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)
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome
Sponsor: Chiesi Farmaceutici S.p.A.

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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

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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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
Version No.: 4.0
EUDRACT No.: 2020-002632-75 – IND No: 153286
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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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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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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Clinical Study Code No.: CLI-050000-04
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Date:  02 MAR 2021
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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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Date:  02 MAR 2021
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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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Version No.: 4.0
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Date:  02 MAR 2021
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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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Date:  02 MAR 2021
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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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Clinical Study Code No.: CLI-050000-04
Version No.: 4.0
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Date:  02 MAR 2021
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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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Date:  02 MAR 2021
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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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Date:  02 MAR 2021
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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

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
CONFIDENTIAL
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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 

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
CONFIDENTIAL
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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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Clinical Study Code No.: CLI-050000-04
Version No.: 4.0
EUDRACT No.: 2020-002632-75 – IND No: 153286
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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 
 Safety Contact using the paper Pregnancy Report Form that will be 

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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 
opinion of the Investigator, compromise the potential life-saving effect of the study treatment, 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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APPENDIX 1 - Approval of the protocol by clinical investigator(s)

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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

Clinical Study Protocol – Appendix 1
Clinical Study Code No.: CLI-050000-04
Version No.: 4.0
EUDRACT No.: 2020-002632-75 – IND No: 153286
Date:  02 MAR 2021
CONFIDENTIAL
Page 49/49
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