Clinical trial NCT04502433
Conditions: Acute Respiratory Distress Syndrome
Keywords: acute respiratory distress syndrome ARDS Adults Surfactant Poractant alfa (porcine surfactant, Curosurf®), Curosurf® Coronavirus disease (COVID-19) Coronavirus 2019 Disease
Sponsor: Chiesi Farmaceutici S.p.A.
Start date: 2021-01-06; Completion date: 2022-03-17
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of poractant alfa (Curosurf®), administered by endotracheal (ET) instillation in hospitalized adult patients diagnosed with SARS-COV-19 acute respiratory distress syndrome (ARDS).

Detailed description:
This was a multicentre, open-label, randomized phase II proof-of-concept study.

The efficacy and safety of poractant alfa was evaluated in terms of ventilatory free days during the 21 days after randomization, in adult patients diagnosed with ARDS due to SARS-COV-19 infection.

Each patient randomized to the study treatment received 3 administrations of Curosurf ® with a 24 hours dosing interval. The assessment collection was up to Day 28, when the evaluation occurred at the Intensive Care Unit (ICU), or by phone call if the patient has already been discharged.

Seventy patients were planned to be randomized in the study with a ratio 3:2 (i.e. 42 patients in the poractant alfa arm and 28 in the control arm). The control arm population received Standard of Care (SoC). This study was conducted in United Kingdom (UK), United States of America (US), and Italy.

Overall, 13 patients (Curosurf ® group) and 8 patients (control group) were randomised in the study. Due to low recruitment rate the study was terminated early for non-safety reasons.

Curosurf® is a pulmonary surfactant of natural origin which, when delivered endotracheally (ET). Curosurf® is currently approved for marketing as treatment of premature neonates with RDS or at risk of Respiratory Distress Syndrome (RDS). Chiesi Farmaceutici S.p.A (Chiesi) conducted this study with its porcine-derived surfactant, Curosurf® (poractant alfa), to evaluate the efficacy and safety in ventilated adult patients who were critically unwell in intensive care with SARS-COV-19 ARDS.

Arms: arm 1: Patients treated with standard-of-care (SoC), as control cohort arm 2: Patients treated with CUROSURF® (poractant alfa), as an add-on to standard-of-care (SoC)
Interventions: intervention 1: CUROSURF® (poractant alfa)
Intervention descriptions: intervention 1: Three administrations with a 24 hours dosing interval.

Each endotracheal (ET) administration 1, 2, and 3 consisted of poractant alfa bolus:

30mg /kg (Lean Body Weight-LBW) = 0.375ml /kg LBW, diluted with normal saline up to 2ml /kg LBW.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
STUDY CODE No.: CLI-050000-04
EUDRACT No.: 2020-002632-75
IND No.: 153286
Multicenter, open-label, randomised trial to assess the efficacy and tolerability of poractant alfa 
(porcine surfactant, Curosurf®) in hospitalized patients with SARS-COV-19 acute respiratory 
distress syndrome (ARDS)
Version No.: 4.0 
Date:   02 MAR 2021
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
NCT number: NCT04502433


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Clinical Study Code No.: CLI-050000-04
Version No.: 4.0 
EUDRACT No.: 2020-002632-75 – IND No: 153286
Date: 02 MAR 2021
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GENERAL INFORMATION
SPONSOR
Chiesi Farmaceutici S.p.A.* 
Via Palermo 26/A
43122 Parma – Italy
+ 39 0521 2791
*also reported as Chiesi throughout the text
SPONSOR MEDICAL EXPERT
(Clinical Research Physician)
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A, 
43122 Parma – Italy
E-mail: 
Telephone: 
Readily available in case of medical questions
Coordinating INVESTIGATOR
(United Kingdom)
UCL EGA Institute for Women’s Health, Faculty of 
Population Health Sciences, University College 
London, United Kingdom
E-mail: 
:
Scientific COMMITTEE
(Italy)
,
Intensive Care Unit, University of Modena, Italy.
E-mail: 
            
Intensive Care Unit, University of Bologna, Italy
E-mail: 
CLINICAL PROGRAM LEADER
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A, 
43122 Parma – Italy
E-mail: 
MONITORING CRO
DATA MANAGEMENT / STATISTICS 
CRO:


Clinical Study Protocol
Clinical Study Code No.: CLI-050000-04
Version No.: 4.0
EUDRACT No.: 2020-002632-75 – IND No: 153286
Date:  02 MAR 2021
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VERSION HISTORY
Version 
Date 
Change History
1.0
25 May 2020
First version
2.0
08 June 2020
Second version due to MHRA requests: 
sample size justification and C-Reactive Protein 
abbreviation clarification
3.0
30 June 2020
Third version due to drug administration update 
and REC requests (clarified inclusion criterion for 
ECMO patient cohort, references updated, 
exploratory laboratory assessment reworded)
4.0
 02 March 2021
For detailed list of changes see the Summary of 
Changes from Protocol v 3.0 to Protocol v 4.0


Clinical Study Protocol
Clinical Study Code No.: CLI-050000-04
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Date:  02 MAR 2021
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PROTOCOL OUTLINE
Study title
Multicenter, open-label, randomised trial to assess the efficacy and 
tolerability of poractant alfa (porcine surfactant, Curosurf®) in hospitalized 
patients with SARS-COV-19 acute respiratory distress syndrome (ARDS)
Sponsor
Chiesi Farmaceutici S.p.A. - Via Palermo 26/A 
43122 Parma - Italy 
Name of the Product
CUROSURF® 
Centre(s)
Approximately 7 centers in UK and USA
Indication 
ARDS in COVID 19 adult patients
Study design
Multicenter, open-label, randomised, phase II Proof of Concept (POC) 
study
Study phase
Phase II – Proof of Concept study
Objectives
To evaluate the efficacy and safety of poractant alfa (porcine surfactant, 
Curosurf®), administered by endotracheal (ET) instillation, in terms of 
ventilatory free days during the 21 days after randomization, in adult 
patients with ARDS due to SARS-COV-19 infection. 
Treatment duration
Three administrations with a 24 hours dosing interval. 
Each ET administration 1, 2 and 3 will consist of poractant alfa bolus: 
30mg /kg (Lean Body Weight-LBW) = 0.375ml /kg LBW. Dilution with 
normal saline up to 2ml /kg LBW. 
Test product 
dose/route/regimen  
CUROSURF® (poractant alfa) 240mg / 3ml 
It is a sterile suspension in 3.0 ml glass vials with a total concentration of 
80 mg/ml for endotracheal 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.
Reference product 
dose/route/regimen 
NA
Number of patients
Seventy patients will be randomised in the study with a ratio 3:2 (i.e. 42 
patients in the poractant alfa arm and 28 in the control arm). 
Study population
Adult patients with ARDS due to COVID-19 (positive by rtPCR 
confirmation) and endotracheally intubated.
Inclusion/exclusion criteria
Inclusion criteria
Participants are eligible to be included in the study if the following criteria 
apply:
1.
Male or female ≥18 and ≤ 80 years of age 
2.
Informed consent for participation in the study (refer to section 15 


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for detailed informed consent procedure) 
3.
Positive 2019-nCoV rt-PCR before randomisation
4.
PaO2/FiO2 ratio < 150 mmHg
5.
Lung compliance ≤45 ml/cmH20
6.
Intubated and artificially ventilated less than 48 hours before the 
first poractant alfa administration
Exclusion criteria
Participants are excluded from the study if any of the following criteria 
apply:
1.
Any contraindications to surfactant administration e.g., 
pulmonary haemorrhage and pneumothorax) 
2.
Weight < 40kg 
3.
Stage 4 severe chronic kidney disease (i.e., eGFR < 30)
4.
Pregnancy 
5.
Administration of any nebulized surfactant in the 48 hours before 
the first poractant alfa administration 
6.
Extracorporeal membrane oxygenation
Study plan
After verification of any inclusion/exclusion criteria the patients will be 
included in the study and randomised to the poractant alfa group or to 
standard of care one.
Poractant alfa group
-
Starting from patient intubation and mechanical ventilation, 
defined assessments will be collected (for details see study 
schedule 7.1). 
-
Patients will receive three poractant alfa endotracheal 
administrations 24 hours apart.
-
Defined assessments will be collected before randomisation and 
at 6 -12 - 24 hours after each poractant alfa administration till 72 
hours since the first administration.
-
From Day 4 to Day 27 assessment collection will occur every 24 
hours until Intensive Care Unit (ICU) discharge. Whenever the 
discharge occurs, additional safety lab and SOFA assessments 
will be collected. 
-
At Day 28 the last follow up evaluation will occur on the ICU if 
still requiring critical care, or by phone call if the patient has been 
discharged from ICU by that time.
Control group
-
Starting from patient intubation and mechanical ventilation 
defined assessments will be collected (for details see study 
schedule 7.1).  
-
Defined assessments will be collected before randomisation and 
at specific timepoints (according to study schedule 7.1) from 


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randomisation up to 72 hours.
-
From Day 4 to Day 27 assessment data collection (according to 
study schedule 7.1) will occur every 24 hours until Intensive Care 
Unit (ICU) discharge. Whenever discharge occurs, assessment 
data will be collected at the corresponding Day X.
-
At Day 28 the last follow up evaluation will occur on the ICU, or 
by phone call if the patient has already been discharged.
Most relevant allowed 
concomitant treatments
Concomitant treatments are allowed. 
Concomitant medications in a critically ill SARS-COV19 population are 
numerous may change daily are consequently difficult to collect, and are 
unlikely, to be related to therapeutic success and or safety evaluations.
Therefore, only selected concomitant medications will be specifically 
recorded in this trial:  
1)
Antiviral drugs; 
2)
Monoclonal antibodies; 
3)
Antibiotics;
4)
Systemic corticosteroids; 
5)
Heparin or any other anticoagulants;
6)
Plasma administration from immunized patients;
7)
Nitric Oxide therapy;
8)
Any other treatments for pneumonia/ARDS/ SARS-COV19 
ARDS;
9)
Medications prescribed to treat adverse events (AEs).
Most relevant forbidden 
concomitant treatments
No concomitant treatment is forbidden
Efficacy variables
Primary Endpoint
The primary outcome variable will be the number of days alive and 
ventilator-free, defined as the number of days the patient is alive and is not 
receiving mechanical ventilation over the 21 days following 
randomisation. Mechanical ventilation will be defined as invasive and non-
invasive. Patient will be defined free of mechanical ventilation after 12 
hours from the suspension of either invasive and non-invasive ventilation. 
Patients who die or are mechanically ventilated longer than this period are 
assessed as zero ventilator-free days.
Key secondary
Percentage of patients alive and free of respiratory failure (i.e., need for 
mechanical ventilation, ECMO (Extracorporeal Membrane Oxygenation), 
non-invasive ventilation, or high-flow nasal cannula oxygen delivery) at 
Day 28.
Secondary
-
Number of days alive and ventilator-free at Day 28
-
Mortality at Day 21 and Day 28


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-
Number of alive and free from invasive ventilation at Day 21 and 
Day 28
-
Number of alive and free from non-invasive ventilation (NIV) at 
Day 21 and Day 28
-
Percentage of patients with improvement in severity status 
defined as a decrease in the severity score at Day 28 or 
Discharge, whichever comes first. Severity score will be defined 
as Mild, Moderate, Severe or Death based on PaO2/FiO2 ratio 
and patient status at Day 28 and numerically rated from 1-4 
respectively:
Severity
Variable
Criteria
Mild -1
PaO2/FiO2 Ratio
200 mmHg < PaO2/FIO2 ≤ 300 
mmHg
Moderate-2
PaO2/FiO2 Ratio
100 mmHg < PaO2/FIO2 ≤ 200 
mmHg
Severe-3
PaO2/FiO2 
Ratio PaO2/FIO2 ≤ 100 mmHg
Death-4
Patient Status
Yes/No
-
Change from baseline in PaO2/FiO2 ratio at 6 and 12 hours 
following administration of each dose in the treated group and 
at similar timepoints in the control group (6, 12, 30, 36, 54 and 
60 hours after randomisation) 
-
Change from baseline in PaO2/FiO2 ratio at additional 
timepoints (i.e. every 24 hours after treatment/randomisation 
until the patient is discharged from the ICU) 
-
Percentage of patients alive and with PaO2/ FiO2 improvement 
>20% at 6 and 12 hours following administration of each dose 
in the treated group and at similar timepoints in the control group 
(6, 12, 30, 36, 54 and 60 hours after randomisation)
-
Percentage of patients alive and with PaO2/FiO2 improvement 
of >20% at the additional timepoints (i.e. every 24 hours after 
treatment/randomisation until the patient is discharged from the 
ICU)
-
Change from baseline in FiO2 at 6 and 12 hours following 
administration of each dose in the treated group and at similar 
timepoints in the control group (6, 12, 30, 36, 54 and 60 hours 
after randomisation) 
-
Change from baseline in FiO2 at additional timepoints (i.e. every 
24 hours after treatment/randomisation until the patient is 
discharged from the ICU)  
-
Length of ICU stay (days) at Day 28. Patients who die or are 
mechanically ventilated longer than this period are assigned with 
28 days
-
Percentage of patients alive and out of ICU at Day 28


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-
Delta SOFA Score and sub-score components measured on Day 
3 and Day 28 or Discharge whichever comes first
-
Percentage of patients alive and organ failure free (SOFA 
score=0) at Day 28 or Discharge whichever comes first
-
Change from baseline in ventilatory parameters [tidal volume 
(TV), respiratory rate (RR), dynamic compliance (Cdyn), static 
compliance (Cstat), positive end-expiratory pressure (PEEP), 
peak inspiratory pressure (PIP), plateau pressure (Pplat)] 
measured at 6-12-24h after each poractant alfa administration up 
to 72 hours and at similar timepoints in the control group (6, 12, 
24, 30, 36, 48, 54, 60 and 72 hours after randomisation) and then 
every 24 hours until the patient is discharged from the ICU 
-
Change from baseline in blood gas analysis acid-base balance 
parameters (i.e. pH, pCO2, pO2, HCO3, lactate) measured at 6-
12-24h after each poractant alfa administration up to 72 hours 
and at similar timepoints in the control group (6, 12, 24, 30, 36, 
48, 54, 60 and 72 hours after randomisation) and then every 24 
hours till the patient is discharged from the ICU.
Exploratory (to be applied only in patients from UK) 
The following parameters will be measured at 12, 24, 48, 72 and 96 hrs 
after start of treatment (first dose in the poractant alfa group and after 
randomisation in the control group):
-
Change from baseline in lowest and dynamic surface tensions 
(mN/m) from TA samples 
-
Change from baseline in concentrations of surfactant 
phospholipids (mg/ml) and proteins (ng/ml) from TA samples
-
Change from baseline in inflammatory indices such as cellular 
and cytokine (pg/ml) inflammatory markers (e.g. IL-1, IL-6, TNF 
alpha, IFN gamma and lymphocyte markers) from TA and blood 
samples
Safety variables
-
Adverse events (AEs)
-
Laboratory Parameters (Blood count, bilirubin, creatinine, LDH, 
D-dimer, CRP (C-Reactive Protein), procalcitonin)
-
Vital Signs (Blood pressures and pulse rate)
Sample size calculation
A total of 70 patients will be randomised with a ratio 3:2 (i.e. 42 patients 
randomised to the poractant alfa group and 28 in the control group). 
Assuming patients in the control arm being free from ventilation on 
average 1 week (i.e. 7 days), this sample size achieves 84% power to detect 
a difference of 4 days (i.e. on average 11 ventilation-free days for patients 
treated with poractant alfa), assuming a standard deviation of 5.5 and a 
two-sided significance level (alpha) of 0.05 using a two-sample t-test. 
Statistical methods
Populations for analysis

Intention-to-Treat population (ITT): all randomised patients 
(analysed as randomised).


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
 Safety population: all randomised patients and receive at least 
one dose of the study treatment (Curosurf treated patients) 
(analysed as treated).
The primary analysis population for efficacy will be the ITT. The Safety 
population will be used in the analysis of all safety variables.
Intercurrent Events
Death and Early discontinuation from study drug can be anticipated as 
intercurrent events:
-
Death will be incorporated as a failure outcome for binary 
endpoint using composite strategy;
-
Early discontinuation from study drug will be handled using 
treatment policy strategy: all data collected after discontinuation 
from study drug till Day 28 or death will be included;
-
Change in respiratory parameters will be analysed using while-
alive strategy.
Primary Efficacy Variable

Number of days alive and ventilator-free during the 21 days after 
randomisation will be compared between groups by using the 
ANOVA model including treatment group, age and country 
as factors. Patients who die or are mechanically ventilated 
longer than this period are assessed as zero ventilator-free 
days.
Key secondary endpoint

Percentage of patients alive and free of respiratory failure (i.e., 
need 
for 
mechanical 
ventilation, 
ECMO, 
non-invasive 
ventilation, or high-flow nasal cannula oxygen delivery) at Day 
28 will be analysed using logistic regression including treatment 
group, age and country as factor. Difference in the proportion and 
related 95% confidence interval will be estimated from the 
model.
Secondary Efficacy Variables

Number of days alive and free from ventilation at Day 28, 
number of days alive and free from invasive and non-invasive 
ventilation at Day 21 and Day 28 will be compared between 
groups by the ANOVA model including treatment group, age 
and country as factors.

Mortality at Day 21 and Day 28 will be compared between 
groups by using logistic regression including treatment group, 
age and country as factors. Difference in the proportions and 
related 95% confidence interval will be estimated from the 
model.

Percentage of patients with improvement in severity status 
defined as a decrease in the severity score at Day 28 or 
Discharge, whichever comes first will be compared by groups 
using logistic regression including treatment group, age and 
country as factors. Difference in the proportions and related 95% 
confidence interval will be estimated from the model.


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
Change from baseline in PaO2/FiO2 at 6 and 12 hours after 
each treatment and at similar timepoints in the control group 
will be compared between groups using ANCOVA model 
including group, age and country as fixed effect and baseline 
value as covariate. The same analysis will be performed at 
each additional timepoint. 

Percentage of patients alive and with PaO2/FiO2 improvement 
of >20% at 6 and 12 hours following administration of each 
dose in the treated group and at similar timepoints in the control 
group will be compared by groups using logistic regression 
including treatment group, age and country as factors. Difference 
in the proportions and related 95% confidence interval will be 
estimated from the model.  Patients who die are considered as 
a failure. The same analysis will be performed at each 
additional timepoint.

Change from baseline in FiO2 will be analysed as PaO2/FiO2. 

Length of ICU stay (days) at Day 28 will be compared between 
groups will be compared between groups by using the 
ANOVA model including treatment group, age and country as 
factors. Patients who die or are mechanically ventilated longer 
than this period are assigned with 28 days.

Percentage of patients alive and out of ICU at Day 28 using 
logistic regression including treatment group, age and country 
as factors. Difference in the proportions and related 95% 
confidence interval will be estimated from the model.

Delta SOFA Score and sub-score components at Day 3 and Day 
28 or Discharge, whichever comes first, will be analysed at 
each timepoint using ANCOVA model including group, age 
and country as fixed effect and baseline value as covariate. 

Percentage of patients alive and free of organ failure (i.e. SOFA 
score=zero) at Day 28 or Discharge, whichever comes first will 
be compared by groups using logistic regression including 
treatment group, age and country as factors. Difference in the 
proportions and related 95% confidence interval will be 
estimated from the model.

Change from baseline in ventilator parameters (TV, RR, Cdyn, 
Cstat, PEEP, PIP, Pplat) will be summarized by means of 
descriptive statistics or frequency distribution, as appropriate by 
group at each timepoint.

Change from baseline in BGA acid-base balance parameters (i.e. 
pH, pCO2, pO2, HCO3, lactate) will be summarized by means of 
descriptive statistics by group at each timepoint.
Exploratory Efficacy Variables (to be applied only in patients from UK)

Exploratory parameters from TA aspirates and blood samples 
will be summarized both as absolute values and as change 
from baseline values by treatment group at each timepoint 
using descriptive statistics. 
Safety Variables


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
Incidence of all the AEs, AEs related to poractant alfa (treated 
group) (ADRs), serious AEs (SAEs) and AEs leading to death 
will be summarized by group both in terms of frequency of 
patients with at least one AE and in terms of the frequency of 
AEs (number of events). 

Vital sign values and their change from baseline will be 
summarized by group at each timepoint using descriptive 
statistics. 

Laboratory parameters and their change from baseline will be 
summarized by group at each timepoint using descriptive 
statistics.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ADR
Adverse Drug Reaction
ARDS
Acute Respiratory Distress Syndrome
AE
Adverse Event
ABG
Arterial Blood Gas
ANOVA
Analysis of Variance
BAL
Bronchoalveolar Lavage 
Cdyn
Dynamic compliance
CRA
Clinical Research Associate
CRF
Case Report Form
CRP
C-Reactive Protein
CRO
Contract Research Organization
Cstat
Static compliance
FPFV
First Patient First Visit
ET
Endotracheal
vvECMO
Veno Venous-Extracorporeal Membrane Oxygenation
ICH
International Conference on Harmonization
ICU
Intensive Care Unit
ITT
Intention to Treat
LPLV
Last Patient Last Visit
LBW
Lean Body Weight
MedDRA
Medical Dictionary for Regulatory Activities
MV
Mechanical Ventilation
NIV
Non-invasive Ventilation
PEEP
Positive End-Expiratory Pressure
PIP
Peak Inspiratory Pressure
Pplat
Plateau pressure
RR
Respiratory Rate
rtPCR
Real Time Polymerase Chain Reaction
SAE
Serious Adverse Event
SmPC
Summary of Product Characteristics
SOFA
Sequential Organ Failure Assessment
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA
Tracheal Aspirate 
TV
Tidal Volume


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CONTENT
GENERAL INFORMATION.......................................................................................................................................................2
PROTOCOL OUTLINE...............................................................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................................................12
CONTENT....................................................................................................................................................................................13
1.
INTRODUCTION..............................................................................................................................................................15
1.1 BACKGROUND INFORMATION...............................................................................................................................................15
1.2 STUDY RATIONALE...............................................................................................................................................................15
1.3 RISK/BENEFIT ASSESSMENT .................................................................................................................................................17
2.
STUDY OBJECTIVES......................................................................................................................................................17
2.1 PRIMARY OBJECTIVE(S).......................................................................................................................................................17
2.2 SECONDARY OBJECTIVE(S)..................................................................................................................................................18
2.3 EXPLORATORY OBJECTIVE(S)..............................................................................................................................................18
3.
STUDY DESIGN................................................................................................................................................................18
3.1 STUDY DESIGN ....................................................................................................................................................................18
3.2 END OF TRIAL DEFINITION...................................................................................................................................................19
4.
PATIENT SELECTION CRITERIA...............................................................................................................................19
4.1 PATIENT RECRUITMENT.......................................................................................................................................................19
4.2 INCLUSION CRITERIA ...........................................................................................................................................................19
4.3 EXCLUSION CRITERIA ..........................................................................................................................................................19
4.4 PATIENT WITHDRAWALS .....................................................................................................................................................20
5.
PATIENT CONCOMITANT MEDICATIONS..............................................................................................................20
5.1 PERMITTED CONCOMITANT MEDICATIONS ..........................................................................................................................20
5.2 NON-PERMITTED CONCOMITANT MEDICATIONS..................................................................................................................20
6.
TREATMENT(S) ...............................................................................................................................................................21
6.1 APPEARANCE AND CONTENT ...............................................................................................................................................21
6.2 DOSAGE AND ADMINISTRATION ..........................................................................................................................................21
6.3 PACKAGING..........................................................................................................................................................................22
6.4 LABELLING ..........................................................................................................................................................................22
6.5 TREATMENT ALLOCATION....................................................................................................................................................22
6.6 TREATMENT CODE...............................................................................................................................................................22
6.7 TREATMENT COMPLIANCE ...................................................................................................................................................22
6.8 DRUG STORAGE ...................................................................................................................................................................22
6.9 DRUG ACCOUNTABILITY......................................................................................................................................................23
7.
STUDY PLAN ....................................................................................................................................................................23
7.1 STUDY SCHEDULE................................................................................................................................................................23
7.2 INVESTIGATIONS..................................................................................................................................................................29
7.2.1 LABORATORY ASSESSMENTS ............................................................................................................................................29
7.2.1.1 BLOOD SAMPLE COLLECTION (AS PER STUDY SCHEDULE 7.1).......................................................................................29
7.2.1.2 URINE PREGNANCY TEST................................................................................................................................................29
7.2.2 CLOSED SUCTION TRACHEAL ASPIRATE (TA) SAMPLES ....................................................................................................29
7.2.3 LABORATORIES INVOLVED................................................................................................................................................30
8.
EFFICACY ASSESSMENTS ...........................................................................................................................................31
9.
SAFETY ASSESSMENTS ................................................................................................................................................33
10.
ADVERSE EVENT REPORTING...................................................................................................................................33
10.1 DEFINITIONS ......................................................................................................................................................................33


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10.2 EXPECTEDNESS ..................................................................................................................................................................34
10.3 INTENSITY OF ADVERSE EVENT.........................................................................................................................................34
10.4 CAUSALITY ASSESSMENT ..................................................................................................................................................35
10.5 ACTION TAKEN WITH THE STUDY DRUG DUE TO AN AE.....................................................................................................35
10.6 OTHER ACTIONS TAKEN .....................................................................................................................................................35
10.7 OUTCOME ..........................................................................................................................................................................35
10.8 RECORDING ADVERSE EVENTS..........................................................................................................................................36
10.9 REPORTING SERIOUS ADVERSE EVENTS TO CHIESI ...........................................................................................................36
10.10 REPORTING SERIOUS ADVERSE EVENTS TO REGULATORY AUTHORITIES/ETHICS COMMITTEES.....................................37
10.11 GENERAL NOTES..............................................................................................................................................................37
11.
DATA MANAGEMENT ...................................................................................................................................................38
12.
STATISTICAL METHODS .............................................................................................................................................38
12.1 SAMPLE SIZE......................................................................................................................................................................38
12.2 POPULATIONS FOR ANALYSIS.............................................................................................................................................38
12.3 STATISTICAL ANALYSIS .....................................................................................................................................................39
13.
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD APPROVAL ..........................................................41
14.
REGULATORY REQUIREMENTS ...............................................................................................................................41
15.
INFORMED CONSENT ...................................................................................................................................................41
16.
SOURCE DOCUMENTS/DATA......................................................................................................................................42
16.1 RECORDING OF SOURCE DATA............................................................................................................................................42
16.2 DIRECT ACCESS TO SOURCE DOCUMENT/DATA ..................................................................................................................42
17.
STUDY MONITORING....................................................................................................................................................42
18.
QUALITY ASSURANCE..................................................................................................................................................43
19.
INSURANCE AND INDEMNITY....................................................................................................................................43
20.
CONFIDENTIALITY........................................................................................................................................................43
21.
PREMATURE TERMINATION OF THE STUDY.......................................................................................................43
22.
CLINICAL STUDY REPORT..........................................................................................................................................44
23.
RECORD RETENTION ...................................................................................................................................................44
24.
PUBLICATION OF RESULTS........................................................................................................................................44
25.
REFERENCES...................................................................................................................................................................44
APPENDIX 1 - APPROVAL OF THE PROTOCOL BY CLINICAL INVESTIGATOR(S)..............................................47


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1.
INTRODUCTION
1.1 Background information
The 2019 novel coronavirus (SARS-COV-19) has spread rapidly since its recent identification 
in patients with severe pneumonia in Wuhan, China.
The World Health Organization (WHO) on March 11 declared COVID-19 a pandemic, 
highlighting the sustained risk of further global diffusion.
The COVID-19 pandemic threatens patients, societies and healthcare systems around the world. 
Host immunity determines the progress of the disease and its lethality. The associated cytokine 
storm mainly affects the lungs, leading to acute lung injury of variable severity [1][2][3][4][5].
In epidemiological Chinese studies 17% -29% of hospitalised patients developed ARDS [6][7].
For COVID-19 patients treated on ICU, a mortality rate of 30–70% is expected. For older 
patients with ARDS, this mortality rate is comparable to other severe pulmonary infections 
[1][3][5][8][9].
The acute respiratory distress syndrome (ARDS) is a clinical syndrome defined by acute onset 
hypoxemia (PaO2:FiO2 ratio < 300) and bilateral pulmonary opacities not fully explained by 
cardiac failure or volume overload [10]. The Berlin consensus definition of ARDS, like the 
American-European Consensus definition that preceded it, has enabled clinicians and 
researchers alike to prospectively identify patients with ARDS, implement lung protective 
ventilation strategies, and enrol patients in clinical trials. ARDS remains under-recognized 
clinically, however; therapies are limited, and mortality remains high [10]. Under-recognition of 
ARDS may stem in part from the considerable clinical heterogeneity observed among patients 
who meet standard ARDS criteria. The syndrome may be triggered, for example, by pulmonary 
or extrapulmonary sepsis, aspiration, trauma, blood product transfusion, or pancreatitis [11]. 
Pulmonary infiltrates can be focal or diffuse. Hypoxemia can range from mild to severe, and 
duration of respiratory failure can be brief or prolonged. Many of these clinical variations may 
reflect underlying biological differences between ARDS patients that are now recognized as 
important drivers of treatment response and ultimate outcomes [12].
1.2 Study rationale
Chiesi Farmaceutici S.p.A intends to conduct a proof of concept study with its porcine derived 
surfactant, Curosurf® - poractant alfa (porcine surfactant), in ventilated adult patients who are 
critically unwell in intensive care.
Curosurf® is a pulmonary surfactant of natural origin which, when delivered endotracheally 
(ET), compensates for the deficiency of endogenous pulmonary surfactant that causes neonatal 
Respiratory Distress Syndrome (RDS) in babies [13]. Curosurf® is supplied as a saline 
suspension of alveolar surface phospholipid extracted from porcine lung; it consists of 99% polar 
lipids (mainly phospholipids with variable R substituents) and 1% hydrophobic low molecular 
weight proteins (surfactant associated protein SP-B and SP-C). 
The Curosurf® formulation allows uniform distribution within the lungs and spreading of the 
phospholipids at the air-liquid interface in the alveoli; hence, it reduces alveolar surface tension, 
prevents alveolar collapse and enables gas exchange and alveolar ventilation at low 


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transpulmonary pressures [14]. Curosurf® was developed by Curstedt and Robertson at the 
Karolinska Institute of Stockholm and licensed to Chiesi Farmaceutici S.p.A. It is currently 
approved for marketing as treatment of premature neonates with respiratory distress syndrome 
(RDS) or at risk of RDS (see SmPC and investigator’s brochure). ARDS in COVID-19 has 
clinical and lung pathophysiological similarities with newborn RDS (in which there is an 
alveolar collapse due to surfactant-deficiency due to immature alveolar type II epithelial cells 
[15][16]). In COVID-19, damage to the alveolar epithelial type II cells is caused by the viral 
infection and inactivation of surfactant results from the host inflammatory reaction.
It has been known that, the novel Coronavirus SARS-COV-19, invades human cells via the 
receptor angiotensin converting enzyme II (ACE2). Moreover, lung alveolar epithelial type 2 
cells that have high ACE2 expression may be the main target cells during SARS-COV-19 
infection. Evidence, obtained through scRNA-seq data analyses, has shown that the organs at 
risk, (such as lung, heart, oesophagus, kidney, bladder, and ileum), with their located specific 
cell types (i.e., type II alveolar cells (AT2), myocardial cells, proximal tubule cells of the kidney, 
ileum and oesophagus epithelial cells, and bladder urothelial cells), are vulnerable to SARS-
COV-19infection [17]. Damage to the type II alveolar cells leads to surfactant depletion and the 
ensuing inflammation, inactivates existing surfactant leading to loss of alveolar stability and 
impaired pulmonary compliance.
This hypothesis has been confirmed from histopathological autopsy findings from patients who 
died from COVID-19 showed lung lesions, including alveolar exudate, inflammation and hyaline 
membranes formation similar to that classically seen in surfactant deficiency in the newborn 
[18].
This  study is targeted, to a specifically selected population of patients with SARS-CoV 19 ARDS, 
offering  a potential efficacious treatment during a public health emergency, whilst simultaneously, 
addressing the mistakes of previous surfactant studies due to heterogenous ARDS types and, non-
standardised treatment application [19][20][21][22][23].
This protocol will consider only COVID patients on invasive MV for less than 48 hours, with a 
PaO2/FiO2 < 150mmHg and lung compliance < 45ml/cmH2O; a well- defined treatment scheme has 
been identified in terms of dose and administration as early as possible after intubation.
Recently [24], the need for conducting such a study was highlighted. It is true that these patients are 
well managed by assisted ventilation, but surfactant deficiency increases the alveolar surface tension 
and generates a low-pressure area in the interstitial space, during inspiration. This area attracts liquid 
and substances which are often inflammatory and which organize over time, giving rise to surfactant 
inactivation and interstitial pneumonia. These phenomena could potentially be prevented by 
surfactant replacement therapy.
Exploratory mechanistic assessment rationale
As presented above, the rationale behind the proposed trial of surfactant therapy for COVID-19 
patients requiring ventilator support, is that endogenous surfactant is dysfunctional. This could 
be due to decreased concentration of surfactant phospholipid and protein, altered surfactant 
phospholipid composition, surfactant protein proteolysis and/or oedema protein inhibition of 


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surfactant surface tension function as a consequence of inflammation. However, there is no 
empirical evidence to establish any of these mechanisms. Mechanistic approaches to address 
unanswered questions are set out below.
This study aims to address the following questions:  

Is the concentration/composition of pulmonary surfactant phospholipid and protein 
altered in patients with COVID-19? Surfactant phosphatidylcholine (PC) is enriched in 
dipalmitoyl PC (DPPC) and phosphatidylglycerol (PG). ARDS patients exhibit altered 
percentage composition of surfactant PC, with decreased DPPC and increased surface 
tension-inactive unsaturated species, and decreased concentrations of both total PC and 
PG.  Anti-inflammatory surfactant proteins SP-A and SP-D concentrations are decreased 
in a variety of inflammatory lung diseases including cystic fibrosis, chronic obstructive 
lung disease and severe asthma, with increased SP-D concentration in plasma. 
Additionally, proteolytic fragments of SP-D are detected in lung infections- are they in 
COVID-19?

Are the surface tension-lowering properties of BAL/ tracheal suction derived surfactant 
airway sampling impaired?

Does viral infection decrease synthesis of surfactant phospholipid and protein by ATII 
cells?

What are the features of the inflammatory response in COVID-19 infection? 

Does surfactant therapy modulate the immune/inflammatory response?

Does exogenous administration of surfactant combat the inhibitory activity of plasma 
proteins and the inflammatory reaction on endogenous surfactant function?
1.3 Risk/benefit assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of porcine surfactant (Curosurf®), when used in neonates, may be found in the 
Investigator’s Brochure of the drug.
The choice of dosing is based on prior beneficial adult ARDS studies [25][26][27][28], and the rapid 
pharmacodynamic response that would be expected if underlying surfactant inhibition or deficiency 
is a feature of COVID-19 disease. 
Although adult ARDS trials have had some high-profile failures, investigation of fluid dynamic 
modelling and review of the original studies that showed efficacy suggests that larger fluid volumes 
and distal intrabronchial drug delivery are likely to be advantageous and may maximize alveolar 
surfactant delivery [29].
This trial will be conducted in compliance with the Declaration of Helsinki (1964 and amendments) 
current ICH E6 Good Clinical Practices and all other applicable laws and regulations.
2.
STUDY OBJECTIVES
2.1 Primary Objective(s)
To evaluate the efficacy and safety of poractant alfa (porcine surfactant, Curosurf®), 
administered by endotracheal (ET) instillation, in terms of ventilatory free days during the 21 
days after randomization, in adult patients with ARDS due to SARS-COV-19infection. 


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2.2 Secondary Objective(s)
To evaluate the efficacy and safety of poractant alfa administered by ET Instillation compared to 
control group, in terms of oxygenation (PaO2 / FiO2), FiO2, free days from invasive and non-invasive 
mechanical ventilation, length of ICU stay, mortality at 28 days, SOFA score (overall organ -failure 
measurement), incidence of AEs, vital signs and laboratory parameters. 
2.3 Exploratory Objective(s)
To investigate possible mechanism that could impact on surfactant functionality in COVID-19 
infected patients requiring ventilator support: decreased concentration of surfactant phospholipid and 
protein, altered surfactant phospholipid composition, surfactant protein proteolysis and/or oedema 
protein inhibition of surfactant surface tension function as a consequence of inflammation. 
These assessments will be done on closed suction deep tracheal aspirate (TA) samples and 
inflammatory indices such as cellular and cytokine inflammatory markers e.g. IL-1, IL-6, TNF alpha, 
IFN gamma and lymphocyte markers) from TA and blood samples before the first surfactant dose, 
after 12, 24, 48, 72, 96 hrs and corresponding timepoints in the control group after randomisation. 
Surplus bronchoalveolar lavage fluid collected for diagnostic clinical reasons will also undergo 
analysis when available.
These exploratory parameters will be assessed only for UK patients enrolled in the study. Given the 
current pandemic situation and the samples delivery procedures within 48h, it has been deemed 
appropriate to avoid additional burden for US sites.
3.
STUDY DESIGN
This clinical plan is written at the time of the coronavirus pandemic during which in some countries 
(e.g. UK) the number of people who get infected or hospitalized for respiratory complication may be 
dramatically high. Therefore, the clinical and operational scenario is extremely variable, and it is 
expected that it will remain so for an unforeseeable time. In addition, limited evidence is available on 
the course of the disease and on the significance of intermediate end-points, before the use of the 
experimental drug.
It is therefore anticipated in advance that the present protocol may need amendments to comply with 
evolving knowledge on the pandemic, the rate of complications, and the therapeutic scenario for 
patients who develop ARDS
3.1 Study design
This is a multi-center, open-label, randomised study that includes a group of patients treated with 
poractant alfa and a control group on standard of care (SOC). Curosurf® represents an adding therapy, 
potentially beneficial on top of the current standard of care in intubated SARS-COV-19 patients. 
Besides respiratory support, standard of care includes possible treatments under efficacy evaluation: 
i.e. antiviral drugs, monoclonal antibodies.
The study will be conducted in approximately 7 UK and USA Intensive Care Units (ICU). 
 Forty-two (42) patients with ARDS due to SARS-COV-19 will be randomised in the poractant alfa 
treated group and 28 patients randomised in the control one. 


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3.2 End of trial definition
A participant is considered to have completed the study if he/she has completed the last scheduled 
procedure shown in the schedule of assessments: follow up at Day 28. The end of the study is defined 
as the date of the last follow up visit at Day 28 for the last participant in the trial globally.
Some recruited and treated patients are likely to be transferred during the study period from the ICU 
to another hospital department for continuation of their clinical care. In this case the patient will 
remain in the study and relevant data will still be recorded through review of the medical chart or by 
phone call by the Investigator to the physician of the other department. Similarly checks for the 
occurrence of any adverse event as well as of any change in relevant concomitant medications will 
be made and recorded.
4.
PATIENT SELECTION CRITERIA
4.1 Patient Recruitment
The evaluation of the patients will occur in the screening phase and reviewed to confirm that potential 
participants meet eligibility criteria. The investigator will maintain a screening log to record details 
of all participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
The inclusion of a diverse population helps to ensure that medical products are safe and effective for 
everyone; for this reason, the enrolment of populations most affected by COVID-19, specifically 
racial and ethnic minorities is encouraged.
4.2 Inclusion Criteria 
Participants are eligible to be included in the study if the following criteria apply:
1. Male or female ≥18 and ≤ 80 years of age 
2. Informed consent for participation in the study (refer to section 15  for detailed informed 
consent procedure) 
3. Positive SARS-COV-19 rt-PCR before randomisation
4. PaO2/FiO2 ratio < 150 mmHg
5. Lung compliance ≤45 ml/cmH20
6. Intubated and artificially ventilated less than 48 hours before the first poractant alfa 
administration
4.3 Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Any contraindications to surfactant administration e.g., pulmonary haemorrhage and 
pneumothorax) 
2. Weight < 40kg 
3. Stage 4 severe chronic kidney disease (i.e., eGFR < 30)
4. Pregnancy 
5. Administration of any nebulized surfactant in the 48 hours before the first poractant alfa 
administration 
6. Extracorporeal membrane oxygenation  


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4.4 Patient Withdrawals
Patients must be discontinued from the study for any of the following reasons:

The patient or the patient’s representative withdraws the consent 

The patient is lost to follow-up. 

The sponsor or the regulatory authorities or the Ethics Committee(s), for any reason, 
terminates the entire study, or terminates the study for this trial site or this particular 
patient. 
It is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable.
Should a patient withdraw from the study, all efforts will be made to complete and report the 
observations as thoroughly as possible.
Patient who discontinues study treatment should not be considered automatically withdrawn from the 
study (except if the reason is consent withdrawal or lost to follow up). The investigator and study 
staff must discuss with the patient (or with the patient’s representative) asking to continue attending 
the remaining study visits even though the treatment has been terminated prematurely.
In case of withdrawal, the Investigator must fill in the “Study Termination” page in the CRF reporting 
the main reason for withdrawal.   
5.
PATIENT CONCOMITANT MEDICATIONS
5.1 Permitted concomitant Medications
Concomitant treatments are allowed. 
Concomitant medications in a critically ill SARS-COV19 population are numerous, and may change 
daily are consequently difficult to collect, and are unlikely, to be related to therapeutic success or 
safety evaluations. Therefore, only selected concomitant medications will be specifically recorded in 
this trial:  
1. Antiviral drugs; 
2. Monoclonal antibodies;  
3. Antibiotics; 
4. Systemic corticosteroids; 
5. Heparin or any other anticoagulants;   
6. Plasma administration from immunized patients; 
7.
Nitric Oxide therapy; 
8. Any other treatments for pneumonia/ARDS/SARS COVID 19 ARDS; 
9.
Medications prescribed to treat adverse events (AEs).
The list of medications will be assessed only from intubation to Day 28 or until discharge whichever 
is earlier.
5.2 Non-permitted concomitant Medications
None.


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6.
TREATMENT(S)
The study medications will be supplied to the clinical site under the responsibility of the Sponsor, 
who will also provide the Pharmacist/Investigator with appropriate certificates of analytical 
conformity.
6.1 Appearance and Content
6.1.1
Poractant alfa (Curosurf®)
Poractant alfa (Curosurf®) is a standard natural surfactant treatment prepared from porcine lungs for 
endotracheal 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.
6.2 Dosage and Administration 
6.2.1
Selection of doses in the study
The choice of the poractant alfa (Curosurf®) dose for this study is based on prior beneficial adult 
ARDS studies [25][26][27][28] and the rapid pharmacodynamic response that would be expected if 
underlying surfactant inhibition or deficiency is a feature of COVID-19 disease. 
Although adult ARDS trials have had some high-profile failures, investigation of fluid dynamic 
modelling and review of the original studies that showed efficacy,  suggests that larger fluid volumes 
and distal intrabronchial drug delivery are likely to be advantageous and to maximize alveolar 
surfactant delivery [29].
6.2.2
Dosage
The poractant alfa (Curosurf®) dose used in the study will consist of poractant alfa boluses: 30mg / 
kg (Lean Body Weight-LBW) = 0.375ml /kg LBW. (LBW calculated according to Hume formula) 
[30]. 
Diluted with normal saline up to approximately 2ml /kg LBW (for details refer to CTS Instruction 
for use). 
6.2.3
Administration
Before treatment, patients transiently will receive 100% oxygen.
Poractant alfa boluses, 30 mg per kilogram of lean body weight, will be administered through a sterile 
syringe connected to an opaque catheter inserted into the endotracheal tube with the distal end 
approximately 
1cm 
above 
the 
carina.
The first half of the dose will be administered during a pause in mechanical ventilation in which PEEP 
will be maintained and the patient will be in the left or right lateral decubitus position, and the second 
half will be administered similarly 5 minutes lateral, with the patient in the opposite lateral decubitus 
position [20].
When possible, tube suctioning should be avoided for 3 hours after the administration.
Patients will receive a total of three administrations, 24 hours apart.
For details on study medication dosage and administration please refer to the IMP Management 
manual.
6.2.4
Patient Training
Not applicable.


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6.3 Packaging 
Chiesi Farmaceutici S.p.A. will supply the study medication for the study to the investigational sites.
Single labelled glass vial of 3 ml each of Curosurf® will be packed in a labelled box. 
6.3.1
Primary packaging
Labelled glass vial, with a blue topper, of 3 ml volume at a concentration of 80 mg/ml.
6.3.2
Secondary packaging
Labelled box containing one labelled glass vial of 3 ml volume.
6.3.3
Tertiary packaging 
Not applicable.
6.4 Labelling 
All labelling will be in local language and according to local law and regulatory requirements and 
will be compliant with Annex 13 to the Volume 4 of the GMP.
6.5 Treatment allocation
Balanced block randomisation scheme stratified by site will be prepared via a computerised system 
by the Statistics and Data Management Department of Chiesi Farmaceutici S.p.A. Separate 
randomisation list will be prepared for each site. 
The randomisation will assure a 3:2 ratio between poractant alfa arm and control arm in each cohort 
(i.e., 42 subjects in poractant alfa and 28 subjects in control arm).
The randomisation numbers will consist of 4-digit numbers ranging from 1001 to 2000.
Patients will be sequentially assigned the lowest available randomisation number. Replacements are 
not expected.
6.6 Treatment Code
Study drug will be packaged and uniquely numbered. Each primary packaging in the medication kit 
will have a numbered label that matches the kit number on the label of the outside packaging. 
This is an open-label study.
An individual randomization code envelope will be supplied to the Investigator for each patient and 
will contain the assignment treatment group for that patient.  The Investigator will keep the treatment 
code envelopes in a locked, secure storage facility. Allocation of each patient to the assigned 
treatment group will be performed after opening the individual envelope associated with the lowest 
randomisation number. 
6.7 Treatment compliance
The effective doses of study drugs received by each participant during the study will be recorded in 
the eCRF.
6.8 Drug Storage 
The Pharmacist/Investigator or delegated research team will be responsible for the safe storage of all 
medications assigned to this study, in a secure place with restricted access, and maintained within the 
appropriate ranges of temperature.


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Curosurf® will have to be stored between 2˚ and 8˚C, protected from light (please refer to - CTS 
Instructions for use).
6.9 Drug Accountability
The Investigator, or the designated/authorized representative, is responsible for the management of 
all the study medications to be used for the study. Study medications that should be stored in a locked, 
secure storage facility with access limited to those individuals authorized to dispense the study 
medications.
An inventory will be maintained by the Investigator or pharmacist (or other designated individual), 
to include a signed account of all the study medication(s) received, dispensed and returned by each 
patient during the trial. 
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 will be given for any 
discrepancies.
All the study medications supplied, used or unused, will be returned to Chiesi or to the designated 
CRO under Sponsor’s responsibility or destroyed directly from the Investigator by the centre. In this 
case, a destruction certificate must be asked to the investigational centre and filed both at site and at 
Sponsor. Return and destruction will not occur until authorized by Chiesi.
7.
STUDY PLAN
7.1 Study Schedule 
ICU stay period
ICU discharge
Last FUP
Poractant 
alfa treated 
group
Screening7
Day 1
(Randomi
sation) 
Day 2
Day 3
Day 4 – 27
Day X
Day 28
Before randomisation/treatment and 
6-12-24h after each administration
up to 72 hours
Every 24h 
till ICU 
discharge
Whenever it 
occurs
Control group
Screening
Time 72 h
Day 4 – 27
Day X
Day 28
Before randomisation and at 6, 12, 24, 
30, 36, 48, 54, 60, 72 h since 
randomisation 
Every 24h 
till ICU 
discharge
Whenever it 
occurs
Assessments
Informed 
consent
X
Inclusion and 
exclusion 
criteria
X
Demography
X


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ICU stay period
ICU discharge
Last FUP
Poractant 
alfa treated 
group
Screening7
Day 1
(Randomi
sation) 
Day 2
Day 3
Day 4 – 27
Day X
Day 28
Before randomisation/treatment and 
6-12-24h after each administration
up to 72 hours
Every 24h 
till ICU 
discharge
Whenever it 
occurs
Control group
Screening
Time 72 h
Day 4 – 27
Day X
Day 28
Before randomisation and at 6, 12, 24, 
30, 36, 48, 54, 60, 72 h since 
randomisation 
Every 24h 
till ICU 
discharge
Whenever it 
occurs
Vital signs 
(blood 
pressure, heart 
rate)
X
Once
Treated group: 24 - 48 - 72h 
post start of treatment
Control group: 24 - 48 - 72h 
post randomisation
X
X
X
Full physical 
examination 
including 
height and 
weight
X
Medical 
history (SARS 
COVID-19 
ADRS, past 
and current 
relevant 
medical 
conditions)
X
Arterial Blood 
Gas (ABG) 
Analysis1
 X (If the 
screening 
assessment is 
done just 
before 
randomization 
no need to 
repeat the 
assessment)
Treated group: Before randomisation 
and 6-12-24h after each administration 
up to 72 hours
Control group: Before randomisation 
and at 6, 12, 24, 30, 36, 48, 54, 60, 72h 
since randomisation
Every 24h
X
Once if not 
discharged 
from ICU
Respiratory 
support 
assessment 
Ventilator 
parameters2
 X (If the 
screening 
assessment is 
done just 
before 
randomization 
no need to 
repeat the 
assessment)
Treated group: Before randomisation 
and 6-12-24h after each administration 
up to 72 hours
Control group: Before randomisation 
and at 6, 12, 24, 30, 36, 48, 54, 60, 72h 
since randomisation
Every 24h
X
Once if not 
discharged 
from ICU


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ICU stay period
ICU discharge
Last FUP
Poractant 
alfa treated 
group
Screening7
Day 1
(Randomi
sation) 
Day 2
Day 3
Day 4 – 27
Day X
Day 28
Before randomisation/treatment and 
6-12-24h after each administration
up to 72 hours
Every 24h 
till ICU 
discharge
Whenever it 
occurs
Control group
Screening
Time 72 h
Day 4 – 27
Day X
Day 28
Before randomisation and at 6, 12, 24, 
30, 36, 48, 54, 60, 72 h since 
randomisation 
Every 24h 
till ICU 
discharge
Whenever it 
occurs
Mechanics 
Laboratory 
assessments3
Treated group: Before randomisation 
and 12, 24, 48, 72, after first 
administration
Control group: Before randomisation 
and 12, 24, 48, 72, after randomisation
Treated 
group: 96h 
after first 
administrati
on
Control 
group: 96h 
after 
randomisati
on
Laboratory 
assessments4
 X
Once
Treated 
group: 
24h post last 
treatment
Control 
group: 
72h post 
randomisation
X
Once if not 
discharged 
from ICU
SOFA score5
X
Once
Treated 
group: 
24h post last 
treatment
Control 
group: 
72h post 
randomisation
X
Once if not 
discharged 
from ICU
Thoracic CT 
scan or Chest 
XR6
X
Curosurf 
administration 
(intreated 
group)
Three ET administrations with a 
24 hours interval (Day 1, Day 2 
and Day 3)
Concomitant 
Medications
X
X
X
X
X
X
X


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ICU stay period
ICU discharge
Last FUP
Poractant 
alfa treated 
group
Screening7
Day 1
(Randomi
sation) 
Day 2
Day 3
Day 4 – 27
Day X
Day 28
Before randomisation/treatment and 
6-12-24h after each administration
up to 72 hours
Every 24h 
till ICU 
discharge
Whenever it 
occurs
Control group
Screening
Time 72 h
Day 4 – 27
Day X
Day 28
Before randomisation and at 6, 12, 24, 
30, 36, 48, 54, 60, 72 h since 
randomisation 
Every 24h 
till ICU 
discharge
Whenever it 
occurs
Adverse 
Events
X
X
X
X
X
X
X
Ventilatory 
support 
X
X
X
X
X
X
X
Concomitant 
procedures
X
X
X
X
X
X
X
- 1 Arterial blood gas (ABG) analysis: pH, pCO2, pO2, HCO3, lactate.
- 2 Ventilatory parameters: PaO2/FiO2, FiO2, TV (tidal volume), RR (respiratory rate), Cstat (static compliance), 
Cdyn (dynamic compliance), PEEP (positive end-expiratory pressure), PIP (peak inspiratory pressure), Pplat 
(plateau Pressure). 
-
3 For mechanics assessments: blood sampling and tracheal aspirates (TA). Bronchoscopic washings performed as 
clinically indicated only, with surplus samples retrieved for mechanistic study as available. They are planned only 
for patients recruited in UK. 
-
4 Blood count, bilirubin, creatinine, eGFR, glucose, AST, ALT, LDH, D-dimer, CRP (C-reactive protein), 
procalcitonin. Urine beta HCG at screening only. 
-
5 SOFA score is calculated considering PaO2/FiO2, Glasgow coma scale, mean arterial pressure, and bilirubin, 
platelet and creatinine levels. SOFA score can be calculated only after the patient is included in the study (after 
the ICF signature) and in case not all the SOFA parameters are available before randomization, the calculation can 
be based on historical data collected (within 24 hours) as per standard practice. 
- 6 Already available as part of the standard care procedures.
- 7 All screening procedures have to be completed/performed before the randomization. 
The following time deviations from theoretical post-dose times will be allowed: 
Post-dose time assessments 
Allowed deviations 
≤ 72 hours
± 1 hour
>72 hours 
± 2 hours
7.1.1
Screening and eligibility assessment 
Screening evaluations must be completed and reviewed to confirm that potential participants meet 
eligibility criteria. The investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable.


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Procedures conducted as part of the participant’s routine clinical management (e.g. blood count) and 
obtained before informed consent may be used for screening or baseline purposes provided the 
procedures meet the protocol-specified criteria. 
All screening procedures have to be completed/performed before the randomization. 
After verification of any inclusion/exclusion criteria, those intubated patients with ARDS due to 
COVID-19 will be included in the study.
Date of patient intubation and mechanical ventilation start time is recorded for both the groups.
The following assessment will be collected:
-
Informed consent for participation in the study (refer to section 15 for detailed informed 
consent procedure) 
-
Demographics 
-
Medical history (includes past and current relevant medical conditions)
-
Full physical examination including height and weight
-
Arterial Blood Gas (ABG) Analysis 
-
Ventilatory support
-
Ventilatory parameters: PaO2/FiO2, FiO2, tidal volume (TV), respiratory rate (RR), static 
compliance (Cstat), dynamic compliance (Cdyn), PEEP (positive end-expiratory pressure), 
PIP (peak inspiratory pressure), Plateau Pressure (Pplat). 
-
Laboratory assessments: blood count, bilirubin, creatinine, eGFR, LDH, D-dimer, CRP, 
procalcitonin and urine beta HCG (only for eligibility criteria). SARS-Cov-19 rtPCR (as 
available, at least before randomization)
-
Vital signs will be obtained as appropriate
-
SOFA score is calculated considering PaO2/FiO2, Glasgow coma scale, mean arterial 
pressure, and bilirubin, platelet and creatinine levels
-
Thoracic CT scan or Chest XR already available as part of the standard care  
-
AEs review (including SAEs)
-
Concomitant medications and procedure review
7.1.2
Day 1, Day 2 and Day 3 for treated group [up to 72 hours for control group]
On Day 1, within 48 hr after intubation, the patients will be randomised in the poractant alfa treated 
group or in the control one with the 3:2 ratio.
In case the patient will be assigned to the poractant alfa treated group, the treatment must start soon 
after the randomization (max 2 hr), and within 48hr after intubation
The following procedures for treated group or for control group will be conducted according to the 
frequencies reported in the above flowchart:
-
Treatment procedure for poractant alfa as described in detail in section 6.2. One 
administration per day with a 24 hours interval
-
Arterial Blood Gas (ABG) Analysis 
-
Ventilatory support
-
Ventilatory parameters: PaO2/FiO2, FiO2, tidal volume (TV), respiratory rate (RR), static 
compliance (Cstat), dynamic compliance (Cdyn), PEEP (positive end-expiratory pressure), 
PIP (peak inspiratory pressure), Plateau Pressure (Pplat)
-
Laboratory assessments for mechanistic analysis: blood sampling and bronchial washings; 
bronchoscopic washings performed as clinically indicated only, with surplus samples 
retrieved for mechanistic study as available (for more details ref. to section 7.2)


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-
Laboratory assessments: blood count, bilirubin, creatinine, eGFR, LDH, D-dimer, CRP, 
procalcitonin
-
Vital signs will be obtained as appropriate
-
SOFA score is calculated considering PaO2/FiO2, Glasgow coma scale, mean arterial 
pressure, and bilirubin, platelet and creatinine levels
-
AEs review (including SAEs)
-
Concomitant medications and procedure review as applicable
7.1.3
Day 4 – 27 recording: 
The following procedures for treated group or for control group will be conducted according to the 
above flowchart 
-
Arterial Blood Gas (ABG) Analysis
-
Ventilatory support: extubation date recorded (as applicable) and following ventilation 
procedures recorded
-
Ventilatory parameters: PaO2/FiO2, FiO2, tidal volume (TV), respiratory rate (RR), static 
compliance (Cstat), dynamic compliance (Cdyn), PEEP (positive end-expiratory pressure), 
PIP (peak inspiratory pressure), Plateau Pressure (Pplat)
-
Vital signs will be obtained as appropriate
-
AEs review (including SAEs)
-
Concomitant medications and procedure review as applicable
-
Discharge date from ICU if applicable
-
Laboratory assessments for mechanistic analysis (only at 96h): bronchial washings, and 
blood samples, bronchoscopic washings performed as clinically indicated only, with surplus 
samples retrieved for mechanistic study as available (for more details ref. to section 7.2).  
They are planned only for patients recruited in UK
7.1.4
 ICU discharge (Day X – whenever it occurs)
-
Arterial Blood Gas (ABG) Analysis
-
Ventilatory support: extubation date recorded (as applicable) and following ventilation 
procedures recorded
-
Ventilatory parameters: PaO2/FiO2, FiO2, tidal volume (TV), respiratory rate (RR), static 
compliance (Cstat), dynamic compliance (Cdyn), PEEP (positive end-expiratory pressure), 
PIP (peak inspiratory pressure), Plateau Pressure (Pplat)
-
Laboratory assessments blood count, bilirubin, creatinine, eGFR, LDH, D-dimer, CRP, 
procalcitonin 
-
Vital signs will be obtained as appropriate
-
SOFA score is calculated considering PaO2/FiO2, Glasgow coma scale, mean arterial 
pressure, and bilirubin, platelet and creatinine levels
-
AEs review (including SAEs)
-
Concomitant medications and procedure review as applicable
-
Discharge date from ICU
7.1.5
Day 28
It’s the last day of follow up. Whenever the patient has been discharged home from ICU a phone call 
FUP is requested.
The following procedures will be followed if the patient is still hospitalized:
-
Arterial Blood Gas (ABG) Analysis


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-
Ventilatory support: extubation date recorded (as applicable) and following ventilation 
procedures recorded
-
Ventilatory parameters: PaO2/FiO2, FiO2, tidal volume, respiratory rate, static compliance 
(Cstat), dynamic compliance (Cdyn), PEEP (positive end-expiratory pressure), PIP (peak 
inspiratory pressure), Plateau Pressure 
-
Laboratory assessments: blood count, bilirubin, creatinine, eGFR, LDH, D-dimer, CRP, 
procalcitonin
-
Vital signs will be obtained as appropriate
-
SOFA score is calculated considering PaO2/FiO2, Glasgow coma scale, mean arterial 
pressure, and bilirubin, platelet and creatinine levels
-
AEs review (including SAEs)
-
Concomitant medications review as applicable
7.2 Investigations
The following samples for laboratory assessments need to be taken for a combination of main trial 
assessments and mechanistic studies. 
7.2.1
Laboratory assessments 
7.2.1.1 Blood Sample Collection (as per study schedule 7.1) 
Blood samples (10 mls EDTA and 9 mls for Transfix) will be taken at intubation start as screening 
evaluation, then 24h after last treatment for poractant alfa group and 72h after randomization for 
control group. Then at Day 28 or at ICU discharge whichever occurs earlier. In particular:
-
Laboratory analysis: blood count, bilirubin, creatinine, eGFR, glucose, AST, ALT, LDH, 
D-dimer, CRP, procalcitonin
-
Arterial blood gas (ABG) analyses: approximately (~1 ml) of blood sample for the analysis 
of pH, pCO2, pO2, HCO3, lactate will be taken at screening, before randomisation and 6,12, 
24h after each administration up to 72 hours for poractant alfa group; before randomisation 
and at 6, 12, 24, 30, 36, 48, 54, 60, 72h after randomisation for control group. Then every 
24 hours until day 28 or ICU discharge whichever occurs earlier
-
Mechanistic blood laboratory analysis: inflammatory indices such as cellular and cytokine 
inflammatory markers and lipid mediators before randomisation and 12, 24, 48, 72, 96h 
after first administration (while hospitalised) and relative timepoints in the control group 
since randomization. These analyses are planned only in the UK subpopulation
7.2.1.2 Urine pregnancy test 
Urine will be tested for β HCG at screening for female of childbearing potential. As patients will not 
have the capacity to confirm their medical history in relation to their childbearing potential and this 
information may not be available in their medical notes, investigator discretion will be used to confirm 
whether pregnancy testing is required.  
7.2.2
Closed suction tracheal aspirate (TA) samples 
Closed suction tracheal aspirate (TA) samples will be taken before the first surfactant dose and after 
12, 24, 48, 72, 96h and relative timepoints in the control group since randomisation.
The subsequent samples will be used for the mechanistic studies outlined above (section 2) and will 
assess the efficacy of surfactant administration. 
The TA samples will consist of blind suctioning by a cannula introduced through a port into the 
endotracheal tube. A volume of 20-50 ml saline will be administered, with an estimated recovery of 
8-10 ml. This procedure will not interrupt the ventilator circuit and will not result in desaturation. 


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Blind suctioning following the administration of small volumes of saline is routine practice for the 
clearance of secretions in ventilated patients.
7.2.3
Laboratories involved
The above-mentioned analysis is a part of the standard care for these patients and will be carried out 
by local hospital laboratories. Specific assessments concerning to the mechanistic investigations will 
be performed at the University College London laboratory and at Imperial College, London.
The sample collection, processing storage and shipment for analysis will be described in a laboratory 
manual.
These exploratory parameters will be assessed only on UK patients enrolled in the study. Given the 
current pandemic situation and the samples delivery procedure within 48h, it has been deemed 
appropriate to avoid additional burden for American sites.
Surfactant lipid composition and concentration (University College London)
Mass spectrometric analysis of molecular species compositions of phosphatidylcholine (PC), 
sphingomyelin (SM), phosphatidylglycerol (PG) and phosphatidylinositol (PI) in small volume BAL 
samples.  It would be expected a reduced surfactant concentration and altered composition in baseline 
samples taken immediately before surfactant administration. These would both change after 
surfactant is given, and the aim is to assess the ratio of exogenous to endogenous surfactant from 
these two different compositions [31][32]. 
Analysis of sequential samples will provide an indication of exogenous surfactant turnover. Liquid 
Chromatography with Mass spectrometric analyses will also be performed to establish corresponding 
lipidomic profiles of matching plasma and airway samples, that will include analyses of related lipid 
species and lipid derived inflammatory mediators.
Surfactant function (Imperial College, London)
Surfactant function will be determined by measuring surfactant adsorption to the air: liquid interface 
in a Langmuir trough. The tensioactive properties of lung surfactant from patients’ BAL will be 
measured. It will be investigated whether isolated surfactant will have compromised function by the 
inhibition of plasma proteins, and whether the function can be recovered after administration of 
supplemented surfactant. Maximum reduction of the surface tension over continuous compression: 
expansion cycles models the physiological breathing cycles of intubated patients and will be carried 
out on a captive bubble surfactometer or similar device. Adsorption analysis of the equilibrium 
surface tension, together with kinetics of the process, will explore inhibition processes in surfactant 
function.
Immunological and inflammatory assessment (University College London)
Immune cellular components will be profiled to depth and soluble fluids for soluble mediators 
including those that imply a bacterial or fungal co-infection. The volume needed would depend on 
the concentration of the cellular component. Fixed blood will be split into 3 and then to each, a 
cocktail of antibodies will be added to enumerate all T cell subsets and markers of their subtype and 
activation. B cell subsets and their antibody isotype will also be investigated. The proportions of cells 
identified will be compared to normal ranges within each age group. We will be specifically looking 
at the neutrophil to lymphocyte ratio that is described to be inverted in patients with the disease. Mast 
cell activation may play an important role in the adverse host response and this will be assessed by 
the measurement of lipid mediators such as leukotrienes and prostaglandins in airway samples and 
blood. Multiplex cytokine analysis on tracheal aspirates and blood will characterize the impact of 
surfactant therapy on the inflammatory cytokine storm.


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The level of the immunomodulatory surfactant protein D (SP-D) in serum has shown to be a 
promising biomarker for lung inflammation (and hence low levels in BAL), and we will quantify the 
level of SP-D in both BAL and plasma using our established ELISA. We will also quantify the level 
of C-reactive protein in BAL as a biomarker for blood contamination of surfactant together with total 
protein concentration. We have seen that an inflammatory response to infections can results in 
specific degradation dependent on the infectious agent. We will analyse the degradation of SP-D and 
its sister protein SP-A using SDS-PAGE and Western Blot analysis to evaluate if COVID-19 infection 
results in degradation. 
8.
EFFICACY ASSESSMENTS
Primary Endpoint
The primary outcome variable will be the number of days alive and ventilator-free defined as the 
number of days the patient is alive and not receiving mechanical ventilation over the 21 days 
following randomisation. 
Mechanical ventilation will be defined as invasive and non-invasive. Patient will be defined free of 
mechanical ventilation after 12 hours from the suspension of either invasive and non-invasive 
ventilation. Patients who die or are mechanically ventilated longer than this period are assessed as 
zero ventilator-free days.
Key secondary endpoint

Percentage of patients alive and free of respiratory failure (i.e., need for mechanical 
ventilation, ECMO, non-invasive ventilation, or high-flow nasal cannula oxygen delivery) 
at Day 28
Secondary endpoints

Number of days alive and ventilator-free at Day 28

Mortality at Day 21 and Day 28

Number of days alive and free from invasive ventilation at Day 21 and Day 28

Number of days alive and free from non-invasive ventilation (NIV) at Day 21 and Day 28

Percentage of patients with improvement in severity status defined as a decrease in the 
severity score at Day 28 or Discharge, whichever comes first. Severity score will be 
defined as Mild, Moderate, Severe or Death based on PaO2/FiO2 ratio and patient status 
at Day 28 and numerically rated from 1-4 respectively:
Severity
Variable
Criteria
Mild -1
PaO2/FiO2 Ratio
200 mmHg < PaO2/FIO2 ≤ 300 mmHg
Moderate - 2
PaO2/FiO2 Ratio
100 mmHg < PaO2/FIO2 ≤ 200 mmHg
Severe - 3
PaO2/FiO2 
Ratio PaO2/FIO2 ≤ 100 mmHg
Death - 4
Patient Status
Yes/No

Change from baseline in PaO2/FiO2 ratio at 6 and 12 hours following administration of 
each dose in the treated group and at the similar timepoints in the control group (6, 12, 30, 
36, 54 and 60 hours after randomisation) 


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
Change from baseline in PaO2/FiO2 ratio at additional timepoints (i.e. every 24 hours after 
treatment/randomisation until the patient is discharged from the ICU)  

Percentage of patients alive and with PaO2/FiO2 improvement of >20% at 6 and 12 hours 
following administration of each dose in the treated group and at similar timepoints in 
the control group (6, 12, 30, 36, 54 and 60 hours after randomisation) 

Percentage of patients alive and with PaO2/FiO2 improvement of >20% at the additional 
timepoints (i.e. every 24 hours after treatment/randomisation till the patient is discharged 
from the ICU)  

Change from baseline in FiO2 at 6 and 12 hours following administration of each dose 
in the treated group and at similar timepoints in the control group (6, 12, 30, 36, 54 and 60 
hours after randomisation) 

Change from baseline in FiO2 at additional timepoints (i.e. every 24 hours after 
treatment/randomisation until the patient is discharged from the ICU)  

Length of ICU stay (days) at Day 28. Patients who die or are mechanically ventilated 
longer than this period are assigned with 28 days

Percentage of patients alive and out of ICU at Day 28

Delta SOFA Score and sub-score component measured on Day 3 and Day 28 or Discharge 
whichever comes first 

Percentage of patients alive and organ failure free (SOFA score=0) at Day 28 or Discharge 
whichever comes first

Change from baseline in ventilatory parameters [tidal volume (TV), respiratory rate (RR), 
dynamic compliance (Cdyn), static compliance (Cstat), positive end-expiratory pressure 
(PEEP), peak inspiratory pressure (PIP), plateau pressure (Pplat)] measured at 6-12-24h 
after each poractant alfa administration up to 72 hours and at similar timepoints in the 
control group (6, 12, 24, 30, 36, 48, 54, 60 and 72 hours after randomisation) and then 
every 24 hours till the patient is discharged from the ICU

Change from baseline in blood gas analysis acid-base balance parameters (i.e. pH, pCO2, 
pO2, HCO3, lactate) measured at 6-12-24h after each poractant alfa administration up to 
72 hours and at similar timepoints in the control group (6, 12, 24, 30, 36, 48, 54, 60 and 72 
hours after randomisation) and then every 24 hours till the patient is discharged from the 
ICU
Exploratory endpoints 
The following parameters will be measured only on UK patients at 12, 24, 48, 72 and 96 hrs after 
start of treatment (first dose in the poractant alfa group) or after randomisation (in the control group):

Change from baseline in lowest and dynamic surface tensions (mN/m) from TA samples

Change from baseline in concentrations of surfactant phospholipids (mg/ml) and proteins 
(ng/ml) from TA samples

Change from baseline in inflammatory indices such as cellular and cytokine (pg/ml) 
inflammatory markers (e.g. IL-1, IL-6, TNF alpha, IFN gamma and lymphocyte markers) 
from TA and blood samples


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9.
SAFETY ASSESSMENTS

Adverse events (AEs)

Laboratory Parameters (Blood count, bilirubin, creatinine, LDH, D-dimer, PRC, 
procalcitonin)

Vital Signs (Blood pressures and heart rate)
10. 
ADVERSE EVENT REPORTING
10.1
Definitions
An Adverse Event is “any untoward medical occurrence in a patient or clinical trial patient 
administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment”.
An adverse event can therefore be any unfavourable and unintended sign (including abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal 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 a medicinal 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 considered if it 
is 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.
-
Is life-threatening
Life-threatening refers to an event in which the patient was at risk of death at the time of the event. 
The term does not refer to an event which hypothetically might have caused death if it were more 
severe.
-
Requires hospitalisation or prolongation of existing hospitalisation
Hospitalization refers to a situation whereby an AE is associated with unplanned formal 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 hospitalisation are AEs. If a complication prolongs 
hospitalisation, 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).


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As the enrolled patients will already be hospitalized at inclusion and during the first weeks of the 
study the above definition relating to hospital admissions and emergency room attendance will not 
be relevant during that inpatient period.
-
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 patient’s physical or psychological well-being to the extent that the patient is 
unable to function normally.
-
Is a congenital anomaly or birth defect
-
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 hospitalisation may jeopardise the patient’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 hospitalisation; or development 
of drug dependency or drug abuse.
Medical and scientific judgment should be exercised in deciding whether an event is serious because 
and 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.
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 section 6.3.1.1 of the Curosurf® 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 Reference Safety Information would be considered as 
“unexpected”. Examples of such events are: (a) acute renal failure as a labelled 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
Each Adverse Event must be rated on a 3-point scale of increasing intensity:

Mild:  The event causes a minor discomfort or patient does not lead to either modification 
of test treatment dosage or establishment of a correcting treatment

Moderate: The event leads to a temporary interruption of the test treatment administration 
or to the establishment of a correcting treatment (local or non-invasive)

Severe:  The event causes severe discomfort. It may be of such severity to cause the 
definitive interruption of test treatment and invasive treatment


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10.4
Causality Assessment
The following “binary” decision choice will be used by the Investigator to describe the causality 
assessment:

Reasonable possibility of a relatedness

No reasonable possibility of relatedness
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 and event’s onset

Dechallenge (did the event abate after stopping drug?)

Rechallenge (did the event reappear after reintroduction?)

Medical history

Study treatment(s)

Mechanism of action of the study drug

Class effects

Other treatments-concomitant or previous

Withdrawal of study treatment(s)

Lack of efficacy/worsening of existing condition

Erroneous treatment with study medication (or concomitant)

Protocol related process
It should be emphasized that ineffective treatment should not be considered as causally related in the 
context of AE reporting.
10.5
Action taken with the study drug due to an AE

Dose not changed

Drug permanently withdrawn

Not applicable
10.6
Other actions taken

Specific therapy/Medication

Concomitant Procedure
10.7
Outcome
Each Adverse Event must be rated by choosing among:

Recovered/resolved

Recovering/resolving


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
Not recovered/not resolved

Recovered with sequelae/resolved with sequelae

Fatal

Unknown
10.8
Recording Adverse Events
All Adverse Events occurring during the course of the study must be documented in the Adverse 
Event page of the electronic Case Report Form (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) 
derived by spontaneous, unsolicited reports of patients, by observation and by routine open 
questionings.
For the purpose of this trial, “acute renal failure” occurrences will not be considered and recorded as 
adverse events, since well described as a part of the COVID19 syndrome, and highly prevalent in the 
involved population. They will be recorded as adverse events only if assessed as cause of patient’s 
death.
The recording period for Adverse Events is the period starting from the date of screening until the 
patient’s study participation ends.
Clinically significant abnormalities detected at study entry not due to a pre-existing condition or 
clinically significant changes at the following visits in the medical opinion of the investigator must 
be reported as adverse events in the eCRF.
If a clinically significant abnormal laboratory finding or other abnormal assessment meets the 
definition of an AE, 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 AE eCRF page. If no diagnosis is known and 
clinical signs and symptoms are not present, then the abnormal finding should be recorded.
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 patient 
is lost to follow-up. Follow-up may therefore continue after the patient 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. 
10.9
Reporting Serious Adverse Events to Chiesi
The Investigator must report all Serious Adverse Events in the SAE Form and provide it to the 
 email: 
, fax: 
, within 24 
hours of awareness. The information must be sent by providing the completed Serious Adverse Event 
form. At a later date, the 
 Safety Contact will report all information to Chiesi Global 
Pharmacovigilance, the Clinical Project Manager and the Clinical Research Physician. 


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Name and Title
Telephone no.
Fax no.
E-mail
 
Safety Contact
 
 
 
Chiesi Safety Contact

Reporting of SAEs from the investigator site is from the time of screening and until the 
patient’s study participation ends. After this date, even if no active monitoring of patients 
is required, SAEs occurring to a patient should be reported if the investigator becomes 
aware of them. 

Up to the closure of the site, SAE reports should be reported to the 
 Safety 
Contact. New serious adverse events occurring after the site is closed should be reported 
directly to the Chiesi Safety Contact.
10.10 Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees/IRBs
The Sponsor or designated CRO will report adverse events to the regulatory authorities/ethics 
committees in compliance with the timelines and standards of reporting according to local UK 
regulations and according to the US “Guidance for industry and Investigators-Safety Reporting 
Requirements for INDs and BA/BE studies, December 2012”.  
Investigators and Central IRB will be informed as well in case of SUSARs.
With regard to regulations in force for Pharmacovigilance, the Investigator must fulfil his/her 
obligation according to the law in force in his country. 
10.11 General Notes

In case of death, a comprehensive narrative report of the case should be prepared by the 
Investigator and sent to the 
 Safety Contact within the Serious Adverse 
Event form.

If an autopsy is performed, copy of autopsy report should be actively sought by the 
Investigator and sent to the 
 Safety Contact as soon as available, 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 
patient’s data must be redacted.

If a patient is transferred to another hospital department for continuation of their clinical 
care, the investigator should ensure that the receiving department is aware that the patient 
is participating to the present study and communication should be maintained in order to 
timely record any adverse event. 

In case of pregnancy, the patient will be immediately withdrawn from the study and she 
will be followed with due diligence until the outcome of the pregnancy is known and till 
the age of one year of the child to detect any congenital anomaly or birth defect. The 
pregnancy must be reported by the investigator within 24 hours by e-mail to the 
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provided upon request. The 
 Safety Contact will inform Chiesi of the 
pregnancy within one working day of being notified. 

If the pregnancy’s outcome meets the criteria for immediate classification of a SAE (e.g. 
spontaneous or therapeutic abortion, stillbirth, neonatal death, congenital anomaly, birth 
defect) the Investigator should follow the procedure for reporting SAEs.
11.
DATA MANAGEMENT
An electronic CRF (
) will be filled-in by the Investigator and/or his/her 
representative designee. Screening failure data won’t be recorded in the eCRF.
Front-end edit checks will run at the time of data collection and back-end edit checks will be used by 
the Data Manager to check for discrepancies and to ensure consistency and completeness of the data. 
Medical history, adverse events and concomitant procedures will be coded using the MedDRA 
dictionary; medications will be coded using the WHO Drug dictionary and Anatomical Therapeutic 
Chemical classification (ATC). 
External data (laboratory assessments for mechanics assessments) will be processed centrally, sent to 
the designated CRO and reconciled with the corresponding information recorded in the CRF.
Access to electronic systems used for data collection will be granted to the study personnel only after 
appropriate training. 
After the completion of data collection and cleaning, a review meeting will be held to determine the 
occurrence of any protocol violation and to define the patient populations for the analysis. Once the 
database has been declared to be complete and accurate, it will be locked and the planned statistical 
analysis will be performed. 
If the database is unlocked after the initial lock, the process must be carefully controlled and 
documented; updates to the study data must be authorized by Chiesi. 
At the study conclusion, a complete copy of the study data will be created for archival purposes at 
Chiesi. The investigators will receive copies of the patient data for retention at the investigational 
sited documented; updates to the study data must be authorized by Chiesi. 
12.
STATISTICAL METHODS
12.1
 Sample Size
A total of 70 patients will be randomised in the study with a ratio 3:2 (i.e. 42 patients randomised to 
the poractant alfa group and 28 in the control group). Assuming patients in the control arm being free 
from ventilation on average 1 week (i.e. 7 days), this sample size achieves 84% power to detect a 
difference of 4 days (i.e. on average 11 ventilation-free days for patients treated with poractant alfa), 
assuming a standard deviation of 5.5 and a two-sided significance level (alpha) of 0.05 using a two-
sample t-test. 
12.2
Populations for analysis

Intention-to-Treat population (ITT): all randomised patients (analysed as randomised).

Safety population: all randomised patients and receive at least one dose of the study 
treatment (Curosurf treated patients) (analysed as treated).
The primary analysis population for efficacy will be the ITT. The Safety population will be used in 
the analysis of all safety variables.


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12.3
Statistical analysis
A detailed statistical analysis plan will be described in the Statistical Analysis Plan. The plan might 
be reviewed and updated as a result of the data review and will be finalized before database lock. 
Intercurrent Events
Death and Early discontinuation from study drug can be anticipated as intercurrent events: 
-
Death will be incorporated as a failure outcome for binary endpoints using composite 
strategy;
-
Early discontinuation from study drug will be handled using treatment policy strategy: all 
data collected after discontinuation from study drug till Day 28 or death will be included;
-
Change in respiratory parameters will be analysed using while-alive strategy.
12.3.1 Descriptive Statistics 
General descriptive statistics for numeric variables will include the n (number of observed values), 
the mean, the standard deviation, the median, the minimum, and the maximum values. For categorical 
variables, the number and percent of patients 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. Other critical missing data, if any, will be discussed during the review of the data before 
database lock and decisions will be fully documented in the Data Review Report.
12.3.3 Patient demographics and baseline characteristics
Demographics and baseline variables will be summarized separately in each cohort by treatment 
group using descriptive statistics for the ITT population.
12.3.4 Primary efficacy variable 
Number of ventilator-free days during the 21 days after randomisation will be compared between 
groups by using an ANOVA model including treatment group, age and country as factors. Patients 
who die or are mechanically ventilated longer than this period are assessed as zero ventilator-free 
days.
12.3.4.1 Key secondary variable 
Percentage of patients alive and free of respiratory failure (i.e., need for mechanical ventilation, 
ECMO, non-invasive ventilation, or high-flow nasal cannula oxygen delivery) at Day 28 will be 
analysed using logistic regression including treatment group, age and country as factor. Difference in 
the proportion and related 95% confidence interval will be estimated from the model.
12.3.5 Secondary efficacy variables

Number of days alive and free from ventilation at Day 28, number of days alive and free 
from invasive and non-invasive ventilation at Day 21 and Day 28 will be compared 
between groups by using an ANOVA model including treatment group, age and 
country as factors.

Mortality at Day 21 and Day 28 will be compared by groups using logistic regression 
including treatment group, age and country as factors. Difference in the proportions and 
related 95% confidence interval will be estimated from the model.

Percentage of patients with improvement in severity status defined as a decrease in the 


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severity score at Day 28 or Discharge, whichever comes first, will be compared by groups 
using logistic regression including treatment group, age and country as factors. Difference 
in the proportions and related 95% confidence interval will be estimated from the model.

Change from baseline in PaO2/FiO2 at 6 and 12 hours after each treatment and relative 
timepoints in the control group will be compared between groups using an ANCOVA 
model including group, age and country as fixed effect and baseline value as covariate. The 
same analysis will be performed at each additional timepoint.

Percentage of patients alive and with PaO2/ FiO2 improvement of >20% at 6 and 12 hours 
following administration of each dose in the treated group and at similar timepoints in 
the control group will be compared by groups using logistic regression including treatment 
group, age and country as factors. Difference in the proportions and related 95% confidence 
interval will be estimated from the model.  Patients who die are considered as a failure. 
The same analysis will be performed at each additional timepoints.

Change from baseline in FiO2 will be analysed as PaO2/FiO2.

Length of ICU stay (in days) at Day 28 will be compared between groups using ANOVA 
model including group, age and country as fixed effect. Patients who die or are 
mechanically ventilated longer than this period are assigned with 28 days.

Percentage of patients alive and out of ICU at Day 28 using logistic regression including 
treatment group, age and country as factors. Difference in the proportions and related 95% 
confidence interval will be estimated from the model.

Delta SOFA Score and sub-score components at Day 3 and Day 28 or Discharge, 
whichever comes first, will be analysed at each timepoint using ANCOVA model 
including group, age and country as fixed effect and baseline value as covariate.

Percentage of patients alive and organ failure free (SOFA score=0) at Day 28 or 
Discharge, whichever comes first will be compared by groups using logistic regression 
including treatment group, age and country as factors. Difference in the proportions and 
related 95% confidence interval will be estimated from the model.

Change from baseline in ventilator parameters (TV, RR, Cdyn, Cstat, PEEP, PIP, Pplat) 
will be summarized by means of descriptive statistics or frequency distribution, as 
appropriate by group at each timepoint.

Change from baseline in BGA acid-base balance parameters (i.e. pH, pCO2, pO2, HCO3, 
lactate) will be summarized by means of descriptive statistics by group at each timepoint.
12.3.6 Exploratory Efficacy Variables
Exploratory parameters from TA aspirates and blood samples will be summarized only in the 
subgroup of UK patients both as absolute values and as change from baseline values by treatment 
group at each timepoint using descriptive statistics. 
12.3.7 Safety variables
Adverse Events
The number of patients who experienced at least one AE, AEs related to poractant alfa (treated group) 
(ADRs), serious AEs (SAEs) and AEs leading to death will be summarized by group. Summaries 
will be presented overall (number and percentage of patients having at least one event, total number 
of events) and by system organ class and preferred term (number and percentage of patients having 
at least one occurrence of that event). 


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All adverse events will be listed.
Vital Signs
Vital sign values and their change from baseline will be summarized by group at each timepoint using 
descriptive statistics. 
Laboratory data
Laboratory parameters and their change from baseline will be summarized by group at each timepoint 
using descriptive statistics. 
All laboratory data will be listed.
12.3.8 Interim analysis
Interim analysis not planned.
13.
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD APPROVAL 
The study proposal will be submitted to the Research Ethics Committee/HRA/MHRA and IRB/FDA 
in accordance with the requirements in England and US. 
The REC//HRA/MHRA and IRB/FDA 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 REC/HRA and IRB will be provided to the Sponsor.  
The Investigator should provide written reports to the REC/HRA/MHRA and IRB annually or more 
frequently if requested on any changes significantly affecting the conduct of the trial and/or increasing 
risk to the patients (according to the requirements of each country).
14.
REGULATORY REQUIREMENTS
The study will be notified to the Health Authorities (or authorized by) according to the legal 
requirements in each participating country.  
Selection of the patients will not start before the approval of the Ethics Committee/Institutional 
Review Board has been obtained and the study notified to Health Authorities (or authorized by).
15.
INFORMED CONSENT 
It is the responsibility of the Investigator to obtain informed consent/eConsent for each patient before 
performing any trial related procedure by using the latest REC/HRA or IRB approved version of the 
document.
It is not expected that patients considered for enrolment in this study will have the capacity to consent 
to take part due to the nature of the underlying disease process, as they will be under sedation and 
will be mechanically ventilated. 
Regarding UK sites, if the patient is incapable of giving informed consent, consent should be sought 
from the patient’s personal legal representative. This person must not be connected with the conduct 
of the trial and must be suitable to act as the legal representative by virtue of their relationship with 
the patient and is available and willing to do so (e.g. a friend or relative). In the case that the patient’s 
personal legal representative is not available to provide consent, without a delay that would, in the 
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consent should be sought from a professional legal representative. This person is identified, according 
to the UK regulations, as a person not connected with the conduct of the trial, who may be the doctor 
primarily responsible for the medical treatment of the patient or a person nominated by the institution
Regarding USA sites, if the patient is incapable of giving informed consent it must be obtained from 
their legally authorized representatives.
For both the USA and UK population, if a patient is consented to the study by a third party (according 
to the requirements set out in this section above) and they regain capacity, it is expected that the 
participant is informed and provides their consent to continue participation in the trial. 
This consent from the patient to remain in the study from the patient should be sought as soon the 
condition of the patient will allow it.
The same procedure applies to processing of personal data of the patient and providing of consent to 
the processing of personal data according to the European Regulation n. 2016/679 on the Protection 
of Personal Data, the Personal Data Protection Act 2018 and subsequent amendments and additions, 
the provisions and guidelines of the National Data Protection Authorities, as well as any other 
applicable data protection laws and regulations.
Each patient’s or acceptable third party’s signed informed consent(s) must be kept on file by the 
Investigator. One copy must be given to the patient or the person consenting on their behalf. 
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 electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents. 
16.2
Direct access to source document/data
The Investigators or designated must permit trial-related monitoring, audits, Ethics 
Committee/Institutional Review Board review or regulatory inspection, providing direct access to 
source data/documents.
17.
STUDY MONITORING
Monitoring will be performed by the CRO 
 who has been designated by Chiesi.
It is understood that the monitor(s) will contact and visit the Investigator/centre 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 patient confidentiality is respected.
The purposes of these visits are:

To assess the progress of the study;

To review the compliance with the study protocol;


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
To discuss any emergent problem;

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 case report forms. 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.
Given the current pandemic situation the proper approaches will be implemented remotely to allow 
the performance of the monitoring activities.
18.
QUALITY ASSURANCE
The R&D Quality Assurance Department of Chiesi 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 the protocol. 
19.
INSURANCE AND INDEMNITY 
Chiesi holds and will maintain an adequate insurance policy covering damages arising out of Chiesi’s 
sponsored clinical research studies.
Chiesi 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.
The Investigator must notify Chiesi 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.
The Investigator must assure the patient’s anonymity will be maintained. The Investigator will keep 
a separate list with at least the initials, the patient’s study numbers, names, and 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.
21.
PREMATURE TERMINATION OF THE STUDY 
Both the Sponsor 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 Ethics 
Committee/Institutional Review Board providing the justification of premature ending or of the 
temporary halt.


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22.
CLINICAL STUDY REPORT
The clinical study report, including the statistical and clinical evaluations, shall be prepared and sent 
to the Coordinating Principal Investigator for agreement and signature.
At the end of the trial a summary of the clinical study report will be provided to all Ethics 
Committees/Institutional Review Boards, to the Competent Authority of the UK and USA concerned 
and to 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 before destroying any trial-related documentation. In 
addition, all patients’ medical records and other source documentation will be kept for the maximum 
time permitted by the institution.
24.
PUBLICATION OF RESULTS
Chiesi 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. 
Chiesi furthermore reserves the right to use such data for industrial purposes. 
In the absence of a Study Steering Committee, Investigators will inform Chiesi 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 
according to the relevant regulatory requirements. 
25.
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adults with Acute Respiratory Distress Syndrome? Am J Respir Crit Care Med. 2017;195: 
538-540
[30] Hume, R "Prediction of lean body mass from height and weight.". J Clin Pathol. 1966; 
19(4):389-91.
[31] Giambelluca S, Ricci F, Simonato M, Correani A, Casiraghi C, Storti M. Estimating the 
contribution of surfactant replacement therapy to the alveolar pool. An in vivo study based 
on 13C natural abundance in rabbits. Journal of Mass Spectrometry. 2018; 53(7):560-564  
[32] Giambelluca S, Ricci F, Simonato M, Vedovelli L, Traldi U, Correani A, Tracing 
exogenous surfactant in vivo in rabbits by the natural variation of 13 C. Respiratory 
research. 2019;20 (1),158. 


Clinical Study Protocol – Appendix 1
Clinical Study Code No.: CLI-050000-04
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APPENDIX 1 - Approval of the protocol by clinical investigator(s)


Clinical Study Protocol – Appendix 1
Clinical Study Code No.: CLI-050000-04
Version No.: 4.0
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Date:  02 MAR 2021
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MULTICENTER OPEN LABEL RANDOMISED TRIAL TO ASSESS THE EFFICACY 
AND TOLERABILITY OF PORACTANT ALFA (PORCINE SURFACTANT, 
CUROSURF®) IN HOSPITALIZED PATIENTS WITH SARS-COV-19 ACUTE 
RESPIRATORY DISTRESS SYNDROME (ARDS)
Product: Curosurf® 
Pharmaceutical Form: poractant alfa 
Approval of Clinical Study Protocol by the Coordinating Investigator (United Kingdom): 
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 Research 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 all participating patients and appropriately 
documented, prior to their 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 patients.
Coordinating Investigator’s Name: _____________________, MD
Centre No.: 
_____________________
Signature
     Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy


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MULTICENTER OPEN LABEL RANDOMISED TRIAL TO ASSESS THE EFFICACY 
AND TOLERABILITY OF PORACTANT ALFA (PORCINE SURFACTANT, 
CUROSURF®) IN HOSPITALIZED PATIENTS WITH SARS-COV-19 ACUTE 
RESPIRATORY DISTRESS SYNDROME (ARDS)
Product: Curosurf®  
Pharmaceutical Form: poractant alfa 
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 Research 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 all participating patients and appropriately 
documented, prior to their 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 patients.
Principal Investigator’s Name: ____________________, MD
Centre No.: 
__________________________
Signature
     Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy

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STATISTICAL ANALYSIS PLAN
STUDY CODE No.: CLI-050000-04 
Multicenter, open label, randomised trial to assess the efficacy and tolerability of poractant 
alfa (porcine surfactant, Curosurf®) in hospitalized subjects with SARS-COV-19 acute 
respiratory distress syndrome (ARDS) 
Version No.: 1.0 
Date: 27 July 2022 
Authors: 
, 
 Biostatistician , 
 
, 
 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. 
NCT number: NCT04502433


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Contents 
LIST OF ABBREVIATIONS ................................................................................................. 5 
1 
INTRODUCTION............................................................................................................ 8 
2 
STUDY DESIGN .............................................................................................................. 8 
3 
STUDY OBJECTIVES .................................................................................................. 12 
3.1 
PRIMARY OBJECTIVE ................................................................................................ 12 
3.2 
SECONDARY OBJECTIVES .......................................................................................... 13 
3.3 
EXPLORATORY OBJECTIVES ...................................................................................... 13 
4 
STUDY VARIABLES .................................................................................................... 13 
4.1 
EFFICACY VARIABLES............................................................................................... 13 
4.1.1 Primary Efficacy Variable ................................................................................... 13 
4.1.2 Secondary Efficacy Variables .............................................................................. 13 
4.1.3 Exploratory Efficacy Variables............................................................................ 15 
4.2 
SAFETY VARIABLES .................................................................................................. 15 
5 
SAMPLE SIZE ............................................................................................................... 15 
6 
ANALYSIS SET ............................................................................................................. 15 
6.1 
SAFETY SET .............................................................................................................. 16 
6.2 
INTENTION-TO-TREAT SET ....................................................................................... 16 
6.3 
OTHER POPULATIONS DEFINED FOR TABLES AND LISTINGS ..................................... 16 
7 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS ...................... 16 
7.1 
STATISTICAL SIGNIFICANCE ...................................................................................... 16 
7.2 
INTERCURRENT EVENTS ............................................................................................ 16 
7.3 
MULTIPLICITY ........................................................................................................... 16 
7.4 
HANDLING OF MISSING DATA ................................................................................... 17 
7.5 
COVARIATES ............................................................................................................. 18 
7.6 
INTERIM ANALYSES .................................................................................................. 18 
7.7 
EXAMINATIONS OF SUBGROUPS ................................................................................ 18 
7.8 
DESCRIPTIVE STATISTICS .......................................................................................... 18 
7.9 
DEFINITIONS ............................................................................................................. 18 
7.9.1 Baseline ................................................................................................................ 18 
7.9.2 Date of First and Last Study Medication Administration .................................... 19 
7.9.3 Study Day ............................................................................................................. 19 
7.9.4 Visit Dates ............................................................................................................ 19 
7.9.5 Duration of Adverse Events or Medications ........................................................ 19 
7.10 
DIARY DATA ............................................................................................................. 20 
7.11 
DATA RE-ALLOCATION AND DUPLICATION ............................................................... 20 
7.12 
EXCLUSION OF DATA FROM THE STATISTICAL ANALYSES ........................................ 20 
7.13 
LISTINGS ................................................................................................................... 20 
7.14 
CODING ..................................................................................................................... 20 
8 
STUDY POPULATION ................................................................................................ 20 
8.1 
DISPOSITION OF SUBJECTS AND DISCONTINUATIONS ................................................ 20 
8.1.1 Disposition of Subjects ......................................................................................... 20 


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8.1.2 Discontinuation from the Study ........................................................................... 21 
8.1.3 Protocol Deviations and Analysis Sets ................................................................ 21 
8.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................... 21 
8.2.1 Demographic and Baseline Characteristics ........................................................ 21 
8.2.2 SAS COVID-19 ARDS History ............................................................................. 22 
8.2.3 Other Baseline and Disease Characteristics ....................................................... 22 
8.3 
MEDICAL HISTORY AND CONCOMITANT DISEASES ................................................... 22 
8.4 
MEDICATIONS ........................................................................................................... 22 
8.5 
PROCEDURES ............................................................................................................ 23 
8.6 
COMPLIANCE ............................................................................................................ 24 
9 
EFFICACY ANALYSES .............................................................................................. 24 
9.1 
PRIMARY EFFICACY VARIABLE ................................................................................. 24 
9.2 
KEY SECONDARY EFFICACY VARIABLE .................................................................... 24 
9.3 
OTHERS SECONDARY EFFICACY VARIABLES ............................................................ 25 
9.3.1 Number of Days Alive and Ventilator-free at Day 28.......................................... 25 
9.3.2 Mortality at Day 21 and Day 28 .......................................................................... 25 
9.3.3 Number of Days Alive and Free from invasive and Non-Invasive ventilation at 
Day 21 and Day 28 .......................................................................................................... 25 
9.3.4 Improvement in Severity Status at Day 28 or Discharge ..................................... 26 
9.3.5 Change from Baseline in PaO2/FiO2 Ratio at each Timepoint After Treatment 26 
9.3.6 Percentage of Subjects with PaO2/FiO2 Ratio Improvement of >20% Compared 
to Baseline at each Timepoint After Treatment ............................................................... 26 
9.3.7 Change from Baseline in FiO2 at each Timepoint After Treatment..................... 27 
9.3.8 Length of ICU Stay at Day 28 .............................................................................. 27 
9.3.9 Percentage of Subjects Alive and Out of ICU at Day 28 ..................................... 27 
9.3.10 
Change from Baseline in SOFA Score ............................................................. 28 
9.3.11 
Percentage of Subjects Alive and Organ Failure Free (SOFA score=0) at Day 
28 or Discharge ............................................................................................................... 28 
9.3.12 
Change from Baseline in Ventilatory Parameters ........................................... 28 
9.3.13 
Change from Baseline in Blood Gas Analysis Parameters ............................. 28 
9.4 
EXPLORATORY EFFICACY VARIABLES ...................................................................... 28 
10 SAFETY ANALYSES ................................................................................................... 29 
10.1 
EXTENT OF EXPOSURE .............................................................................................. 29 
10.2 
ADVERSE EVENTS ..................................................................................................... 29 
10.3 
VITAL SIGNS ............................................................................................................. 30 
10.4 
LABORATORY PARAMETERS ..................................................................................... 30 
11 OTHER ANALYSES ..................................................................................................... 30 
12 CHANGES IN THE PLANNED ANALYSES FROM STUDY PROTOCOL ........ 30 
13 OUTPUT ......................................................................................................................... 31 
13.1 
SOFTWARE ................................................................................................................ 31 
13.2 
REPORTING CONVENTIONS ....................................................................................... 32 
13.2.1 
Treatment and Timepoints Descriptors ........................................................... 32 
13.2.2 
Decimal Places ................................................................................................ 32 
13.2.3 
Other Reporting Conventions .......................................................................... 34 
13.3 
FORMAT .................................................................................................................... 34 


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13.4 
QUALITY CONTROL ................................................................................................... 36 
14 SAS CODE ...................................................................................................................... 36 
15 REFERENCES ............................................................................................................... 36 
16 LIST OF TABLES, LISTINGS AND FIGURES ........................................................ 37 
16.1 
TABLES ..................................................................................................................... 37 
16.2 
LISTINGS ................................................................................................................... 52 
16.3 
FIGURES .................................................................................................................... 63 


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List of Abbreviations 
ADaM 
Analysis Dataset Model 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ARDS 
Acute Respiratory Distress Syndrome 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
Cdyn 
Dynamic Compliance 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
Cstat 
Static Compliance 
CRP 
C-Reactive Protein 
DBP 
Diastolic Blood Pressure 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
ET 
Endotracheal 
GCP 
Good Clinical Practice 
hrs 
Hours 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
ITT 
Intention-To-Treat 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
NIV 
Non-Invasive Ventilation 
PEEP 
Positive End-Expiratory Pressure 
PIP 
Peak Inspiratory Pressure 
Pplat 
Plateau Pressure 
PT 
Preferred Term 
RR 
Respiratory Rate 
rtPCR 
Real Time Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SARS 
Severe Acute Respiratory Syndrome 
SOC 
System Organ Class 
SOFA 
Sequential Organ Failure Assessment 
TA 
Tracheal Aspirate 
TEAE 
Treatment Emergent Adverse Event 
TV 
Tidal Volume 
UK 
United Kingdom 
vvECMO 
Veno-Venous Extracorporeal Membrane Oxygenation 


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WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 


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VERSION HISTORY 
Version 
Date 
Change History 
0.1 
07 Aug 2020 
Not Applicable 
0.2 
01 Oct 2020 
Updates following Chiesi review: Add of D21 
mortality description, modification of Safety 
population definition. 
0.3 (Stable 
version) 
08 Oct 2020 
Minor updates. 
0.4 
31 Aug 2021 
Update according to protocol amendment. 
Protocol 
(protocol 
version 
4.0, 
dated 
02March2021. 
-
The ECMO cohort has been removed
-
Central Laboratory assessments will be
performed only for UK patients
-
Allowed Time windows have been identified
and implemented
-
Clarify the inclusion of Death as intercurrent
event in the primary endpoint
-
Key secondary endpoint added to comply
with FDA request and guideline.
-
Additional timepoint for assessment added at
Day 28 in line with FDA guideline.
-
New endpoints added to incorporate Death
as intercurrent event in the evaluation
0.5 
29  Jun 2022 
 Simplification of the analyses planned due to a 
lower recruitment. Slight update on footnotes 
and reference listings. 
1.0 
27 July 2022 
Final version 


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1 Introduction 
This document presents the Statistical Analysis Plan (SAP) for Chiesi Farmaceutici S.p.A. 
protocol CLI-050000-04: Multicenter, open label, randomised trial to assess the efficacy and 
tolerability of poractant alfa (porcine surfactant, Curosurf®) in hospitalized subjects with 
SARS-COV-19 acute respiratory distress syndrome (ARDS). 
This analysis plan is based on the protocol (version 4.0), dated 02March2021 and the final 
electronic case report form (eCRF) (version 4.0) dated 03Jun2021.  
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. 
2 Study Design 
This is a phase 2- proof of concept, multicentre, open-label, randomised study that includes a 
group of subjects treated with poractant alfa and a control group on standard of care.  
Approximately 42 subjects with ARDS due to SARS-COV-19 will be randomized in the 
poractant alfa group and 28 subjects randomized in the control one.  
Date of randomisation is considered Day 1 for both groups. This study consists a total of 28 
days, as follows (refer to the Study Schedule in Table 1 for more details): 
•
Screening: from intubation to randomization (Day 1).
•
Treatment period:
o
For poractant alfa group: from Day 1 till Day 3. Subjects receive three poractant
alfa endotracheal administrations with a 24 hours interval.
o
For control group: standard of care from randomization on Day 1 till ICU
discharge.
•
Follow up period:
o
For poractant alfa group: from Day 4 to Day 28.
o
For control group: from ICU discharge to Day 28.
A participant is considered to have completed the study if he/she has completed the last 
scheduled procedure shown in the schedule of assessments, i.e., follow up at Day 28. The end 
of the study is defined as the date of the last follow up visit at Day 28 for the last participant in 
the trial. 
Some recruited and treated subjects are likely to be transferred during the study period from 
the ICU to another hospital department for continuation of their clinical care. In this case the 
subject will remain in the study and relevant data will still be recorded through review of the 
medical chart or phone call by the Investigator to the physician of the other department also to 
check the occurrence of any adverse event as well as of any change in relevant concomitant 
medications. 


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The study schedule (Table 1) summarizes the study assessments by study day. 
Table 1: Study Schedule 


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The following time deviations from theoretical post-dose times will be allowed: 
3 Study Objectives 
3.1 Primary Objective 
•
To evaluate the efficacy and safety of poractant alfa, (porcine surfactant, Curosurf®)
administered by endotracheal (ET) instillation in terms of ventilatory free days during


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the 21 days after randomization, in adult subjects with ARDS due to SARS-COV-19 
infection.  
3.2 Secondary Objectives 
•
To evaluate the efficacy and safety of poractant alfa administered by ET Instillation
compared to control group, in terms of oxygenation (PaO2/FiO2), FiO2, free days from
invasive and non-invasive mechanical ventilation, length of ICU stay, mortality at 28
days, SOFA score (overall organ -failure measurement), incidence of AEs, vital signs
and laboratory parameters.
3.3 Exploratory Objectives 
•
To investigate possible mechanism that could impact on surfactant functionality in
COVID-19 infected subjects requiring ventilator support: decreased concentration of
surfactant phospholipid and protein, altered surfactant phospholipid composition,
surfactant protein proteolysis and/or oedema protein inhibition of surfactant surface
tension function as a consequence of inflammation.
These exploratory parameters will be assessed only for UK subject enrolled in the
study. Given the current pandemic situation and the samples delivery procedures within
48h, it has been deemed appropriate to avoid additional burden for US sites.
4 Study Variables 
4.1 Efficacy Variables 
4.1.1 Primary Efficacy Variable 
The primary efficacy variable is the number of days alive and ventilator-free defined as the 
number of days the subjects is alive and not receiving mechanical ventilation over the 21 days 
following randomisation.  
Mechanical ventilation is defined as invasive and non-invasive. Subject is defined as free of 
mechanical ventilation after 12 hours from the suspension of either invasive or non-invasive 
ventilation. Subjects who die or are mechanically ventilated longer than this period are assessed 
as zero ventilator-free days. 
4.1.2 Secondary Efficacy Variables 
4.1.2.1 Key Secondary Efficacy Variable 
•
Percentage of subjects alive and free of respiratory failure (i.e., need for mechanical
ventilation, ECMO, non-invasive ventilation, or high-flow nasal cannula oxygen
delivery) at Day 28.
4.1.2.2 Others Secondary Efficacy Variables 
•
Number of days alive and ventilator-free at Day 28
•
Mortality at Day 21 and Day 28
•
Number of days alive and free from invasive ventilation at Day 21 and Day 28


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•
Number of days alive and free from non-invasive ventilation (NIV) at Day 21 and Day
28
•
Percentage of subjects with improvement in severity status defined as a decrease in the
severity score at Day 28 or Discharge, whichever comes first. Severity score will be
defined as Mild, Moderate, Severe or Death based on PaO2/FiO2 ratio and subject
status at Day 28 and numerically rated from 1-4 respectively:
•
Change from baseline in PaO2/FiO2 ratio at 6 and 12 hours following administration
of each dose in the treated group and at the similar timepoints in the control group (6,
12, 30, 36, 54 and 60 hours after randomisation)
•
Change from baseline in PaO2/FiO2 ratio at additional timepoints (i.e. every 24 hours
after treatment/randomisation until the subject is discharged from the ICU)
•
Percentage of subjects alive and with PaO2/FiO2 improvement of >20% at 6 and 12
hours following administration of each dose in the treated group and at similar
timepoints in the control group (6, 12, 30, 36, 54 and 60 hours after randomisation)
•
Percentage of subjects alive and with PaO2/FiO2 improvement of >20% at the
additional timepoints (i.e. every 24 hours after treatment/randomisation till the subject
is discharged from the ICU)
•
Change from baseline in FiO2 at 6 and 12 hours following administration of each
dose in the treated group and at similar timepoints in the control group (6, 12, 30, 36,
54 and 60 hours after randomisation)
•
Change from baseline in FiO2 at additional timepoints (i.e. every 24 hours after
treatment/randomisation until the subject is discharged from the ICU)
•
Length of ICU stay (days) at Day 28. Subjects who die or are mechanically ventilated
longer than this period are assigned with 28 days
•
Percentage of subjects alive and out of ICU at Day 28
•
Delta SOFA Score and sub-score component measured on Day 3 and Day 28 or
Discharge whichever comes first
•
Percentage of subjects alive and organ failure free (SOFA score=0) at Day 28 or
Discharge whichever comes first
•
Change from baseline in ventilatory parameters [tidal volume (TV), respiratory rate
(RR),dynamic compliance (Cdyn), static compliance (Cstat), positive end-expiratory
pressure (PEEP), peak inspiratory pressure (PIP), plateau pressure (Pplat)] measured at
6-12-24h after each poractant alfa administration up to 72 hours and at similar


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timepoints in the control group (6, 12, 24, 30, 36, 48, 54, 60 and 72 hours after 
randomisation) and then every 24 hours till the subject is discharged from the ICU 
•
Change from baseline in blood gas analysis acid-base balance parameters (i.e. pH,
pCO2, pO2, HCO3, lactate) measured at 6-12-24h after each poractant alfa
administration up to 72 hours and at similar timepoints in the control group (6, 12, 24,
30, 36, 48, 54, 60 and 72 hours after randomisation) and then every 24 hours till the
subject is discharged from the ICU
4.1.3 Exploratory Efficacy Variables 
The following parameters will be measured only on UK subjects at 12, 24, 48, 72 and 96 hrs 
after start of treatment (first dose in the poractant alfa group) or after randomisation (in the 
control group): 
•
Change from baseline in Surfactant Function measuring surface tension (mN/m) from
TA samples.
•
Change from baseline in Mass spec lipid analysis (%) from TA samples.
•
Change from baseline in Surfactant Protein D Enzyme Linked Immunosorbent Assay
(ng/mL) from TA samples.
•
Change from baseline in Surfactant Protein D Enzyme Linked Immunosorbent Assay
(ng/mL) from Blood samples.
4.2  Safety Variables 
•
Adverse events (AEs).
•
Laboratory parameters.
•
Vital signs (blood pressures and pulse rate).
5 Sample Size 
A total of 70 subjects will be randomised in the study with a ratio 3:2 (i.e. 42 subjects 
randomised to the poractant alfa group and 28 in the control group). Assuming subjects in the 
control arm being free from ventilation on average 1 week (i.e. 7 days), this sample size 
achieves 84% power to detect a difference of 4 days (i.e. on average 11 ventilation-free days 
for subjects treated with poractant alfa), assuming a standard deviation of 5.5 and a two-sided 
significance level (alpha) of 0.05 using a two-sample t-test.  
6 Analysis Set 
The definition of the analysis set is summarized below. A final agreement on the subjects to be 
included in or excluded from the analysis set will be reached during the review of the data 


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before database lock. Inclusions and exclusions from the analysis set will be fully documented 
in the Data Review Report.  
6.1 Safety Set 
All randomised subjects and receive at least one dose of the study treatment (Curosurf treated 
patients) (analysed as treated). The Safety Set will be used for all safety analyses. 
6.2 Intention-To-Treat Set 
All randomised subjects who have at least one post baseline efficacy data analysed as 
randomised. The ITT Set will be used for all efficacy analysis. 
6.3 Other Populations Defined for Tables and Listings 
For the purposes of tables and listings the following population is defined: 
•
Enrolled Set: all subjects who have a signed informed consent for the study.
Note: the informed consent can be signed by subject himself when feasible or, in case of 
unconscious subject, by a third party (legal representative or by the physician only) according 
to  the local regulations and the pre-defined rules suitable for a trial conducted at Intensive Care 
Units. In case the subject is consented to the study by a third party and they regain capacity, 
the participant was informed and their consent was requested to continue the participation in 
the trial. 
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, if applicable. 
7.2 Intercurrent Events 
Death and Early discontinuation from study drug can be anticipated as intercurrent events: 
•
Death will be incorporated as a failure outcome for binary endpoints using composite
strategy;
•
Early discontinuation from study drug will be handled using treatment policy strategy:
all data collected after discontinuation from study drug till Day 28 or death will be
included;
•
Change in respiratory parameters will be analysed using while-alive strategy.
7.3 Multiplicity 
No multiplicity adjustment will be performed. 


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7.4 Handling of Missing Data 
In general, except as described below, missing data will not be imputed. 
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. 
Other critical missing data, if any, will be discussed during the review of the data before 
database lock. Decisions will be fully documented in the Data Review Report. 
Medications: Missing/Incomplete Date 
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: 
1. Concomitant medication;
2. Maintained medication;
3. Prior medication.
Procedures: Missing/Incomplete Date 
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: 
1. Concomitant procedure;
2. Maintained procedure;
3. Prior procedure.


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Adverse Events (AEs): Missing/Incomplete Date 
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: 
1. Treatment emergent;
2. Pre-treatment.
Adverse Events (AEs): Missing Severity 
In case of missing severity, the severity will not be imputed and will be reported as 
“Missing”. For the table of TEAEs by maximum severity, the maximum severity will be 
considered as the maximum of the non-missing severities for the relevant subject and 
preferred term. 
7.5 Covariates 
Not applicable. All data will be summarized by means of descriptive statistics. 
7.6 Interim Analyses 
No interim analysis will be performed. 
7.7 Examinations of Subgroups 
Exploratory parameters from TA aspirates and blood samples will only be analysed for UK 
subjects. 
7.8 Descriptive Statistics 
General descriptive statistics for quantitative variables will include the n (the number of non-
missing values), the mean, the standard deviation (SD), the median, the minimum (min) and 
the maximum values (max).  
For categorical variables, the number (n) and percentage (%) of subjects with a specific level 
of the variable will be presented. 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 
treatment group. 
7.9 Definitions 
7.9.1 Baseline  
Baseline is defined as the last non-missing value available before randomisation (for control 
group)/first treatment dose (for poractant alfa group). 
Change from baseline will be derived as follows: 


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Assessment value at the timepoint - Assessment value at baseline 
7.9.2 Date of First and Last Study Medication Administration 
The date of first study medication administration is the earliest date of study medication 
administrated considering the eCRF data, corresponding to the date part of the variable 
RFXSTDTC in the study data tabulation model (SDTM) dataset DM. 
The date of last study medication administration is the latest date of study medication 
administrated considering the eCRF data, corresponding to the date part of the variable 
RFXENDTC in the study data tabulation model (SDTM) dataset DM. 
7.9.3 Study Day 
If not otherwise specified, all assessment days will be related to date of randomization. 
The randomization date is referred to as Day 1.  
•
If the date of the assessment is on or after the randomisation, then
Study Day = (date of assessment – randomisation date) + 1.
•
If the date of the assessment is prior to the randomisation, then
Study Day = (date of assessment – randomisation date).
7.9.4 Visit Dates 
For each visit, the variable SVSTDTC in the SDTM SV dataset will be considered as the visit 
date in all the algorithms and the listings. SVSTDTC corresponds to the minimum of all 
assessment dates performed for a visit. 
ATPT variable derived in ADaM datasets will be considered for the timepoint analyses. In the 
listings, --TPT variables of SDTM datasets will be used unless specified otherwise. 
For the end of randomized treatment date, if the visit end date (SVENDTC) is different from 
the visit start date (i.e. at least one day after) (SVSTDTC) and if the subject is still under 
randomized treatment, the end of randomized treatment date will be SVENDTC. 
7.9.5 Duration of Adverse Events or Medications  
The duration of an AE or medication will be calculated as follows: 
•
AE/Medication End date – AE/Medication Start date + 1 (when both dates are
completely known);
•
Date of study completion/discontinuation – AE/Medication Start date + 1 (when the
start date is fully known but the AE or medication still ongoing at the end of the trial):
in this case the duration will be presented as “>x” days in the listing rather than “x”
days;


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•
Missing (when the start date is incomplete or unknown, or when the AE or medication
ended but with an incomplete or unknown end date, or when the start date is greater
than date of study completion/discontinuation).
7.10 Diary Data 
Not applicable. Diary data are not collected in this study. 
7.11 Data Re-allocation and duplication 
In general, for by timepoint summaries, data recorded at the nominal timepoint will be 
presented. Data collected at unscheduled timepoints will be reviewed during the review of the 
data before database lock. Any re-allocation of unscheduled data will be described and justified 
in the Data Review Report, which will be finalized prior to database lock. In any case, listings 
will include scheduled, unscheduled and early discontinuation data. 
Duplicated data reported twice at 2 different timepoints will be reported only once in both 
listings and tables at the first occurrence for post dose/post randomization and the last 
occurrence for pre dose/ pre randomisation. 
7.12 Exclusion of Data from the Statistical Analyses 
All data collected in the database will be used in all statistical analyses. 
7.13 Listings 
All data collected in the eCRF will be presented in the individual listings. All listing will be 
presented for the ITT set (equal to the randomised set), unless otherwise specified. 
7.14 Coding 
Medical and surgical history, concomitant diseases, procedures and adverse events will be 
coded according to Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or 
higher. 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
version March 2020 or later. 
8 Study Population 
8.1 Disposition of Subjects and Discontinuations 
8.1.1 Disposition of Subjects 
The number of subjects screened, randomised will be presented by country, site and treatment 
group. 
A flow chart will be produced. 


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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. 
An individual subject listing will be provided for the disposition data. 
8.1.3 Protocol Deviations and Analysis Sets 
All important clinical deviations, including Good clinical Practice (GCP) ones, will be 
discussed during Data Review meeting to evaluate impact on analyses population and 
described in the Data Review Report.  
The following categories will be classified as important protocol deviations: 
•
Discontinuation
•
Inclusion/Exclusion Criteria
•
Informed Consent
•
Safety Reporting
•
Study Intervention
•
Trial Procedures
Other categories may be added and will be discussed during the DRM and documented in the 
DRR before the data base lock. 
All important clinical deviations will be summarized by treatment group and overall. 
The number of subjects included in the ITT set, in the Safety Set will be summarised for each 
treatment 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.  
8.2.1 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group and overall 
using descriptive statistics for ITT Set. These will include age, age category, gender, and 
childbearing potential or not, race, height, weight at baseline and body mass index (BMI) at 
baseline.  
Notes: 
-
BMI will be calculated as: weight (kg) / height (m²).
-
Age categories are: 18-64 (years); 65 + (years). All categories must be reported even if
there are no subjects under a particular category.
An individual subject listing will also be provided for demographic and baseline characteristics 
data. 


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8.2.2 SAS COVID-19 ARDS History 
Days between screening positive SARS-COV-19 rt-PCR test and start of intubation, days 
between ICU admission date and start of intubation, and SARS COVID-19 ARDS medication 
categories recorded at Screening Visit will be presented by treatment group and overall for 
Safety Set.  
In addition, SAS COVID-19 ARDS history data will be presented in an individual listing. 
Notes:  
-
Days between screening positive SARS-COV-19 rt-PCR test and start of intubation =
Start date of intubation – Date of screening positive SARS-COV-19 rt-PCR test + 1.
-
For subject with intubation done after ICU admission: Days between ICU admission:
date and start of intubation = Start date of intubation – Date of ICU admission + 1.
-
For subject with intubation done before ICU admission (transfer from another hospital):
Days between ICU admission date and start of intubation = Start date of intubation –
Date of ICU admission.
8.2.3 Other Baseline and Disease Characteristics 
The following baseline and disease characteristics parameters will be summarised using 
descriptive statistics by treatment group and overall based on ITT Set: 
•
Vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse
rate) at baseline;
•
Ventilatory parameters at baseline (PaO2/FiO2 ratio and FiO2);
•
SOFA score at baseline.
8.3 Medical History and Concomitant Diseases 
Medical/surgical history and concomitant diseases will be summarized by System Organ Class 
(SOC) and Preferred Term (PT), by treatment group and overall, using Safety Set.  
Notes: 
•
Medical/surgical history is defined as conditions in the medical/surgical history and
concomitant diseases eCRF form which are not ongoing at Screening (even if end date
is missing);
•
Concomitant diseases are defined as conditions in the medical/surgical history and
concomitant diseases eCRF form which are ongoing at Screening.
In addition, medical, surgical and concomitant diseases data will be listed. 
8.4 Medications 
Prior medications, medications maintained during the treatment period, and concomitant 
medications will be summarized by treatment group, using Safety Set through frequency 


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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.  
The medications will be classified according to the following rules: 
•
For poractant alfa group:
o
Prior medication: start date < date of first study medication administration and
stop date ≤ date of first study medication administration;
o
Medication maintained during the treatment period: start date < date of first
study medication administration and stop date > date of first study medication
administration or ongoing;
o
Concomitant medication: start date > date of first study medication
administration.
•
For control group:
o
Prior medication: start date < start date of randomization and stop date ≤ start
date of randomisation;
o
Medication maintained during the treatment period: start date < start date of
randomisation and stop date > start date of randomisation or ongoing;
o
Concomitant medication: start date > start date of randomisation.
8.5 Procedures 
Prior procedures, procedures maintained during the treatment period and concomitant 
procedures will be summarized (including intubation) by treatment group, using Safety Set 
through frequency distributions and percentages by SOC and PT.  
The procedures will be classified according to the following rules: 
•
For poractant alfa group:
o
Prior procedure: start date/time (if time is available) < date/time of first study
medication administration and stop date/time (if time is available) ≤ date/time
of first study medication administration;
o
Procedure maintained during the treatment period: start date/time (if time is
available) < date/time of first study medication administration and stop
date/time (if time is available) > date/time of first study medication
administration or ongoing;
o
Concomitant procedure: start date/time (if time is available) > date/time of first
study medication administration.
•
For control group:
o
Prior procedure: start date/time (if time is available) < start date/time of
randomization and stop date/time (if time is available) ≤ start date/time of
randomization;


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o
Procedure maintained during the treatment period: start date/time (if time is
available) < start date/time of randomization and stop date/time (if time is
available) > start date/time of randomization or ongoing;
o
Concomitant procedure: start date/time (if time is available) > start date/time of
randomization.
8.6 Compliance 
Not Applicable. 
9 Efficacy Analyses 
All the efficacy comparisons between the treatment groups will be based on the ITT Set.  
9.1 Primary Efficacy Variable 
The primary efficacy variable is the number of days alive and ventilator-free days, defined as 
the number of days the subject is not receiving mechanical ventilation over the 21 days 
following randomization. Mechanical ventilation is defined as invasive and non-invasive. 
Subject is defined free of mechanical ventilation after 12 hours from the suspension of either 
invasive or non-invasive ventilation. 
Subjects who die or are mechanically ventilated longer than this period are assessed as zero 
ventilator-free days. 
Notes: 
Subjects with at least 12 hours of suspension of ventilation either invasive or non-invasive 
ventilation will be flagged. Then duration will be calculated within the flagged subject’s subset, 
as below: 
-
Ventilator-free days = 21-[MAX (End date of invasive ventilation; End date of non-
invasive ventilation)] – Date of randomisation + 1.
Descriptive summaries of the number of ventilator-free days will be presented by treatment 
group. 
9.2 Key Secondary Efficacy Variable 
The key secondary efficacy variable is the percentage of subjects alive and free of respiratory 
failure (i.e., need for mechanical ventilation, ECMO, non-invasive ventilation, or high-flow 
nasal cannula oxygen delivery) at Day 28. 
Notes:  
The subject will be defined alive and free of respiratory failure if: 
•
On Patient Status form at “D28-FU” visit, the subject is still alive


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AND 
•
On Ventilatory Support form, if start date is not missing, max (end date) for any
ventilator type > date of “D28 – FU” visit
The percentage will be summarized. 
9.3 Others Secondary Efficacy Variables 
9.3.1 Number of Days Alive and Ventilator-free at Day 28 
First, within subject with a start date filled in the ventilator support form, subjects with at least 
12 hours of suspension of ventilation either invasive or non-invasive ventilation will be 
flagged. Then duration will be calculated within the flagged subject’s subset, as below: 
-
Ventilator-free days = 28-[MAX (End date of invasive ventilation; End date of non-
invasive ventilation)] – Date of randomisation + 1].
Subjects who die or are mechanically ventilated longer than this period are assessed as zero 
ventilator-free days. 
Number of ventilator-free days will be described at Day 28.  
9.3.2 Mortality at Day 21 and Day 28 
The number and proportion of deaths at Day 21 and Day 28 will be presented for both groups. 
9.3.3 Number of Days Alive and Free from invasive and Non-Invasive ventilation at 
Day 21 and Day 28 
For Day 21: 
First, subjects with at least 12 hours of suspension of ventilation will be flagged by type (i.e. 
one flag for Non-Invasive, and one for Invasive). Then duration will be calculated within the 
flagged subject’s subsets, as below: 
-
Invasive ventilation-free days = 21-(End date of invasive ventilation) – Date of
randomisation + 1].
-
Non-invasive ventilation-free days = 21-(End date of non-invasive ventilation) – Date
of randomisation + 1].
If subject never started a non-invasive ventilation then the value will be set to 21 days. 
For Day 28: 
First, subjects with at least 12 hours of suspension of ventilation will be flagged by type (i.e. 
one flag for Non-Invasive, and one for Invasive). Then duration will be calculated within the 
flagged subject’s subsets, as below: 
-
Invasive ventilation-free days = 28-(End date of invasive ventilation) – Date of
randomisation + 1].


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-
Non-invasive ventilation-free days = 28-(End date of non-invasive ventilation) – Date
of randomisation + 1].
If subject never started a non-invasive then the value will be set to 28 days. 
Subjects who die or are mechanically ventilated longer than this period are assessed as zero 
ventilator-free days. 
9.3.4 Improvement in Severity Status at Day 28 or Discharge 
The severity status will be based on the ventilatory parameters form for PaO2/FiO2 ratio at 
baseline and at Day 28 or Discharge (whichever comes first) and on Study Termination form 
for the death, according to the scale below: 
In case of multiple assessments done on same date, the last assessment will be taken into 
account for the severity status definition. 
The severity status, the number and percentage of subjects with an improvement (i.e. a decrease 
of at least one point of severity) from baseline to Day 28 or Discharge will be summarized. 
A shift table displaying the severity at baseline and at day 28 or Discharge will also be provided. 
9.3.5 Change from Baseline in PaO2/FiO2 Ratio at each Timepoint After Treatment 
Actuals values and change from baseline in PaO2/FiO2 ratio at 6 and 12 hours following each 
treatment medication administration and then each 24 hours till the subject is discharged from 
the ICU in the poractant alfa group and similar timepoints in the control group (defined as 6 
and 12 hours post randomization for Day 1, 30 and 36 hours post randomization for Day 2 and 
54 and 60 hours post randomization for Day 3 and then each 24 hours till the subject is 
discharged from the ICU) will be described by treatment group. 
A graph displaying the mean value and SD for each timepoint will be also provided for each 
treatment group. 
9.3.6 Percentage of Subjects with PaO2/FiO2 Ratio Improvement of >20% Compared 
to Baseline at each Timepoint After Treatment 
The number and percentage of subjects with PaO2/FiO2 ratio improvement of >20% compared 
to baseline at 6 and 12 hours following each dose administration and then each 24 hours till the 
subject is discharged from the ICU in the poractant alfa group and similar timepoints in the 
control group (defined as 6 and 12 hours post randomization for Day 1, 30 and 36 hours post 


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randomization for Day 2 and 54 and 60 hours post randomization for Day 3 and then each 24 
hours till the subject is discharged from the ICU) will be described.  
Subjects who die before the analysis timepoint will be considered as a failure. 
Notes:  
-
% change in PaO2/FiO2 ratio = [(Value – baseline)/baseline]x100
-
If % change in the ratio >20%, then PaO2/FiO2 ratio improvement=’>20%’, else
’<=20%’
9.3.7 Change from Baseline in FiO2 at each Timepoint After Treatment 
Actual values and change from baseline in FiO2 at 6 and 12 hours following each treatment 
medication administration in the poractant alfa group and then each 24 hours till the subject is 
discharged from the ICU and similar timepoints in the control group (defined as 6 and 12 hours 
after randomization for Day 1, 30 and 36 hours after randomization for Day 2 and 54 and 60 
hours post randomization for Day 3 and then each 24 hours till the subject is discharged from 
the ICU) will be described.  
9.3.8 Length of ICU Stay at Day 28 
The length of ICU stay (in days) will be calculated as: MIN (date of ICU discharge, date of 
Day 28) – date of ICU entrance + 1.  
In case of readmission in ICU, the duration of the primary one and the readmission will be 
added. Lengths of ICU stay will be presented in total. 
Subjects who die or are mechanically ventilated longer than this period will be assigned with a 
28 days length value. 
Those subjects will be identified using: 
•
On Study Completion form, death date is filled and < MIN (date of ICU discharge, date
of Day 28)
•
On Ventilatory Support form the subtype Invasive- Mechanical ventilation is ticked and
(End Date – Start Date) +1 > 28 Days or if Ongoing is ticked (i.e. subject still under
mechanical ventilation at the end of the Study).
In case of multiple sessions of Invasive- Mechanical ventilator support without any discharge 
in between the MIN start date and the MAX end date will be taken into account. 
It will be presented using descriptive statistics by treatment group. 
A graph displaying the mean and SD for each timepoint (until the subject is discharged 
form ICU) will be also provided for each treatment group. 
9.3.9 Percentage of Subjects Alive and Out of ICU at Day 28 
The subject will be defined alive and out of ICU at Day 28 if: 
•
On Patient Status form at “D28 – FU” visit, the subject is still alive
AND 


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•
Date of ICU discharge Visit < Date of “Day 28 – FU” visit
The percentage will be summarized. 
9.3.10 Change from Baseline in SOFA Score 
SOFA sub-score and total score actual values and change from baseline will be presented using 
descriptive statistics at Day 3, ICU discharge or Day 28 (whichever comes first).by treatment 
group. The change from baseline to Day 3 and to ICU Discharge or Day 28 difference between 
the two groups for each sub-score and for total score will be described. 
A graph displaying the means and SD for each timepoint (until the subject is discharged form 
ICU) will be also provided for each treatment group. 
9.3.11 Percentage of Subjects Alive and Organ Failure Free (SOFA score=0) at Day 28 
or Discharge 
The subject will be defined alive and organ failure free at Day 28 or Discharge if: 
•
Date of Death is missing or > MIN (Date of Day 28 or Date of Discharge)
AND 
•
Total SOFA Score = 0 at Day 28 or at Discharge
The percentage will be summarized. 
9.3.12 Change from Baseline in Ventilatory Parameters 
Ventilatory parameters actual values and change from baseline (TV, RR, Cdyn, Cstat, PEEP, 
PIP, and Pplat) will be presented using descriptive statistics by timepoint and treatment group. 
A graph displaying the means and SD for each timepoint (until the subject is discharged form 
ICU) will be also provided for each treatment group and parameter. 
9.3.13 Change from Baseline in Blood Gas Analysis Parameters 
Acid-base balance blood gas analysis parameters actual values and change from baseline (pH, 
pCO2, paO2, HCO3, lactate) will be presented using descriptive statistics by time point and 
treatment group.  
9.4 Exploratory Efficacy Variables 
Only for the UK subgroup of subjects: 
Exploratory parameters from tracheal aspirates and blood samples: 
-
Surfactant Function measuring surface tension (mN/m) from TA samples.
-
Mass spec lipid analysis (%) from TA samples.


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-
Protein D Enzyme Linked Immunosorbent Assay (ng/mL) from TA samples.
-
Surfactant Protein D Enzyme Linked Immunosorbent Assay (ng/mL) from Blood
samples.
will be summarized by actual and change from baseline values by treatment group at each time 
point using descriptive statistics on ITT set. 
Cytospin values will only be listed. 
In case of sample not done or if some values are under the lower limit of quantitation (BLOQ), 
the values will be considered as missing data. 
10 Safety Analyses 
Safety analysis will be based 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 poractant alfa group. Actual diluted volume administered (ml) will be 
summarized using summary statistics. 
10.2 Adverse Events 
An adverse event (AE) will be classified as follow: 
•
For poractant alfa group:
o
Pre-treatment AE: if it starts before the first study medication administration
(AE onset date/time < date/time of first study medication administration);
o
Treatment emergent AE (TEAE): if it starts on or after the first dose of study
medication administration (AE onset date/time > date/time of first study
medication administration).
•
For control group:
o
Pre-treatment AE: if it starts before the randomisation date (AE onset date/time
< start date/time of randomisation);
o
Treatment emergent AE (TEAE): if it starts on or after the randomization date
(AE onset date/time > start date/time of randomisation).
An adverse drug reaction (ADR) is an AE related to study medication. A serious ADR is a 
serious AE (SAE) related to study medication. 
A severe AE is an AE with severe intensity. Refer to Section 7.3 for missing severity. 
An AE leading to discontinuation is an AE with action taken with study drug equal to “Drug 
Permanently Withdrawn”. 
An AE leading to death is an AE with outcome equal to “Fatal”. 


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Pre-treatment AEs, and TEAEs will be presented separately. Pre-treatment AEs will be 
presented in the listings only. 
Two AEs with the same PT and classified in the same category (pre-treatment AE or TEAE) 
will be considered as two different events when calculating the “number of events” in the 
tables.  
A summary table displaying the number and the percentage of subjects experiencing at least 
one TEAE, serious TEAEs, non-serious TEAEs, ADRs/drug-related TEAE, serious ADRs, 
severe TEAEs, TEAEs leading to study drug discontinuation and TEAEs leading to death, as 
well as the number of events, will be presented by treatment group. 
The SOC and PT will also be used for tabulation using the MedDRA dictionary. The number 
and percentage of subjects with at least one AE and the number of events will be presented by 
SOC and PT by treatment group for treatment emergent AEs, non-serious TEAEs, serious 
TEAEs, ADRs, serious ADRs, severe TEAEs, TEAEs leading to treatment discontinuation and 
TEAEs leading to death.  
 A table presenting the number and percentage of subjects with at least one TEAE will be 
provided by PT. The number of subjects with TEAEs will be also displayed by SOC and PT 
and maximum severity. The number of events will be also included in these analyses. 
Tables will be presented by SOC and then by PT, alphabetically sorted.  
In addition, TEAEs that are presented by PT will be sorted by decreasing overall frequency. 
An individual subject listing will also be provided for AEs. 
10.3 Vital Signs 
Vital signs parameters actual values and change from baseline (pulse rate, systolic blood 
pressure, and diastolic blood pressure) will be presented using descriptive statistics by 
timepoint for each treatment group.  
An individual subject listing will also be provided for vital signs data. 
10.4 Laboratory Parameters 
Laboratory parameters actual values and change from baseline will be presented using 
descriptive statistics by timepoint for each treatment group.  
An individual subject listing will also be provided for laboratory data. 
11 Other Analyses 
No other analyses planned. All other data collected in the eCRF will be listed. 
12 Changes in the Planned Analyses from Study 
Protocol 


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As this study is specifically linked to the COVID-19 pandemic situation, as there was a global 
improvement in the countries (US, UK, Italy) where the study was done during 2021 (vaccines 
against COVID-19, better treatment, variant less contagious…), the recruitment was lower than 
expected and the study was closed before reaching the target sample size of 70 subjects. 
As a consequence all statistical analysis planned in the protocol were not done considering the 
low sample size:  
•
Statistical Analysis of Days Alive and Free from Ventilation at Day 21
•
Subjects alive and free of respiratory failure at Day 28.
•
Statistical Analysis of Days Alive and Free from Invasive Ventilation Day 28
•
Statistical Analysis of Days Alive and Free from Invasive Ventilation at Day 21 and Day 28
•
Statistical Analysis of Days Alive and Free from Non-Invasive Ventilation at Day 21 and Day
28
•
Statistical Analysis of Mortality at Day 21 and Day 28
•
Statistical Analysis of Proportion of Subjects with Improvement in Severity Status at Day
28/Discharge
•
Statistical Analysis of Change from Baseline in pao2/fio2 Ratio at Each Timepoint
•
Statistical Analysis of Proportion of Subjects with pao2/fio2 Ratio Improvement >20%
Compared to Baseline at Each Timepoint
•
Statistical Analysis of Change from Baseline in fio2 at Each Timepoint
•
Statistical Analysis of Length of ICU Stay (Days) at Day 28
•
Statistical Analysis of Proportion of Subjects Alive and Out of ICU at Day 28
•
Statistical Analysis of Delta SOFA Score at Day 3 and Day 28/ Discharge
•
Statistical Analysis of Delta SOFA Sub Score at Day 3 and Day 28/Discharge
•
Statistical Analysis of Proportion of Subjects Alive and Organ Failure Free at Day 28/Discharge
ITT definition was changed from “all randomised patients (analysed as randomised)” to “all 
randomised subjects who have at least one post baseline efficacy data analysed as randomised”. 
Cytospin analysis was not done by central laboratory University College London (UCL) due 
to freeze of the samples. Freezing destroys the cells in the TA samples and hence it has not 
been possible to do this analysis. Cytospin data won’t be summarized in the tables and will be 
listed as missing in the listings. 
Data on inflammatory indices such as cellular and cytokine (pg/ml) inflammatory markers (e.g. 
IL-1, IL-6, TNF alpha, IFN gamma and lymphocyte markers) from TA and blood samples were 
not provided (i.e., not analysed by the time of DB lock). As a consequence, these won’t be 
summarised and listed. 
13 Output 
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 and Timepoints Descriptors 
In the tables and listings, the treatments, and timepoints will be identified as described below. 
Treatment group 
(as displayed in outputs) 
Descriptor for treatment 
Poractant Alfa 
One or two or three doses of poractant alfa (Curosurf®) 
Control 
Standard of care 
Output 
Descriptor for timepoints 
Tables and 
Figures 
For poractant alfa group: 
Visits: Screening, Day 1, Day 2, …, Day 28, ICU Discharge. 
Timepoints: At intubation, Baseline, 6 hours post first dose, 12 hours post 
first dose, 18 hours post first dose, 24 hours post first dose, 30 hours post 
first dose, 36 hours post first dose, 42 hours post first dose, 48 hours post 
first dose, 54 hours post first dose, 60 hours post first dose, 66 hours post 
first dose, 72 post first dose.  
For control group: 
Visits: Screening, Baseline, Day 2, … Day 28, ICU Discharge. 
Timepoints: At intubation, Baseline, 6 hours post randomisation, 12 hours 
post randomisation, 18 hours post randomisation, 24 hours post 
randomisation, 
30 
hours 
post 
randomisation, 
36 
hours 
post 
randomisation, 
42 
hours 
post 
randomisation, 
48 
hours 
post 
randomisation, 
54 
hours 
post 
randomisation, 
60 
hours 
post 
randomisation, 
66 
hours 
post 
randomisation, 
72 
hours 
post 
randomisation. 
Listings and 
Figures 
For poractant alfa and control groups: 
Visits: Screening, Day 1, Day 2, … Day 28, ICU Discharge. 
Timepoints: At intubation, Baseline, 6 hours, 12 hours, 18 hours, 24 
hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 66 
hours, 72 hours.  
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): 
Variables 
Decimal Places 
•
Number of ventilator-free days
0 decimal 


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Variables 
Decimal Places 
•
Duration of AE, medication (days)
•
Length of ICU stay (days)
•
Days between screening positive SARS-
COV-19 rt-PCR test and start of intubation
•
Days between ICU admission date and start
of intubation
•
BMI (kg/m2)
•
Ventilatory Parameters: TV, RR, Cdyn,
Cstat, PEEP, PIP, and Pplat
1 decimal 
•
PaO2/FiO2 ratio
2 decimals 
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): 
All summary statistics will be rounded (using the SAS® function ROUND) and wherever 
possible data will be decimal aligned. 
Statistic 
Number of decimal places for reporting 
Counts (n) 
None 
Percentages (%)/Proportion 
1 decimal place 
Note: 
If the calculated percentage is >0.0% but <0.1% 
then <0.1% is to be presented in the relevant table 
and/or listing. 
If the calculated percentage is >99.9% but <100.0% 
then >99.9% is to be presented in the relevant table 
and/or listing. 
Mean, Median, SD, Confidence intervals 
Actual data + 1 decimal place 
Difference between percentages (%)/ 
Proportions, Mean and difference between 
means 
Actual data + 1 decimal place 
Min, Max 
Same as actual data 
p-values
3 decimal places. 
Note: 
If the p-value is less than 0.001, it will be presented 
as <0.001.  
If the rounded result is a value of 1.000, it will be 
displayed as >0.999.  


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13.2.3 Other Reporting Conventions 
UK English will be used for all outputs. 
Treatments will be presented with the following order in the tables: poractant alfa, control. 
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. 
In the listings, a unit associated with a variable will be presented only once within parentheses 
either below or next to that variable in the heading portion. If a parameter has multiple units, 
each unit will be displayed only once, as applicable. 
All tables will have their source listing referenced in a footnote. All figures will include the 
source table in a footnote. Listings should be sorted by subject ID and visit (unless otherwise 
specified) and have the SDTM and/or ADaM source data referenced in a footnote. The columns 
of each listing should fit into one page and should not be split into different pages.  
When an output is split in multiple pages, page-break should be adequately controlled. 
When a table is split in multiple pages, breaking of a block information in different pages is 
not allowed.  
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 and any other relevant information 
which is split between 2 pages) must be presented at the beginning of that page. 
When a listing contains a lot of information, in order to optimize space on the page, some 
columns can be merged (e.g. “reported term” and “indication” may be presented in the same 
column. 
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).


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•
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.
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).


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•
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
colours/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.
13.4 Quality Control 
The Quality Control steps will be defined in the Datasets, Tables, Listings, Figures QC Plan. 
14 SAS Code 
Not applicable: data will be summarized by means of descriptive statistics. 
15 References 
1.
Chiesi Farmaceutici S.p.A. TLFs_Library_v1.0_signed. 10 Sep 2019.
2.
Chiesi Farmaceutici S.p.A. Instructions for Producing Statistical Analysis Plan &
Statistical Output. 25 Jan 2016.
3.
ICH E9: Statistical Principles for Clinical Trials. Sept 1998.
4.
 Statistical Analysis Plan v3.0.


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16 List of Tables, Listings and Figures 
16.1 Tables 
Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.1.1.1 
Disposition by Treatment (Enrolled Set) 
DST002 
- Overall column should be
displayed
- Study
discontinuation/completion
status and reason for
discontinuation to be displayed
Source: Listing 16.2.1.1 
Table 14.1.1.2 
Disposition of Subjects by Country and Site 
(Enrolled Set)  
DST004 
Overall column should be 
displayed. 
Display first Country and then 
all site within the country. 
All countries and sites sorted by 
alphabetical order. 
Source: Listing 16.2.1.1 
Table 14.1.1.3 
Important Protocol Deviations (Enrolled Set) 
DVT001 
Overall column should be 
displayed. 
Display only important 
deviation, discard non 
important and no deviations 
lines. 
Source: Listing 16.2.2.2 
Table 14.1.1.4 
Analysis Sets (Enrolled set) 
DST005 
- Overall column should be
displayed
- Safety Set and ITT set to be
displayed. 
Source: Listing 16.2.3.1 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.1.2 
Demographic and Baseline Characteristics 
(Intention-To-Treat Set)  
DMT001 
- Overall column should be
displayed.
- Variables to be summarized:
Age, Age Category, Gender,
Childbearing Potential (only for
females) (yes/no), Race
(categories as per CRF to be
displayed), Height, Weight and
BMI at baseline.
- All categories should be
displayed even if empty.
Source: Listing 16.2.4.1 
Table 14.1.3 
Other Baseline and Disease Characteristics 
(Intention-To-Treat Set)  
BLT001 
- Overall column should be
displayed.
- Variables to display:
– SBP (mmHg)
– DBP (mmHg)
– Pulse Rate (bpm)
– PaO2/FiO2 ratio
– FiO2 (%)
– SOFA Score
Source: Listing 16.2.4.3 
Table 14.1.4 
SAS COVID-19 ARDS History (Safety Set) 
BLT001 
- Overall column should be
displayed.
- Variables to be summarized:
– Days Between Screening
Positive SARS-COV-19 rt-PCR
Test and Start of Intubation
– Days Between ICU
Admission Date and Start of 
Intubation 
– SARS-COV-19 ARDS
Medication Category
(categories as per CRF to be
displayed)
Source: Listing 16.2.4.2 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.1.5.1 
Medical and Surgical History (Safety Set) 
MHT001 
- Overall column should be
displayed.
- Replace
<Condition/Procedure> by
‘Medical History’.
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded
using MedDRA Version 23.0.
Source: Listing 16.2.4.4 
Table 14.1.5.2 
Concomitant Diseases (Safety Set) 
MHT001 
- Overall column should be
displayed.
- Replace
<Condition/Procedure> by 
‘Concomitant Disease’ 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded
using MedDRA Version 23.0.
Source: Listing 16.2.4.5 
Table 14.1.5.3 
Prior Procedures (Safety Set) 
MHT001 
- Overall column should be
displayed.
- Replace
<Condition/Procedure> by
‘Prior Procedure’
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded
using MedDRA Version 23.0.
Source: Listing 16.2.4.6 
Table 14.1.5.4 
Maintained Procedures (Safety Set) 
MHT002 
Same as Table 14.1.5.3 
Table 14.1.5.5 
Concomitant Procedures (Safety Set) 
MHT002 
Same as Table 14.1.5.3 
Table 14.1.6.1 
Prior Medications (Safety Set) 
CMT001 
Overall column should be 
displayed. 
Add the footnote: 
[1] ATCs and Preferred Name
are coded using WHO-DD 
March 2020. 
Source: Listing 16.2.4.7 
Table 14.1.6.2 
Maintained Medications (Safety Set) 
CMT002 
Overall column should be 
displayed 
Same as Table 14.1.6.1 
Table 14.1.6.3 
Concomitant Medications (Safety Set) 
CMT002 
Overall column should be 
displayed 
Same as Table 14.1.6.1 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.2.1 
Summary of Number of Days Alive and 
Ventilator-free at Day 21 (Intention-To-
Treat)  
TPT002 
- Display the number of days
alive and Ventilator-free at Day
21
- Remove ‘95% CI for Mean’,
‘n geometric’, ‘Geometric
mean’ categories.
Add the footnote: 
[1] Subjects who die or are
mechanically ventilated longer 
than this period are assessed as 
zero ventilator-free days. 
Source: Listing 16.2.6.2-b 
Table 14.2.2 
Summary of Proportion of Subjects Alive 
and Free of Respiratory Failure at Day 28 
(Intention-To-Treat)  
TPT006 
- There is only one timepoint to
display: Day28.
- Do not present ‘At Any
timepoint’ line. 
- Do not display ‘Visit’ on the
title line.
Source: Listing 16.2.6.2-b 
Table 14.2.3 
Summary of Number of Days Alive and 
Ventilator-free at Day 28 (Intention-To-
Treat)  
TPT002 
- Display the number of days
alive and Ventilator-free at Day
28.
- Remove ‘95% CI for Mean’,
‘n geometric’, ‘Geometric
mean’ categories.
Add the footnote: 
[1] Subjects who die or are
mechanically ventilated longer 
than this period are assessed as 
zero ventilator-free days. 
Source: Listing 16.2.6.2-b 
Table 14.2.4 
Summary of Mortality at Day 21 and Day 28 
(Intention-To-Treat)  
TPT006 
- Display the number of death
at Day 21 and Day 28.
- Do not present ‘At Any
timepoint’ line. 
Source: Listing 16.2.6.2-b 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.2.5 
Summary of Number of Days Alive and Free 
from Invasive Ventilation at Day 21 and Day 
28 (Intention-To-Treat)  
TPT002 
- Display the number of days
alive and free from invasive
ventilation at Day 21 and Day
28
- Remove ‘95% CI for Mean’,
‘n geometric’, ‘Geometric
mean’ categories.
Add the footnote: 
[1] Subjects who die or are
mechanically ventilated longer 
than this period are assessed as 
zero ventilator-free days. 
Source: Listing 16.2.6.2-b 
Table 14.2.6 
Summary of Number of Days Alive and Free 
from Non-Invasive Ventilation at Day 21 and 
Day 28 (Intention-To-Treat)  
TPT002 
- Display the number of days
alive and free from non-
invasive ventilation at Day 21
and Day 28
- Remove ‘95% CI for Mean’,
‘n geometric’, ‘Geometric
mean’ categories.
Add the footnote: 
[1] Subjects who die or are
mechanically ventilated longer 
than this period are assessed as 
zero ventilator-free days. 
Source: Listing 16.2.6.2-b 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.2.7.1 
Summary of Proportion of Subjects with 
Improvement in Severity Status at Day 
28/Discharge (Intention-To-Treat)  
TPT006 
- Summarize the Severity
Status (Mild -1, Moderate -2,
Severe -3 and Death - 4) at
Baseline and Day 28/Discharge
and then the Proportion of
Subjects with an Improvement
in Severity Status at Day
28/Discharge.
- Do not present ‘At Any
timepoint’ line.
Add the footnotes: 
[1] Mild : 200
mmHg<PaO2/FiO2<=300
mmg
Moderate: 100
mmHg<PaO2/FiO2<=200
mmg
Severe: Ratio
PaO2/FiO2<=100 mmHg
[2] An improvement is defined
by a decrease of at least one
point between baseline and
Day 28/Discharge
Source: Listing 16.2.6.2-b
Table 14.2.7.2 
Severity Status: Shift from Baseline to Day 
28/Discharge (Intention-To-Treat) 
EGT005 
- Do not present the ‘Visit’ line.
- Display the following
categories at Baseline and at
Day 28/Discharge :Mild - 1,
Moderate - 2, Severe - 3, Death
- 4
Add the footnotes 
[1] Mild : 200
mmHg<PaO2/FiO2<=300
mmg
Moderate: 100
mmHg<PaO2/FiO2<=200
mmg
Severe: Ratio
PaO2/FiO2<=100 mmHg
Source: Listing 16.2.6.2-b


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.2.8 
Summary of Actual Values and Change from 
Baseline in PaO2/FiO2 Ratio at Each 
Timepoint (Intention-To-Treat Set)  
TPT001 
- Overall column should not be
displayed.
- Remove ‘95% CI for Mean’,
‘n geometric’, ‘Geometric 
mean’ categories. 
Add the footnote: 
[1] Duplicated data reported
twice at 2 different timepoints
are 
reported 
at 
the 
first
occurrence for post dose/post
randomisation and at the last
occurrence for pre dose/pre
randomisation.
Source: Listing 16.2.6.2-a 
Table 14.2.9 
Summary of Proportion of Subjects with 
PaO2/FiO2 Ratio Improvement >20% 
Compared to Baseline at Each Timepoint 
(Intention-To-Treat Set)  
TPT006 
- Do not present ‘At Any
timepoint’ line.
Add the footnote: 
[1] Duplicated data reported
twice at 2 different timepoints
are 
reported 
at 
the 
first
occurrence for post dose/post
randomisation and at the last
occurrence for pre dose/pre
randomisation.
Source: Listing 16.2.6.2-a 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.2.10 
Summary of Actual Values and Change from 
Baseline in FiO2 at Each Timepoint 
(Intention-To-Treat Set)  
TPT001 
- Overall column should not be
displayed.
- Remove ‘95% CI for Mean’,
‘n geometric’, ‘Geometric
mean’ categories.
Add the footnote: 
[1] Duplicated data reported
twice at 2 different timepoints
are 
reported 
at 
the 
first
occurrence for post dose/post
randomisation and at the last
occurrence for pre dose/pre
randomisation.
Source: Listing 16.2.6.2-a 
Table 14.2.11 
Summary of Length of ICU Stay (Days) at 
Day 28 (Intention-To-Treat Set)  
TPT001 
- Overall column should not be
displayed.
- ICU stays (days) have to be
display by stay and in total (see 
SAP section 9.3.8) - one row by 
stay and total for each 
considered subject. For 
example : First Stay: Duration 
(Days), Second Stay: Duration 
(Days), Total: Duration (Days) 
- Remove ‘95% CI for Mean’,
‘n geometric’, ‘Geometric
mean’ categories.
Add the footnotes: 
[1] The length of ICU stay
(days) is calculated as MIN
(date of ICU discharge, date of
Day 28) – date of ICU
entrance + 1.
[2] Subjects who die or are
mechanically ventilated longer
than this period are assigned
with 28 days.
Source: Listing 16.2.6.2-b 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.2.12 
Summary of Proportion of Subjects Alive 
and Out of ICU at Day 28 (Intention-To-
Treat Set)  
TPT006 
- There is only one timepoint to
display: Day28.
- Do not present ‘At Any
timepoint’ line.
- Do not display ‘Visit’’ on the
title line.
Source: Listing 16.2.6.2-b 
Table 14.2.13 
Summary of Actual Values and Delta SOFA 
Score and Sub-Score from Baseline 
(Intention-To-Treat Set)  
TPT001 
- Replace ‘Visit’ by
‘Timepoint’ with categories:
Day 3, ICU Discharge, Day 28.
- Remove ‘95% CI for Mean’,
‘n geometric’, ‘Geometric
mean’ categories.
- Overall column should not be
displayed.
Source: Listing 16.2.6.3 
Table 14.2.14 
Summary of Proportion of Subjects Alive 
and Organ Failure Free at Day 28/Discharge 
(Intention-To-Treat Set)  
TPT006 
- There is only one timepoint to
be display: Day28/Discharge.
- Do not present ‘At Any
timepoint’ line.
- Do not display ‘Visit’ on the
title line.
Add the footnote: 
[1] Organ Failure Free is
defined as a SOFA score =0
Source: Listing 16.2.6.3 
Table 14.2.15 
Summary of Actual Values and Change from 
Baseline in Ventilatory Parameters 
(Intention-To-Treat Set)  
LBT001 
- See Section 13.2.1 for the list
of timepoints to display.
- Repeat summaries for each
Ventilatory parameter (TV, RR, 
Cdyn, Cstat, PEEP, PIP, and 
Pplat). 
- Overall column should not be
displayed.
Add the footnote: 
[1] Duplicated data reported
twice at 2 different timepoints
are 
reported 
at 
the 
first
occurrence for post dose/post
randomisation and at the last
occurrence for pre dose/pre
randomisation.
Source: Listing 16.2.6.2-a 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.2.16 
Summary of Actual Values and Change from 
Baseline in Blood Gas Analysis Parameters: 
(Intention-To-Treat Set)  
LBT001 
- See Section 13.2.1 for the list
of timepoints to display.
- Repeat summaries for each
Blood Gas Analysis parameter 
(pH, pCO2, pO2, HCO3, 
lactate).  
- Overall column should not be
displayed.
Add the footnote: 
[1] Duplicated data reported
twice at 2 different timepoints
are 
reported 
at 
the 
first
occurrence for post dose/post
randomisation and at the last
occurrence for pre dose/pre
randomisation.
Source: Listing 16.2.6.4 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.2.17 
Summary of Actual Values and Change from 
Baseline in Tracheal Aspirates and Blood 
Samples: (Intention-To-Treat Set)  
LBT001 
- See Section 13.2.1 for the list
of timepoints to display.
- Repeat summaries for each
TA and blood samples
parameters: As specified in
section 9.4:
- Surfactant Function
measuring surface tension 
(mN/m) from TA samples. 
- Mass spec lipid analysis
(%) from TA samples. 
- Protein D Enzyme Linked
Immunosorbent Assay (ng/mL) 
from TA samples. 
- Surfactant Protein D
Enzyme Linked 
Immunosorbent Assay (ng/mL) 
from Blood samples. 
- Add a subtitle to differentiate
Blood and TA samples with
LBSPEC ‘Sample from’ with
Blood or Tracheal Aspirates as
values
- Overall column should not be
displayed.
 Source: Listing 16.2.6.6 
Add the footnotes: 
[1] Sample not done (ND) or
below the lower limit of
quantitation (BLOQ) are not
displayed.


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.3.1 
Summary of Extent of Exposure (Safety Set) 
EXT001 
- Display both treatment
columns but only poractant alfa
group can have data. Display a
‘-’ in the n row for control
group.
Data to display:
- Dose Administrations (1, 2 or
3)
- Actual Diluted Volume
Administered (ml)
Source: Listing 16.2.5 
Table 14.3.2.1 
Summary of Treatment Emergent Adverse 
Events (Safety Set)  
AET001 
Data to display: 
- Number of Subjects with at
Least One TEAE
- Number of Subjects with at
Least One Serious TEAE
- Number of Subjects with at
Least One Non-Serious TEAE
- Number of Subjects with at
Least One ADR
- Number of Subjects with at
Least One Serious ADR 
- Number of Subjects with at
Least One Severe TEAE 
- Number of Subjects with at
Least One TEAE Leading to
Study Drug Discontinuation
- Number of Subjects with at
Least One TEAE Leading to
Death
- Display ‘-’ in the control
group column when the
selection is not applicable.
Source: Listing 16.2.7.2 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.3.2.2 
Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term 
(Safety Set)  
AET003 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded 
using MedDRA Version 23.0. 
Source: Listing 16.2.7.2 
Table 14.3.2.3 
Treatment Emergent Adverse Events by 
Preferred Term (Safety Set)  
AET006 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded
using MedDRA Version 23.0.
[2] TEAEs sorted by
decreasing overall frequency.
Source: Listing 16.2.7.2 
Table 14.3.2.4 
Serious Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term 
(Safety Set)  
AET003 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded 
using MedDRA Version 23.0. 
Source: Listing 16.2.7.3 
Table 14.3.2.5 
Non-Serious Treatment Emergent Adverse 
Events by System Organ Class and Preferred 
Term (Safety Set)  
AET003 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded 
using MedDRA Version 23.0. 
Source: Listing 16.2.7.4 
Table 14.3.2.6 
Treatment Emergent Adverse Drug 
Reactions by System Organ Class and 
Preferred Term (Safety Set)  
AET003 
Display ‘-’ in the first row for 
control group as this is not 
applicable. 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded 
using MedDRA Version 23.0. 
Source: Listing 16.2.7.5 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.3.2.7 
Serious Treatment Emergent Adverse Drug 
Reactions by System Organ Class and 
Preferred Term (Safety Set)  
AET003 
Display ‘-’ in the first row for 
control group as this is not 
applicable. 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded 
using MedDRA Version 23.0. 
Source: Listing 16.2.7.6 
Table 14.3.2.8 
Severe Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term 
(Safety Set)  
AET003 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded 
using MedDRA Version 23.0. 
Source: Listing 16.2.7.7 
Table 14.3.2.9 
Treatment Emergent Adverse Events 
Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term 
(Safety Set)  
AET003 
Display ‘-’ in the first row for 
control group as this is not 
applicable. 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded 
using MedDRA Version 23.0. 
Source: Listing 16.2.7.8 
Table 14.3.2.10 
Treatment Emergent Adverse Events 
Leading to Death by System Organ Class and 
Preferred Term (Safety Set)  
AET003 
Add the footnote: 
[1] System Organ Class and
Preferred Term are coded 
using MedDRA Version 23.0. 
Source: Listing 16.2.7.9 
Table 14.3.4.1 
Vital Signs: Summary of Actual Values and 
Change from Baseline (Safety Set)  
VST001 
- Replace ‘Visit’ by
‘Timepoint’. See Section 13.2.1
for the list of timepoints to
display.
- Repeat summaries for each
parameter (Pulse Rate, Systolic
Blood Pressure, and Diastolic
Blood Pressure).
- Remove ‘95% CI for mean’
category.
Add the footnote: 
[1] Duplicated data reported
twice at 2 different timepoints
are 
reported 
at 
the 
first
occurrence for post dose/post
randomisation and at the last
occurrence for pre dose/pre
randomisation.
Source: Listing 16.2.8.1 


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Table Number 
Table Title 
Template Code 
Notes 
Footnotes/Source Listing 
Number 
Table 14.3.4.2 
Haematology: Summary of Actual Values 
and Change from Baseline (Safety Set)  
LBT001 
- Replace ‘Visit’ by
‘Timepoint’. See Section 13.2.1
for the list of timepoints to
display.
- Repeat summaries for each
parameter on the 
‘Haematology’ CRF page. 
- Remove ‘95% CI for mean’
category.
In case of original unit missing, 
do not display the value in the 
table. 
Source: Listing 16.2.8.2 
Add the footnote: 
[1] Value with original unit
missing are not displayed.
Table 14.3.4.3 
Chemistry: Summary of Actual Values and 
Change from Baseline (Safety Set)  
LBT001 
Same as Table 14.3.6.1 
Source: Listing 16.2.8.3 
Add the footnote: 
[1] Value with original unit
missing are not displayed.


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16.2 Listings 
Listings will include data at observed Timepoints only, without imputation for missing data. 
Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.1.7 
Randomisation Schedule (Enrolled Set) 
DSL001 
Listing 16.2.1.1 
Subjects Disposition (Enrolled Set) 
DSL004 
- ‘Period of last intake of study treatment’ and
‘Last treatment received’ columns not to be
displayed.
- Date of first and last doses are fulfilled only for
poractant alfa group.
Add the following 
footnotes: 
[1] [Day 1] is the
study Day at Date
of Study
Discontinuation
calculated with
reference to the
Informed Consent
Date
[2] [Day 2] is the
study Day at Date
of Study
Discontinuation
calculated with
reference to the
First Dose
[3] [Day 3] is the
study Day at Date
of Study
Discontinuation
calculated with
reference to the Last
Dose Date


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.1.2 
Study Visits (Intention-To-Treat Set) 
SVL001 
- Remove the word ‘Retest’ in header.
Ass the footnote: 
[1] [Study Day] is the
study Day at Visit
calculated with
reference to the
randomization Date
Listing 16.2.2.1 
Violation of Eligibility Criteria (Enrolled 
Set)  
DVL001 
- Only deviations from DV in relation to
inclusion/exclusion criteria.
- Change ‘Visit’ to ‘Timepoint’.
- Remove ‘Reference analysis set’ column.
Listing 16.2.2.2 
Protocol Deviation (Enrolled Set) 
DVL002 
- Include all deviations from DV.
- Remove ‘Randomised sequence’, ‘Period’, and
‘Reference analysis set’ columns.
Listing 16.2.3.1 
Analysis Sets Disposition (Enrolled Set) 
DSL006 
- Remove ‘Period’ and ‘Randomised sequence’
- Include Safety Set and ITT Set
Listing 16.2.3.2 
Exclusion from Safety and Intention-To-
Treat Sets (Enrolled set)  
DSL007 
- Remove ‘Period’ and ‘Randomised sequence’
- Include reason for exclusion from safety set and
form ITT sets
Listing 16.2.4.1 
Demographic Characteristics (Intention-To-
Treat Set)  
DML001 
- Remove Ethnicity’ column.
Listing 16.2.4.2 
SARS-COV-19 ARDS History (Intention-
To-Treat Set)  
SCL001 
The following columns will be presented: 
- Subject ID
- Treatment Group
- Date of Positive SARS-COV-19 rt-PCR
- ICU Admission Date
- Intubation Date/Time
- Medication Category


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.4.3 
Other Baseline and Disease Characteristics 
(Intention-To-Treat Set)  
DML001 
The following columns will be presented: 
- Subject ID
- Treatment Group
- SBP (mmHg)
- DBP (mmHg)
- Pulse Rate (bpm)
- PaO2/FiO2 ratio (mmHg)
- FiO2 (%)
- SOFA Score
Listing 16.2.4.4 
Medical and Surgical History (Intention-
To-Treat Set)  
MHL001 
Add the footnote: 
[1] System Organ
Class and Preferred
Term are coded using
MedDRA Version
23.0.
Listing 16.2.4.5 
Concomitant Diseases (Intention-To-Treat 
Set)  
MHL002 
Same as Listing 
16.2.4.4 
Listing 16.2.4.6 
Procedures (Intention-To-Treat Set) 
PRL001 
- Remove ‘Analysis Period’ in the header
- [CAT]: Prior, Maintained, And Concomitant.
- Drop the last column ‘Indication’
Add the footnote: 
[1] System Organ
Class and Preferred
Term are coded using
MedDRA Version
23.0.
Listing 16.2.4.7 
Medications (Intention-To-Treat Set) 
CML001 
- Remove ‘Analysis Period’ In the header
- [CAT]: Prior, Maintained And Concomitant.
Add the footnote: 
[1] ATCs and
Preferred Name are
coded using WHO-
DD March 2020.
[2] [Day] is the study
Day at Start Date
calculated with
reference to the First
Dose Date


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.4.8 
Thoracic CT or Chest X-Ray (Intention-To-
Treat Set)  
PEL001 
- Remove Analysis Period column
- Display ‘Assessment date/Time [Study Day]’
instead of ‘Assessment date/time [study day /
study day in period]’
- Display ‘Procedure’ instead of Body System’
Listing 16.2.5 
Study Drug Administration (Intention-To-
Treat Set)  
The following columns will be presented: 
- Subject ID
- Randomized Treatment
- Actual Treatment
- Kit Number
- Timepoint
- Date/Time of Administration [Day]
- Planned Vol. to be Admin. (ml)
- Planned Vol. to be Admin. after Dilution (ml)
- Actual Diluted Vol. Admin. (ml)
- Administration Interrupted
Only poractant alfa group should have data listed. 
Listing 16.2.6.1 
Ventilatory Support (Intention-To-Treat 
Set)  
The following columns will be presented: 
- Subject ID
- Randomized Treatment
- Actual Treatment
- Ventilator Type
- Start Date/Time [Day]
- Stop Date/Time [Day] or Ongoing
- Duration of Ventilatory Support (Days) –
displayed by Type of Support (Invasive or Not
Invasive)
- Overall Duration of Ventilator Support
Add the footnotes: 
 [1]: Duration of 
ventilatory support 
have been calculated 
as the difference 
between end date and 
start date +1. 
[2]: Overall duration 
of ventilatory support 
has been calculated as 
the difference 
between the 
maximum end date 
(between invasive 
and non-invasive 
ventilation) and start 
date +1. 


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.6.2-a 
Ventilatory Parameters by Timepoint 
(Intention-To-Treat 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)
- In Test <Unit> column, display:
-
FiO2 (%)
-
Mean Arterial Pressure (mmHg)
-
Dynamic Compliance (ml/cmH2O)
-
Static Compliance (ml/cmH2O)
-
PaO2/FiO2 Ratio
-
Tidal Volume (ml/kg BW)
-
Respiratory Rate (/min)
-
Peak Inspiratory Pressure - PIP
(cmH2O)
-
Plateau Pressure (cmH2O)
-
Positive End-Expiratory Pressure -
PEEP (cmH2O)
-
Blood Flows (L/min)
-
Sweep Gas Flows (L/min)
- Add a last column displaying PaO2/FiO2 Ratio
Improvement (<20%, >=20% or death)
Add the footnotes: 
 [1]: Baseline=Y flags 
baseline value 
[2]: Use=Y: included 
in the analysis 
[3]
Duplicated data
reported twice at 2
different 
timepoints
are reported at the first
occurrence for post
dose/post
randomisation and at
the last occurrence for
pre 
dose/pre
randomisation.


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.6.2-b 
Ventilatory Derived Parameters by 
Timepoint (Intention-To-Treat Set) 
- 
- Display: 
- Subject ID
- Randomized Treatment
- Actual Treatment
- Parameter <Unit>
-
Number of Days Free From Invasive
Ventilation
-
Number of Days Free From Non-invasive
Ventilation
-
Mortality
-
Number of Days Alive and Ventilator-free
-
Alive and Free of Respiratory Failure
-
Alive and Out of ICU
-
Length of Primary ICU Stay (Days)
-
Length of Secondary ICU Stay (Days)
-
Length of Total ICU Stay (Days)
-
Alive and Organ Failure Free
-
Severity PaO2/FiO2 ratio
-
Improvement in Severity PaO2/FiO2 ratio
- Values (display one column for Baseline, one
for  D21 and one for D28 results)
Add the following Flags as relevant at D21 and/or 
D28 results: 
-
Min 12H Ventil. Free
-
Min 12H Inv. Ventil. Free
-
Min 12H NInv. Ventil. Free
Add the footnotes: 
[1] * Flag subject
with minimum 12H
of ventilation free
[2] ^ Flag subject
with min 12H of NIV
free
[3]# Flag subject with
minimum 12H of IV
free


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.6.3 
SOFA Score (Intention-To-Treat Set) 
VSL002 
- Remove ‘Analysis Period’
- Display ‘Assessment date [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)
- Do not display the unit in column ‘Test‘(no unit
for SOFA score)
- In Test column, display:
-
Respiratory system Score
-
Nervous system Score
-
Cardiovascular system Score
-
Liver Score
-
Coagulation Score
-
Kidney Score
-
SOFA Score (derived)
Add the footnotes: 
[1]: Baseline: Y flags 
baseline value 
[2]: Use=Y: included 
in the analysis 
Listing 16.2.6.4 
Blood Gas Analysis (Intention-To-Treat 
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)
- In Test <Unit> column, display:
-
pH
-
pCO2 (mmHg)
-
paO2 (mmHg)
-
HCO3 (mmol/L)
-
Lactate (mmol/L)
Add the footnotes: 
[1]: Baseline: Y flags 
baseline value 
[2]: Use=Y: included 
in the analysis 
[3]
Duplicated data
reported twice at 2
different 
timepoints
are reported at the first
occurrence for post
dose/post
randomisation and at
the last occurrence for
pre 
dose/pre
randomisation.


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.6.5 
Hospitalization (Intention-To-Treat Set) 
Variables to be listed: 
- Subject ID
- Randomized Treatment
- Hospitalization Type
- Admission Date/Time [Day]
- Discharge Date/Time [Day]
- Hospital Stay (days)
- Hospital Transfer (Date [Day]/Destination)
Add the footnote: 
[1] Hospital Stay has
been calculated as the
difference between
discharge date and
admission date +1.
Listing 16.2.6.6 
Tracheal Aspirate and Blood Samples 
(Intention-To-Treat Set)  
LBL001 
- Remove ‘Analysis Period’
- Display ‘Assessment date/Time [Study Day]’
instead of ‘Assessment date/time [study day /
study day in period]’
- Do not display CSA [4] column
- Add a column with LBSPEC ‘Sample from’ with
Tracheal Aspirate and blood as value
- In Test <Unit> column, display:
Surfactant Function measuring surface tension
(mN/m) from TA samples.
-
Mass spec lipid analysis (%) from TA
samples.
-
Protein D Enzyme Linked Immunosorbent
Assay (ng/mL) from TA samples.
-
Surfactant Protein D Enzyme Linked
Immunosorbent Assay (ng/mL) from
Blood samples.
-
Cytospin from TA samples
- 
 
There is no normal range for TA aspirates samples, 
Normal range and ABN column will remain empty. 
Add the footnotes: 
[1] Baseline=Y flags
baseline value
[2] USE=Y: included
in the analysis
[3] H = Abnormally
High Value / L =
Abnormally Low
Value, compared to
the Normal Range.
[4] No Normal range
for tracheal aspirate
samples
[5] ND: Not Done,
BLOQ: Below the
lower limit of
quantitation


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.7.1 
Pre-treatment Adverse Events (Intention-
To-Treat Set)  
AEL001 
- Remove ‘Ethnicity’, ‘Pattern’.
- Replace ‘Concomitant Therapy’
‘Concomitant Procedure’ by ‘Concomitant Therapy
/ Concomitant Procedure’
- Concatenate  AEACN with AEACNOTH (Action
taken : <specify>
Add the footnotes: 
[1] CA = Is a
congenital anomaly
or birth defect; 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] System Organ
Class and Preferred
Term are coded using
MedDRA Version
23.0.
Listing 16.2.7.2 
Treatment Emergent Adverse Events 
(Intention-To-Treat Set)  
AEL002 
- Remove ‘Ethnicity’, ‘Period/Actual Treatment’,
‘Starting dose/dose at onset/weight’ and ‘Pattern’.
- Replace ‘Concomitant Therapy’
‘Concomitant Procedure’ by ‘Concomitant Therapy
/ Concomitant Procedure’
- Concatenate  AEACN with AEACNOTH (Action
taken : <specify>
Same as Listing 
16.2.7.1 
Listing 16.2.7.3 
Serious Treatment Emergent Adverse 
Events (Intention-To-Treat Set)  
AEL002 
Same as Listing 16.2.7.2 
Same as Listing 
16.2.7.1 
Listing 16.2.7.4 
Non-Serious Treatment Emergent Adverse 
(Intention-To-Treat Set)  
AEL002 
Same as Listing 16.2.7.2 
Same as Listing 
16.2.7.1 


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.7.5 
Treatment Emergent Adverse Drug 
Reactions (Intention-To-Treat Set)  
AEL002 
Same as Listing 16.2.7.2 
Same as Listing 
16.2.7.1 
Listing 16.2.7.6 
Serious Treatment Emergent Adverse Drug 
Reactions (Intention-To-Treat Set)  
AEL002 
Same as Listing 16.2.7.2 
Same as Listing 
16.2.7.1 
Listing 16.2.7.7 
Severe Treatment Emergent Adverse 
Events (Intention-To-Treat Set)  
AEL002 
Same as Listing 16.2.7.2 
Same as Listing 
16.2.7.1 
Listing 16.2.7.8 
Treatment Emergent Adverse Events 
Leading to Study Drug Discontinuation 
(Intention-To-Treat Set)  
AEL002 
Same as Listing 16.2.7.2 
Same as Listing 
16.2.7.1 
Listing 16.2.7.9 
Treatment Emergent Adverse Events 
Leading to Death (Intention-To-Treat Set) 
AEL002 
Same as Listing 16.2.7.2 
Same as Listing 
16.2.7.1 
Listing 16.2.8.1 
Vital Signs (Intention-To-Treat Set) 
VSL001 
- Remove ‘Analysis Period’ column.
- Remove ‘Study day in Period’.
- Change ‘Analysis Timepoint’ to ‘Timepoint’.
- Change ‘Body Weight (kg)’ to ‘Pulse Rate’ and
put as last column.
- Do not display ‘CHG [3]’ (Change from pre-
dose)
Add the footnotes: 
[1] Use=Included in
the Analysis; B: Flags
Baseline value
[2] CFB is Change
from Baseline
[3] Duplicated data
reported twice at 2
different timepoints
are reported at the
first occurrence for
post dose/post
randomisation and at
the last occurrence for
pre dose/pre
randomisation.


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Listing Number 
Listing Title 
Template Code 
Notes 
Footnotes 
Listing 16.2.8.2 
Laboratory Results: Haematology 
(Intention-To-Treat Set)  
LBL001 
- Remove ‘Analysis Period’ column.
- Remove ‘Study day in Period’.
- Change ‘Analysis Timepoint’ to ‘Timepoint’.
- Remove ‘Fasted’ column
- Remove ‘CSA’ column.
In case of original unit missing, do not display the 
value. 
Add the footnote: 
[1] Value with
original unit missing
are not displayed.
Listing 16.2.8.3 
Laboratory Results: Chemistry (Intention-
To-Treat Set)  
LBL001 
Same as Listing 16.2.8.1 
Add the footnote: 
[1] Value with
original unit missing
are not displayed.
Listing 16.2.8.4 
Physical Examination (Intention-To-Treat 
Set)  
PEL001 
- Remove ‘Analysis Period’ column.
- Remove ‘Study day in Period’.
Listing 16.2.9 
Comments (Intention-To-Treat Set) 
COL001 
Variables to be listed: 
- Subject ID
- Randomized Treatment
- Assessment
- Comment


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16.3 Figures 
Figure Number 
Figure Title 
Template 
Code 
Notes 
Footnotes/Source Table 
Number 
Figure 14.1.1 
Disposition Flow Chart (Enrolled Set) 
DSF001 
Source: Tables 14.1.1.1 and 
14.1.1.4 
Figure 14.2.1 
PaO2/FiO2 Ratio profile (Intention-To-Treat 
Set)  
TPF002 
- Treatment to be presented in legend
- X-axis should be “Timepoint” including Baseline
- Display below the X-axis, the number of subjects
with available results.
- Display the mean +/- SD
Source: Table 14.2.8 
Footnote: 
[1] Data are displayed until the
subject is discharged from ICU.
[2] Duplicated data reported twice
at 2 different timepoints are
reported at the first occurrence for
post dose/post randomisation and
at the last occurrence for pre
dose/pre randomisation.
Figure 14.2.2 
 FiO2 Profile (Intention-To-Treat Set) 
TPF002 
Same as Figure 14.2.3 
Source: Table 14.2.10 
Footnote: 
[1] Data are displayed until the
subject is discharged from ICU.
[2] Duplicated data reported twice
at 2 different timepoints are
reported at the first occurrence for
post dose/post randomisation and
at the last occurrence for pre
dose/pre randomisation.


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Figure Number 
Figure Title 
Template 
Code 
Notes 
Footnotes/Source Table 
Number 
Figure 14.2.3 
 SOFA Score Profile (Intention-To-Treat 
Set)  
TPF002 
Same as Figure 14.2.3 
Source :Table 14.2.13 
Footnote: 
[1] Data are displayed until the
subject is discharged from ICU.
Figure 14.2.4 
 Ventilatory Parameters Profiles (Intention-
To-Treat Set) -  
TPF002 
- Y-axis should be “Mean values”.
- X-axis should be “Timepoint”.
- Display below the X-axis, the number of subjects
with available results.
- Display the mean values +/- SD.
- Display one parameter per page (TV, respiratory
Rate, Cdyn, Cstat, PEEP, PIP, and Pplat).
Source: Table 14.2.15 
Footnote: 
[1] Data are displayed until the
subject is discharged from ICU.
[2] Duplicated data reported twice
at 2 different timepoints are
reported at the first occurrence for
post dose/post randomisation and
at the last occurrence for pre
dose/pre randomisation.