Previous and Concomitant 
Medications form.
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] **Neonate COVID-19 
Infection during the 
Study.


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Listing Number
Listing Title
Template Code
Notes
Footnotes
Listing 16.2.4.3
Maternal Medical History by System Organ 
Class and Preferred Term (Randomized 
Set) 
MHL001
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add the footnotes 
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
 [2] *Maternal COVID-
19 Infection during 
Pregnancy.
[3] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.4.4
Neonate’s Concomitant Diseases 
(Randomized Set)
MHL002
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add the footnotes 
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
 [2] *Maternal COVID-
19 Infection during 
Pregnancy.
[3] **Neonate COVID-19 
Infection during the 
Study.


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Listing Number
Listing Title
Template Code
Notes
Footnotes
Listing 16.2.4.5
Procedures (Randomized Set) 
PRL001
- Remove Analysis Period in the header
- [CAT]: Prior, Maintained and Concomitant.
- If indication = ‘Other’, then present Other: 
specify (where specify is the specified text)
- If indication = Adverse event, then present 
Adverse Event: XXX (where XXX is the AE 
term), if more than one AE are specified, to be 
listed separated by ‘,’
If indication = Medical History, then present 
Medical History: YYY (where YYY is the MH 
term); if more than one MH are specified, to be 
listed separated by ‘,’
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add the footnotes 
[1] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.
 [2] *Maternal COVID-
19 Infection during 
Pregnancy.
[3] **Neonate COVID-19 
Infection during the 
Study.
Listing 16.2.4.6
Non-Invasive Ventilation Parameters 
(Randomized Set)
Include columns:
- Subject ID
- Randomized Treatment
- Scheduled Time
- NIV Support in Use at the Assessment (CPAP, 
BiPAP, NIPPV, Not Applicable)
- If CPAP, CPAP Pressure (cmH2O)
- If BiPAP,
      - Upper Pressure Level (cmH2O)
      - Lower Pressure Level (cmH2O)
      - Mean Airway Pressure (cmH2O)
- If NIVPP,
      - Peak Respiratory Pressure (cmH2O)
      - Positive End Expiratory Pressure (cmH2O)
      - Mean Airway Pressure (cmH2O)
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] BiPAP = Bi-level 
Positive Airway Pressure; 
CPAP = Continuous 
Positive Airway Pressure; 
NIPPV = Nasal 
Intermittent Positive 
Pressure Ventilation
 [2] *Maternal COVID-
19 Infection during 
Pregnancy.
[3] **Neonate COVID-19 
Infection during the 
Study.


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Listing Number
Listing Title
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Notes
Footnotes
Listing 16.2.4.7
Respiratory Support (Randomized Set)
Include columns:
- Subject ID
- Randomized Treatment
- Any Respiratory Support Provided 
- Oxygen Supplementation without Positive 
Pressure (add details for Other specifications in 
the same column as Other: <Specifications>)
- Non-Invasive Ventilation Method (add details 
for Other specifications in the same column as 
Other <Specifications>)
- Invasive Ventilation Method (add details for 
Other specifications in the same column as Other: 
<Specifications>)
- Reason for Invasive Ventilation (FiO2>=45%, 
Significant Apnea, Respiratory Acidosis, Other, 
add details for Other specifications in the same 
column as Other: <Specifications>)
- FiO2 ***
- SpO2 ***
- Ventilation as title for two columns Start 
Date/Time [Day] and End Date/Time [Day] 
- Indication (add details for Other specifications in 
the same column as Other: <Specifications>)
- If indication = Adverse event, then present 
Adverse Event: XXX (where XXX is the AE 
term), if more than one AE are specified, to be 
listed separated by ‘,’
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add the footnote:
[1]Day = date of 
ventilation – date of first 
randomized treatment + 1
[2] FiO2>=45%’ = FiO2 
>=0.45 to maintain 
preductal SpO2 of 88-
95% for at least 30 
minutes, unless rapid
clinical deterioration 
occurs, 
[3] Significant Apnea = 
Significant Apnea (more 
than four episodes of 
Apnea /hour or more than 
two episodes of Apnea 
/hour if ventilation with 
bag and mask was 
required);
[4] Respiratory Acidosis 
= Respiratory acidosis 
(pCO2 >65 mmHg/8.5 
kPa and pH <7.20 
identified by either 
arterial or capillary blood 
gas monitoring)
[5] *Maternal COVID-19 
Infection during 
Pregnancy.
[6] ** Neonate COVID-
19 Infection during the 
Study
[7] *** at the start of 
invasive ventilation.


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Listing Number
Listing Title
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Notes
Footnotes
Listing 16.2.4.8
Maternal Medications (Randomized Set) 
CML001
- Remove “Analysis Period” In the header
- Remove “Dosage” In the header
- [CAT]: Prior, Maintained and Concomitant.
For Indication, concatenate the Indication (MH, 
Pregnancy complication, Intrapartum 
complication) with the specified text as follow:
- if indication = ‘Medical History’, then present 
Medical History: YYY (where YYY is the MH 
term);
- if Indication = Pregnancy complication, then 
present Pregnancy complication: XXX (where 
XXX is the text reported in the field ‘If pregnancy 
complication, please specify’)
- if Indication = Intrapartum complication, then 
present Intrapartum complication: ZZZ (where 
ZZZ is the text reported in the field ‘If Intrapartum 
complication, please specify’)
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add the footnotes:
[1] ATCs and Preferred 
Name are coded using 
WHO-DD <month year>.
[2] *Maternal COVID-19 
Infection during 
Pregnancy.
[3] ** Neonate COVID-
19 Infection during the 
Study.


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Listing Number
Listing Title
Template Code
Notes
Footnotes
Listing 16.2.4.9
Neonate Medications (Randomized Set)
CML001
- Remove Analysis Period In the header
- [CAT]: Prior, Maintained and Concomitant.
- Start date to include both date and time
- End date to include both date and time
In case of other route, Concatenate the 
specification as Other: <Specification>
For Indication, concatenate the Indication (MH, 
AE, Procedure, Other) with the specified text as 
follow:
- If Indication = ‘Medical History’, then present 
Medical History: YYY (where YYY is the MH 
term);
- If Indication = Adverse Event, then present 
Adverse Event: XXX (where XXX is the AE 
term)
- If Indication = Procedure, then present 
Procedure: ZZZ where (ZZZ is the PR text)
- If indication = ‘Other’, then present Other: 
<Specification>
Dosage is the concatenation of dose per 
administration, Unit and frequency. In case of 
Other specifications (for Dose Unit or Frequency), 
the details will be used for the concatenation
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
-Add flag for sedation
Add the footnotes:
[1] ATCs and Preferred 
Name are coded using 
WHO-DD <month year>.
[2] *Maternal COVID-19 
Infection during 
Pregnancy.
[3] ** Neonate COVID-
19 Infection during the 
Study.
[4] ° Use of sedative and 
/or analgesic
[5] CAT[1]: C = 
Concomitant; M = 
Maintained; P = Prior; PS 
= Post-Study.
Listing 16.2.5.1-a
Study Drug Administration (Randomized 
Set)
The following columns will be presented:
- Subject ID
- Randomized Treatment 
- Randomization Date/Time
- Randomization Number
Add footnotes:
[1] Day = date of 
application/administration 
– date of first randomized 
treatment + 1


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Listing Number
Listing Title
Template Code
Notes
Footnotes
- Kit Number/Catheter Batch Number as title and 
then below 2 columns ‘IRT’ and ‘Used’
- Reason for change from IRT assignment (Kits 
and Catheters) 
- Volume to be Administered (ml) as title and 
then below 2 columns ‘Planned’ and ‘Actual’
- Start Date/Time of Laryngoscopy Application 
[Day]
- Administration as title and then below 2 
columns ‘Start Date/Time [Day]’ and ‘End 
Date/Time [Day]
- Duration of Surfactant Administration 
(Minutes)
- Duration of Overall Procedure (Hours)
- Attempts to Successfully Insert Catheter/ETT 
as title and then below 2 columns ‘Number’ 
and ‘Reason for failure’
Note: in case more than one kit/batch have been 
assigned/used all of them need to be listed,  
separated by ‘,’
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
[2] *Maternal COVID-19 
Infection during 
Pregnancy.
[3] ** Neonate COVID-
19 Infection during the 
Study
Listing 16.2.5.1-b
Study Drug Administration (Randomized 
Set)
The following columns will be presented:
- Subject ID
- Randomized Treatment 
- Randomization Date/Time
- Number of Device Misallocations (for LISA 
Group only)
- Number of Maneuvers Discontinued due to 
Neonate’s Severe Destabilization
- Date/Time of Removal of the Catheter/ETT
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] ** Neonate COVID-
19 Infection during the 
Study


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Listing Number
Listing Title
Template Code
Notes
Footnotes
- Administration Interrupted Without 
Completing the Planned Administration 
<Reason for Interruption>
- Surfactant Administration  According to the 
Randomization Group <Specification>  (note 
for programmers: in Specification if surfactant 
administration according to randomization 
group is =’No’, concatenate the actual method 
used and reason separate by “/” 
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Listing 16.2.5.2-a
Second Surfactant Dose (Randomized Set)
The following columns will be presented:
- Subject ID
- Randomized Treatment
- Second Dose of Curosurf Administered
- Reason for Second Dose (Lack of efficacy, 
Clinical deterioration, Intubation criterion: 
Fio2>=0.45, Intubation criterion: significant 
Apnea’, Intubation criterion: respiratory acidosis, 
Other <Specification>)
- Method of Administration 
- Kit Number/Catheter Batch Number as title and 
then below 2 columns ‘IRT’ and ‘Used’
- Reason for change from IRT assignment (Kits 
and Catheters)
- Volume to be Administered (ml) as title and then 
below 2 columns ‘Planned’ and ‘Actual’
- Start Date/Time of Laryngoscopy Application 
[Day]
- Administration as title and then below 2 columns 
‘Start Date/Time [Day]’ and ‘End Date/Time 
[Day]
Add footnotes:
[1] Day = date of 
application/administration 
– date of first randomized 
treatment + 1
[2] Lack or efficacy = 
Lack of efficacy of the 
first dose (FiO2 >= 0.30 
to maintain SpO2 in the 
range 88-95%); 
Clinical deterioration = 
Clinical deterioration 
(FiO2 >= 0.30 to maintain 
SpO2 in the range 88-
95%);
Intubation criterion: 
Fio2>=0.45 = Meeting 
criteria for intubation and 
MV: FiO2 >= 0.45 to 
maintain SpO2 between 
88-95% for at least 30 


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- Attempts to Successfully Insert Catheter/ETT as 
title and then below 2 columns ‘Number’ and 
‘Reason for failure’
Note: in case more than one kit/batch have been 
assigned/used all of them need to be listed, 
separated by ‘,’
min (or rapid clinical 
deterioration);
Intubation criterion: 
significant Apnea = 
Meeting criteria for 
intubation and MV: 
significant Apnea;
Intubation criterion: 
respiratory acidosis = 
Meeting criteria for 
intubation and MV: 
respiratory acidosis
[3] *Maternal COVID-19 
Infection during 
Pregnancy.
[4] ** Neonate COVID-
19 Infection during the 
Study
Listing 16.2.5.2-b
Second Surfactant Dose (Randomized Set)
The following columns will be presented:
- Subject ID
- Randomized Treatment 
- Randomization Date/Time
- Number of Device Misallocations (for LISA 
Group only)
- Number of Maneuvers Discontinued due to 
Neonate’s Severe Destabilization
- Date/Time of Removal of the Catheter/ETT
- Administration Interrupted Without Completing 
the Planned Administration <Reason for 
Interruption>
- Surfactant Administration  According to the 
Randomization Group <Specification>  (note for 
programmers: in Specification if surfactant 
administration according to randomization group 
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] ** Neonate COVID-
19 Infection during the 
Study


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Footnotes
is =’No’, concatenate the actual method used and 
reason separate by “/”
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Listing 16.2.5.3
Third Surfactant Dose (Randomized Set)
The following columns will be presented
- Subject ID
- Randomized Treatment
- Third Dose of Curosurf Administered?
- Reason for Third Dose (Lack of efficacy, 
Clinical deterioration, Intubation criterion: 
Fio2>=0.45, Intubation criterion: significant 
Apnea’, Intubation criterion: respiratory acidosis, 
Other: <Specification>)
- Method of Administration
- Kit Number/Catheter Batch Number as title and 
then below 2 columns ‘IRT’ and ‘Used’
- Reason for Change from IRT assignment
- Volume to be Administered (ml) as title and then 
below 2 columns ‘Planned’ and ‘Actual’
- Administration as title and then below 2 columns 
‘Start Date/Time [Day]’ and ‘End Date/Time 
[Day]
- Administration Interrupted Without Completing 
the Planned Administration <Reason for 
Interruption>
Note: in case two kits have been assigned/used 
both need to be listed,  separated by ‘,’
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] Day = date of 
application/administration 
– date of first randomized 
treatment + 1
[2] Lack or efficacy = 
Lack of efficacy of the 
first dose (FiO2 ≥0.30 to 
maintain SpO2 in the 
range 88-95%); 
Clinical deterioration = 
Clinical deterioration 
(FiO2 ≥0.30 to maintain 
SpO2 in the range 88-
95%);
Intubation criterion: Fio2 
≥0.45 = Meeting criteria 
for intubation and MV: 
FiO2 >= 0.45 to maintain 
SpO2 between 88-95% 
for at least 30 min (or 
rapid clinical 
deterioration);
Intubation criterion: 
significant Apnea = 
Meeting criteria for 
intubation and MV: 
significant Apnea;
Intubation criterion: 
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Meeting criteria for 
intubation and MV: 
respiratory acidosis
[3] *Maternal COVID-19 
Infection during 
Pregnancy.
[4] ** Neonate COVID-
19 Infection during the 
Study
Listing 16.2.5.4
Respiratory Medications at Discharge 
Home or 40 Weeks PMA (Randomized Set)
The following columns will be presented
- Subject ID
- Actual Treatment
- Visit
- “Treatment for BPD” as header for the following 
4 columns “Diuretics”, “Inhaled Steroids”, 
“Systemic Steroids”, “Inhaled Bronchodilators”.
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] BPD = 
Bronchopulmonary 
Dysplasia
[2] *Maternal COVID-19 
Infection during 
Pregnancy.
[3] ** Neonate COVID-
19 Infection during the 
Study


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Listing 16.2.5.5
Listing of Exposure and Compliance 
(Randomized Set)
The following columns will be presented
- Subject ID
-Randomized Treatment
- Actual Treatment
- Number of Poractant Alfa Doses Administered
- Total Volume Administered (ml)
- Treatment Compliance (%)
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] Treatment 
Compliance = Volume 
administered/Volume 
scheduled*100% = % of 
administered volume; 
where volume scheduled 
= 2.5ml x neonate’s birth 
weight (kg) for first dose 
and 1.5 (ml) x neonate’s 
birth weight for second 
and third doses.
[2] *Maternal COVID-19 
Infection during 
Pregnancy.
[3] ** Neonate COVID-
19 Infection during the 
Study


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Footnotes
Listing 16.2.6.1
Mechanical Ventilation/Intubation, Non-
Invasive Ventilation and Oxygen 
Supplementation (Randomized Set)
The following columns will be presented:
- Subject ID
- Randomized Treatment 
- Neonate Needing IMV in first 72 Hours of 
Life. If yes, concatenate with the Duration 
(Hours)
- Neonate Needing IMV in first 28 Days PNA. If 
yes, concatenate with the duration (Days)
-  Neonate Needing IMV within 36 Weeks PMA. 
If yes, concatenate with the duration (Days)
- Neonate Needing Intubation Procedure in First 
72 Hours of Life
- Neonate Needing Intubation Procedure in First 
28 Days PNA
- Neonate Needing Intubation Procedure within 
36 Weeks PMA
- Duration of Oxygen Supplementation (Days)
- Duration of Non-Invasive Ventilation (Days)
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] IMV = Invasive 
Mechanical Ventilation; 
PMA = Post-menstrual 
Age; PNA = Post-natal 
Age
[2] *Maternal COVID-19 
Infection during 
Pregnancy.
[3] ** Neonate COVID-
19 Infection during the 
Study


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Listing 16.2.6.2
SpO2, FiO2 and SpO2/FiO2 Values 
(Randomized Set)
VSL001
- Remove ‘Analysis Period’
- Change the column Subect ID/Sex/Age to 
“Subect ID/Sex/Age (Hours)”
-Present Randomized Treatment in place of 
Actual Treatment
- Display “Assessment Date/Time [Study Day]” 
instead of “Assessment Date/time [study day / 
study day in period]”
- Skip the last column (Change from pre-dose)
- Display values for:
-
SpO2 (%)
-
FiO2 (Fraction)
-
SpO2/FiO2
-Present CHG and change annotation to [2] 
instead of [3], do not present CFB
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] Pre-procedure =B 
flags pre-procedure value
[2] Use=Y: included in 
the analysis
CHG is change from pre-
procedure
[3] FiO2 = Fraction of 
Inspired Oxygen; SpO2 = 
Preductal Oxygen 
Saturation
[4] *Maternal COVID-19 
Infection during 
Pregnancy.
[5] ** Neonate COVID-
19 Infection during the 
Study


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Listing 16.2.6.3
Blood Gas Analysis (Randomized Set)
LBL001
-Remove ‘Analysis Period’
-Display “Assessment date/Time [Study Day]” 
instead of “Assessment date/time [study day / 
study day in period]”
- Remove ‘Fasted’
- Do not display [H] flag. 
- Do not display Normal Range column
-Replace Change from Baseline with Change from 
Pre-procedure
-In Test <Unit> column, display:
-
pH
-
pCO2 (mmHg)
-
pO2 (mmHg)
-
HCO3 (mEq/L)
-
Lactate (mmol/L)
-
Base Excess (mEq/L)
- Sort test alphabetically
-Add a column displaying ‘Sample Type’ 
(LBSPEC) betweenAssessment  Date/Time and 
Result column
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] Pre-procedure =Y 
flags pre-procedure value
[2] Use=Y: included in 
the analysis
[3] CSA=Abnormal, 
Clinically Significant
[4] pCO2 = Partial 
Pressure of Carbon 
Dioxide; pO2 = Partial 
Pressure of Oxygen; 
HCO3 = Bicarbonates
[5] *Maternal COVID-19 
Infection during 
Pregnancy.
[6] ** Neonate COVID-
19 Infection during the 
Study


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Listing 16.2.7.1
Pre-treatment Adverse Events (Randomized 
Set)
AEL001
- Remove Age, Race, Ethnicity, and Pattern.
- Remove Action Taken with study drug
- Remove Causality
- Add Gestational Age (Weeks)
- Add all the possible options for ‘Other action 
taken’, including specifications where available
- Outcome in a separate column
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add the footnotes:
[1] Adverse events 
starting before the first 
randomized study 
medication administration 
are defined as pre-
treatment AEs as well as
Adverse events starting 
between the procedure 
start and medication start.
[2] DI = Results in 
persistent or significant 
disability or incapacity; 
DTH = Results in death; 
HSP = Requires 
hospitalization or 
prolongation of existing 
hospitalization; LTH = Is 
life-threatening; SIG = Is 
a medically significant 
adverse event.
 [3] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x. 
[4] *Maternal COVID-19 
Infection during 
Pregnancy.
[5] ** Neonate COVID-
19 Infection during the 
Study


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Listing 16.2.7.2
Treatment Emergent Adverse Events 
(Randomized Set)
AEL002
- Remove Ethnicity, Period/Randomized 
Treatment, Starting dose/dose at onset/weight and 
Pattern.
- Remove Period/, only present Actual Treatment
- Remove [D2] from ‘Onset Date’, annotate End 
Date with [D2] instead of [D3]
- Remove ‘Action Taken with study drug’
- Add column reporting if the event started during 
First or Second procedure
- Add a separate column for Causality; it should 
reflect the answers for relationship to study drug, 
study procedure and study device;
- Add a column to show if the relationship is to the 
first or second administration;
- Add all the possible options for ‘Other Action 
Taken’ including specifications where available
- Outcome in a separate column
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add a flag for Complication of prematurity ‘#’ for 
each Concerned AE (Refer to section 10.2 for 
further details.)
Add the footnotes:
[1] DI = Results in 
persistent or significant 
disability or incapacity; 
DTH = Results in death; 
HSP = Requires 
hospitalization or 
prolongation of existing 
hospitalization; LTH = Is 
life-threatening; SIG = Is 
a medically significant 
adverse event.
[2] D1 = is the study Day 
at Onset Date calculated 
with reference to the date 
of first randomized 
treatment administration
[3] D2 = is the Study Day 
at End Date calculated 
with reference to the date 
of first randomized 
treatment administration
[4] System Organ Class 
and Preferred Term are 
coded using MedDRA 
Version xx.x.’
[5] *Maternal COVID-19 
Infection during 
Pregnancy.
[6] ** Neonate COVID-
19 Infection during the 
Study
[7] # Complication of 
Prematurity


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Listing Number
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Footnotes
Listing 16.2.7.3
Serious Treatment Emergent Adverse 
Events (Randomized Set)
AEL002
Repeat Listing 16.2.7.2 for SAEs
Listing 16.2.7.4
Treatment Emergent Adverse Drug 
Reactions (Randomized Set)
AEL002
Repeat Listing 16.2.7.2 for ADRs
Listing 16.2.7.5
Treatment Emergent Adverse Events 
Leading to Death (Randomized Set)
AEL002
Repeat Listing 16.2.7.2 for TEAEs leading to 
death
Listing 16.2.7.6
Neonatal Complications of Prematurity 
(Randomized Set)
The following columns will be presented:
- Subject ID
- Actual Treatment
- Start Date/Time [Day]
- End Date/Time [Day]
- Event
- Air Leaks specifications
- Germinal Matrix Hemorrhage/ Intraventricular 
Hemorrhage Severity Grades.
- Necrotizing Enterocolitis Severity Stages
- Retinopathy of prematurity Severity Stages
- Plus Disease < Impacted Eye>
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add a flag to identify TEAE
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] ** Neonate COVID-
19 Infection during the 
Study.
[3] $ = Treatment 
Emergent Adverse Event.


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Listing 16.2.7.7
Bronchopulmonary Dysplasia Evaluation 
(Randomized Set)
The following columns will be presented:
- Subject ID
- Actual Treatment 
- Assessment Date/Time
- BPD [3]  / BPD Grade 
- Requirement for Supplemental Oxygen and if 
Yes: < FiO2 (Fraction)>
- Positive Pressure for Respiratory Support 
- Respiratory Support via Nasal Cannula in title 
and display below 2 columns with Flow Rate 
(L/min) and Oxygen Concentration in the Gas 
Mixture (%)
 (%)
- Non-Invasive Ventilation
- Mechanical Ventilation via ETT
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] ** Neonate COVID-
19 Infection during the 
Study
[3] Neonates treated with 
Oxygen >21% for at least 
28 Days


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Listing 16.2.7.8
Neonatal Co-Morbidities at Discharge or 40 
Weeks PMA (Randomized Set)
The following columns will be presented:
- Subject ID
- Randomized Treatment
- Actual Treatment
Create a column "Neonatal Co-Morbidities" and 
list for each subject only the morbidities when Yes 
is ticked including those variables below:
- Gastroesophageal Reflux Requiring 
Treatment 
- Retinopathy of Prematurity
-Treatment for Retinopathy of 
Prematurity if yes add Impacted Eye 
<Unilateral: Left Eye/Right Eye, 
Bilateral> and Stage
- Treated with Laser, Cryotherapy and/or 
Anti-VEGF therapy
- Vitrectomy
- Apnea of Prematurity Requiring 
Treatment
- Pulmonary Hypertension
 - Medication 
- Patent Ductus Arteriosus
- Medication to Treat Seizures Required
- Ventricular Shunt in place
- Ileostomy / Ostomy
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] ** Neonate COVID-
19 Infection during the 
Study


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Listing Number
Listing Title
Template Code
Notes
Footnotes
Listing 16.2.7.9
Device Deficiency (Randomized Set)
The following columns will be presented:
- Subject ID
- Randomized Treatment
- Actual Treatment
- Device Deficiency encountered
- Device Deficiency Number
- Device Deficiency Observed
- Batch number
- Expiration date
- Date of Device Deficiency Observation
- Immediate Action <Specification>
- Reason for the Device Deficiency 
<Specification>
- Device Deficiency Leading to an AE 
Concatenated with the AE #
- Description of the Device Deficiency


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Notes
Footnotes
Listing 16.2.8.1
Vital Signs (Randomized Set) 
VSL002
-Remove ‘Analysis Period’
-Display Assessment Date/Time [Study Day] 
instead of Assessment date/time [study day / 
study day in period]
- Do not display [H] flag in Change from baseline 
column
- Skip the last column (Change from pre-dose) 
and replace Change from Baseline with Change 
from Pre-procedure
-In Test <Unit> column, display:
-
Systolic Blood Pressure (mmHg)
-
Diastolic Blood Pressure (mmHg)
-
Mean Blood Pressure (mmHg)
-
Heart Rate (beats/min)
-
Respiratory Rate (breaths/min)
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] Baseline =Y flags pre-
procedure value
[2] Use=Y: included in 
the analysis
 [3] *Maternal COVID-
19 Infection during 
Pregnancy.
*[4] * Neonate COVID-
19 Infection during the 
Study
Listing 16.2.8.2
Pain Assessment (Randomized Set)
The following columns will be presented:
- Subject ID
- Actual Treatment
- Timepoint
- Date /time of Assessment [Day]
- PIPP Total Score at T0 (derivation made directly 
in the eCRF collected data)
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] PIPP = Premature 
Infant Pain Profile
[2] Day = Date of PIPP 
Assessment  – first 
randomized treatment 
date + 1
[3] Total PIPP score is 
the sum of individual 
scores.
[4] *Maternal COVID-19 
Infection during 
Pregnancy.
[5] ** Neonate COVID-
19 Infection during the 
Study


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Footnotes
Listing 16.2.8.3
Feeding and Hearing Status at Discharge 
Home or 40 Weeks PMA (Randomized Set)
The following columns will be presented:
- Subject ID
- Actual Treatment
- Visit
- Feeding Status
      - Receiving Feedings via a Nasogastric Tube
      - Receiving Feeding via a Nasojejunal Tube
      - Subject have a Gastrostomy
      - Receiving Overnight Enteral Feeding
      - Require an Enteral Feeding Pump at 
Discharge
- Hearing Status
      - Otoacoustic Audio Test Performed
    If Yes concatenate the specification <Right Ear 
/ Left Ear>
      - Auditory Brainestem Response test 
Performed
     If Yes concatenate the specification <Right Ear 
/ Left Ear>
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] ** Neonate COVID-
19 Infection during the 
Study
Listing 16.2.8.4
Growth Assessment (Randomized Set)
VSL001
- Remove “Analysis Period” column.
- Remove “Study day in Period”.
- Present Actual Treatment
- Change body weight to Weight (kg), SBP to 
OFC (cm) and DBP to Length (cm)
- Do not present Use, CFB and CHG
- Only present the test result but this label should 
be removed
- Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] OFC = Occipital-
Frontal Circumference 
[2] *Maternal COVID-19 
Infection during 
Pregnancy.
[3] ** Neonate COVID-
19 Infection during the 
Study


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Notes
Footnotes
Listing 16.2.8.5
Respiratory Support Evaluation at 
Discharge Home or 40 weeks PMA 
(Randomized Set)
The following columns will be presented:
- Subject ID
- Actual Treatment
- Treated with Oxygen > 21% for at Least 28 Days
- Receiving any Supplementary Oxygen, if Yes: < 
FiO2 (Fraction)>
- Oxygen Saturation Target in title and display 
below 2 columns with Lower Target (%) and 
Higher Target (%)
- Supplementary Oxygen Delivered in the Last 24 
Hours
- Respiratory Support via Nasal Cannula in title 
and display below 2 columns with Flow Rate 
(L/min) and Oxygen Concentration in the Gas 
Mixture (%)
- Non-Invasive Ventilation
- Mechanical Ventilation via ETT
- Tracheostomy
- Additional Aid at Discharge, if Yes: 
<Specification>
Note: if ‘Other’ is selected, to be showed ‘Other: 
XXX’ where XXX is the text reported in If Other, 
please specify
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] ** Neonate COVID-
19 Infection during the 
Study
Listing 16.2.8.6
Hospital Transfer (Randomized Set)
The following columns will be presented:
- Subject ID
- Randomized Treatment
- Actual Treatment
- Date/ Time of Hospital Transfer
- Discharge summary from the receiving hospital, 
if No: <Specification>


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Footnotes
Listing 16.2.8.7
Comments (Randomized Set)
COL001
Variables to be listed:
- Subject ID
- Randomized Treatment
- Assessment
- Timepoint
- Comment
Add annotations ‘*’ or ‘**’ to subject ID as 
applicable
Add footnotes:
[1] *Maternal COVID-19 
Infection during 
Pregnancy.
[2] ** Neonate COVID-
19 Infection during the 
Study


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16.3 Figures
Figure Number
Figure Title
Template code
Notes
Footnote / source Table 
number
Figure 14.1.1
Disposition Flow Chart (Enrolled Set)
DSF001
Source: Tables 14.1.1.1 
and 14.1.1.2
Figure 14.1.2
Flow Chart of Analysis Sets (Randomized 
Set)
DSF003
Present Safety Set and Intention-To-Treat Set.
Source: Table 14.1.1.6
Figure 14.2.1
SpO2: Mean Values over Time (Intention-
To-Treat Set)
TPF002
- Present absolute SpO2 values on Y-axis.
- Timepoints to be presented are Day 1 (T0), 
Day 1 (5 min post-procedure), […], Day 1 (24h 
post-procedure), Day 2, Day 3, Day 5, on X-
Axis.
Please show number of subjects only at baseline 
and at each day (24 Hours, 48Hours, 72Hours 
and 120 Hours).
Source: Table 14.2.2.1-a
Figure 14.2.2
SpO2: Forest Plot (Intention-To-Treat Set)
TPF003
Present adjusted mean difference between 
treatments (95%CI) on X-Axis.
- Timepoints to be presented are Day 1 (T0), 
Day 1 (5 min post-procedure), …, Day 1 (24h 
post-procedure), Day 2, Day 3, Day 5 and 
averaged over the 120 hours post-treatment on 
Y-axis
Source: Table 14.2.2.2
Figure 14.2.3
FiO2: Mean Values over Time (Intention-
To-Treat Set)
TPF002
Repeat Figure 14.2.1 for FiO2
Source: Table 14.2.3.1-a
Figure 14.2.4
FiO2: Forest Plot (Intention-To-Treat Set)
TPF003
Repeat Figure 14.2.2 for FiO2
Source: Table 14.2.3.2
Figure 14.2.5
SpO2/FiO2 Ratio: Mean Values over Time 
(Intention-To-Treat Set)
TPF002
Repeat Figure 14.2.1 for SpO2/FiO2 Ratio
Source: Table 14.2.4.1-a
Figure 14.2.6
SpO2/FiO2 Ratio: Forest Plot (Intention-To-
Treat Set)
TPF003
Repeat Figure 14.2.2 for SpO2/FiO2 Ratio
Source: Table 14.2.4.2


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APPENDIX I
COMPLICATIONS OF PREMATURITY 

Air leaks 

Apnea of prematurity

Focal intestinal perforation (Neonatal spontaneous intestinal perforation) 

Germinal matrix hemorrhage/Intraventricular hemorrhage: to be classified according to 
the following: 
o
Grade I - Germinal matrix hemorrhage only or germinal matrix hemorrhage plus 
intraventricular hemorrhage less than 10% of ventricular area.
o
Grade II – Germinal matrix hemorrhage and intraventricular hemorrhage; 10 to 
50% of ventricular area.  
o
Grade III - Germinal matrix hemorrhage and intraventricular hemorrhage 
involving more than 50% of ventricular area; lateral ventricles are usually 
distended.
o
Grade IV: Hemorrhagic infarction in periventricular white matter ipsilateral to 
intraventricular 
hemorrhage 
(also 
called 
periventricular 
hemorrhagic 
infarction).

Necrotizing enterocolitis, to be classified according to modified Bell staging criteria

Patent ductus arteriosus

Periventricular leukomalacia

Pulmonary hemorrhage

Pulmonary interstitial emphysema

Retinopathy of prematurity – classification related to stage, localization and extent 
according to “The International Classification of Retinopathy of Prematurity Revisited”


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APPENDIX II
List of sedative and analgesic
Drug Name
ATC codes
FENTANYL
N01AH, 
N02AB
FENTANYL CITRATE
N01AH, 
N02AB
FENTANYL HYDROCHLORIDE
N01AH, 
N02AB
ALFENTANIL
N01AH
ALFENTANIL HYDROCHLORIDE
N01AH
SUFENTANIL
N01AH, 
N02AB
SUFENTANIL CITRATE
N01AH, 
N02AB
REMIFENTANIL
N01AH
REMIFENTANIL HYDROCHLORIDE
N01AH
CLONIDINE;FENTANYL
N01AH
CLONIDINE HYDROCHLORIDE;FENTANYL CITRATE
N01AH
THIOPENTAL
N01AF, 
N05CA
KETAMINE
N01AX
KETAMINE HYDROCHLORIDE
N01AX
FENTANYL
N01AH, 
N02AB
PROPOFOL
N01AX
CLONIDINE;FENTANYL
N01AH
SODIUM CARBONATE ANHYDROUS;THIOPENTAL
N01AF
KETAMINE;PROPOFOL
N01AX
1-(P-AETHOXYPHENYL)-1-DIAETHYLAMINO-3-M;CODEINE 
PHOSPHATE;PROPYPHENAZONE
N02AG
1-(P-AETHOXYPHENYL)-1-DIAETHYLAMINO-3-
M;CODEINE;PROPYPHENAZONE
N02AG
ATROPINE SULFATE;CODEINE PHOSPHATE;METAMIZOLE 
SODIUM;PROMETHAZINE HYDROCHLORIDE
N02AG
ALVERINE CITRATE;OXYCODONE
N02AG
ALVERINE;OXYCODONE
N02AG
AMINOPHENAZONE;CODEINE PHOSPHATE;PAPAVERINE 
HYDROCHLORIDE;PHENAZONE
N02AG
AMINOPHENAZONE;CODEINE;PAPAVERINE;PHENAZONE
N02AG
CAFFEINE;CODEINE PHOSPHATE;HYOSCYAMINE 
SULFATE;METAMIZOLE;PARACETAMOL
N02AG
ATROPA BELLADONNA EXTRACT;CAFFEINE;CODEINE PHOSPHATE 
HEMIHYDRATE;PARACETAMOL
N02AG
ATROPA BELLADONNA EXTRACT;CAFFEINE;CODEINE;PARACETAMOL
N02AG


STUDY CODE No.: CCD-050000-01
SAP Version Final 1.0 18Nov2022)
CONFIDENTIAL
104/110
ATROPA BELLADONNA EXTRACT;CAFFEINE;PAPAVER SOMNIFERUM 
TINCTURE;PARACETAMOL
N02AG
ATROPA BELLADONNA;CAFFEINE;CODEINE;PARACETAMOL
N02AG
ATROPA BELLADONNA;CAFFEINE;PAPAVER 
SOMNIFERUM;PARACETAMOL
N02AG
ATROPINE SULFATE;BENZYL ALCOHOL;PETHIDINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE MONOHYDRATE;HYDROCOTARNINE 
HYDROCHLORIDE MONOHYDRATE;OXYCODONE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;BENZYL ALCOHOL;PETHIDINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;CODEINE HYDROCHLORIDE;MORPHINE 
HYDROCHLORIDE;NOSCAPINE HYDROCHLORIDE;PAPAVERINE 
HYDROCHLORIDE
N02AG
ATROPINE SULFATE;CODEINE PHOSPHATE;METAMIZOLE 
SODIUM;PROMETHAZINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;DIHYDROMORPHINE
N02AG
ATROPINE SULFATE;HYDROMORPHONE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE SULFATE
N02AG
ATROPINE SULFATE;MORPHINE;PAPAVERETUM;PAPAVERINE 
HYDROCHLORIDE;PROPYPHENAZONE
N02AG
ATROPINE SULFATE;OPIUM ALKALOIDS TOTAL
N02AG
ATROPINE SULFATE;OPIUM ALKALOIDS TOTAL;PAPAVERINE 
HYDROCHLORIDE
N02AG
ATROPINE;BENZYL ALCOHOL;PETHIDINE
N02AG
ATROPINE;CODEINE;METAMIZOLE;PROMETHAZINE
N02AG
ATROPINE;CODEINE;MORPHINE;NOSCAPINE;PAPAVERINE
N02AG
ATROPINE;HYDROCOTARNINE;OXYCODONE
N02AG
ATROPINE;HYDROMORPHONE
N02AG
ATROPINE;MORPHINE
N02AG
ATROPINE;MORPHINE SULFATE
N02AG
ATROPINE;MORPHINE;PAPAVERETUM;PAPAVERINE;PROPYPHENAZON
E
N02AG
ATROPINE;OPIUM ALKALOIDS TOTAL
N02AG
ATROPINE;OPIUM ALKALOIDS TOTAL;PAPAVERINE
N02AG
ATROPINE;OXYCODONE
N02AG
ATROPINE;PETHIDINE HYDROCHLORIDE;PROMETHAZINE 
HYDROCHLORIDE
N02AG
ATROPINE;PETHIDINE;PROMETHAZINE
N02AG
CODEINE;HOMATROPINE;SPARTEINE SULFATE
N02AG
EPHEDRINE HYDROCHLORIDE;HYOSCYAMINE 
HYDROBROMIDE;OXYCODONE HYDROCHLORIDE
N02AG
CAFFEINE;CODEINE PHOSPHATE;HYOSCYAMINE 
SULFATE;METAMIZOLE;PARACETAMOL
N02AG
CAFFEINE;CODEINE;HYOSCINE HYDROBROMIDE;PARACETAMOL
N02AG
CAFFEINE;CODEINE;HYOSCINE;PARACETAMOL
N02AG
CAFFEINE;CODEINE;HYOSCYAMINE;METAMIZOLE;PARACETAMOL
N02AG
CALCIUM CARBONATE;KAOLIN, LIGHT;MORPHINE
N02AG


STUDY CODE No.: CCD-050000-01
SAP Version Final 1.0 18Nov2022)
CONFIDENTIAL
105/110
CALCIUM CARBONATE;KAOLIN, LIGHT;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
CHLORDIAZEPOXIDE;DEXTROPROPOXYPHENE 
HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CHLORDIAZEPOXIDE;DEXTROPROPOXYPHENE;DICYCLOVERINE;PAR
ACETAMOL
N02AG
CHLORMEZANONE;CODEINE PHOSPHATE;PARACETAMOL;PIPOXOLAN 
HYDROCHLORIDE
N02AG
CHLORMEZANONE;CODEINE;PARACETAMOL;PIPOXOLAN
N02AG
CODEINE HYDROCHLORIDE;HYOSCINE METHONITRATE;MORPHINE 
HYDROCHLORIDE;NOSCAPINE HYDROCHLORIDE;PAPAVERINE 
HYDROCHLORIDE
N02AG
CODEINE HYDROCHLORIDE;HYOSCINE METHONITRATE;MORPHINE 
HYDROCHLORIDE;NOSCAPINE HYDROCHLORIDE;PAPAVERINE 
HYDROCHLORIDE;PHENOBARBITAL
N02AG
CODEINE PHOSPHATE HEMIHYDRATE;DROTAVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CODEINE PHOSPHATE HEMIHYDRATE;ETHENZAMIDE;TROSPIUM 
CHLORIDE
N02AG
CODEINE PHOSPHATE HEMIHYDRATE;FENPIVERINIUM 
BROMIDE;PARACETAMOL;PITOFENONE HYDROCHLORIDE
N02AG
CODEINE PHOSPHATE;DICYCLOVERINE 
HYDROCHLORIDE;POTASSIUM CHLORIDE;SODIUM 
CHLORIDE;SODIUM CITRATE
N02AG
CODEINE PHOSPHATE;DROFENINE 
HYDROCHLORIDE;PROPYPHENAZONE
N02AG
CODEINE PHOSPHATE;DROTAVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CODEINE PHOSPHATE;FENPIVERINIUM 
BROMIDE;PARACETAMOL;PITOFENONE HYDROCHLORIDE
N02AG
CODEINE PHOSPHATE;HYOSCINE BUTYLBROMIDE;METAMIZOLE 
SODIUM
N02AG
CODEINE PHOSPHATE;HYOSCINE HYDROBROMIDE;MORPHINE 
HYDROCHLORIDE;NOSCAPINE HYDROCHLORIDE;PAPAVERINE 
HYDROCHLORIDE
N02AG
CODEINE PHOSPHATE;METAMIZOLE 
SODIUM;SECBUTABARBITAL;VALETHAMATE BROMIDE
N02AG
CODEINE PHOSPHATE;METAMIZOLE SODIUM;TIEMONIUM 
METHYLSULPHATE
N02AG
CODEINE;DICYCLOVERINE;POTASSIUM;SODIUM CHLORIDE;SODIUM 
CITRATE
N02AG
CODEINE;DROFENINE;PROPYPHENAZONE
N02AG
CODEINE;DROTAVERINE;PARACETAMOL
N02AG
CODEINE;ETHENZAMIDE;METAMIZOLE SODIUM;MILVERINE 
HYDROCHLORIDE;PITOFENONE
N02AG
CODEINE;ETHENZAMIDE;METAMIZOLE;MILVERINE;PITOFENONE
N02AG
CODEINE;ETHENZAMIDE;TROSPIUM
N02AG
CODEINE;FENPIVERINIUM;PARACETAMOL;PITOFENONE
N02AG
CODEINE;HOMATROPINE;SPARTEINE
N02AG


STUDY CODE No.: CCD-050000-01
SAP Version Final 1.0 18Nov2022)
CONFIDENTIAL
106/110
CODEINE;HOMATROPINE;SPARTEINE SULFATE
N02AG
CODEINE;HYOSCINE;METAMIZOLE
N02AG
CODEINE;HYOSCINE;MORPHINE;NOSCAPINE;PAPAVERINE
N02AG
CODEINE;HYOSCINE;MORPHINE;NOSCAPINE;PAPAVERINE;PHENOBAR
BITAL
N02AG
CODEINE;METAMIZOLE;SECBUTABARBITAL;VALETHAMATE
N02AG
CODEINE;METAMIZOLE;TIEMONIUM
N02AG
CODEINE;MORPHINE HYDROCHLORIDE;NOSCAPINE;PAPAVERINE 
HYDROCHLORIDE;THEBAINE
N02AG
CODEINE;MORPHINE;NOSCAPINE;PAPAVERINE;THEBAINE
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CALCIUM CARBONATE;KAOLIN, LIGHT;MORPHINE HYDROCHLORIDE
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
DEXTROPROPOXYPHENE NAPSILATE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
DEXTROPROPOXYPHENE;DICYCLOVERINE;PARACETAMOL
N02AG
CODEINE PHOSPHATE;DICYCLOVERINE 
HYDROCHLORIDE;POTASSIUM CHLORIDE;SODIUM 
CHLORIDE;SODIUM CITRATE
N02AG
DICYCLOVERINE HYDROCHLORIDE;PARACETAMOL;TRAMADOL 
HYDROCHLORIDE
N02AG
DICYCLOVERINE;PARACETAMOL;TRAMADOL
N02AG
DICYCLOVERINE;PARACETAMOL;TRAMADOL HYDROCHLORIDE
N02AG
ATROPINE SULFATE;HYDROMORPHONE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;HYDROMORPHONE HYDROCHLORIDE
N02AG
DIMETHYL-3,3-DIPHENYL-1-METHYLALLYLAMINE 
HCL;KETOBEMIDONE
N02AG
DIMETHYL-3,3-DIPHENYL-1-METHYLALLYLAMINE 
HCL;KETOBEMIDONE HYDROCHLORIDE
N02AG
CODEINE;ETHENZAMIDE;METAMIZOLE SODIUM;MILVERINE 
HYDROCHLORIDE;PITOFENONE
N02AG
CODEINE PHOSPHATE;HYOSCINE BUTYLBROMIDE;METAMIZOLE 
SODIUM
N02AG
EPHEDRINE HYDROCHLORIDE;HYOSCYAMINE 
HYDROBROMIDE;OXYCODONE HYDROCHLORIDE
N02AG
EPHEDRINE;HYOSCYAMINE;OXYCODONE
N02AG
CODEINE PHOSPHATE;METAMIZOLE 
SODIUM;SECBUTABARBITAL;VALETHAMATE BROMIDE
N02AG
EPINEPHRINE;HYOSCINE HYDROBROMIDE;PAPAVER SOMNIFERUM 
LATEX;PROCAINE HYDROCHLORIDE
N02AG
EPINEPHRINE;HYOSCINE;PAPAVER SOMNIFERUM;PROCAINE
N02AG
CODEINE PHOSPHATE;DROFENINE 
HYDROCHLORIDE;PROPYPHENAZONE
N02AG
CAFFEINE;CODEINE;HYOSCINE HYDROBROMIDE;PARACETAMOL
N02AG
FENPIPRAMIDE HYDROCHLORIDE;METHADONE
N02AG


STUDY CODE No.: CCD-050000-01
SAP Version Final 1.0 18Nov2022)
CONFIDENTIAL
107/110
FENPIPRAMIDE;METHADONE
N02AG
ATROPA BELLADONNA EXTRACT;CAFFEINE;CODEINE;PARACETAMOL
N02AG
ATROPINE SULFATE;MORPHINE SULFATE
N02AG
ATROPINE SULFATE;DIHYDROMORPHINE
N02AG
ATROPINE SULFATE;HYDROMORPHONE HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE HYDROCHLORIDE;SPARTEINE 
SULFATE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE SULFATE
N02AG
HYOSCINE HYDROBROMIDE;OPIUM ALKALOIDS TOTAL
N02AG
HYOSCINE HYDROBROMIDE;OXYCODONE HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;OXYCODONE 
HYDROCHLORIDE;RACEPHEDRINE HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;PAPAVERETUM
N02AG
HYOSCINE HYDROBROMIDE;PETHIDINE 
HYDROCHLORIDE;PROMETHAZINE HYDROCHLORIDE
N02AG
HYOSCINE;MORPHINE
N02AG
HYOSCINE;MORPHINE
N02AG
HYOSCINE;MORPHINE;SPARTEINE
N02AG
HYOSCINE;OPIUM ALKALOIDS TOTAL
N02AG
HYOSCINE;OXYCODONE
N02AG
HYOSCINE;OXYCODONE;RACEPHEDRINE
N02AG
HYOSCINE;PAPAVERETUM
N02AG
HYOSCINE;PETHIDINE;PROMETHAZINE
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
DIMETHYL-3,3-DIPHENYL-1-METHYLALLYLAMINE 
HCL;KETOBEMIDONE HYDROCHLORIDE
N02AG
DIMETHYL-3,3-DIPHENYL-1-METHYLALLYLAMINE 
HCL;KETOBEMIDONE HYDROCHLORIDE
N02AG
ATROPA BELLADONNA EXTRACT;CAFFEINE;PAPAVER SOMNIFERUM 
TINCTURE;PARACETAMOL
N02AG
FENPIPRAMIDE HYDROCHLORIDE;METHADONE
N02AG
ALVERINE CITRATE;OXYCODONE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE;MORPHINE SULFATE
N02AG
ATROPINE;MORPHINE SULFATE
N02AG
ATROPINE SULFATE;MORPHINE SULFATE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE SULFATE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE SULFATE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG


STUDY CODE No.: CCD-050000-01
SAP Version Final 1.0 18Nov2022)
CONFIDENTIAL
108/110
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE HYDROCHLORIDE
N02AG
CODEINE PHOSPHATE HEMIHYDRATE;DROTAVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CODEINE PHOSPHATE;HYOSCINE HYDROBROMIDE;MORPHINE 
HYDROCHLORIDE;NOSCAPINE HYDROCHLORIDE;PAPAVERINE 
HYDROCHLORIDE
N02AG
ATROPINE SULFATE;HYDROMORPHONE HYDROCHLORIDE
N02AG
CODEINE;MORPHINE HYDROCHLORIDE;NOSCAPINE;PAPAVERINE 
HYDROCHLORIDE;THEBAINE
N02AG
CODEINE;MORPHINE HYDROCHLORIDE;NOSCAPINE;PAPAVERINE 
HYDROCHLORIDE;THEBAINE
N02AG
HYOSCINE;OPIUM ALKALOIDS TOTAL
N02AG
ATROPINE SULFATE;OPIUM ALKALOIDS TOTAL
N02AG
HYOSCINE;OPIUM ALKALOIDS TOTAL
N02AG
OPIOIDS IN COMBINATION WITH ANTISPASMODICS
N02AG
HYOSCINE HYDROBROMIDE;OPIUM ALKALOIDS TOTAL
N02AG
CODEINE PHOSPHATE HEMIHYDRATE;ETHENZAMIDE;TROSPIUM 
CHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;OXYCODONE HYDROCHLORIDE
N02AG
HYOSCINE;OXYCODONE
N02AG
ATROPINE;PETHIDINE HYDROCHLORIDE;PROMETHAZINE 
HYDROCHLORIDE
N02AG
ATROPINE SULFATE;HYDROMORPHONE HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;PETHIDINE 
HYDROCHLORIDE;PROMETHAZINE HYDROCHLORIDE
N02AG
ATROPINE SULFATE;OPIUM ALKALOIDS TOTAL;PAPAVERINE 
HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;PAPAVERETUM
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
ATROPINE SULFATE MONOHYDRATE;HYDROCOTARNINE 
HYDROCHLORIDE MONOHYDRATE;OXYCODONE HYDROCHLORIDE
N02AG
CHLORDIAZEPOXIDE;DEXTROPROPOXYPHENE 
HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
DICYCLOVERINE HYDROCHLORIDE;PARACETAMOL;TRAMADOL 
HYDROCHLORIDE
N02AG
CHLORMEZANONE;CODEINE PHOSPHATE;PARACETAMOL;PIPOXOLAN 
HYDROCHLORIDE
N02AG
CHLORMEZANONE;CODEINE PHOSPHATE;PARACETAMOL;PIPOXOLAN 
HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;OXYCODONE 
HYDROCHLORIDE;RACEPHEDRINE HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE HYDROCHLORIDE
N02AG
HYOSCINE HYDROBROMIDE;MORPHINE HYDROCHLORIDE;SPARTEINE 
SULFATE
N02AG


STUDY CODE No.: CCD-050000-01
SAP Version Final 1.0 18Nov2022)
CONFIDENTIAL
109/110
HYOSCINE HYDROBROMIDE;MORPHINE HYDROCHLORIDE
N02AG
1-(P-AETHOXYPHENYL)-1-DIAETHYLAMINO-3-M;CODEINE 
PHOSPHATE;PROPYPHENAZONE
N02AG
ATROPINE SULFATE;OPIUM ALKALOIDS TOTAL;PAPAVERINE 
HYDROCHLORIDE
N02AG
CODEINE PHOSPHATE;DROFENINE 
HYDROCHLORIDE;PROPYPHENAZONE
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CODEINE PHOSPHATE;DROFENINE 
HYDROCHLORIDE;PROPYPHENAZONE
N02AG
CODEINE PHOSPHATE;DROFENINE 
HYDROCHLORIDE;PROPYPHENAZONE
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CODEINE HYDROCHLORIDE;HYOSCINE METHONITRATE;MORPHINE 
HYDROCHLORIDE;NOSCAPINE HYDROCHLORIDE;PAPAVERINE 
HYDROCHLORIDE
N02AG
CODEINE HYDROCHLORIDE;HYOSCINE METHONITRATE;MORPHINE 
HYDROCHLORIDE;NOSCAPINE HYDROCHLORIDE;PAPAVERINE 
HYDROCHLORIDE;PHENOBARBITAL
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CODEINE PHOSPHATE HEMIHYDRATE;FENPIVERINIUM 
BROMIDE;PARACETAMOL;PITOFENONE HYDROCHLORIDE
N02AG
CODEINE PHOSPHATE;FENPIVERINIUM 
BROMIDE;PARACETAMOL;PITOFENONE HYDROCHLORIDE
N02AG
DEXTROPROPOXYPHENE NAPSILATE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
ATROPINE SULFATE;CODEINE HYDROCHLORIDE;MORPHINE 
HYDROCHLORIDE;NOSCAPINE HYDROCHLORIDE;PAPAVERINE 
HYDROCHLORIDE
N02AG
ATROPINE SULFATE;MORPHINE;PAPAVERETUM;PAPAVERINE 
HYDROCHLORIDE;PROPYPHENAZONE
N02AG
DEXTROPROPOXYPHENE HYDROCHLORIDE;DICYCLOVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
ATROPA BELLADONNA EXTRACT;CAFFEINE;CODEINE PHOSPHATE 
HEMIHYDRATE;PARACETAMOL
N02AG
EPINEPHRINE;HYOSCINE HYDROBROMIDE;PAPAVER SOMNIFERUM 
LATEX;PROCAINE HYDROCHLORIDE
N02AG
AMINOPHENAZONE;CODEINE PHOSPHATE;PAPAVERINE 
HYDROCHLORIDE;PHENAZONE
N02AG
DICYCLOVERINE;PARACETAMOL;TRAMADOL HYDROCHLORIDE
N02AG
DICYCLOVERINE HYDROCHLORIDE;PARACETAMOL;TRAMADOL 
HYDROCHLORIDE
N02AG
CODEINE PHOSPHATE;DROTAVERINE 
HYDROCHLORIDE;PARACETAMOL
N02AG
CODEINE PHOSPHATE;METAMIZOLE SODIUM;TIEMONIUM 
METHYLSULPHATE
N02AG


STUDY CODE No.: CCD-050000-01
SAP Version Final 1.0 18Nov2022)
CONFIDENTIAL
110/110
MORPHINE
N02AA
ETOMIDATE
N01AX
LORMETAZEPAM
N05CD
MIDAZOLAM
N03AE, 
N05CD
MIDAZOLAM HYDROCHLORIDE
N03AE, 
N05CD
MIDAZOLAM MALEATE
N05CD