Conditions: Respiratory Distress Syndrome, Adult
Keywords: ARDS, human Acute Respiratory Distress Syndrome Respiratory Insufficiency
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 301
Healthy volunteers: no

Brief summary:
In this study effectiveness and safety of a new drug FP-1201-lyo (recombinant human interferon beta-1a) is compared to placebo. Investigation is conducted with patients who have acute respiratory distress syndrome (ARDS). The new drug is expected to reduce the time which a patient need to be on the ventilator and improve patient's chances of survival. Currently there are no approved drugs for treating moderate or severe ARDS patients.

Detailed description:
This is a Phase III clinical study to investigate the efficacy and safety of FP-1201-lyo (recombinant human interferon \[IFN\] beta-1a) compared to placebo in patients diagnosed with moderate or severe acute respiratory distress syndrome (ARDS). Primary objective is to demonstrate the efficacy of FP-1201-lyo in improving the clinical course and outcome based on survival and need for mechanical ventilation. Currently there are no approved drugs for treating moderate or severe ARDS patients.

FP-1201-lyo is a lyophilised powder form of recombinant human IFN beta-1a reconstituted in water for injection and is administered intravenously.

Recombinant human IFN beta-1a is an approved treatment for patients for other indication and its safety profile in such patients is well characterised.

Arms:
arm 1: FP-1201-lyo 10 μg (Interferon beta-1a) will be administered once daily as an intravenous bolus injection for 6 days.

Investigational product is lyophilisate for solution for injection which will be reconstituted in water for injection. arm 2: FP-1201-lyo Placebo will be administered once daily as an intravenous bolus injection for 6 days.

Investigational placebo product is lyophilisate for solution for injection which will be reconstituted in water for injection.

Interventions: intervention 1: Interferon beta-1a intervention 2: Placebo
Intervention descriptions: intervention 1: Investigational drug intervention 2: Placebo for investigational drug

Protocol document:
Prot_000.pdf: 
 
COVER PAGE FOR STUDY PROTOCOL 
 
Official Study Title:  A Phase III Double-blind, Randomised, Parallel-Group Comparison of the 
Efficacy and Safety of FP-1201-lyo (Recombinant Human Interferon Beta-1a) and Placebo in the 
Treatment of Patients with Moderate or Severe Acute Respiratory Distress Syndrome 
 
Unique Protocol ID: FPCLI002 (INTEREST Study)  
 
Date of the Study Protocol: 29 August 2017 (version 6.0) 
 
NCT Number: NCT02622724 
 
 


TITLE: A Phase III Double-blind, Randomised, Parallel-Group Comparison of 
the Efficacy and Safety of FP-1201-lyo (Recombinant Human Interferon Beta-1a) 
and Placebo in the Treatment of Patients with Moderate or Severe Acute 
Respiratory Distress Syndrome  
 
INTEREST study 
 
Sponsor: 
Faron Pharmaceuticals Ltd 
Joukahaisenkatu 6 
FIN-20520 Turku 
Finland 
Global Co-ordinating Investigators 
 
 
Sponsor Protocol No.: 
FPCLI002 
EudraCT No.: 
2014-005260-15 
Study Drug Name: 
FP-1201-lyo 
Development Phase: 
III 
Date of Protocol: 
29 Aug 2017, Final Version 6.0 
Includes: 
Amendment 1 (19 October 2015)  
Amendment 2 (22 October 2015) 
Non-Substantial Amendment 3 (30 June 
2016) 
Non-Substantial Amendment 4 (2 May 2017) 
Amendment 5 (29 Aug 2017) 
Date of Previous Protocol: 
2 May 2017, Final Version 5.0 
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice, with the Declaration of Helsinki and with other applicable regulatory requirements. 
This document contains confidential information of Faron Pharmaceuticals Ltd. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 






Faron Pharmaceuticals Ltd 
Clinical Study Protocol 
Protocol Number: FPCLI002 
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Declaration of the National Co-ordinating Investigator 
Title: A Phase III Double-blind, Randomised, Parallel-Group Comparison of the 
Efficacy and Safety of FP-1201-lyo (Recombinant Human Interferon Beta-1a) 
and Placebo in the Treatment of Patients with Moderate or Severe Acute 
Respiratory Distress Syndrome 
This study protocol including Amendments 1, 2, 3, 4 and 5 was subjected to critical 
review and has been approved by the Sponsor. The information it contains is 
consistent with the current risk/benefit evaluation of the investigational product as 
well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, as amended in 2013, and the ICH guidelines on 
Good Clinical Practice. 
 
National Co-ordinating Investigator 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 
 


Faron Pharmaceuticals Ltd 
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Protocol Number: FPCLI002 
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Declaration of the Investigator 
Title: A Phase III Double-blind, Randomised, Parallel-Group Comparison of the 
Efficacy and Safety of FP-1201-lyo (Recombinant Human Interferon Beta-1a) 
and Placebo in the Treatment of Patients with Moderate or Severe Acute 
Respiratory Distress Syndrome 
All documentation for this study that is supplied to me, and that has not been 
previously published will be kept in the strictest confidence. This documentation 
includes this study protocol, Investigator’s Brochure, electronic Case Report Form, 
and other scientific data. 
The study will not commence without the prior written approval of a properly 
constituted Independent Ethics Committee (IEC). No changes will be made to the 
study protocol without the prior written approval of the Sponsor and the IEC, except 
where necessary to eliminate an immediate hazard to the patients. 
I have read and understood and agree to abide by all the conditions and instructions 
contained in this protocol including Amendments 1, 2, 3, 4 and 5. 
 
Responsible Investigator of the local study centre 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 


Faron Pharmaceuticals Ltd 
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Protocol Number: FPCLI002 
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PROTOCOL SYNOPSIS 
Title 
A Phase III Double-blind, Randomised, Parallel-Group 
Comparison of the Efficacy and Safety of FP-1201-lyo 
(Recombinant Human Interferon Beta-1a) and Placebo in 
the Treatment of Patients with Moderate or Severe Acute 
Respiratory Distress Syndrome 
Sponsor Study No. 
FPCLI002 
Phase 
III 
Sponsor 
Faron Pharmaceuticals Ltd 
Global Co-ordinating 
Investigators 
 
 
Study Centre(s) 
Approximately 70-80 investigational sites located in Europe 
will participate in the study 
Objectives 
 
Primary Objective To demonstrate the efficacy of FP-1201-lyo in improving 
the clinical course and outcome based on survival and need 
for mechanical ventilation in patients with moderate or 
severe acute respiratory distress syndrome (ARDS) 
Secondary Objectives Safety 
• To assess the safety of FP-1201-lyo compared with 
placebo 
Efficacy 
• To evaluate 28-day all-cause mortality of 
FP-1201-lyo compared with placebo 
• To evaluate all-cause mortality at other selected 
time points 
• To evaluate the efficacy of FP-1201-lyo compared 
with placebo by assessing: 
- 
days free of organ failure 
- 
days free of renal support  
- 
days free of vasoactive support 
- 
days free of mechanical ventilation 
- 
number of intensive care unit (ICU)-free days  
- 
number of days in hospital  
• To evaluate the immunogenicity of FP-1201-lyo by 
monitoring neutralising antibodies to interferon 
(IFN) beta-1a 
• 
To evaluate the pharmacodynamics (PD) of 
FP-1201-lyo with myxovirus resistance protein A 
(MxA) 


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• 
To evaluate patient outcomes for respiratory (forced 
expiratory volume in 1 second [FEV1]) and 
neurological functioning (6-minute walk test 
[6MWT]) and quality of life (QoL) (EuroQol 5-
Dimensions 3-Levels questionnaire [EQ-5D-3L]) 
measured at selected time points 
Pharmacoeconomics 
• 
To evaluate selected pharmacoeconomic parameters 
Exploratory Objectives Exploratory 
• 
To evaluate gas exchange (partial pressure of 
oxygen/fraction of inspired oxygen [PaO2/FiO2] 
ratio) during mechanical ventilation as an 
indicator of improving lung function on treatment 
• 
To evaluate the PD of FP-1201-lyo using the 
cluster of differentiation (CD)73 biomarker  
• 
To evaluate selected potential inflammatory 
markers (PIMs) 
• 
To obtain a blood sample for future 
pharmacogenetic analysis 
• 
To evaluate all-cause mortality, QoL, and 
respiratory and neurological functioning at 
extended follow-up (Day [D]360) 
Design Double-blind, randomised, parallel-group evaluation of 
FP-1201-lyo compared with placebo 
Patients in the ICU will undergo screening during which 
informed consent will be obtained and eligibility 
assessed. No more than 48 hours may elapse between 
confirmation of moderate or severe ARDS and 
administration of the first dose of study drug 
Following randomisation, stratified by country and 
ARDS severity, patients will be treated daily with 
FP-1201-lyo 10 µg or placebo for 6 days and will 
undergo daily assessments while in the ICU for a 
maximum of 28 days. Long-term follow-up will occur at 
D90 (visit or telephone contact), D180, and an extended 
follow-up visit at D360, which is the final visit.  The 
main analysis and reporting will use D28 and long-term 
follow up D90 data. The results of the long-term follow 
up visit (D180) and the extended follow-up visit (D360) 
will each be reported separately as addendums to the 
Clinical Study Report 
An Independent Data Monitoring Committee will be 
established to monitor safety 


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Treatment FP-1201-lyo 10 µg (recombinant human IFN beta-1a) or 
placebo will be administered once daily as an 
intravenous bolus injection for 6 days 
FP-1201-lyo is a lyophilised powder reconstituted in 
water for injection 
Number of Patients 300 patients will be randomised with the aim of having 
272 evaluable patients at 70–80 investigational sites 
Population Adult patients diagnosed with moderate or severe ARDS. 
The inclusion and exclusion criteria apply during 
screening and prior to administration of the first dose of 
study drug on D1 
Inclusion Criteria All patients must be intubated and mechanically 
ventilated to diagnose ARDS and be eligible for the 
study 
1. Patient has a diagnosis of moderate or severe 
ARDS according to the Berlin definition of 
ARDS: 
1.1 
Acute onset of respiratory failure within 1 
week of a known clinical insult or new or 
worsening respiratory symptoms 
1.2 
Respiratory failure associated with known 
ARDS risk factors and not fully explained by 
either cardiac failure or fluid overload (an 
objective assessment of cardiac failure or fluid 
overload is needed if no risk factors for ARDS 
[moderate or severe ARDS] are present) 
1.3 
Radiological abnormalities on chest X-ray or 
on computerised tomography scan, i.e., 
bilateral opacities that are not fully explained 
by effusions, nodules, masses or lobar/lung 
collapse 
1.4 
Hypoxaemia: 
• 
Moderate ARDS: PaO2/FiO2 >100 mmHg 
(>13.3 kPa) to ≤200 mmHg (≤26.6 kPa) 
with positive end expiratory pressure 
(PEEP) ≥5 cmH2O 
• 
Severe ARDS: PaO2/FiO2 ≤100 mmHg 
(≤13.3 kPa) with PEEP ≥5 cmH2O 
2. The radiological and hypoxaemia criteria (1.3 
and 1.4) must be met within the same 24-hour 
period. The time of onset of ARDS is when the 
last of the two specified ARDS criteria is met 
3. Administration of the first dose of study drug 
must be planned to take place within 48 hours of 
moderate or severe ARDS diagnosis.  


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4. Patient is intubated and mechanically ventilated 
5. A signed informed consent form from the patient 
or the patient’s personal legal representative or a 
professional legal representative must be 
available 
6. Patient is aged ≥18 years 
Exclusion Criteria 
1. Woman known to be pregnant, lactating or with a 
positive (urine or serum test) or indeterminate 
(serum test) pregnancy test 
2. Patient is simultaneously taking part in another 
pharmacotherapy protocol 
3. Patient is not expected to survive for 24 hours 
4. Patient has an underlying clinical condition 
where, in the opinion of the Investigator, it would 
be extremely unlikely that the patient would 
come off ventilation, e.g., motor neurone disease, 
Duchenne muscular dystrophy or rapidly 
progressive interstitial pulmonary fibrosis 
5. Patient has severe chronic obstructive pulmonary 
disease requiring long-term home oxygen therapy 
or mechanical ventilation (non-invasive 
ventilation or via tracheotomy) except for 
continuous positive airway pressure (CPAP) or 
bi-level positive airway pressure used solely for 
sleep-disordered breathing 
6. Patient has congestive heart failure, defined as 
New York Heart Association class IV 
7. Patient has acute left ventricular failure 
8. Patient has liver failure (Child–Pugh grade C) 
9. Patient has received any prior interferon 
10. Patient has known hypersensitivity to natural or 
recombinant IFN beta or to any of the excipients 
11. Patient is receiving renal dialysis therapy for 
chronic renal failure 
12. Patient is receiving extra-corporeal membrane 
oxygenation, high-frequency oscillatory 
ventilation or any form of extra-corporeal lung 
support 
13. Patient has had any form of mechanical 
ventilation (invasive or non-invasive, excluding 
CPAP alone) for longer than 48 hours prior to the 
diagnosis of ARDS 
Non-invasive ventilation has to be continuously 
applied for at least 12 hours per day in these 
48 hours 
14. Patient has burns to ≥15% of their total body 
surface area 
Criteria for Evaluation 
of Efficacy Primary Efficacy Endpoint: 


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• 
Composite endpoint including any cause of death 
at D28 and days free of mechanical ventilation 
(VFDsurv) within 28 days among survivors 
Secondary Efficacy Endpoints:  
• 
Secondary endpoints relating to the 
efficacy of FP-1201-lyo treatment: 
− 
All-cause mortality at D28, D90 and 
D180 
− 
Mortality in ICU up to D28 
− 
Mortality in hospital up to D28 
• 
Other secondary efficacy endpoints at 
D28 :  
− 
Days free of organ failure (Sequential 
Organ Failure Assessment 
methodology) (D28 or last day in ICU 
if patient has left the ICU earlier than 
D28, or at withdrawal) 
− 
Days free of renal support 
− 
Days free of vasoactive support 
− 
Days free of mechanical ventilation  
− 
Number of ICU-free days  
− 
Number of days in hospital  
• 
Presence of neutralising antibodies to IFN beta-
1a at baseline and D28 (or last day in ICU if 
patient has left the ICU earlier than D28, or at 
withdrawal)  
• 
Evaluation of PD using MxA biomarker from 
baseline to D14 
• 
Long-term secondary endpoints, relating to QoL, 
respiratory and neurological functioning at 
D180: 
− 
EQ-5D-3L 
− 
6MWT  
− 
FEV1  
Criteria for Evaluation 
of Safety 
• 
Adverse events up to D28, AEs occurring after 
D28 if the investigator considers there is a causal 
relationship with the study drug and all deaths up 
to D360 
• 
Physical examination, vital signs and laboratory 
results (biochemistry, haematology and 
urinalysis) up to D28 (or last day in ICU if 
patient has left the ICU earlier than D28, or at 
withdrawal)  
Criteria for Evaluation 
of Pharmacoeconomics 
• 
Endpoints for the evaluation of 
pharmacoeconomics at D28: 


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− 
Days free of organ failure (D28 or last 
day in ICU if patient has left the ICU 
earlier than D28, or at withdrawal) 
− 
Days free of renal support 
− 
Days free of vasoactive support  
− 
Days free of mechanical ventilation 
− 
Number of ICU-free days 
− 
Number of days in hospital  
Criteria for Evaluation 
of Exploratory 
Variables 
• 
Exploratory endpoints relating to the efficacy of 
FP-1201-lyo treatment: 
− 
Composite endpoint including mortality 
and days free of mechanical ventilation 
(VFDsurv) within 90 days among 
survivors 
− 
Ordered categorical endpoint defined as 
improvement (severe to moderate/mild; 
from moderate to mild ARDS), no change 
or worsening (from moderate to 
severe/death; from severe to death) in 
terms of gas exchange (PaO2/FiO2 ratio) 
from baseline to D28 (or last day in ICU 
if patient has left the ICU earlier than 
D28, or at withdrawal) 
• 
Change in the treatment-specific exploratory 
biomarker CD73 concentration from baseline to 
D14 
• 
Changes in levels of PIMs, including but not 
limited to, interleukin-6 and -8 from baseline to 
D14 
• 
A blood sample will be taken for 
pharmacogenetic analysis and correlation with 
other markers of the activity of FP-1201-lyo 
• 
Extended long-term follow-up: 12-month 
mortality rate, EQ-5D-3L, 6MWT and FEV1 
Statistical Methods For 90% power and a two-sided Mann–Whitney U-test at 
the significance level of 0.05, a total of 272 patients are 
required based on the following assumptions: 
• 
mortality rate of 30% in the control group and 
15% in the FP-1201-lyo group at D28 
• 
20% of patients survive but with zero ventilator-
free days (VFDs) in the control group 
• 
A mean difference (FP-1201-lyo minus control) 
of 3.0 days in mean ventilator-free days where 
patients who die are assigned a score of 0  
 
However, assuming 5% of patients (16) drop-out and a 
further 4% (12) of the remaining patients will not be 
evaluable for the efficacy analysis, the study will 


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randomise 300 patients to build in some flexibility 
around the assumptions listed above. 
 
Analysis Sets: 
 
The Full Analysis Set (FAS) will consist of all 
randomised and treated patients 
 
The Per-Protocol Set (PPS) will consist of those patients 
in the FAS excluding patients with major protocol 
violations. A list of major protocol violations relevant for 
excluding data from the PPS will be detailed in the 
Statistical Analysis Plan. The precise definition of the 
PPS at the patient level will be identified at the blinded 
data review meeting 
 
Statistical analyses for the primary and secondary 
endpoints will be performed on both the FAS and PPS 
 
The safety set will consist of all patients who receive at 
least one dose of study drug. The safety and tolerability 
analyses will be based on this analysis set. A patient who 
receives the wrong treatment according to the 
randomisation will be analysed for safety and tolerability 
in the treatment group corresponding to the treatment 
received 
 
Primary Endpoint Analysis 
The primary composite endpoint includes death and days 
free of mechanical ventilation within 28 days among 
survivors. VFDs to D28 is defined as the number of 
calendar days during which the patient is ventilator-free 
including two unassisted breathing (UAB) days to D28, 
assuming that a patient survives for at least two 
consecutive calendar days after initiating UAB. The non-
parametric analysis of the primary composite endpoint 
VFDsurv is based on a scoring scheme with patients who 
do better getting a higher score. All patients who die 
before 28 days will be assigned a VFDsurv score of -1. 
For those patients who survive to D28 the VFDsurv 
score will be equal to the number of VFDs calculated 
according to the above definition. The statistical method 
for group comparison of this endpoint will be based on 
the van Elteren test adjusting for the country, ARDS 
severity and key baseline characteristics. The statistical 
methodology for the scoring scheme is as set down in 
Finkelstein and Schoenfeld. 


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LIST OF STUDY PERSONNEL 
Sponsor 
 
Faron Pharmaceuticals Ltd 
Joukahaisenkatu 6 
FIN-20520 Turku 
Finland 
 
 
Global Co-ordinating 
Investigators 
 
University College London Hospitals, NHS 
Foundation Trust, 
Critical Care Unit, 3rd Floor Tower, 235 Euston 
Road, 
London, NW1 2BU 
UK 
 
 
  
 
 
 
Universita La Sapeinza Policlinico Umberto I, 
Viale del Policlinico, 155, 00186, 
Rome, 
Italy    
 
  
Contract Research 
Organisation 
PPD Global Limited 
Granta Park, Great Abington,  
Cambridge, CB21 6GQ, United Kingdom 
Medical Monitor 
Eligibility Confirmation and Medical Monitor 
 
 
 
 
Medical Monitor local rate phone numbers: 
Finland: 
 
Belgium: 
 
Czech Republic: 
 
France: 
 
Germany: 
 


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Italy:  
 
The Netherlands: 
 
Spain: 
 
UK:  
 
Safety Reporting 
Crown CRO Oy 
Vaisalantie 4 
02130 Espoo 
Finland 
 
 
 
Central Laboratory for 
Analysis of Neutralising 
Antibodies to IFN beta-
1a, MxA and CD73 
Euro Diagnostica AB 
Wieslab AB 
P.O. Box 50117 
SE-202 11 Malmö 
Sweden 
 
Euro Diagnostica AB 
 
 
Wieslab AB 
 
 
Central Laboratory for 
Analysis of PIMs and 
genetic sample 
MediCity Research Laboratory, University of Turku, 
Tykistökatu 6A 
FIN-20520 Turku 
Finland 
 
 
Drug Supply 
Fisher Clinical Services UK Limited 
Langhurstwood Road 
Horsham 
West Sussex, RH12 4QD 
UK 
 
 
Responsible Statistician  
 
Data Magik Ltd., UK 
 
Interactive Web-
Response System (IWRS) 
For contact details please refer to the IWRS User 
Manual in the Investigator Package 
 


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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ........................................................................................................ 6 
LIST OF STUDY PERSONNEL .............................................................................................. 13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................................... 19 
1 
INTRODUCTION ........................................................................................................ 21 
1.1 
BACKGROUND .............................................................................................................. 21 
1.1.1 
Acute Respiratory Distress Syndrome ............................................................... 21 
1.1.2 
FP-1201-lyo in Moderate or Severe Acute Respiratory Distress Syndrome ....... 22 
1.2 
RATIONALE .................................................................................................................. 23 
1.3 
RISK/BENEFIT ASSESSMENT ............................................................................................ 24 
2 
STUDY OBJECTIVES ................................................................................................... 25 
2.1 
PRIMARY OBJECTIVE ..................................................................................................... 25 
2.2 
SECONDARY OBJECTIVES ................................................................................................ 25 
2.2.1 
Safety Objectives .............................................................................................. 25 
2.2.2 
Efficacy Objectives ............................................................................................ 25 
2.2.3 
Pharmacoeconomic Objectives ......................................................................... 25 
2.2.4 
Exploratory Objectives ...................................................................................... 25 
3 
OVERALL DESIGN AND PLAN OF THE STUDY .............................................................. 26 
3.1 
OVERVIEW .................................................................................................................. 26 
3.2 
CRITERIA FOR EVALUATION OF THE STUDY ........................................................................ 29 
3.2.1 
Criteria for Evaluation of Efficacy ..................................................................... 29 
3.2.2 
Criteria for Evaluation of Safety ........................................................................ 29 
3.2.3 
Criteria for Evaluation of Pharmacoeconomics ................................................ 29 
3.2.4 
Criteria for Evaluation of Exploratory Endpoints .............................................. 30 
3.3 
JUSTIFICATION OF THE STUDY DESIGN .............................................................................. 30 
4 
STUDY POPULATION ................................................................................................. 31 
4.1 
INCLUSION CRITERIA ..................................................................................................... 31 
4.2 
EXCLUSION CRITERIA ..................................................................................................... 31 
4.3 
CONFIRMATION OF PATIENT ELIGIBILITY ........................................................................... 32 
4.4 
PATIENT WITHDRAWAL AND REPLACEMENT ...................................................................... 33 
4.4.1 
Discontinuation Criteria .................................................................................... 33 
4.4.2 
Replacement Policy ........................................................................................... 34 
4.5 
PLANNED SAMPLE SIZE AND NUMBER OF STUDY CENTRES ................................................... 34 
4.6 
PATIENT IDENTIFICATION AND RANDOMISATION ................................................................ 34 
4.6.1 
Patient Identification ........................................................................................ 34 
4.6.2 
Randomisation Scheme .................................................................................... 35 
4.6.3 
Randomisation of Patients to Treatment ......................................................... 35 
5 
STUDY DRUG ............................................................................................................ 36 
5.1 
IDENTITY ..................................................................................................................... 36 
5.2 
ADMINISTRATION ......................................................................................................... 36 
5.3 
PACKAGING, LABELLING AND STORAGE ............................................................................ 36 
5.4 
BLINDING AND BREAKING THE BLIND ............................................................................... 37 
5.5 
DRUG ACCOUNTABILITY ................................................................................................. 37 
5.6 
COMPLIANCE ............................................................................................................... 38 
5.7 
PREVIOUS AND CONCOMITANT MEDICATIONS ................................................................... 38 
6 
VARIABLES AND METHODS OF ASSESSMENT ............................................................ 39 


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6.1 
EFFICACY VARIABLES ..................................................................................................... 39 
6.1.1 
Primary Efficacy Variables ................................................................................ 39 
6.1.2 
Secondary Efficacy Variables ............................................................................ 39 
6.2 
SAFETY VARIABLES ........................................................................................................ 42 
6.2.1 
Adverse Events .................................................................................................. 42 
6.2.2 
Laboratory Variables ........................................................................................ 47 
6.2.3 
Vital Signs ......................................................................................................... 48 
6.2.4 
ECG ................................................................................................................... 48 
6.2.5 
Physical Examinations ...................................................................................... 48 
6.3 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................................. 48 
6.3.1 
Patient Demography ......................................................................................... 49 
6.3.2 
Disease History ................................................................................................. 49 
6.3.3 
Medical History ................................................................................................. 49 
6.3.4 
Previous and Concomitant Medications ........................................................... 52 
6.4 
PHARMACOECONOMIC EVALUATION ................................................................................ 52 
6.5 
EXPLORATORY VARIABLES .............................................................................................. 52 
6.5.1 
Improvement in Gas Exchange ......................................................................... 52 
6.5.2 
Biomarkers: CD73 and Potential Inflammatory Markers (PIM) ........................ 52 
6.5.3 
Pharmacogenetics ............................................................................................ 52 
7 
STUDY CONDUCT ...................................................................................................... 54 
7.1 
SCHEDULE OF PROCEDURES ............................................................................................ 55 
7.2 
PROCEDURES BY VISIT ................................................................................................... 58 
7.2.1 
Pre-screening Evaluation and Screening Log .................................................... 58 
7.2.2 
Screening Assessments and Pre-dose Procedures ............................................ 58 
7.2.3 
Treatment Period: D1 Dosing and Post-dose .................................................... 61 
7.2.4 
Treatment Period: D2 to D6 .............................................................................. 61 
7.2.5 
Short-term Follow-up Period: D7 to D14 ........................................................... 62 
7.2.6 
Short-term Follow-up Period: D15 to D27 ......................................................... 63 
7.2.7 
Short-term Follow-up Period: Last Day in ICU ................................................... 63 
7.2.8 
Short-term Follow-up Period: D28 .................................................................... 64 
7.2.9 
Long-term Follow-up Period: D90 and D180 ..................................................... 64 
7.2.10 
Extended Long-term Follow-up: D360 .............................................................. 64 
7.2.11 
Early Termination Visit ...................................................................................... 65 
8 
STATISTICAL METHODS ............................................................................................. 66 
8.1 
STUDY PATIENTS .......................................................................................................... 66 
8.1.1 
Disposition of Patients ...................................................................................... 66 
8.1.2 
Protocol Deviations ........................................................................................... 66 
8.1.3 
Analysis Sets ..................................................................................................... 66 
8.2 
GENERAL CONSIDERATIONS ............................................................................................ 67 
8.2.1 
Analysis and Data Conventions ......................................................................... 67 
8.3 
DEMOGRAPHICS, MEDICAL HISTORY, BASELINE CHARACTERISTICS AND CONCOMITANT 
MEDICATIONS ........................................................................................................................ 68 
8.4 
TREATMENT COMPLIANCE ............................................................................................. 68 
8.5 
EFFICACY ANALYSES ...................................................................................................... 68 
8.5.1 
Primary Efficacy Analysis .................................................................................. 68 
8.5.2 
Secondary Efficacy Analyses ............................................................................. 69 
8.6 
SAFETY ANALYSES ......................................................................................................... 70 
8.6.1 
Adverse Events .................................................................................................. 71 
8.6.2 
Vital Signs ......................................................................................................... 71 
8.6.3 
Clinical Laboratory and Urinalysis Variables ..................................................... 71 
8.6.4 
Physical Examination ........................................................................................ 71 


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8.6.5 
Independent Data Monitoring Committee ....................................................... 71 
8.7 
PHARMACOECONOMICS ................................................................................................ 71 
8.8 
EXPLORATORY ANALYSES ............................................................................................... 72 
8.8.1 
Composite Endpoint at 90 Days ........................................................................ 72 
8.8.2 
Gas Exchange Ratio .......................................................................................... 72 
8.8.3 
CD73 and Potential Inflammatory Markers; Pharmacogenetic Analysis .......... 72 
8.8.4 
Extended Follow-up .......................................................................................... 72 
8.9 
INTERIM ANALYSES ....................................................................................................... 72 
8.10 
DETERMINATION OF SAMPLE SIZE ................................................................................ 72 
9 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ...................................................... 75 
9.1 
DATA QUALITY ASSURANCE ............................................................................................ 75 
9.1.1 
Database Management and Quality Control .................................................... 75 
9.2 
CASE REPORT FORMS AND SOURCE DOCUMENTATION ....................................................... 75 
9.2.1 
Data Collection ................................................................................................. 75 
9.3 
ACCESS TO SOURCE DATA .............................................................................................. 76 
9.4 
ARCHIVING STUDY RECORDS .......................................................................................... 76 
9.5 
GOOD CLINICAL PRACTICE .............................................................................................. 76 
9.6 
INFORMED CONSENT .................................................................................................... 76 
9.6.1 
Consent Procedure ............................................................................................ 77 
9.6.2 
Patient Consent ................................................................................................ 77 
9.6.3 
Personal Legal Representative Consent ............................................................ 78 
9.6.4 
Professional Legal Representative Consent ...................................................... 78 
9.6.5 
Retrospective Patient Informed Consent .......................................................... 78 
9.6.6 
Withdrawal of Consent ..................................................................................... 78 
9.7 
PROTOCOL APPROVAL AND AMENDMENT ......................................................................... 79 
9.8 
INDEPENDENT DATA MONITORING COMMITTEE ................................................................ 79 
9.9 
STEERING COMMITTEE .................................................................................................. 79 
9.10 
DURATION OF THE STUDY ........................................................................................... 80 
9.11 
PREMATURE TERMINATION OF THE STUDY .................................................................... 80 
9.12 
CONFIDENTIALITY ...................................................................................................... 80 
9.13 
OTHER ETHICAL AND REGULATORY ISSUES .................................................................... 80 
9.14 
PUBLICATION POLICY ................................................................................................. 81 
10 
REFERENCE LIST ..................................................................................................... 82 
11 
APPENDIX 1: GUIDANCE ON SUPPORTIVE CARE MEASURES .................................. 84 
11.1 
GUIDANCE ON SUPPORTIVE CARE MEASURES ................................................................ 84 
11.2 
REFERENCE LIST ........................................................................................................ 90 
12 
APPENDIX 2: GUIDELINES FOR THE SIX-MINUTE WALK TEST .................................. 91 
 


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Tables 
Table 1 
The Berlin ARDS Definition ................................................................ 21 
Table 2 
SOFA Scoring ...................................................................................... 40 
Table 3 
Laboratory Assessments ....................................................................... 47 
Table 4 
APACHE II score ................................................................................. 50 
Table 5 
Schedule of Procedures ........................................................................ 55 
Table 6 
Values for Power for Various Mortality Rates per Treatment Group 
(n=300) ................................................................................................. 73 
Table 7 
Conservative Fluid Management Algorithm ........................................ 88 
 
Figures 
Figure 1: Study Design ........................................................................................ 27 
Figure 2: Flow Chart of Screening and Randomisation Procedures .................... 28 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
A-aDO2 
Alveolar-arterial oxygen difference 
AE 
Adverse Event 
ALI 
Acute Lung Injury 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
ARDS 
Acute Respiratory Distress Syndrome 
BIPAP 
Bilevel Positive Airway Pressure 
BP 
Blood Pressure 
CAPD 
Continuous Ambulatory Peritoneal Dialysis 
CD73 
Cluster of differentiation 73 
CDMS 
Clinical Data Management System 
CI 
Confidence Interval 
CPAP 
CRA 
Continuous Positive Airway Pressure 
Clinical Research Associate (Monitor) 
CT 
Computerised Tomography 
D 
Day (as in treatment day) 
ECG 
Electrocardiogram 
e-CRF 
Electronic Case Report Form 
EQ-5D-3L 
EuroQol 5-Dimensions 3-Levels questionnaire 
FAS 
Full Analysis Set  
FEV1 
Forced Expiratory Volume in 1 second 
FiO2 
Fraction of inspired oxygen 
FU 
Follow-up 
GCS 
Glasgow Coma Scale  
HD 
Haemodialysis 
HFOV 
High-Frequency Oscillatory Ventilation 
HR 
Heart Rate 
ICD 
Informed Consent Document 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IVRS 
Interactive Voice-Response System 
IWRS 
Interactive Web-Response System  


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MM 
Medical Monitor 
MIU 
Million International Units 
MxA 
Myxovirus resistance protein A 
NOAEL 
No Observed Adverse-Effect Level 
OTD 
Optimum Tolerated Dose 
PaO2 
Partial pressure of oxygen 
PBW 
Predicted Body Weight 
PEEP 
Positive End Expiratory Pressure 
PerLR 
Personal Legal Representative 
PD 
Pharmacodynamics 
PHT 
Portal hypertension 
PIM 
Potential Inflammatory Marker 
PPS 
Per-Protocol Set  
PrfLR 
Professional Legal Representative 
QoL  
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOFA 
Sequential Organ Failure Assessment 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
UAB 
Unassisted breathing 
VFD 
Ventilator-Free Day 
VFDsurv 
Composite endpoint including any cause death at D28 and days free of 
mechanical ventilation within 28 days among survivors 
WFI 
Water For Injection  
6MWT 
6-Minute Walk Test 
 


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1 
INTRODUCTION 
This is a Phase III clinical study to investigate the efficacy and safety of FP-1201-lyo 
(recombinant human interferon [IFN] beta-1a) in patients diagnosed with moderate or 
severe acute respiratory distress syndrome (ARDS). FP-1201-lyo is a lyophilised 
powder form of recombinant human IFN beta-1a reconstituted in water for injection 
and is administered intravenously. Recombinant human IFN beta-1a is an approved 
treatment for patients with relapsing-remitting multiple sclerosis and its safety profile 
in such patients is well characterised. 
1.1 
Background 
1.1.1 
Acute Respiratory Distress Syndrome 
ARDS is a type of acute diffuse lung injury associated with recognised risk factors 
that is characterised by inflammation leading to increased pulmonary vascular 
permeability and loss of aerated lung tissue. ARDS is a serious clinical disorder, 
which follows a variety of severe lung insults. Such insults include, among others, 
pneumonia, aspiration of gastric contents, non-pulmonary sepsis and major trauma. 
ARDS is characterised by injury to the endothelial barriers and alveolar epithelium of 
the lung, acute lung inflammation and protein-rich pulmonary oedema leading to 
acute respiratory failure. In the Berlin definition of ARDS (see Table 1 (Ref: ARDS 
Definition Task Force 2012)) severity can range from mild, through moderate, to severe 
ARDS. 
Table 1 
The Berlin ARDS Definition 
Characteristic 
Mild ARDS 
 
Moderate ARDS 
Severe ARDS 
Timing 
Acute onset within 1 week of a known clinical insult or new or worsening 
respiratory symptoms 
Hypoxaemia 
PaO2/FiO2  
>200–≤300 mmHg 
with PEEP or CPAP 
≥5 cmH2O 
PaO2/FiO2  
>100– ≤200 mmHg  
with PEEP ≥5 cmH2O 
PaO2/FiO2  
≤100 mmHg  
with PEEP ≥5 cmH2O 
Origin of 
oedema 
Respiratory failure associated with known ARDS risk factors and not fully 
explained by cardiac failure or fluid overload. An objective assessment of 
cardiac failure or fluid overload is needed if no ARDS risk factors are present 
Radiological 
abnormalities 
(chest X-ray or 
CT scan) 
Bilateral opacities not fully explained by effusions, nodules, masses or 
lobar/lung collapse 
Abbreviations: ARDS=acute respiratory distress syndrome; CPAP=continuous positive airway 
pressure; CT=computerised tomography; PaO2/FiO2=partial pressure of oxygen/fraction of inspired 
oxygen; PEEP=positive end expiratory pressure. 
The mortality rates in patients with ARDS range from approximately 20% to 40% 
across all severities, and can be even higher when associated with dysfunction in 
other organs. Although mortality from ARDS has decreased in the last decade due to 
improvements in supportive care and in the treatment of underlying conditions, it still 
remains at a high level. 
ARDS is also costly in health economics terms. Patients with ARDS consume 
significantly more resources than matched patients without moderate or severe ARDS 


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because they require longer intensive care unit (ICU) and hospital stays. The quality 
of life (QoL) of these patients may also be significantly impacted, with 35% of 
patients with moderate or severe ARDS unable to return to work 24 months after 
hospital discharge. 
There are currently no approved pharmacological therapies for ARDS. ARDS has no 
primary treatments proven to improve outcomes other than supportive care. 
1.1.2 
FP-1201-lyo in Moderate or Severe Acute Respiratory Distress Syndrome 
In serious life-threatening situations, such as infection leading to sepsis or trauma 
causing massive tissue injuries, an escalation of the systemic inflammatory response 
leads to multiple organ failure including ARDS. In the case of ARDS, a key 
pathophysiological result is increased vascular leakage, which has been suggested to 
be related to a lack of adenosine, which acts to enhance endothelial barrier function. 
Therefore any biological substances that act to increase adenosine levels should 
reduce vascular leakage and be of benefit in ARDS. Such a substance is cluster of 
differentiation 73 (CD73) – a cell surface enzyme. Interferons, such as IFN beta-1a, 
have been shown to up-regulate CD73 and therefore could be a potential treatment for 
moderate or severe ARDS. Preclinical studies have shown that CD73 expression on 
endothelial cells is up-regulated by IFN beta-1a treatment in a time- and dose-
dependent fashion. (Ref: Kiss et al 2007) Furthermore, in a mouse multi-organ failure model, 
IFN beta-1a was shown to be of benefit in protecting the alveolar structure from 
damage compared with controls. In addition, IFN beta-1a treatment has been shown 
to prevent leakage in animal models of acute lung injury (ALI). Enhanced adenosine 
production also controls leucocyte infiltration, thus reducing the escalation of 
inflammation in lungs. 
The studies conducted by Faron Pharmaceuticals Ltd to date have been performed 
with the lyophilised product (FP-1201-lyo) intended to be used in clinical studies and 
subsequent commercial use. A 28-day safety study was conducted in cynomolgus 
monkeys at three dose levels. This study showed that treatment with intravenous 
FP-1201-lyo at dose levels of 0.25, 1.0 and 3.0 million international units (MIU)/kg/d 
was well tolerated. FP-1201-lyo treatment was associated with minor changes in 
haematological and clinical chemistry variables, including an expected increase in 
concentrations of myxovirus resistance protein A (MxA) in the blood and increased 
neutralising antibody activity on completion of treatment, particularly at the highest 
dose. 
The no observed adverse-effect level (NOAEL) for IFN beta-1a in cynomolgus 
monkeys was considered 3.0 MIU/kg/d for 28 days. In a 70 kg human this would 
translate to a dose of 210 MIU/d or a total dose of 1260 MIU over 6 days. The 
proposed daily dose for this clinical study is 2.7 MIU/d (10 µg/d), i.e., a total of 16.2 
MIU (60 µg) over 6 days. The NOAEL is therefore 77.7 times the proposed 6-day 
exposure to IFN beta-1a. 
Recombinant human IFN beta-1a (FP-1201) was assessed for the treatment of ALI 
and ARDS (1994 American-European Consensus Conference definition of 
ALI/ARDS (Ref: Bernard et al 1994)) in a Phase I/II study (FPCLI001) (Ref: Bellingan et al 2014). 
This open-label study included 37 patients with ALI/ARDS and the optimum 
tolerated dose (OTD) was shown to be FP-1201 10 µg daily for 6 days. The primary 
efficacy endpoint was the Day 28 mortality rate, which was 8.1% in the safety 
population – well below that normally seen in ICUs in the UK for patients with 
ALI/ARDS. From the literature, Day 28 mortality rates for ALI/ARDS vary from 


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20% (ALI) to over 60% (ARDS), with a generally accepted figure of approximately 
40%. (Ref: Phua et al 2009, Doyle et al 1995, Zilberberg et al 1998, Sloane et al 1992) The long-term efficacy 
endpoint of 6-month mortality also demonstrated a mortality rate well below that 
expected for this population of patients. Four of the 37 patients died before the 6-
month time point. 
Pyrexia was the most common drug-related treatment-emergent adverse event 
(TEAE) in the study. All pyrexia events resolved rapidly without sequelae. Clinically 
significant low haemoglobin values were recorded in all cohorts at different time 
points during the study (including both at screening and at Day 28). No other trends 
in laboratory values or other safety variables were observed from baseline to Day 28. 
Data from the measurements of vital signs, electrocardiograms (ECGs), other 
laboratory data (biochemistry and haematology) and physical examinations showed 
no clear trends. At Day 28, chest X-rays for 19 patients showed improvements since 
the previous assessment. 
Since the completion of the Phase I/II study the terminology relating to ALI and 
ARDS has been reviewed and revised. The term ALI has been dropped and ARDS is 
now defined as mild, moderate or severe, with clearly defined criteria applied for: 
timing of symptom onset; severity of hypoxaemia; origin of lung oedema; and level 
of radiological abnormality as assessed by chest X-ray. The revision of the American-
European Consensus Conference definition of ARDS was presented at the meeting of 
the European Society of Intensive Care Medicine held in Berlin, Germany, on 5 
October 2011. The Berlin definition (Ref: ARDS Definition Task Force 2012) (see Table 1) will be 
used in this Phase III study. 
Further details can be found in the Investigator’s Brochure, which contains 
comprehensive information on the investigational product. Also see Section 3.1 for 
details concerning the design of the current study and Section 3.3 for justification of 
the design of this study. 
1.2 
Rationale 
The results of the Phase I/II study (FPCLI001) provided evidence for the beneficial 
effect of FP-1201 –intravenously administered IFN beta – in patients with ARDS and 
fully supported the conduct of a pivotal and well-controlled Phase III study. 
The dose selected for this study (10 µg) is based on information from the previous 
study, where the maximum tolerated dose was found to be 22 µg. A dose of 10 µg 
was shown to be the OTD based on information from dose-limiting toxicity and 
proven markers of IFN beta-1a biological activity. An expansion cohort of 22 patients 
treated with the OTD (10 µg) demonstrated clear preliminary evidence for the 
efficacy and biological activity of IFN beta-1a using proven surrogate markers 
without major safety concerns. 
Early diagnosis and treatment is essential for effectively treating ARDS before it 
becomes so severe that organ damage or death is almost inevitable. The rapid 
systemic exposure of medication provided by administering the drug intravenously 
makes this the appropriate route of administration in this patient population. In 
severely ill sedated patients, poor peripheral circulation may result in drugs given 
subcutaneously not being adequately distributed. 
In relation to the treatment duration of only 6 days, the pathogenesis of ARDS is 
divided into three distinct phases – acute (days 1–6), sub-acute (days 7–14) and 
chronic (day 15+) – with fibrosis of the lungs beginning within the first week after 


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initial insult. Almost all patients who fail to improve or deteriorate after 1 week of 
ventilation have evidence of lung fibrosis. Administering treatment beyond 6 days 
would add little value to patients included in this study. This 6-day dosing regimen 
has therefore been selected as the optimal treatment regimen. 
1.3 
Risk/Benefit Assessment 
Non-clinical data reveal no special hazard for humans treated with FP-1201 in 
conventional studies of safety, pharmacology, repeated-dose toxicity and 
genotoxicity. 
ARDS is a severe condition with a high mortality rate, despite progress in ICU 
medicine. Currently there is no approved pharmacological therapy available for 
ARDS. Patients with ARDS are treated with intensive support, which includes 
various strategies for assisted ventilation. The results of the Phase I/II study 
(FPCLI001) provided evidence for the beneficial effect of FP-1201 in patients with 
ARDS and fully supported the conduct of a pivotal and well-controlled Phase III 
study. 
IFNs were the first cytokines to be administered to humans; they are endogenous 
pyrogens and fever has been recognised as a frequent event. The febrile response 
varies with the dose, type and route of administration. Fever is characterised by 
preceding mild malaise and shaking chills that lead to elevation of body temperature. 
IFNs only occasionally cause rigors, in contrast to tumour necrosis factors. There is a 
well-described thermal ceiling, which means that fever does not exceed certain levels, 
regardless of the dose of IFN used. In addition, pyrogenic tolerance often develops 
with daily administration. This gradual diminution in pyrogenicity is one of the 
hallmarks of IFN therapy, a characteristic not shared by therapy with other pyrogenic 
cytokines. 
On the first day of IFN therapy, the patient’s temperature characteristically reaches 
38–39°C (orally) 5–6 hours after IFN administration, and this elevation persists for 
around 2 hours. The temperature elevations experienced by patients vary substantially 
between individuals. The pyrogenic effect (high fever, rigors and chills) of IFN beta-
1a was observed in the Phase I/II study at the highest dose of FP-1201 22 µg; this was 
shown to be the maximum tolerated dose. 
IFN-induced fever responds to antipyretic analgesic drugs and they are recommended 
to decrease or prevent the flu-like symptoms associated with FP-1201-lyo 
administration. 
The objectives of the Phase I/II clinical study were to assess the safety, tolerability 
and preliminary efficacy of the optimal tolerated dose, which was shown to be 10 µg 
daily for 6 days. The scientific rationale is that a biological substance, which acts to 
increase adenosine levels, should reduce vascular leakage and be of benefit in ARDS. 
The benefit of interferon beta-1a in the Phase I/II was shown by the fall in the 
mortality rate and the number of ICU days. The pivotal clinical study, FPCLI002, is 
being conducted to confirm the safety and efficacy of interferon beta-1a (FP-1201-
lyo) in patients with moderate to severe ARDS. 
The available information suggests that the present study has a favourable risk/benefit 
ratio. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to demonstrate the efficacy of FP-1201-lyo in 
improving the clinical course and outcomes based on survival and need for 
mechanical ventilation in patients with moderate or severe ARDS. 
2.2 
Secondary Objectives 
2.2.1 
Safety Objectives 
• 
To assess the safety of FP-1201-lyo compared with placebo 
2.2.2 
Efficacy Objectives 
• 
To evaluate 28-day all-cause mortality of FP-1201-lyo compared with placebo 
• 
To evaluate all-cause mortality at other selected time points 
• 
To evaluate the efficacy of FP-1201-lyo compared with placebo by assessing: 
- 
Days free of organ failure 
- 
Days free of renal support 
- 
Days free of vasoactive support 
- 
Days free of mechanical ventilation 
- 
Number of ICU-free days 
- 
Number of days in hospital 
• 
To evaluate the immunogenicity of FP-1201-lyo by monitoring neutralising 
antibodies to IFN beta-1a 
• 
To evaluate the pharmacodynamics (PD) of FP-1201-lyo with MxA  
• 
To evaluate patient outcomes for respiratory (forced expiratory volume in 1 
second [FEV1]) and neurological functioning (6-minute walk test [6MWT] (Ref: 
Holland et al 2014)) and QoL (EuroQol 5-Dimensions 3-Levels questionnaire [EQ-5D-
3L]) measured at selected time points 
2.2.3 
Pharmacoeconomic Objectives 
• 
To evaluate selected pharmacoeconomic parameters 
2.2.4 
Exploratory Objectives 
• 
To evaluate gas exchange (partial pressure of oxygen/fraction of inspired oxygen 
[PaO2/FiO2] ratio) during mechanical ventilation as an indicator of improving 
lung function on treatment 
• 
To evaluate the PD of FP-1201-lyo using the biomarker CD73 
• 
To evaluate selected potential inflammatory markers (PIMs) 
• 
To obtain a blood sample for future pharmacogenetic analysis 
• 
To evaluate all-cause mortality, QoL, and respiratory and neurological functioning 
at extended follow-up (Day [D]360) 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This is a multicentre, Phase III, double-blind, randomised, parallel-group comparison 
study of the efficacy and safety of FP-1201-lyo compared with placebo in adult 
patients diagnosed with moderate or severe ARDS. A composite endpoint of death 
and days free of mechanical ventilation within 28 days among survivors is the 
primary endpoint; all-cause mortality at D28 is one of the secondary endpoints. Both 
treatment groups will receive supportive care (see Appendix 1, Section 11.1). 
A total of 300 patients will be randomised into the study to achieve 272 patients are 
evaluable for efficacy. 
Patients in the ICU will undergo screening during which written informed consent 
will be obtained and eligibility assessed. Not more than 48 hours may elapse between 
confirmation of moderate or severe ARDS and administration of the first dose of 
study drug. An interactive web-response system (IWRS) will be used to randomise 
the patients using country and ARDS severity as stratification parameters. 
Following randomisation, patients will be treated daily with FP-1201-lyo 10 µg or 
placebo intravenously as a bolus for 6 days and will undergo daily assessments while 
in the ICU for a maximum of 28 days. The main analysis and reporting will use D28 
and long-term follow-up D90 data. Long-term follow-up will occur at D180 and an 
extended follow-up at D360, the results of which will each be reported separately as 
addendums to the Clinical Study Report. The overall duration of the study for a 
patient is therefore 12 months, including the 6-month extended follow-up phase. 
During the long-term and extended follow-up periods, and after the end of the 
extended follow-up visit (D360), patient care will follow normal hospital procedures, 
as appropriate. The study will be completed when the final patient completes their 
D360 study assessment. No interim analyses are planned. The study design is 
summarised in Figure 1, and a more detailed flow chart showing the screening and 
randomisation procedures is shown in Figure 2. 
Discontinuation criteria for individual patients and the entire study are described in 
Section 4.4.1. 
The study design incorporates an Independent Data Monitoring Committee (IDMC) 
that will review ongoing safety (i.e., adverse events [AEs] and serious AEs [SAEs]), 
and will also make recommendations to the Sponsor as described in the IDMC 
charter. Details of the IDMC are given in Section 9.8. 
A schedule for the tests and assessments to be conducted during this study is given in 
Section 7.1 (Table 5). 
 
 


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Figure 1: Study Design 
 
 
 
 
 
FP-1201- 
lyo 10 µg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
-48 h 
pre-dose on D1          D1–D6 
D7–D28 
D90c 
D180 
D360 
Visit 
Screening 
Randomisation 
 
Double-
blind 
treatment 
period 
Short-
term FU 
Long-term FU 
Extended 
FU 
 
Baseline 
includes pre-dose on D1a 
Daily assessments up to 
D28 while in ICUb  
 
 
End of Study 
 
 
   CSR  
Addendum 
to CSR 
Addendum to 
CSR 
a 
Not more than 48 hours may elapse between confirmation of moderate or severe ARDS during 
screening and administration of the first dose of study drug on D1. Once eligibility has been met, 
randomisation can occur during screening or pre-dose on D1. 
b 
Assessments are described in the Schedule of Procedures in Table 5 for the patient’s last day in the 
ICU. These will be done on D28 or earlier, according to the clinical progress of the patient. If a 
patient leaves the ICU before D28, their survival status and other endpoints must be assessed on 
D28 (see schedule in Table 5). 
c 
Can be visit or telephone contact. 
 
Abbreviations: CSR=Clinical Study Report; D=day; FU=follow-up; ICU=intensive care unit. 
 
 


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Figure 2: Flow Chart of Screening and Randomisation Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PATIENT IS INTUBATED AND MECHANICALLY VENTILATED (exclude elec9ve post-opera9ve pa9ents) 
Does the pa*ent have a PaO2/FiO2 ra*o consistent with moderate or severe ARDS? 
Has mechanical ven*la*on been for less than 48 hours? 
YES 
Pa*ent assessed by ICU clinician for diagnosis of moderate or severe ARDS. 
Radiological and hypoxaemic criteria must occur within the same 24-hour period. 
Record the 9mes of the P/F ra9o AND chest X-ray/CT scan. 
The later 9me is the 9me of ﬁrst ARDS diagnosis. 
Moderate or severe ARDS diagnosed? 
Has the pa*ent been assessed against the 
other inclusion and exclusion criteria? 
YES 
NO 
NO 
Trial is discussed with pa*ent or legal 
representa*ve and trial informa*on provided 
WriQen informed consent obtained? 
NO 
Eligibility conﬁrma*on process (sec*on 4.3): 
Fill out all orange boxes of Scr-Elig 1 page. 
More than 36 hours from ﬁrst diagnosis? 
Night *me (22:00-08:00)? 
Direct call to MM 
for fast procedure 
Wait for MM conﬁrma*on 
Call MM if no response in 60 min 
Excluded: 
- not mee*ng inclusion criteria 
- mee*ng exclusion criteria 
- declined consent 
- no pre-dose conﬁrma*on  
- chest X-ray not consistent  
YES 
YES 
NO 
ELIGIBILITY CONFIRMED? 
YES 
PRE-DOSE CHECK OF ELIGIBILITY:  Get a new P/F ra*o 
P/F ≤100? 
RANDOMIZATION 
Severe group 
P/F >100 and ≤200 
RANDOMIZATION 
Moderate group 
P/F >200 
Pa*ent allocated randomiza*on number;  IMP number  
Chest X-ray not consistent? 
Pa*ent is deﬁnitely excluded 
NO 
Telephone or email 
discussion with MM 
Chest X-ray equivocal? 
Pa*ent is reassessed (new CXR/CT 
scan) 
First DOSE 
Maximum 48 hours con*nuous 
NIV (>12 hours/day) or 
mechanical ven*la*on to 
diagnosis of ARDS  
Max 48 hours from  ARDS diagnosis to ﬁrst DOSE  
ITT starts from here 


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3.2 
Criteria for Evaluation of the Study 
3.2.1 
Criteria for Evaluation of Efficacy 
Primary Efficacy Endpoint: 
• 
Composite endpoint including any-cause death at D28 and days free of 
mechanical ventilation (VFDsurv) within 28 days among survivors 
Secondary Endpoints:  
• 
Secondary endpoints relating to the efficacy of FP-1201-lyo treatment: 
- 
All-cause mortality at D28, D90 and D180 
- 
Mortality in ICU up to D28 
- 
Mortality in hospital up to D28 
• 
Other efficacy endpoints at D28: 
- 
Days free of organ failure (Sequential Organ Failure Assessment [SOFA] 
methodology) (D28 or last day in ICU if patient has left the ICU earlier 
than D28, or at withdrawal) 
- 
Days free of renal support 
- 
Days free of vasoactive support 
- 
Days free of mechanical ventilation 
- 
Number of ICU-free days 
- 
Number of days in hospital 
• 
Presence of neutralising antibodies to IFN beta-1a at baseline and D28 (or last day 
in ICU if patient has left the ICU earlier than D28, or at withdrawal) 
• 
Evaluation of PD using MxA biomarker from baseline to D14 
• 
Long-term secondary endpoints, relating to QoL, respiratory and neurological 
functioning at D180: 
- 
EQ-5D-3L 
- 
6MWT 
- 
FEV1 
3.2.2 
Criteria for Evaluation of Safety 
• 
AEs up to D28, AEs occurring after D28 if the investigator considers there is a 
causal relationship with the study drug and all deaths up to D360 
• 
Physical examination, vital signs and laboratory results (biochemistry, 
haematology and urinalysis) up to D28 
3.2.3 
Criteria for Evaluation of Pharmacoeconomics 
 
• 
Days free of organ failure up to D28 (or last day in ICU if patient has left the ICU 
earlier than D28, or at withdrawal) 
• 
Days free of renal support up to D28 
• 
Days free of vasoactive support up to D28  
• 
Days free of mechanical ventilation up to D28 
• 
Number of ICU-free days up to D28 


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• 
Number of days in hospital up to D28 
3.2.4 
Criteria for Evaluation of Exploratory Endpoints 
• 
Exploratory endpoints relating to the efficacy of FP-1201-lyo treatment: 
- 
Composite endpoint including mortality and days free of mechanical 
ventilation (VFDsurv) within 90 days among survivors 
- 
Ordered categorical endpoint defined as improvement (from severe to 
moderate/mild; from moderate to mild ARDS), no change or worsening 
(from moderate to severe/death; from severe to death) in terms of gas 
exchange (PaO2/FiO2 ratio) from baseline to D28 
• 
Change in the treatment-specific exploratory biomarker CD73 concentration from 
baseline to D14 
• 
Change in PIMs, including but not limited to, interleukin-6 and -8 from baseline 
to D14 
• 
A blood sample will be taken for pharmacogenetic analysis and correlation with 
other markers of the activity of FP-1201-lyo 
• 
Extended long-term follow-up: 12-month mortality rate, EQ-5D-3L, 6MWT and 
FEV1  
3.3 
Justification of the Study Design 
This is a Phase III study to evaluate the efficacy and safety of FP-1201-lyo in the 
treatment of patients with moderate or severe ARDS. The study is designed as a 
double-blind, randomised, parallel-group, placebo-controlled, multicentre clinical 
study. 
At present there is no approved pharmacological treatment that could be considered 
as an active comparator for studies of ARDS. The only currently available treatment 
for ARDS patients is intensified supportive care. Therefore, the current approach to 
ARDS study design should be to show superiority of the investigated study drug to 
the best method of care. The study drug will be used as additive treatment to 
supportive care and therefore it is most appropriate to use placebo as a comparator. 
A different primary endpoint is used in this study to that described in the European 
Medicines Agency guideline on clinical investigation of medicinal products in the 
treatment of patients with ARDS. The guideline recommends using all-cause 
mortality at D28. (Ref: Committee for Medicinal Products for Human Use 2006) The Sponsor has 
discussed the primary endpoint with the European Medicines Agency and it was 
agreed that the composite endpoint would be more sensitive in picking up effect 
signals. In addition, this study has a double-blind design, so the decision to wean the 
patient from mechanical ventilation should not be influenced by the treatment group. 
Owing to the randomisation procedure and the double-blind nature of this study the 
potential bias of the study results is minimised. 


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4 
STUDY POPULATION 
The study population will consist of patients with moderate or severe ARDS. Patients 
must meet all the inclusion criteria and none of the exclusion criteria to be enrolled in 
the study. The inclusion and exclusion criteria apply during screening and prior to 
administration of the first dose of study drug on D1. 
4.1 
Inclusion Criteria 
 
All patients must be intubated and mechanically ventilated to diagnose ARDS and be 
eligible for the study. 
1. Patient has a diagnosis of moderate or severe ARDS according to the Berlin 
definition of ARDS (Ref: ARDS Definition Task Force 2012) 
1.1 
Acute onset of respiratory failure within 1 week of a known clinical insult or 
new or worsening respiratory symptoms 
1.2 
Respiratory failure associated with known ARDS risk factors and not fully 
explained by either cardiac failure or fluid overload (an objective assessment of 
cardiac failure or fluid overload is needed if no risk factors for ARDS 
[moderate or severe ARDS] are present) 
1.3 
Radiological abnormalities on chest X-ray or on computerised tomography 
(CT) scan, i.e., bilateral opacities that are not fully explained by effusions, 
nodules, masses or lobar/lung collapse 
1.4 
Hypoxaemia: 
• Moderate ARDS: PaO2/FiO2 >100 mmHg (>13.3 kPa) to ≤200 mmHg 
(≤26.6 kPa) with positive end expiratory pressure (PEEP) ≥5 cmH2O 
• Severe ARDS: PaO2/FiO2 ≤100 mmHg (≤13.3 kPa) with PEEP ≥5 cmH2O 
2. The radiological and hypoxaemia criteria (1.3 and 1.4) must occur within the same 
24-hour period. The time of onset of ARDS is when the last of the two specified 
ARDS criteria is met 
3. Administration of the first dose of study drug must be planned to take place within 
48 hours of moderate or severe ARDS diagnosis. 
4. Patient is intubated and mechanically ventilated 
5. A signed written informed consent form from the patient or the patient’s personal 
legal representative (PerLR) or a professional legal representative (PrfLR) must be 
available 
6. Patient is aged ≥18 years 
4.2 
Exclusion Criteria 
1. Woman known to be pregnant, lactating or with a positive (urine or serum test) or 
indeterminate (serum test) pregnancy test 
2. Patient is simultaneously taking part in another pharmacotherapy protocol 
3. The patient is not expected to survive for 24 hours 


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4. Patient has an underlying clinical condition where, in the opinion of the Investigator, 
it would be extremely unlikely that the patient would come off ventilation, e.g., motor 
neurone disease, Duchenne muscular dystrophy, or rapidly progressive interstitial 
pulmonary fibrosis 
5. Patient has severe chronic obstructive pulmonary disease requiring long-term home 
oxygen therapy or mechanical ventilation (non-invasive ventilation or via 
tracheotomy) except for continuous positive airway pressure (CPAP) or bi-level 
positive airway pressure (BIPAP) used solely for sleep-disordered breathing 
6. Patient has congestive heart failure, defined as New York Heart Association class IV 
(Ref: Committee for Medicinal Products for Human Use 1994)  
7. Patient has acute left ventricular failure 
8. Patient has liver failure (Child–Pugh grade C) 
9. Patient has received any prior IFN 
10. Patient has known hypersensitivity to natural or recombinant IFN beta or to any of 
the excipients 
11. Patient is receiving renal dialysis therapy for chronic renal failure 
12. Patient is receiving extra-corporeal membrane oxygenation, high-frequency 
oscillatory ventilation (HFOV) or any form of extracorporeal lung support 
13. Patient has had any form of mechanical ventilation (invasive or non-invasive, 
excluding CPAP alone) for longer than 48 hours prior to the diagnosis of ARDS 
Non-invasive ventilation has to be continuously applied for at least 12 hours per day 
in these 48 hours 
14. Patient has burns to ≥15% of their total body surface area 
4.3 
Confirmation of Patient Eligibility 
To ensure appropriate enrolment into the study there will be a formal 
confirmation of eligibility process utilising a two-step procedure: 
In Step 1, there will be an electronic Case Report Form (e-CRF) with 
mandatory fields for completion and a checklist of inclusion and exclusion 
criteria; all items will need to be completed. The Clinical Data Management 
System (CDMS) will not allow a patient to progress to randomisation if these 
have been left unpopulated. 
In Step 2, for situations where a chest CT scan is not available for confirming the 
radiological aspect of the diagnosis and chest X-ray is used for diagnosis, the 
enrolling clinician will match their patient’s chest X-ray against a panel of 12 chest 
X-rays from the Berlin ARDS Definition (ARDS Definition Task Force 2012) and tick to show 
which lung fields are the closest match. After including their name, direct e-mail 
and telephone contact details, and on requesting ‘Eligibility Confirmation’, the 
CDMS will automatically inform the Medical Monitor (MM) who will then review 
the e-CRF:  
 
1. If the tick corresponds to a positive Moderate/Severe ARDS image, 
the MM will make the patient available to be randomised and the 
CDMS will send an automatic email to the site that the patient has 


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passed screening. 
2. If the tick is against an equivocal Moderate/Severe ARDS image, the 
MM uses the contact details for the site and contacts the sender to 
continue standard therapy and possibly undertake further thoracic 
imaging after 8–12 hours. This may be repeated twice as long as the 
imaging is clinically indicated and the time to diagnosis does not 
exceed 48 hours from the start of mechanical ventilation. 
3. If the tick is against a negative Moderate/Severe ARDS image, the 
MM will contact the sender to inform them that the patient cannot be 
randomised and discuss further options. 
 
With this method, only those patients whose data are recorded as meeting eligibility 
criteria can be randomised.  
4.4 
Patient Withdrawal and Replacement 
4.4.1 
Discontinuation Criteria 
Patients may withdraw from the entire study, including follow-up, at any time 
without penalty and for any reason without prejudice to their future medical care; 
they are not obliged to state their reasons for withdrawing. The decision to withdraw 
can be made by the patient or their PerLR or PrfLR. 
Patients may be withdrawn from the study under the following circumstances: 
• 
Protocol violations including non-compliance with study procedures or patient 
lost to follow-up 
• 
AEs 
• 
Administrative reasons 
• 
Patient, PerLR or PrfLR request 
• 
Sponsor request 
• 
Investigator request 
The Investigator must ensure that the status page in the e-CRF for the end of the 
study is completed. 
Patients may be required to withdraw from study drug after discussion with the 
Sponsor and/or Investigator for the following reasons: 
• 
AEs 
• 
At the discretion of the Investigator or if it is considered to be in the patient’s best 
interest 
Patients who discontinue study drug may continue in the study. The Investigator must 
ensure that the status page in the e-CRF for the end of study is completed. 
In all cases, the reason(s) for withdrawal, including the primary reason, must be 
recorded in the e-CRF. If a patient is prematurely withdrawn from the study drug for 
any reason, the Investigator must make every effort to perform the evaluations 
described for the follow-up visits. Any on-going AEs should be followed up to 
resolution or D28 whichever is the sooner. See also Sections 9.6.5 and 9.6.6. 


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If a patient (or their representative) withdraws consent and still agrees to undergo a 
final examination, this will be documented in the e-CRF and the Investigator’s copy 
of the Informed Consent Document (ICD), which will be countersigned and dated by 
the patient (or PerLR or PrfLR). 
Patients who withdraw consent for their data to be analysed will be identified in the 
CDMS. Any data collected will not be deleted, but will not be used in any subsequent 
outputs. 
Withdrawn patients will not be replaced. 
The study will be terminated if, in the opinion of the Sponsor, significant safety 
concerns arise during the conduct of the study. 
4.4.1.1 
Non-attendance of Follow-up Assessments 
Attempts should be made to contact patients discharged from hospital who do not 
attend their study follow-up assessments to ensure their well-being. In such cases, the 
patient will be contacted at least twice by telephone and once by letter to request that 
they attend the scheduled follow-up assessment. If patients do not respond they will 
be considered as withdrawn at that time point (lost to follow-up). If a patient is lost to 
follow-up, wherever possible mortality data will be sought at all remaining mortality 
time points from alternative sources such as the patient’s local physician. 
4.4.2 
Replacement Policy 
A screen failure patient is defined as any patient who did not comply with the 
inclusion and exclusion criteria during screening and prior to receiving the first dose 
of study drug. Patients who become ineligible after consenting, and before treatment, 
will be deemed to be screen failures and will be replaced. 
It is possible that a patient may be randomised to a study group following successful 
screening but may become ineligible prior to administration of the first dose of study 
drug. For example, prior to the first dose of study drug a patient may be extubated and 
so is no longer being mechanically ventilated or a patient may have an improved 
oxygenation status, which no longer meets the moderate or severe ARDS criteria. 
Such patients will be classed as screen failures and will be replaced. 
Patient numbers (and randomisation numbers if applicable) of screen failures will not 
be reallocated. A new patient will be enrolled and assigned the next available number. 
Patients who complete screening and are randomised and receive the first dose of 
study drug will not be replaced even if later withdrawn or lost to follow-up. 
4.5 
Planned Sample Size and Number of Study Centres 
It is planned to randomise 300 patients at approximately 70 - 80 centres in 9 countries 
for this study. See Section 8.10 for a discussion of sample size. 
4.6 
Patient Identification and Randomisation 
4.6.1 
Patient Identification 
Patients will be allocated a unique 5-digit patient number (patient identification 
number), which will include the country number (1 digit), the site number (2 digits), 
as well as a consecutive individual number (2 digits). The patient number will be 
assigned at the study centre on enrolment (i.e., provision of written informed consent) 


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in chronological order of screening and will be used throughout the study. If a patient 
is not subsequently randomised, their screening number will not be reallocated. Each 
screened patient will therefore have a unique identifier. 
4.6.2 
Randomisation Scheme 
Patients will be randomised on a 1:1 basis to FP-1201-lyo or placebo. IWRS will be 
used to obtain randomisation details. 
To ensure that conclusions are not dominated by data from a small number of centres, 
and also to obtain a broad spread of patients and centres within the constraints of the 
inclusion/exclusion criteria, each centre will be allowed to include up to, but no more 
than, 30 patients. 
Randomisation will be stratified by country and ARDS severity (moderate or severe), 
and a sequence of randomisation numbers will be assigned to each study centre. 
Refer to Section 5.4 for details of blinding and breaking the blind. 
4.6.3 
Randomisation of Patients to Treatment 
Randomisation of patients to treatment will occur during screening or on D1 after all 
screening procedures have been performed and eligibility for inclusion in the study 
has been confirmed. Each randomised patient will receive a unique randomisation 
number. Randomised patients who terminate their study participation for any reason, 
regardless of whether study drug was taken or not, will retain their randomisation 
number. 
The Investigator will use IWRS for randomisation of patients. Details can be found in 
the study file. 


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5 
STUDY DRUG 
5.1 
Identity 
Rentschler Biotechnologie GmbH, Laupheim, Germany manufacture lyophilised 
FP-1201-lyo (recombinant human IFN beta-1a) and the matched placebo. Both 
FP-1201-lyo and placebo powders are free of animal serum and human serum 
albumin. Vetter Pharma International Services, Ravensburg, Germany manufacture 
pre-filled water for injection (WFI) diluent syringes.  
A MixJect® transfer device will be used in this study. This MixJect® transfer device is 
a single unit for reconstituting a powdered drug with a diluent pre-filled syringe. 
Upon reconstitution, the drug is available for immediate injection. The MixJect® 
transfer device enables the safe, rapid and easy preparation of lyophilised drugs. The 
MixJect® transfer device is manufactured by West Pharmaceutical Services GmbH, 
Germany/Medimop Medical Projects, Ra’anana, Israel. The device carries the CE 
mark and has 510(k) approval by the United States Food and Drug Administration. 
Fisher Clinical Services Ltd, Horsham, UK, is responsible for the packaging of 
FP-1201-lyo and matched placebo in a carton box. The pre-filled WFI diluent 
syringe, the MixJect® transfer device and the reconstitution instructions are packaged 
in the accessorial carton kit. Fisher Clinical Services Ltd is responsible for 
distributing the investigational medicinal product to the study sites. 
5.2 
Administration 
FP-1201-lyo 10 µg (or placebo) will be diluted in WFI near the patient/in the ICU. 
Once prepared, the dose must be administered to the patient immediately. The diluted 
FP-1201-lyo or placebo will be administered as an intravenous bolus injection via a 
central or peripheral line. The injection will be followed with a 5 mL flush of sterile 
saline (not provided). 
FP-1201-lyo and placebo injections will be given once daily for 6 days. The injection 
should be given at the same time each day ±1 hour providing the patient’s condition 
allows this. If for any reason this is not possible, the treatment window may be 
extended by up to 4 hours. The reason for the delay must be entered in the e-CRF. 
Subsequent doses should not be delayed and should revert to the original time 
schedule (e.g., if the D1 dose was at 13:00, the D2 dose was delayed and given at 
17:00, the D3 dose should be given at 13:00 ±1 hour). 
No dose modifications or temporary cessations of study drug administration are 
allowed. If a delay beyond the 4-hour window described above is required, the patient 
must be withdrawn from study drug but all data must continue to be collected per 
protocol. Administration of a second course of study drug is not permitted. 
5.3 
Packaging, Labelling and Storage 
FP-1201-lyo and matched placebo are packaged in a carton. The pre-filled WFI 
diluent syringe and the MixJect® transfer device are packaged in an accessorial carton 
kit. 
Six investigational medicinal products and six accessorial carton kits are reserved for 
each patient to cover the 6-day treatment period. 
Labelling will be prepared by Fisher Clinical Services Ltd to meet the local 
regulatory requirements. 


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All study drug supplies must be stored in accordance with the manufacturer’s 
instructions, i.e., FP-1201-lyo and placebo are to be stored at 2–8°C and the 
accessorial carton kits are to be stored at room temperature. Until dispensed to the 
patients, the study drug will be stored in a securely locked area, accessible to 
authorised personnel only. 
The investigational medicinal product and the accessorial carton kits are dispensed 
only by the Investigator or by a member of staff specifically authorised by the 
Investigator, or by a pharmacist, as appropriate. 
5.4 
Blinding and Breaking the Blind 
The study will be performed in a double-blind manner. All study drugs will be 
supplied in identical vials and will be similar in colour and appearance, thereby 
enabling double-blind conditions. 
The treating physician (investigator) is responsible for the medical care of the trial 
patient and the study set up allows the investigator to rapidly break the treatment code 
in an emergency situation. 
The study blind should only be broken in a medical emergency (where knowledge of 
the study drug received would affect the treatment of the emergency) or as a 
regulatory requirement (e.g., for SAEs or death). Note that there is no specific 
antidote or method of removing the study drug from the body (such as dialysis) and 
the best available care for the patient should be continued.  
If the blind is broken, the date, time and reason must be recorded in the patient’s e-
CRF and any associated AE report. It is the responsibility of the investigator to 
promptly document and explain any unblinding to the sponsor/CRO. 
Detailed instructions for the use of the IWRS in order to break the study blind for a 
patient are provided in a separate document that will be filed in the Site File and Trial 
Master File. As well as the IWRS, a backup system enabling unblinding of treatment 
is provided to the sites. 
After a patient has been unblinded data collection should continue as per protocol.  
Suspected unexpected serious adverse reactions (SUSARs), which are subject to 
expedited reporting, should be unblinded before submission to the regulatory 
authorities and Independent Ethics Committees (IECs). 
The overall randomisation code will be broken only for reporting purposes. This will 
occur once all D90 clinical data have been entered into the database and all data 
queries related to D90 have been resolved, and the assignment of patients to the 
analysis sets has been completed. 
5.5 
Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability 
records throughout the study. 
Each dispensing of study drug will be documented in the e-CRF. 


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The Investigator is responsible for ensuring all unused medication is destroyed at the 
investigational site following the appropriate drug accountability procedures. 
5.6 
Compliance 
The study drug is administered intravenously at the study site, so it is not necessary to 
monitor patient compliance with the study drug regimen. 
5.7 
Previous and Concomitant Medications 
Any medication the patient takes other than the study drug between screening and 
D28, including herbal and other non-traditional remedies, is considered to be a 
concomitant medication. All concomitant medications must be recorded in the e-CRF 
except for nutritional and volume therapy, electrolyte support, vitamins and 
supportive therapies such as artificial tears, ointments, etc. The following information 
must be recorded in the e-CRF for each concomitant medication: generic name, route 
of administration, start date, stop date, dosage and indication. Any changes in the 
dosage or regimen of a concomitant medication must be recorded in the e-CRF. If a 
patient is discharged from the hospital prior to D28 then the patient must be 
instructed that the Investigator should be informed about additional medication up to 
D28. 
Concomitant medications or therapies that are considered necessary for the patient’s 
welfare and that will not interfere with the study drug may be given at the discretion 
of the Investigator. 
All patients in this study will be managed with supportive care measures according to 
the best practice established locally in each ICU. Due consideration must be given to 
the study guidance on supportive measures given in Appendix 1, Section 11.1. 
At screening, patients (or their relatives) will be asked what medications they have 
taken during the last month. In connection with the 6MWT at D180 and D360, 
patients (or their carers or relatives) will be asked what medications the patients have 
taken during the last 24 hours. 
There are no prohibited co-medications in this study. 


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6 
VARIABLES AND METHODS OF ASSESSMENT 
The timing of the assessments of the variables is shown in the Schedule of Procedures 
(Table 5 in Section 7.1). 
6.1 
Efficacy Variables 
The following efficacy variables will be assessed: 
• 
Mortality 
• 
Days on mechanical ventilation 
• 
SOFA 
• 
Days in ICU 
• 
Days in hospital 
• 
Days on vasoactive support 
• 
Days on renal support 
• 
Neutralising antibodies 
• 
Biomarker MxA 
• 
QoL 
• 
Respiratory functioning (FEV1) 
• 
Neurological functioning (6MWT) 
6.1.1 
Primary Efficacy Variables 
All-cause mortality will be assessed at D28 (primary) and also at D90 and D180, and 
at the extended long-term follow-up at D360. All deaths shall be recorded as SAEs up 
to D360. The patient’s location at the time of death (ICU or hospital) will also be 
recorded. 
For the composite primary endpoint, ventilator-free days (VFDs) will be calculated. 
A patient will be reported as ventilator free after two consecutive calendar days of 
unassisted breathing (UAB). UAB is defined as: 
• 
Spontaneously breathing with face mask, nasal prong oxygen or room air 
• 
T-piece breathing 
• 
Tracheostomy mask breathing 
• 
CPAP ≤5 cmH2O without pressure support or intermittent mandatory ventilation 
assistance 
• 
Use of CPAP or BIPAP solely for sleep apnoea management 
Patients still on positive pressure ventilation/receiving assisted breathing who are 
transferred to another hospital or healthcare facility prior to D28 will be followed up 
to assess the VFD outcome at D28. 
These variables will also be assessed at D90 in an exploratory analysis. 
6.1.2 
Secondary Efficacy Variables 
6.1.2.1 
Sequential Organ Failure Assessment 
Organ failure status will be assessed using the SOFA score, which assesses six organ 
systems: respiration, coagulation, liver, cardiovascular, central nervous system and 


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renal (Table 2). (Ref: Grissom et al 2010) A patient will be defined as being free of organ 
failure when the SOFA score is zero. The score will be assessed pre-dose on D1 and 
daily up to D14, at D21 and at D28 while the patient is in the ICU, based on worst 
daily values. 
The SOFA score variables to be assessed daily from baseline to D28/leaving the ICU 
are: 
• 
PaO2/FiO2 (mmHg) 
• 
Platelets × 103/mm3 
• 
Bilirubin (µmol/L or mg/dL) 
• 
Hypotension/use of vasopressors 
• 
Glasgow Coma Scale (GCS) 
• 
Creatinine (µmol/L or mg/dL) 
 
Table 2 
SOFA Scoring 
SOFA score 
0 
1 
2 
3 
4 
Respiration 
 
 
 
 
 
PaO2/FiO2, 
mmHg 
>400 
>300–≤400 
>200–≤300  
>100–≤200  
≤100 
 
 
 
 
---with respiratory support--- 
Coagulation 
 
 
 
 
 
Platelets × 103/µL 
>150 
>100–≤150  
>50–≤100  
>20–≤50 
≤20 
 
 
 
 
 
 
Liver 
 
 
 
 
 
Bilirubin, mg/dL 
<1.2 
≥1.2–<2.0 
≥2.0–<6.0 
≥6.0–<12.0 
≥12.0 
(µmol/L) 
(<20) 
(≥20–<33) 
(≥33–<102) 
(≥102–<204) 
(≥204) 
 
 
 
 
 
 
Cardiovascular 
 
 
 
 
 
Hypotensiona 
No 
hypo-
tension 
MAP 
<70 mmHg 
Dopamine ≤5 
or dobutamine 
(any dose) 
Dopamine >5 or 
epinephrine ≤0.1 or 
norepinephrine ≤0.1 
Dopamine >15 or 
epinephrine >0.1 or 
norepinephrine >0.1 
Central nervous 
system 
 
 
 
 
 
Glasgow Coma 
Scaleb, c 
15 
13–14 
10–12 
6–9 
<6 
 
 
 
 
 
 
Renal 
 
 
 
 
 
Creatinine, mg/dl 
<1.2 
≥1.2–<2.0 
≥2.0–<3.5 
≥3.5–<5.0 
≥5.0 
or µmol/L or 
urine output 
<110 
≥110–<171 
≥171–<300 
≥300–<440 or 
<500 mL/d 
≥440 or 
<200 mL/d 
a Adrenergic agents administered for at least 1 hour (doses are given in µg/kg/min). 
b For patients who are intubated, the verbal response is scored as: 
 
 5 – Seems able to talk  
 
 3 – Questionable ability to talk 
 
 1 – Generally unresponsive. 


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c For patients who are sedated use an estimated score for GCS (the assumption is 15, if no other 
factors than sedation affect GCS) 
Abbreviations: MAP=mean arterial pressure; PaO2/FiO2=partial pressure of oxygen/fraction of 
inspired oxygen; SOFA=Sequential Organ Failure Assessment. 
 
6.1.2.2 
Renal Support 
Any renal support given to the patient will be recorded on a specific page in the e-
CRF. 
6.1.2.3 
Vasoactive Support 
Any vasoactive support given to the patient will be recorded on a specific page in the 
e-CRF. Vasoactive support includes: catecholamine and non-catecholamine 
vasopressors, inotropes and vasodilating agents. 
6.1.2.4 
Neutralising Antibodies to Interferon Beta-1a 
Blood samples (2.5 mL) will be taken on D1 pre-dose (baseline) and D28 (or on last 
day in ICU or at withdrawal, if earlier) to determine the presence of neutralising 
antibodies to IFN beta-1a. 
Neutralising antibody blood sample preparation and sample storage details are 
provided Laboratory Manual. It is essential that the actual time and date of collection 
of each antibody sample be recorded in the sample collection form provided with the 
laboratory kits. 
Neutralising antibody samples will be analysed centrally at Wieslab AB, Malmö, 
Sweden. 
6.1.2.5 
Myxovirus Resistance Protein A 
Whole blood samples (2 mL) will be taken pre-dose on D1 and daily from D2 to D14 
for analysis of MxA levels. For details of sample preparation and storage refer to the 
Laboratory Manual. MxA samples will be analysed centrally at Wieslab AB. 
6.1.2.6 
Quality of Life, Respiratory Functioning and Neurological Functioning  
Health-related QoL (EQ-5D-3L), respiratory functioning via FEV1 and neurological 
functioning via the 6MWT, will be assessed at D180 (6 months). If the patient is 
unable to come to the hospital for the FEV1 and 6MWT assessments, the QoL 
information should still be obtained by telephone interview. Additional data will be 
collected at D360 (12 months) to form part of the extended long-term follow-up. 
EQ-5D-3L Questionnaire 
EQ-5D-3L provides a simple descriptive profile and a single index value of health 
status that can be used in clinical research and economic evaluation of healthcare as 
well as in population health surveys. The questionnaire is cognitively undemanding, 
designed for self-completion and takes only a few minutes to complete. 
At the time when the patients are screened/enrolled in the study it may not be possible 
to directly obtain baseline information on their pre-admission QoL. In these cases, a 
description of the patient’s pre-study functioning at home should be obtained from 
their relatives, recorded in the e-CRF and used as the reference value. This 
information will be checked by the patient at a later stage and correspondingly 
updated in the e-CRF. 


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Forced Expiratory Volume in 1 second 
Measuring FEV1 assesses pulmonary function (airway obstruction, 
bronchoconstriction or bronchodilation). FEV1 is the volume exhaled during the first 
second of a forced expiratory manoeuvre, starting from the level of total lung 
capacity. 
Six-minute Walk Test  
The 6MWT measures (Ref: Holland et al 2014) the distance that a patient can quickly walk on 
a flat, hard surface in a period of 6 minutes. According to the current standard the test 
should be done twice and the best result is used. It evaluates the global and integrated 
responses of all systems involved during exercise, including the pulmonary and 
cardiovascular systems, systemic circulation, peripheral circulation, blood and 
neuromuscular units and muscle metabolism. The self-paced 6MWT assesses the sub-
maximal level of functional capacity and may better reflect the functional exercise 
level for daily activities. 
6.2 
Safety Variables 
6.2.1 
Adverse Events 
6.2.1.1 
Collection of Adverse Events 
It is the responsibility of the Investigator to collect all AEs (both serious and non-
serious) derived by observation, by spontaneous unsolicited reports of patients, and, 
where appropriate, by routine open questioning, e.g., “How have you felt since I last 
saw you?” 
6.2.1.2 
Definitions 
Definitions of AEs and SAEs and their documentation and reporting within this study 
follow International Conference on Harmonisation (ICH) Good Clinical Practice, 
European Union, and national regulations and requirements. 
An AE is defined as any untoward medical occurrence that occurs in a patient or 
clinical investigation subject administered a pharmaceutical product, and which does 
not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of an investigational 
product, whether or not considered related to the product. 
All AEs up to D28 are collected. AEs occurring after D28 should be reported to the 
Sponsor if the Investigator considers there is a causal relationship with the study 
drug. All AEs up to D360, which lead to death, are reported as SAEs. Concomitant 
illnesses, which existed before entry into the study, will not be considered AEs unless 
there is any deterioration from baseline that is considered clinically relevant or 
significant during treatment or follow-up period until D28 or discharge from ICU. All 
AEs must be documented, regardless of the source of identification (e.g., physical 
examination, laboratory assessment, ECG, reported by patient).   
Pre-existing conditions will be recorded in the e-CRF on the Medical History or 
appropriate page. 
 
Development of barotrauma shall be recorded as an AE. 
 


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A TEAE is defined as an AE that begins or that worsens in severity after at least one 
dose of study drug has been administered up to D28. 
See 6.2.1.4 for the schedule of collection of adverse events 
6.2.1.3 
Assessment of Adverse Events 
It is recognised that the patient population in the ICU will experience a number of 
common aberrations in laboratory values, signs and symptoms due to the severity of 
their underlying disease and the impact of standard therapies. These will not 
necessarily constitute an AE unless they require significant intervention, lead to 
discontinuation of blinded study drug or are considered to be of concern in the 
Investigator’s clinical judgement. 
Each AE will be assessed by the Investigator with regard to the following categories: 
6.2.1.3.1 Seriousness 
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening. This means that the patient is at risk of death at the time of the 
event. It does not mean that the event hypothetically might have caused death if it 
were more severe 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event that may not be immediately life-threatening or 
result in death or hospitalisation but that may jeopardise the patient or 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 a case is 
serious and whether expedited reporting is appropriate. However, all deaths up to 
D360 will be reported as a SAE. 
“At any dose” does not imply that the patient is receiving study treatment at the time 
of the event. Study drug doses may have been given during treatment cycles or 
interrupted temporarily prior to the onset of the SAE, but may have contributed to the 
event. 
6.2.1.3.2 Intensity 
Classical reporting of mild, moderate and severe AEs making reference to the 
patient’s functional status is difficult for a randomised study in critically ill patients. 
Patients enrolled in this study will primarily be mechanically ventilated and comatose 
due to their underlying condition and/or the drugs they are prescribed for sedation and 
analgesia in the ICU. Therefore, the classical approach to AE reporting, which 
requires patient communication and evaluation of the impact on functioning will be 
adapted to the ICU environment. The Investigator will be responsible for the 
assessment of severity, using the categories of mild, moderate or severe to describe 
each AE as: 
• 
Mild: Does not interfere with patient’s usual function 


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• 
Moderate: Interferes to some extent with patient’s usual function 
• 
Severe: Interferes significantly with patient’s usual function 
Note the distinction between serious and severe AEs. Severe is a measure of intensity 
whereas an event must meet one of the criteria for serious events listed in 
Section 6.2.1.3.1 to be considered serious; thus, a severe reaction is not necessarily a 
serious reaction. For example, a headache may be severe in intensity, but would not 
be classified as serious unless it met one of the criteria for serious events listed in 
Section 6.2.1.3.1. 
6.2.1.3.3 Causality 
The Investigator will assess the causality/relationship between the study drug and the 
AE and record that assessment in the e-CRF. Causality will be assessed as: 
• 
Not related: AE is obviously explained by another cause; OR the time of 
occurrence of AE is not reasonably related to administration of the study drug 
• 
Possibly related: Study drug administration and AE occurrence are reasonably 
related in time; AND AE is explained equally well by causes other than study 
drug 
• 
Probably related: Study drug administration and the occurrence of the AE are 
reasonably related in time; AND the AE is more likely explained by exposure to 
study drug than by other mechanisms 
The most likely cause of an AE (e.g., disease under treatment, concomitant disease, 
concomitant medication, other) will be indicated in the e-CRF with details of the 
concomitant disease or medication or other cause.  
6.2.1.3.4 Clinical Laboratory Adverse Event  
Abnormal laboratory findings (e.g., biochemistry, haematology, urinalysis) or other 
abnormal assessments (e.g., vital signs) that are judged by the Investigator as 
clinically significant will, if certain requirements are met, be recorded as AEs or 
SAEs. Clinically significant abnormal laboratory findings or other abnormal 
assessments that meet the definition of an AE or SAE and are detected during the 
study, or are present at baseline and significantly worsen following the start of the 
study, will be reported as AEs or SAEs. However, clinically significant abnormal 
laboratory findings or other abnormal assessments that are associated with the disease 
being studied (unless judged by the Investigator as more severe than expected for the 
patient’s condition), or that are present or detected at the start of the study and do not 
worsen, will not be reported as AEs or SAEs. 
The Investigator will exercise their medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
6.2.1.4 
Recording Adverse Events 
AE reporting will extend from signing of informed consent. AEs occurring after D28 
should be reported to the Sponsor by the Investigator if the Investigator considers 
there is a causal relationship with the study drug. However, all deaths will be 
recorded and reported as SAEs throughout the study (up until D360). 
All AE reports should contain a brief description of the event, date and time of onset, 
date and time of resolution, intensity, treatment required, relationship to study drug, 


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action taken with the study drug, outcome, and whether the event is classified as 
serious. 
Recording a diagnosis (when possible) is preferred to recording a list of associated 
signs and symptoms. However, if a diagnosis is known but there are associated signs 
or symptoms not generally attributed to the diagnosis, the diagnosis and each sign or 
symptom must be recorded separately. 
6.2.1.5 
Reporting Serious Adverse Events 
According to applicable European Union regulations and requirements, an SAE must 
be reported to the Sponsor from the trial site as soon as possible within 24 hours of 
becoming aware of the SAE. A medically qualified person at the trial site identified 
on the Delegation of Authority Log with this responsibility must assess the SAE. Any 
member of the clinical trial site staff can assist in reporting an initial SAE. The 
Principal Investigator or delegated sub-investigators are responsible for the SAE 
reporting procedures at the site during the trial, and must always sign-off on each 
SAE even if other site staff have reported the event on behalf of the investigators. A 
delegation log at each trial site will clearly show delegation of responsibilities 
regarding SAE reporting. 
The SAE form must be completed with all the relevant information and forwarded to 
Crown Pharmacovigilance by: 
• 
 
 
• 
 
If the SAE is urgently reported by telephone, a paper SAE form must always be 
completed and forwarded to Crown Pharmacovigilance as soon as possible. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each 
SAE report and the seriousness and the causal relationship of the event to study 
treatment will be evaluated. In addition, the Sponsor (or Sponsor’s designated agent) 
will evaluate the expectedness according to the reference document (Investigator 
Brochure). Based on the Investigator and Sponsor’s assessment of the event, a 
decision will be made concerning the need for further action. 
If consensus on the assessment cannot be reached between the parties (e.g., 
Investigator and Sponsor/Sponsor’s delegate), all opinions will be provided in the 
Council for International Organizations of Medical Sciences Form I report and 
reporting to the CA and IEC should be based on the highest degree of causality 
provided. 
Details for reporting SUSARs can be found in Section 6.2.1.7. 
All SAEs will be recorded that occur between signing of informed consent and D28. 
Events occurring after D28 and coming to the attention of the Investigator should be 
reported only if they are considered in the opinion of the Investigator to be causally 
related to the investigational drug.  However, all deaths up to D360 will be reported 
as SAEs. 
All SAEs occurring as described above, must be reported within 24 hours by email 
or fax to Crown Pharmacovigilance.  
The minimum information required for an initial report is: 
• 
Details of person sending the report (i.e., name and address of Investigator) 


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• 
Patient identification details (screening/randomisation number, age, sex, NOT 
patient name) 
• 
Protocol number 
• 
Description of SAE 
• 
Causality assessment 
However, all points on the SAE form should be covered in the initial report and the 
completed SAE form itself must be emailed or faxed to Crown Pharmacovigilance.  
After receipt of the initial report, Crown Pharmacovigilance will review the 
information and, if necessary, contact the Investigator to obtain further information 
for assessment of the event. Crown CRO will be responsible for all information 
processing and reporting according to local legal requirements.  
Detailed instructions concerning SAE reporting procedures will be described in a 
Safety Management Plan written by Crown Pharmacovigilance. SAE Report Form 
and contact information for reporting SAEs will be provided to the sites. 
6.2.1.6 
Follow-up of Adverse Events  
All AEs experienced by a patient, irrespective of the suspected causality, will be 
monitored until: the AE has resolved; any abnormal laboratory values have returned 
to baseline or stabilised at a level acceptable to the Investigator and Medical Monitor; 
there is a satisfactory explanation for the changes observed; the patient is lost to 
follow-up; or the patient has died. 
6.2.1.7 
Suspected Unexpected Serious Adverse Reactions  
Any AE that is serious, associated with the use of the study drug, and unexpected 
(SUSAR) has additional reporting requirements, as described below. 
• 
If the SUSAR is fatal or life threatening, associated with use of the study drug and 
unexpected, regulatory authorities and IECs must be notified within 7 calendar 
days after the Sponsor learns of the event. Additional follow-up information 
(cause of death, autopsy report and hospital report) should be reported within an 
additional 8 days (15 days total). 
• 
If the SUSAR is not fatal or life threatening but is otherwise serious, associated 
with the use of the study drug and unexpected, regulatory authorities and IECs 
must be notified within 15 calendar days after the Sponsor learns of the event. 
The Sponsor will notify the Investigators in a timely fashion of relevant information 
about SUSARs that could adversely affect the safety of patients. Follow-up 
information may be submitted if necessary. 
The Sponsor will also provide annual safety updates to the regulatory authorities and 
IECs responsible for the study. These updates will include information on SUSARs 
and other relevant safety findings. 
6.2.1.8 
Pregnancy 
Monitoring of pregnancies is not applicable to this study because pregnancy is an 
exclusion criterion and a pregnancy test is performed in all women of childbearing 
potential at screening. Owing to the nature of the study involving short (6-day) 
treatment with the study drug in an ICU setting, it is not possible for women to 
become pregnant during treatment and for there to be any foetal exposure to the study 
drug. 


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6.2.2 
Laboratory Variables 
The biochemistry and haematology analysis will be performed at the hospital 
laboratories of the individual Investigator sites. Copies of laboratory accreditation and 
relevant reference ranges will be provided to the Sponsor or representative prior to 
the analysis of the first patient sample at that site. 
The laboratory variables measured in the study will be as detailed in Table 3. 
Blood samples for determination of biochemistry and haematology will be taken at 
screening, pre-dose on D1 (baseline value) and daily up to D28 while the patient is in 
the ICU, as detailed in the Schedule of Procedures in Section 7.1, Table 5. The date 
and time of sample collection will be recorded in the e-CRF. 
Dipstick urinalysis will be taken in the ICU (if urine is being produced) pre-dose on 
D1 (baseline value) and daily up to D28 while the patient is in the ICU, as detailed in 
the Schedule of Procedures in Section 7.1, Table 5. The date and time of sample 
collection will be recorded in the e-CRF. 
Table 3 
Laboratory Assessments 
6.2.2.1 
Haem
atolo
gy: 
Haemoglobin 
Haematocrit 
Erythrocytes 
MCV 
Platelets 
Leucocytes 
Differential counts of: 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
6.2.2.2 
Bioc
hemi
stry: 
Albumin 
Creatine kinase 
Creatinine 
Glucose 
Triglycerides 
Urea 
Bilirubin 
Total protein 
Alkaline phosphatase 
AST 
ALT 
Lactate 
Sodium (blood gas value acceptable) 
Potassium 
Bicarbonate 
Calcium (total calcium corrected for 
albumin level) 
Chloride  
6.2.2.3 
Urina
lysis: 
pH 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
 
 
6.2.2.4 
Pregn
ancy 
test: 
In women with child-bearing potential only. A urine pregnancy test will be performed 
unless the patient is not producing urine in which case a serum pregnancy test will be 
performed instead 
Abbreviations: AST=aspartate transaminase; ALT=alanine transaminase; MCV=mean corpuscular 
volume. 
A maximum of 100 mL of blood will be taken for study-specific testing during the 
study in addition to sampling for routine analysis of haematology and biochemistry 
variables. 


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6.2.3 
Vital Signs 
Vital signs will be measured supine pre-dose on D1 (baseline) and daily up to D28 
while the patient is in the ICU, as detailed in the Schedule of Procedures (Section 7.1, 
Table 5). The date and time of collection of each parameter will be recorded in the e-
CRF. 
Vital sign variables are: 
• 
Blood pressure (systolic, diastolic and mean; mmHg): to be recorded via an 
arterial line 
• 
Heart rate (HR; bpm): measured as per clinical practice in each ICU 
• 
Total respiratory rate (breaths per minute) 
• 
Temperature (°C): core temperature to be measured according to the site’s usual 
practices and the site of measurement should be recorded in the e-CRF 
6.2.4 
ECG 
Refer to the Schedule of Study Procedures (Table 5) for the timings of individual 
measurements. 
Twelve-lead ECGs will be obtained after the patient has rested in a supine position 
for at least 10 minutes. All 12-lead ECGs should be recorded while the patient is in 
the supine position. The investigator or designated physician will review the paper 
copies of each of the timed 12-lead ECGs on each of the study days when they are 
collected. ECGs will be recorded at 25 mm/s or at 50 mm/s. If anything clinically 
significant is observed on the ECG, the investigator will record it as part of the 
medical history, where the finding represents a change from baseline. 
6.2.5 
Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of 
Procedures (Table 5). 
A physical examination covering the major body systems (general appearance, head 
[ear, nose and throat], cardiovascular, eyes, respiratory, abdomen, urogenital, 
musculoskeletal, neurological, lymph nodes and skin) will be performed at 
screening (baseline), last day at ICU and at D28 (or when patient withdraws from the 
study prior to D28). 
At screening the physical examination will also include:  
• 
Predicted body weight (PBW). Calculate the PBW (kg) using the following 
formulae: 
For men: 50 + 0.91(height in cm – 152.4) 
For women: 45.5 + 0.91(height in cm – 152.4) 
• 
Actual height (in cm). The patient’s height does not need to be measured 
immediately if recorded elsewhere in the medical records or provided 
‘anecdotally’ by relatives (the PBW can then be calculated as described above). 
6.3 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics consist of those variables that are assessed 
only at screening/baseline. 


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6.3.1 
Patient Demography 
Patient demography consists of: 
• 
Age at screening 
• 
Race 
• 
Sex 
6.3.2 
Disease History 
For disease history, the following will be documented: 
• 
Time and date of moderate or severe ARDS diagnosis 
• 
Underlying aetiology of moderate or severe ARDS 
• 
Chest X-ray or CT scan 
• 
PaO2/FiO2 ratio element of moderate or severe ARDS diagnosis along with 
associated PEEP 
The chest X-ray or CT scan and the confirmatory assessment of PaO2/FiO2 ratio 
along with associated PEEP must occur within the same 24-hour period. 
6.3.3 
Medical History 
For documentation of the medical history, any relevant previous and ongoing medical 
conditions with a start date before the time of informed consent should be 
documented. Conditions that resolved long before informed consent and have no 
impact on the disease being studied should not be listed. 
The medical history should be obtained by inspecting the patient’s medical records or 
by interviewing the patient or their relatives. 


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Table 4 
APACHE II score 
 
VARIABLE 
Recorded 
value 
Points 
scored 
POINT VALUE RANGE 
+4 
+3 
+2 
+1 
+0 
+1 
+2 
+3 
+4 
Core temperature (°C) 
 
 
≥41 
39.0-40.9 
 
38.5-38.9 
36.0-38.4 
34.0-35.9 
32.0-33.9 
30.0-31.9 
≤29.9 
Mean arterial pressure (mmHg) 
 
 
≥160 
130-159 
110-129 
 
70-109 
 
50-69 
 
≤49 
Heart rate (beats/min) 
 
 
≥180 
140-179 
110-139 
 
70-109 
 
55-69 
40-54 
≤39 
Respiratory rate (breaths/min) 
 
 
≥50 
35-49 
 
25-34 
12-24 
10-11 
6-9 
 
≤5 
If FiO2 ≥ 0.5 use A-aDO2 (kPa) 
 
(mmHg) 
 
 
>67 
≥500 
47-66 
350-499 
27-46 
200-349 
 
<27 
<200 
 
 
 
 
If FiO2 < 0.5 use PaO2 
(kPa) 
 
(mmHg) 
 
 
 
 
 
 
>9.3 
>70 
8.1. – 9.2 
61-70 
 
7.3-8.0 
55-60 
<7.2 
<55 
Arterial pH 
 
 
≥7.7 
7.6-7.69 
 
7.5-7.59 
7.33 – 7.49 
 
7.25-7.32 
7.15-7.24 
<7.15 
If no ABG use HCO3 (mmol/L) 
 
 
≥52 
41-51.9 
 
32-40.9 
22-31.9 
 
18-21.9 
15-17.9 
<15 
Sodium (mmol/L) 
 
 
≥180 
160-179 
155-159 
150-154 
130-149 
 
120-129 
110-119 
≤110 
Potassium (mmol/L) 
 
 
≥7 
6-6.9 
 
5.5-5.9 
3.5-5.4 
3-3.4 
2.5-2.9 
 
<2.5 
Creatinine (µmol/L)* 
 
 
>309 
309-177 
176-133 
 
132-53 
 
<53 
 
 
Haematocrit (%) 
 
 
≥60 
 
50-59.9 
46-49.9 
30-45.9 
 
20-29.9 
 
<20 
White blood count (109/L) 
 
 
≥40 
 
20-39.9 
15-19.9 
3-14.9 
 
1-2.9 
 
<1 
Clinical & laboratory points 
 
 
 
 
 
 
 
 
 
 
 
* If the patient has acute renal failure then the score for serum creatinine will be doubled  
 


               
           
                 
          

         
      
         

                        
        
                


         

           
       
         
         

        

             
         
           
           
             
         

                 

               
             
             
                
         

                

           
                
               

                
          
                
           


   
     
     
     
   

 
 
 
 
 

                       
                       
              
                            
                       
                                    
                
                    
  









  










                     
                         
                 

          
 

               

 
             
 
      
 
           
        
        


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6.3.4 
Previous and Concomitant Medications 
Previous (in the month before screening) and concomitant medications will be 
documented as described in Section 5.7. 
6.4 
Pharmacoeconomic Evaluation 
Variables that will be measured as part of cost-effectiveness at D28 are: 
• 
Days free of organ failure (SOFA methodology) (D28 or last day in ICU if 
patient has left the ICU earlier than D28, or at withdrawal) 
• 
Days free of renal support 
• 
Days free of vasoactive support 
• 
Days free of mechanical ventilation 
• 
Number of ICU-free days 
• 
Number of days in hospital 
6.5 
Exploratory Variables 
6.5.1 
Improvement in Gas Exchange 
The gas exchange (PaO2/FiO2 ratio) of patients on mechanical ventilation will be 
evaluated. The PaO2/FiO2 ratio will be used as an indicator of lung function. 
6.5.2 
Biomarkers: CD73 and Potential Inflammatory Markers (PIM) 
Blood samples for the CD73 and PIM assessments will be collected pre-dose on 
D1 (baseline) and daily from D2 to D14 as detailed in the Schedule of Procedures 
(Section 7.1, Table 5). Fourteen samples of 2.5 mL will be collected for CD73 and 
PIM; from these, samples will be prepared for the CD73 and PIM testing. CD73 and 
PIM blood sample preparation and sample storage details are provided in the 
Laboratory Manual. It is essential that the actual time and date of collection of each 
sample is recorded in the sample collection form provided with the laboratory kits. 
CD73 samples will be analysed centrally by Wieslab AB; PIM samples will be 
analysed at MediCity Research Laboratory, University of Turku, Turku, Finland. 
6.5.3 
Pharmacogenetics 
The genetic sample can be taken at any time that the patient is in the ICU if consent 
has been obtained. The objectives of the genetic sampling are to obtain blood for 
extraction of DNA to identify factors that may be involved in the response or non-
response of diseases to FP-1201-lyo and comparator compounds. 
The blood sample will be taken for extraction of DNA. This is optional for all 
patients entering the study and will involve a separate patient consent procedure. 
Consenting to genetic sampling is not a prerequisite to participating in the main 
study. 
A 10 mL blood sample will be collected; sample preparation and sample storage 
details are provided in the Laboratory Manual.  
The samples and data for genetic analysis in this study will be coded. Samples will 
not carry any personal identifiers. DNA samples will be destroyed 15 years after 


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completion of this study. If the patient withdraws the consent, the sample will be 
destroyed without undue delay. 


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7 
STUDY CONDUCT 
For the purposes of this study, study day 1 (D1) is defined as the first calendar day 
(from midnight to the following midnight) of treatment with FP-1201-lyo or placebo. 
All days thereafter are defined as “Dn” (e.g., D2, D3, etc.) until D28. After D28 the 
study assessments are performed on D90 (3 months; either a clinic visit or telephone 
contact), D180 (6 months) and D360 (12 months). 
Baseline assessments are defined as those assessments carried out in the screening 
period and before the first dose of study drug on D1. It is critical that the time from 
diagnosis of moderate or severe ARDS to administration of the first dose of 
FP-1201-lyo or placebo is less than 48 hours. 
Unless withdrawn from study, all patients will receive study drug for 6 days. 
All assessments in the period up to D28 are only to be performed when a patient is in 
the ICU. If an improving patient is discharged from the ICU during the short-term 
follow-up period then the assessments under ‘last day in the ICU’ will be carried out 
and the survival status and other endpoints must be assessed on D28. 
There are three follow-up periods: 
• 
Short term: 
D7 to D28 
• 
Long term: 
D90 [3 months] and D180 [6 months] 
• 
Extended: 
D360 [12 months] (last visit) 
The end of the study will be the date of last patient/last visit at D360. 
 


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7.1 
Schedule of Procedures 
Table 5 
Schedule of Procedures 
 
Screen
-ing 
period 
Double-blind treatment 
period 
Days 1-6 
Short-term follow-up until D28 or 
discharge from ICU (whichever is earlier) 
Long-term 
follow-up 
Extended 
follow-up 
Baseline period 
 
D7–D28 
Procedure 
48 ha 
D1 
pre-
dose 
D1  
D2–D6 
D7–D14 
D15–
D27 
Last day 
in ICUb 
D28c 
D90d 
+14 days 
D180 
+14 days 
D360     
+14 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Demographic details 
X 
 
 
 
 
 
 
 
 
 
 
Documentation of chest X-ray or 
CT scan 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xe  
 
 
 
 
 
 
 
 
 
Randomisation 
Xf 
 
 
 
 
 
 
 
 
 
Administration of study drug 
 
 
X 
X 
 
 
 
 
 
 
 
Survival 
 
 
 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
On mechanical ventilation? (Y/N) 
 
 
 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
In ICU/in hospital? (Y/N) 
 
 
 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
SOFA 
 
X 
 
X 
X 
D21 
X 
X o 
 
 
 
GCS (for SOFA and APACHE II) 
X 
X 
 
X 
X 
D21 
X 
X o 
 
 
 
APACHE II 
X g 
 
 
 
 
 
 
 
 
 
 
Renal and vasoactive support? 
(Y/N) 
 
X 
 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
 
 
 
Administration of study drug 


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Screen
-ing 
period 
Double-blind treatment 
period 
Days 1-6 
Short-term follow-up until D28 or 
discharge from ICU (whichever is earlier) 
Long-term 
follow-up 
Extended 
follow-up 
Baseline period 
 
D7–D28 
Procedure 
48 ha 
D1 
pre-
dose 
D1  
D2–D6 
D7–D14 
D15–
D27 
Last day 
in ICUb 
D28c 
D90d 
+14 days 
D180 
+14 days 
D360     
+14 days 
Blood sample: IFN beta-1a 
neutralising antibodies 
 
Xh 
 
 
 
 
X 
X 
 
 
 
Blood sample: MxA 
 
Xh 
 
X 
X  
 
 
 
 
 
 
EQ-5D-3L, FEV1 and 6MWT  
 
EQ-
5D-3Li 
 
 
 
 
 
 
 
X 
X 
PaO2/FiO2  
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Blood sample: CD73 and PIM 
 
Xh 
 
X 
X 
 
 
 
 
 
 
Pharmacoeconomics 
 
 
 
 
 
 
X 
X 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
X o 
 
 
 
Vital signs 
Xj 
X 
 
X 
X 
X 
X 
X o 
 
 
 
ECG 
 
X 
 
 
D7 
 
 
 
 
X 
X 
Haematology, chemistry, 
urinalysisk 
Xj 
X 
 
X 
X 
X 
X 
X o 
 
 
 
Pregnancy test in women of 
childbearing potential 
X 
 
 
 
 
 
 
 
 
 
 
Previous and concomitant 
medications and therapies 
Xl 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -X 
 
 
 
Adverse events 
Xm 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
Xn 
Xn 
Xn 
Blood sample: genetic analysis 
(requires separate consent) 
X - - - - - - - - - - - - - 1 sample at any time while in ICU - - - - - - - - -X 
 
a No more than 48 hours may elapse between confirmation of moderate or severe ARDS and administration of the first dose of study drug. 
Administration of study drug 


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b These assessments will be done on the day the patient leaves the ICU, which will either be on D28 or earlier, according to the clinical progress of the patient. If the patient 
is still in the ICU on D28, the next visit or telephone contact will be at D90. If a patient leaves the ICU before D28, the survival status and other endpoints must be assessed 
on D28. 
c D28 procedures apply for patients leaving the ICU before D28 and for patients withdrawing from the study before D28. For patients withdrawing from the study before 
D28 a sample should be taken for neutralising antibodies on the day they leave the ICU. 
d D90 can either be a visit or telephone contact. 
e Reconfirm inclusion/exclusion criteria before dosing, including that patient requires mechanical ventilation and is in the ICU (patients requiring ECMO after 
randomisation but before the first dose of IMP may still be included). 
f Randomise after consent obtained and once eligibility criteria confirmed. 
g Within 24 hours of ICU admission 
h Within 1hour pre-dose. 
i Baseline EQ-5D-3L to be obtained from relatives and checked later with patient. 
j For APACHE II scoring. 
k Samples should be taken in the morning between 04:00 and 10:00. 
l Medicines and therapies in previous month. 
m Adverse events will be recorded after informed consent is obtained. 
n  Deaths are reported as SAE 
0 if it is possible to be performed by the investigator 
Abbreviations: APACHE II=Acute Physiology and Chronic Health Evaluation; CD=cluster of differentiation; CT=computerised tomography; D=study day; 
ECG=electrocardiogram; ECMO=extra-corporeal membrane oxygenation; EQ-5D-3L=EuroQol 5-Dimensions 3-Levels questionnaire; FEV1=forced expiratory 
volume in 1 second; GCS=Glasgow Coma Scale; ICU=intensive care unit; IFN=interferon; MxA=myxovirus resistance protein A; PaO2/FiO2=partial pressure of 
oxygen/fraction of inspired oxygen; PIM=potential inflammatory marker; SOFA=Sequential Organ Failure Assessment; 6MWT=6-minute walk test;. 
 


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7.2 
Procedures by Visit 
All times should be recorded using 24-hour clock (i.e., 23:20 not 11:20 pm). Where a 
patient’s condition precludes an assessment taking place as scheduled, the assessment 
should be performed within ±4 hours of the scheduled time; if this is not possible, the 
assessment will not be performed and the reason for non-performance should be 
recorded. 
7.2.1 
Pre-screening Evaluation and Screening Log 
A complete screening and pre-first-dose evaluation will be conducted including the 
procedures outlined in Sections 7.2.2.1 and 7.2.2.2 below. 
Patients will be considered for entry into the study when a diagnosis of moderate or 
severe ARDS has been made. Before being randomised, patients will be assessed to 
ensure that all eligibility criteria are met. Patients not meeting the eligibility criteria 
must not be randomised. Faron Pharmaceuticals Ltd will not permit any exceptions to 
the eligibility criteria and protocol waivers will not be given. 
When considering patients for the study, the investigational site will review: 
• 
The criteria for moderate or severe ARDS diagnosis to verify that all elements are 
present (refer to Inclusion Criterion 1 as per Section 4.1) 
• 
The time of moderate or severe ARDS diagnosis to ensure the 48-hour study 
treatment window is still available (refer to Inclusion Criterion 3 as per 
Section 4.1) 
• 
All eligibility criteria (refer to Sections 4.1 and 4.2) 
• 
Provision of informed consent. Study-specific procedures must be performed after 
informed consent for the study is given. Note: When the ICU normal procedures 
of patients are in line with the study procedures, and if the timing of moderate 
or severe ARDS diagnosis, consent and dosing preclude repeat of procedures for 
the purposes of the study, then normal patient care test results may be used for 
screening even if prior to consent. 
Investigational sites will review all ICU patients daily in order to identify potential 
patients for this study. Only patients that are intubated and mechanically ventilated 
are eligible for the study. Investigational sites will maintain a log for all patients that 
fulfil the intubation, mechanical ventilation and hypoxaemia (PEEP ≥ 5 cmH2O and 
PaO2/FiO2 ≤ 200 mmHg) inclusion criteria. For patients meeting these criteria the 
other criteria for ARDS diagnosis according to Berlin definition (Ref: ARDS Definition Task 
Force 2012) as well as the other study inclusion and exclusion criteria shall be reviewed 
and documented on the log, whether or not the patient is entered into the study. 
The log will be sent to the CRO on a weekly basis while the investigational site is 
open for recruitment. 
7.2.2 
Screening Assessments and Pre-dose Procedures 
7.2.2.1 
Screening Assessments to Be Performed After Moderate or Severe ARDS 
Diagnosis and Within 48 hours Prior to the First Dose of Study Drug 
Screening assessments will be carried out after informed consent and must be 
completed before the first dose of study drug is administered. The first dose of study 
drug must be administered within 48 hours of moderate or severe ARDS being 
diagnosed. 


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The following parameters will be reviewed and the data will be recorded in the e-CRF 
once the patient has given informed consent (refer to Schedule of Procedures in Table 
5): 
• 
Date and time of informed consent 
• 
Allocated patient screening number 
• 
Moderate or severe ARDS disease history including: 
- 
Time and date of moderate or severe ARDS diagnosis 
- 
Underlying aetiology of moderate or severe ARDS 
- 
Documentation of chest X-ray or CT scan 
- 
PaO2/FiO2 ratio element of moderate or severe ARDS diagnosis along with 
associated PEEP 
• 
Medical history including any concomitant diseases within the last 1 month before 
screening 
• 
Date and time of entry to ICU 
• 
Date and time of intubation and mechanical ventilation 
• 
Review of the inclusion and exclusion criteria 
• 
Demographic data including age at screening, race and sex  
• 
Physical examination of major body systems including PBW (refer to 
Section 6.2.4 for the calculation formula) and height 
• 
Pregnancy test: All women of childbearing potential must have a pregnancy test. 
The patient will be considered to lack childbearing potential if surgically sterile 
(e.g., hysterectomy, bilateral oophorectomy) or postmenopausal (amenorrhoea 
>12 months). A urine pregnancy test will be performed; if the patient is not 
producing urine a serum pregnancy test will be performed instead 
• 
APACHE II score; this is based on the worst values in the first 24 hours following 
admission to the ICU of the following 12 variables (see Table 4) but before the 
first dose 
o 
A-aDO2 or PaO2 (depending on FiO2) 
o 
Temperature (rectal or other core site) 
o 
Mean arterial pressure 
o 
Arterial pH 
o 
Heart rate 
o 
Respiratory rate 
o 
Sodium 
o 
Potassium 
o 
Creatinine 
o 
Haematocrit 
o 
White blood cell count 
o 
Glasgow Coma Scale 
• 
Genetic sample obtained if consent has been given (refer to Section 6.5.3). The 
genetic sample can be taken at any time while the patient is in the ICU if consent 
has been obtained 


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• 
Randomisation to a study treatment group may occur when all the 
inclusion/exclusion criteria are met and must follow the pre-dose eligibility check 
as described in Figure 2. The randomisation number along with the date and time 
of randomisation will be recorded 
• 
AEs 
• 
Previous and concomitant medications and therapies 
7.2.2.2 
Pre-dose Procedures to Be Performed on D1 Before the First Dose of Study 
Drug is Administered 
Note: Prior to the first administration of any study drug on D1, the patient’s moderate 
or severe ARDS status (as per Inclusion Criterion 1 in Section 4.1) must be 
confirmed. That the patient continues to be on mechanical ventilation must also be 
confirmed. If both criteria are not confirmed, the patient should be withdrawn from 
the study and will be classed as a screen failure.  
On D1 all pre-dose procedures and assessments are to be performed before the first 
dose of study drug. 
The following procedures and assessments will be performed: 
 
• 
Review of the inclusion and exclusion criteria to ensure continued eligibility, 
including a check that the patient is in the ICU and on ventilation  
• 
Check PaO2/FiO2 ratio 
• 
Randomisation: randomisation number and date and time of randomisation will be 
recorded 
• 
SOFA scoring will be done pre-dose based on the worst value so far that day for 
each of the following parameters: 
− 
PaO2/FiO2 (mmHg) 
− 
platelets × 103/mm3 
− 
bilirubin (µmol/L or mg/dL) 
− 
hypotension/use of vasopressors 
− 
GCS 
− 
creatinine (µmol/L or mg/dL) or urine output 
• 
APACHE II scoring will be done on the worst values in the 24 hours following 
ICU admission or up to the time of the first dose if the patient has been on the ICU 
less than 24 hours (see Table 4). 
• 
The following ventilation variables should be recorded in the morning between 
04:00 to 10:00 using the values closest to 10:00 (if these values are representative 
of the patient’s condition), whenever possible: 
− 
Mode of ventilation (whether predominantly volume or pressure set) 
− 
Tidal volume (ml) 
− 
Respiratory rate (breaths per min) - total respiratory rate will be used if the 
patient is breathing spontaneously on a mechanical ventilator 
− 
Peak inspiratory pressure (cmH2O) 
− 
Plateau pressure (cmH2O) - if set 
− 
Mean airway pressure (cmH2O) 
− 
PEEP 


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• 
All ventilator assessments must be taken at the same time point whenever possible 
and should be representative of the values over the recent past. PEEP is not 
available if using HFOV. 
• 
Recording of vasoactive drugs and renal support 
• 
Perform ECG  
• 
Vital signs (respiratory rate, temperature, blood pressure [BP] and HR) must be 
measured and recorded in the morning between 04:00 and 10:00 using the values 
closest to 10:00 (if these values are representative of the patient’s condition). All 
vital sign assessments must be taken at the same time point whenever possible 
• 
Blood biochemistry: samples must be taken in the morning between 04:00 and 
10:00 using the values closest to 10:00 (refer to Section 6.2.2 for specific 
biochemistry variables) 
• 
Haematology: samples must be taken in the morning between 04:00 and 10:00 
using the values closest to 10:00 (refer to Section 6.2.2 for specific haematology 
variables) 
• 
Urinalysis (if the patient is producing urine): samples for the urinalysis dipstick 
must be taken in the morning between 04:00 and 10:00 using the values closest to 
10:00 (refer to Section 6.2.2 for specific urinalysis variables) 
• 
Neutralising antibody sample for central testing (refer to Section 6.1.2.4) 
• 
MxA sample for central testing taken within 1 hour pre-dose (refer to Section 
6.1.2.5) 
• 
CD73 and PIM biomarker samples for central testing taken within 1 hour pre-dose 
(refer to Section 6.5.2) 
• 
Obtain baseline EQ-5D-3L from relatives 
• 
Recording of concomitant medications and therapies 
• 
Recording AEs 
7.2.3 
Treatment Period: D1 Dosing and Post-dose 
• 
Day 1: The first dose of study drug (FP-1201-lyo or placebo) will be administered 
as an intravenous bolus injection (see Section 5.2). 
• 
Record SOFA scores. Note: The worst daily value of each element should be used 
to calculate the overall SOFA score 
• 
Recording of concomitant medications and therapies 
• 
Recording of AEs 
7.2.4 
Treatment Period: D2 to D6 
Assessments from D2 to D6 are only performed when a patient is in the ICU. The 
following assessments are to be done daily: 
• 
Check patient survival 
• 
Confirm patient is in the ICU 
• 
Check whether the patient is on ventilation (refer to Section 6.1.1 for definition of 
UAB) 
• 
Administer the study drug (FP-1201-lyo or placebo) as an intravenous bolus 
injection 24 hours ±1 hour after the previous day’s administration. If for any 


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reason this is not possible, the dosing window may be extended by up to 4 hours. 
The reason for the delay must be entered in the e-CRF (see Section 5.2) 
Subsequent doses should not be delayed and should revert to the original time 
schedule. 
• 
Record SOFA scores  
• 
Recording of vasoactive drugs and renal support 
• 
Vital signs (temperature, BP and HR) must be measured and recorded in the 
morning between 04:00 and 10:00 using the values closest to 10:00 (if these 
values are representative of the patient’s condition). All vital sign assessments 
must be taken at the same time point whenever possible. 
• 
Haematology, biochemistry and urinalysis: samples must be taken daily in the 
morning between 04:00 and 10:00 using the values closest to 10:00 
• 
MxA, CD73 and PIM samples for central testing are taken within 22 hours 
±2 hours after the previous day’s administration of study drug, however before the 
next study drug dose. 
• 
Recording of concomitant medications and therapies 
• 
Recording of AEs 
7.2.5 
Short-term Follow-up Period: D7 to D14 
On D8 to D14 all assessments should be performed at the same time of day as the D7 
assessments were performed. The following study assessments and procedures will be 
performed: 
• 
Check patient survival 
• 
Confirm whether patient is still in hospital 
• 
Confirm whether patient is in the ICU. Patients still requiring intensive care who 
are transferred to another hospital or healthcare ICU facility prior to D14 will be 
followed up to assess the days in ICU at D28 
• 
Check whether the patient is on ventilation (refer to Section 6.1.1 for definition of 
UAB). Patients still on positive pressure ventilation who are transferred to another 
hospital or healthcare facility prior to D14 will be followed up to assess the VFD 
outcome at D28 
• 
Record SOFA scores 
• 
Recording of vasoactive drugs and renal support 
• 
ECG is taken on D7 
• 
Vital signs (temperature, BP and HR) must be measured and recorded in the 
morning between 04:00 and 10:00 using the values closest to 10:00 (if these 
values are representative of the patient’s condition). All vital sign assessments 
must be taken at the same time point whenever possible 
• 
Haematology, biochemistry and urinalysis: Samples must be taken daily in the 
morning between 04:00 and 10:00 using the values closest to 10:00 
• 
MxA, CD73 and PIM samples for central testing taken at the same time as on D6 
±2 hours 
• 
Recording of concomitant medications and therapies 
• 
Recording of AEs 


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7.2.6 
Short-term Follow-up Period: D15 to D27 
• 
Check patient survival 
• 
Confirm whether patient is still in hospital 
• 
Confirm whether patient is in the ICU. Patients still requiring intensive care who 
are transferred to another hospital or healthcare ICU facility prior to D27 will be 
followed up to assess the days in ICU at D28 
• 
Check whether the patient is on ventilation (refer to Section 6.1.1 for definition of 
UAB). Patients still on positive pressure ventilation who are transferred to another 
hospital or healthcare facility prior to D27 will be followed up to assess the VFD 
outcome at D28 
• 
Record SOFA score only on D21 
• 
Recording of vasoactive drugs and renal support 
• 
Vital signs (temperature, BP and HR) must be measured and recorded in the 
morning between 04:00 and 10:00 using the values closest to 10:00 (if these 
values are representative of the patient’s condition). All vital sign assessments 
must be taken at the same time point whenever possible 
• 
Haematology, biochemistry and urinalysis: Samples must be taken daily in the 
morning between 04:00 and 10:00 using the values closest to 10:00 
• 
Recording of concomitant medications and therapies 
• 
Recording of AEs 
7.2.7 
Short-term Follow-up Period: Last Day in ICU 
These assessments will be done on the day the patient leaves the ICU, either on D28 
or earlier, according to the clinical progress of the patient. If the patient is still in the 
ICU on D28, the next visit or telephone contact will be at D90. If a patient leaves the 
ICU before D28, the survival status and other endpoints must be assessed on D28.  
The following should be done: 
• 
Check patient survival 
• 
Confirm whether patient is in the ICU/in hospital 
• 
Check whether the patient is on ventilation 
• 
Record SOFA scores 
• 
Recording of vasoactive drugs and renal support 
• 
Neutralising antibody sample taken for central testing 
• 
Record pharmacoeconomic assessments (see Section 6.4) 
• 
Physical examination of major body systems 
• 
Vital signs (temperature, BP and HR) must be measured and recorded in the 
morning between 04:00 and 10:00 using the values closest to 10:00 (if these 
values are representative of the patient’s condition). All vital sign assessments 
must be taken at the same time point whenever possible 
• 
Haematology, biochemistry and urinalysis: samples must be taken in the morning 
between 04:00 and 10:00 using the values closest to 10:00 
• 
Recording of concomitant medications and therapies 
• 
Recording of AEs 


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7.2.8 
Short-term Follow-up Period: D28 
These procedures apply to patients having left the ICU before D28 and for patients 
withdrawing from the study before D28. 
• 
Check patient survival 
• 
Confirm whether patient is in the ICU/in hospital 
• 
Check whether the patient is on ventilation 
• 
Record SOFA score, to the extent possible at the investigational site 
• 
Recording of vasoactive drugs and renal support 
• 
Physical examination, including vital signs if possible to be completed by the 
investigator 
• 
Haematology, chemistry and urinalysis, if possible to perform at the 
investigational site   
• 
Update pharmacoeconomic assessments (see Section 6.4) 
• 
Recording of concomitant medications and therapies 
• 
Recording of AEs and follow-up on previously reported AEs. 
 
For patients withdrawing from the study, a sample should be taken for neutralising 
antibodies (see Section 7.2.11.1). 
7.2.9 
Long-term Follow-up Period: D90 and D180 
The study has a long-term follow-up period, with assessments at 3 (D90) and 
6 months (D180) after the first dose of study drug was administered. The D90 
assessment can be either a visit or telephone contact. For both D90 and D180 follow-
up, there is a time window of +14 days. 
• 
Check patient survival 
• 
Recording of AEs if the Investigator considers there is a causal relationship with 
the study drug  
• 
Report as SAE if the patient died. 
• 
Confirm whether patient is in the ICU/in hospital 
• 
Check whether the patient is on ventilation 
• 
At D180 only: EQ-5D-3L, FEV1 and 6MWT (including ECG).  
If it is not possible for the patient to attend a physical visit, as much information as 
possible, including QoL, should be obtained by phone. 
7.2.10 Extended Long-term Follow-up: D360 
The study has an extended long-term follow-up period with an assessment at 
12 months (D360) after the first dose of study drug was administered. There is a time 
window of ±14 days for this visit. 
• 
Check patient survival 
• 
Recording of AEs if the Investigator considers there is a causal relationship with 
the study drug  
• 
Report as SAE if the patient died  
• 
Confirm whether patient is in the ICU/in hospital 


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• 
Check whether the patient is on ventilation 
• 
EQ-5D-3L, FEV1 and 6MWT (including ECG).  
If it is not possible for the patient to attend a physical visit, as much information as 
possible, including QoL, should be obtained by phone. 
 
7.2.11 Early Termination Visit 
Patients who discontinue early from the study should, if possible, have an early 
termination visit. The procedures will vary depending on whether the patient 
withdrew on or before D28 (see Section 7.2.11.1) or after D28 (see Section 7.2.11.2). 
This visit should take place as soon as possible after it was learned that the patient 
will not be able to complete follow-up (see also Section 4.4).  
7.2.11.1 Withdrawal Prior to D28 
For patients withdrawing on or before D28, procedures for the last day in the ICU 
should be followed. In addition, a sample should be taken for neutralising antibodies. 
In the case of an ongoing AE, appropriate safety evaluations and/or additional tests 
may be performed at any time when clinically indicated at the discretion of the 
Investigator, until resolution or D28, whichever is first. 
Any ongoing AEs should be followed up to resolution or D28, whichever is the 
sooner. 
If the patient refuses to have any of the above assessments, or if the patient is lost to 
follow-up, then this should be noted in the e-CRF. 
If a patient is lost to follow-up, wherever possible, mortality data will be sought from 
alternative sources, such as the patient’s local physician or available national 
databases and all data obtained reported as SAEs. 
7.2.11.2 Withdrawal after D28 
If a patient withdraws after D28, no further follow-up will be attempted. However, if 
a patient is lost to follow-up, wherever possible, mortality data will be sought from 
alternative sources, such as the patient’s local physician or available national 
databases and all data obtained reported as SAEs. 
 


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8 
STATISTICAL METHODS 
The statistical considerations summarised in this section outline the plan for data 
analysis of this study. 
Before unblinding/database lock, a separate Statistical Analysis Plan (SAP) will be 
finalised, providing detailed methods for the analyses outlined below. After the 
clinical parts of the study have been completed, a blinded review of the data will be 
undertaken according to the SAP. This review will make decisions regarding: the 
handling of missing data and data for withdrawn patients; the handling of countries 
recruiting only a small number of patients in the statistical analyses that include 
country effects; and the definition of the Per-Protocol Set (PPS) at the patient level. 
Any deviations from the planned analyses will be described and justified in the final 
integrated study report. 
8.1 
Study Patients 
8.1.1 
Disposition of Patients 
Disposition and reasons for discontinuation will be summarised for all patients 
together with study drug exposure and study duration by treatment group. 
The number and percentage of patients entering and completing each phase of the 
study will be presented by treatment group. Reasons for withdrawal pre- and 
post-randomisation will also be summarised. 
The disposition of patients will also include information on the number and 
percentage of patients who: 
• 
completed study drug and follow-up 
• 
withdrew from study drug but completed follow-up 
• 
withdrew from study drug and from follow-up 
8.1.2 
Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will 
be classified as “minor” or “major” in conjunction with the Sponsor and Medical 
Monitor. Major deviations from the protocol will lead to the exclusion of that patient 
from the PPS. Deviations will be defined prior to unblinding. 
8.1.3 
Analysis Sets 
The following analysis sets will be defined for statistical analysis: 
The Full analysis set (FAS) will consist of all randomised and treated patients. The 
primary efficacy analyses will be based on this data set. Patients will be included in 
the analysis according to the treatment to which they were randomised. 
The Per-Protocol Set (PPS) will consist of patients in the FAS excluding patients 
with major protocol violations. A list of major protocol violations relevant for 
excluding data from the PPS will be detailed in the SAP. The precise definition of the 
PPS at the patient level will be identified at the blinded data review meeting. 
Statistical analyses for the primary and secondary endpoints will be performed on 
both the FAS and PPS. 
The safety set will consist of all patients who receive at least one dose of study drug. 
All safety and tolerability analyses will be based on this analysis set. A patient who 


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receives the wrong treatment according to their randomisation will be analysed for 
safety and tolerability in the treatment group corresponding to the treatment received. 
Statistical analyses for the primary and secondary endpoints will be performed on 
both the FAS and PPS. The primary efficacy endpoint analysis will be based on the 
FAS; a secondary analysis will also be performed based on the PPS to assess the 
sensitivity of the analysis to the choice of analysis set. All safety analyses will be 
based on the safety set. Demographic and baseline characteristics will be evaluated 
for the FAS. 
8.2 
General Considerations 
All statistical tests will be two sided and will be performed at the significance level of 
0.05, unless otherwise stated. 
Continuous data will be summarised by treatment group using descriptive statistics 
(number, mean, median, standard deviation [SD], minimum and maximum). 
Categorical data will be summarised by treatment group using frequency tables 
(frequencies and percentages). 
8.2.1 
Analysis and Data Conventions 
8.2.1.1 
Definition of Baseline 
The baseline assessment, where relevant, will be the latest available valid pre-dose 
assessment. 
8.2.1.2 
Visit Windows 
Assessments made outside of protocol-mandated windows will be displayed 
according to the e-CRF assessment recorded by the Investigator. 
8.2.1.3 
Unscheduled Assessments 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries. If more than one laboratory value is available for a given 
visit, the first valid observation will be used in summaries and all observations will be 
presented in listings. It is noted that invalid laboratory data will not be used (from 
haemolysed samples, mishandled samples, quantity not sufficient, or other conditions 
that would render values invalid). 
8.2.1.4 
Missing Data Handling 
In general, data will not be imputed for the primary efficacy analysis or the safety 
analysis. For other efficacy analyses, where relevant, imputations will use the last 
observation carried forward method for patients in the analysis. Additional details will 
be given in the SAP. 
Treatment by country interactions will be investigated and if any country has too few 
patients, a pooling strategy will be defined at the blinded data review, prior to 
unblinding. 
The approach to multiplicity testing for the key secondary endpoints is explained in 
Section 8.5.2.1.1. 


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8.3 
Demographics, Medical History, Baseline Characteristics and Concomitant 
Medications 
Baseline assessments will consist of those assessments carried out in the screening 
period and those carried out prior to the first dose of study drug on D1. 
Demographic and baseline characteristics will be summarised by treatment group and 
overall. No formal statistical comparisons will be undertaken to compare treatment 
groups for any of these parameters. 
Demographic data, medical history, concomitant disease and concomitant medication 
will be summarised by descriptive statistics (number, mean, SD, median, minimum 
and maximum) or frequency tables, overall and stratified by treatment. 
A medication given prior to the first injection of study drug will be classified as a 
prior medication. A medication given with or after the first injection of study drug 
will be classified as concomitant. Prior medications continuing during the study will 
be labelled accordingly in the listings. 
8.4 
Treatment Compliance 
As the study drug is administered directly to the patient in the ICU, treatment 
compliance will not need to be measured. 
8.5 
Efficacy Analyses 
8.5.1 
Primary Efficacy Analysis 
8.5.1.1 
Hypotheses to Be Tested 
The following hypotheses will be tested: 
• 
Null hypothesis H0: the value of VFDsurv in the treatment group is equal to that in 
the placebo group 
• 
Alternative hypothesis HA: the value of VFDsurv in the treatment group is not 
equal to that in the placebo group 
8.5.1.2 
Statistical Methods 
The primary composite endpoint includes death and days free of mechanical 
ventilation within 28 days among survivors. VFDs to D28 is defined as the number of 
calendar days during which the patient is ventilator-free including two UAB days to 
D28, assuming that a patient survives for at least two consecutive calendar days after 
initiating UAB. 
For example: If a patient initiates UAB in the afternoon of D16 and survives to D28 
that patient would be assigned a VFD value of 12. If a patient initiates UAB in the 
afternoon of D16 but dies in the afternoon of D25 they would be assigned a VFD 
value of 9. If a patient survives for more than 48 hours after initiating UAB but then 
requires assisted breathing (for any reason) before D28, the VFD value would be the 
total number of UAB days before D28 unless a period of assisted breathing was less 
than 24 hours and the purpose of assisted breathing was a surgical procedure. Patients 
who die without initiating UAB will be assigned a VFD value of 0 and patients who 
require more than 28 days of mechanical ventilation will also be assigned a VFD 
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The non-parametric analysis of the primary composite endpoint VFDsurv is based on 
a scoring scheme with patients who do better getting a higher score. All patients who 
die before 28 days will be assigned a VFDsurv score of -1. For those patients who 
survive to D28 the VFDsurv score will be equal to the VFD value calculated 
according to the above definition. 
The statistical analysis for group comparison of the primary endpoint will then be 
based on the van Elteren test adjusting for country, ARDS severity and key baseline 
characteristics. (Ref: Van Elteren 1960) The statistical methodology with regard to the scoring 
scheme is as set down in Finkelstein and Schoenfeld. (Ref: Finkelstein et al 1999) The primary 
analysis of this endpoint will be based on the FAS, with a sensitivity analysis based 
on the PPS providing supportive information. Each of these analyses will be 
undertaken at the two-sided significance level of 0.05. 
8.5.1.3 
Subgroup Analyses 
The primary endpoint will be summarised by country, treatment severity and key 
baseline characteristics. These analyses will be fully defined in the SAP. 
8.5.2 
Secondary Efficacy Analyses 
8.5.2.1 
All-cause Mortality 
As confirmatory measures of efficacy, the following endpoints will be analysed: 
• 
Mortality up to D28, up to D90 (3 months) and up to D180 (6 months) 
• 
Mortality in ICU up to D28 
• 
Mortality in hospital up to D28 
The primary analysis of the binary mortality endpoints will be based on the FAS and 
will be undertaken using logistic regression adjusting for country, ARDS severity and 
key baseline characteristics. This analysis will be repeated using the PPS as a 
sensitivity analysis. Each of these analyses will be summarised using the observed 
mortality rates for the two treatment groups, a 95% confidence interval (CI) for the 
difference in these rates, an adjusted odds ratio and a 95% CI for the adjusted odds 
ratio. A two-sided significance level of 0.05 will be used for each of these endpoints. 
There will also be an evaluation of the homogeneity of the treatment effect by 
investigating treatment by country, treatment by ARDS severity, and treatment by 
baseline factor interactions in the logistic model. Data for these efficacy endpoints 
will also be presented for key predefined subgroups of patients together with 95% CIs 
for the difference in those rates to supplement the investigation of homogeneity. 
ICU mortality and hospital mortality will be analysed in the same way as overall 
mortality. 
8.5.2.1.1 Control of Multiplicity 
Multiplicity will be controlled across the key secondary endpoints using a pre-
specified hierarchy. The pre-specified hierarchy is: 
1. All-cause mortality at D28  
2. All-cause mortality at D90  
3. All-cause mortality at D180  
4. Mortality in ICU at D28  
5. Mortality in hospital at D28 


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Statistical significance will be declared down to the first non-significant endpoint 
(based on a two-sided significance level of 0.05) in this hierarchy. All p-values at and 
below this level will be considered as providing supportive information only. 
VFDsurv will also be considered as a secondary endpoint, although no formal p-value 
comparisons will be undertaken for that endpoint as patients who die will be excluded 
from such an analysis. 
8.5.2.2 
Days Free of Organ Failure, Renal Support, Vasoactive Support, ICU Care 
and Days in Hospital 
Organ failure-free days are defined as the number of days in the first 28 days after the 
first dose of study drug that the patient is alive and free of organ failure with a SOFA 
score of zero. 
ICU-free days are defined as the number of days from the time of ICU discharge to 
D28, assuming survival for at least two consecutive calendar days after ICU discharge 
and continued stay outside the ICU setting to D28. If a patient returns to the ICU and 
subsequently needs ICU admission to D28, ICU-free days will be counted from the 
end of the last period of ICU discharge to D28. A period of ICU admission lasting 
less than 24 hours in relation to a surgical procedure will not count in the calculation 
of ICU-free days. If a patient was in the ICU at D27 or dies prior to D28, ICU-free 
days will be zero. Patients transferred to another hospital or healthcare facility will be 
followed to D28 to assess this endpoint. 
The statistical methods to be used for these secondary efficacy endpoints will be 
detailed in the SAP. 
8.5.2.3 
Immunogenicity 
The presence of neutralising antibodies to IFN beta-1a at D28 will be summarised by 
treatment groups in terms of counts. 
8.5.2.4 
Myxovirus Resistance Protein A 
Details of the statistical analysis of MxA will be provided in the SAP. 
8.5.2.5 
Quality of Life, Respiratory and Neurological Functioning 
Health-related QoL, respiratory functioning (FEV1) and neurological functioning 
(6MWT) will be assessed at D180 (6 months) and included in the Clinical Study 
Report Addendum. Extended long-term follow-up data will also be gathered at D360 
and submitted as an Addendum to the report (see Section 8.8.4). 
The EQ-5D-3L data will be analysed overall. Summary statistics will also be provided 
in relation to the five individual domains. Further details will be provided in the SAP. 
These data will only be available for survivors at D180. Analyses of these parameters 
will be based on the subset of patients who survive to that time point and not on the 
FAS. Only summary statistics and 95% CIs for treatment differences (for descriptive 
purposes) will be calculated. 
8.6 
Safety Analyses 
These summaries will be based on the safety set. 


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8.6.1 
Adverse Events 
AEs and SAEs will be coded using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA) and will be classified by system organ classes and 
preferred terms. In the event that intensity or relationship of an AE to the study drug 
is missing, a worst-case scenario will prevail (severe in intensity or probably related). 
Only TEAEs (AEs that occur after the first study drug administration, that were not 
pre-existing or that increased in intensity) will be included in the summary tables. 
Counting will be performed for patients and events separately. Patients experiencing 
the same event more than once will have that event counted once within the 
corresponding system organ class and with a unique preferred term. All AEs will be 
included in the data listings. Listings of SAEs, of AEs leading to study drug 
withdrawal and of AEs leading to death will also be provided. 
8.6.2 
Vital Signs 
Vital signs data (BP, HR and temperature) will be summarised using descriptive 
statistics (mean, median, SD, minimum and maximum) by treatment group separately 
at D1 and daily to D28. The maximum change from baseline over the 28-day follow-
up period will be calculated for each patient and summarised. 
8.6.3 
Clinical Laboratory and Urinalysis Variables 
Descriptive statistics (mean, median, SD, minimum and maximum) for biochemistry 
and haematology variables will be obtained and tabulated by treatment group pre-dose 
on D1 and daily to D28. Number and percentage will be obtained for each category 
for urinalysis and tabulated by treatment group at the same time points. 
Shift tables (within, below and above the normal range) will also be provided for each 
parameter in relation to the maximum change from baseline from D1 over the 
complete 28-day follow-up period. 
8.6.4 
Physical Examination  
The incidence of physical examination findings will be summarised by treatment 
group. 
8.6.5 
Independent Data Monitoring Committee 
An IDMC will be established for the study to monitor safety (see Section 9.8). No 
formal interim analyses will be performed. 
8.7 
Pharmacoeconomics 
The expected incremental cost-effectiveness will be calculated for intravenous 
FP-1201-lyo compared with standard care in the treatment of patients with moderate 
or severe ARDS admitted to ICU in the study-related countries. Criteria that will be 
measured at D28 as part of the cost-effectiveness analyses in this study are: 
• 
Days free of organ failure (D28 or last day in ICU if patient has left the ICU 
earlier than D28, or at withdrawal) 
• 
Days free of renal support 
• 
Days free of vasoactive support  
• 
Days free of mechanical ventilation 
• 
Number of ICU-free days 


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• 
Number of days in hospital  
Details on the statistical analysis of these criteria and their role in the economic 
evaluation will be provided in the SAP. 
8.8 
Exploratory Analyses 
8.8.1 
Composite Endpoint at 90 Days 
The D90 composite VFDsurv endpoint includes death and days free of mechanical 
ventilation within 90 days among survivors. VFDsurv to D90 is defined as the number 
of calendar days after initiating UAB to D90, using the same assumptions as for the 
D28 analysis. 
8.8.2 
Gas Exchange Ratio 
The PaO2/FiO2 ratio will be used as an indicator of lung function. Moderate ARDS is 
defined as PaO2/FiO2 >100 mmHg and ≤200 mmHg with PEEP ≥5 cmH2O; severe 
ARDS is defined as PaO2/FiO2 ≤100 mmHg with PEEP ≥5 cmH2O. 
The ordered categorical endpoint is defined as improvement (from severe to 
moderate/mild; from moderate to mild ARDS), no change, or worsening (from 
moderate to severe/death; from severe to death) in terms of gas exchange (PaO2/FiO2 
ratio) from baseline to D28. The data analysed for this endpoint will be: 
• 
% of patients improving from severe to moderate ARDS or from moderate to mild 
ARDS 
• 
% of patients worsening from moderate to severe ARDS/death or from severe 
ARDS to death 
Details on the statistical analysis of change in lung function will be provided in the 
SAP. 
8.8.3 
CD73 and Potential Inflammatory Markers; Pharmacogenetic Analysis 
Details on the statistical analysis of CD73 and PIM biomarkers will be provided in the 
SAP. 
No statistical analysis is planned for the pharmacogenetic investigation. 
8.8.4 
Extended Follow-up 
Details of the statistical analysis of data from the long-term and extended follow-up 
(D180 and D360) of 6-month and 12-month mortality rates, EQ-5D-3L, 6MWT, and 
FEV1 will be detailed in a separate SAP (as they will be reported separately as 
addendums to the Clinical Study Report). 
8.9 
Interim Analyses 
No interim analyses are planned. 
8.10 Determination of Sample Size 
For 90% power and a two-sided Mann–Whitney U-test at the significance level of 
0.05, a total of 272 patients are required based on the following assumptions: 
 


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• 
mortality rate of 30% in the control group and 15% in the FP-1201-lyo group 
at D28 
• 
20% of patients survive but with zero ventilator-free days (VFDs) in the 
control group 
• 
A mean difference (FP-1201-lyo minus control) of 3.0 days in mean 
ventilator-free days where patients who die are assigned a score of 0 
 
However, assuming 5% of patients (16) drop-out and a further 4% (12) of the 
remaining patients will not be evaluable for the efficacy analysis, the study will 
randomise 300 patients to build in some flexibility around the assumptions listed 
above. 
 
PASS software (Version 11; NCSS LLC, Kaysville, UT, USA) was used to calculate 
the required sample size for this study. Table 6 gives values for power based on this 
sample size and alternative values for the mortality rates in the two treatment groups 
with a total sample size of 300 (including 5% drop-outs and a further 4% non-
evaluable patients). These calculations are based on the construction of two 
multinomial distributions according to the above assumptions and the associated non-
parametric comparison of those distributions. 
Table 6 
Values for Power for Various Mortality Rates 
per Treatment Group (n=300) 
 
1VFDsurv=0 is the number of patients alive at Day 28 but on mechanical ventilation for the whole 28-
day period. 
2Calculated value. 
Mortality)
Exptl.)
group)
)
Mortality)
Control)
group)
)
VFDsurv=02)
Exptl.)
group)
)
VFDsurv=01)
Control)
group)
)
VFDsurv=y)
Exptl.)
Group)
)
VFDsurv=y)
Control)
Group)
)
Difference)
in)mean)
VFD3)
(days)
)
Power)
Total)
sample)
size)
)
15%$
30%$
7%$
20%$
2.8%$
1.8%$
4.0$
90%,$
80%$
194,$
144$
18%$
30%$
4%$
20%$
2.8%$
1.8%$
4.0$
90%,$
80%$
224,$
164$
15%$
30%$
11%$
20%$
2.7%$
$$$$1.8%!
3.5$
90%,$
80%$
238,$
180$
18%$
30%$
8%$
20%$
2.7%$
$$$$1.8%!
3.5$
90%,$
80%$
270,$
206$
15%$
30%$
14%$
20%$
2.5%$
$$$$1.8%!
3.0$
90%,$
80%$
284,$
226$
18%$
30%$
11%$
20%$
2.5%$
$$$$1.8%!
3.0$
90%,!
80%!
340,!
248!
15%$
30%$
18%$
20%$
2.4%$
$$$$1.8%!
2.5$
90%,!
80%!
374,!
262!
18%!
30%!
15%!
20%!
2.4%!
!!!!1.8%!
2.5!
90%,!
80%!
438,!
330!


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3This difference in mean VFD is calculated with deaths within 28 days given a value of 0 for VFD. 
4Assumes 4% non-evaluable rate. 
Abbreviations: Exptl=experimental; VFD=ventilator-free day; VFDsurv=composite endpoint 
including any-cause death at D28 and days free of mechanical ventilation within 28 days among 
survivors. 
 


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9 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to each study centre to 
verify the qualifications of each Investigator, inspect the site facilities and inform the 
Investigator of their responsibilities and the procedures for ensuring adequate and 
correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the study for 
each study participant. All information recorded in the e-CRF for this study must be 
consistent with the patients’ source documentation (i.e., medical records). 
9.1.1 
Database Management and Quality Control 
All study-related data generated by site personnel will be captured electronically at 
each study centre using the e-CRF. 
Central laboratory assays (e.g., PD, genetic) will be managed by the central 
laboratories and results will be transferred for inclusion in the study analysis database. 
Once the e-CRF clinical data have been submitted, corrections to the data fields will 
be captured in an audit trail. The reason for change, the name of the person who 
performed the change, and the time and date will be logged to provide an audit trail. 
The specific procedures to be used for data entry and query resolution using the e-
CRF will be provided to study sites in CRF completion instructions. In addition, site 
personnel will receive training on the e-CRF. Once the source data verification is 
complete and all queries are closed, Data Management will freeze the e-CRF page. 
9.2 
Case Report Forms and Source Documentation 
All data obtained during this study must be promptly entered in the e-CRF. All source 
documents from which e-CRF entries are derived should be placed in the patient’s 
medical records. Measurements for which source documents are usually available 
include laboratory assessments, CT scans and X-rays. 
Data that will be entered directly into the e-CRF (i.e., for which there is no prior 
written or electronic record) are considered to be source data. 
The e-CRF entries for each patient will be checked against source documents at the 
study site by the CRA. 
9.2.1 
Data Collection  
The Investigators (and appropriately authorised staff) will be given access to an online 
web-based electronic data-capture system that is compliant with US Food and Drug 
Administration Title 21 Code of Federal Regulations Part 11. This system is 
specifically designed for the collection of clinical data in electronic format. Access 
rights to the electronic data-capture system will be carefully controlled and configured 
according to each individual’s role throughout the study. Only the Investigator and 
authorised staff will be able to enter and correct data in the e-CRF. 
The e-CRF should be completed for each patient included in the study and should 
reflect the latest observations on the patients participating in the study. Therefore, the 
e-CRF is to be completed as soon as possible during or immediately after the patient’s 
visit or assessment. The Investigator must verify that all data entries in the e-CRF are 


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accurate and correct. If some assessments cannot be done, or if certain information is 
unavailable, not applicable or unknown, the Investigator should indicate this in the e-
CRF. 
Computerised data-check programs and manual checks will identify any data 
discrepancies for resolution. Corresponding queries will be generated in the system 
and the site will be informed online about new issues to be resolved. All discrepancies 
must be resolved online directly by the Investigator or by staff authorised to do this by 
Delegation of Authority. 
After completion, the Investigator will be required to electronically sign off the 
clinical data. 
9.3 
Access to Source Data 
During the study, the CRO site CRA will make regular site visits to review protocol 
compliance, conduct source data verification by comparing e-CRF entries and 
individual patient’s medical records, assess drug accountability and management, 
assess laboratory procedures and ensure that the study is being conducted according to 
pertinent regulatory and protocol requirements. The review of medical records will be 
performed in a manner that ensures patient confidentiality is maintained. 
Source data verification will be required to monitor the progress of the study. 
Moreover, regulatory authorities in certain countries, IECs and/or the Sponsor’s 
Clinical Quality Assurance Group or designee may wish to carry out such source data 
checks and/or on-site audit inspections. Direct access to source data will be required 
for these inspections and audits; they will be carried out giving due consideration to 
data protection and medical confidentiality. The Investigator must assure the CRO 
and the Sponsor that they will provide the necessary support at all times. 
9.4 
Archiving Study Records 
According to ICH guidelines, essential documents should be retained for a minimum 
of 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. However, these documents should be retained for a longer 
period if required by the applicable legal requirements. 
9.5 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor 
and Investigator abide by the principles of the Good Clinical Practice guidelines of 
the ICH and the Declaration of Helsinki. (Ref: Declaration of Helsinki 2013) The study will also 
be carried out in keeping with local legal requirements. 
9.6 
Informed Consent 
The Investigator at each investigational site is responsible for ensuring that written 
informed consent for study participation is given by each patient or their legal 
representative prior to collection of study data and administration of the study drug. 
Unless the study site is in a country where consent can only be obtained from the 
patient but can be waived and obtained retrospectively, according to local IEC rules, 
the Investigator will not undertake any investigation specifically required only for the 


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clinical study until valid consent has been obtained. If consent has not been obtained, 
a patient cannot be randomised into the study. 
Consent will be sought from the patients themselves, if this is possible. However, it is 
recognised that most patients will be unable to give written informed consent 
themselves due to alteration in their level of consciousness caused by therapeutic 
sedation. Written informed consent will be sought from a PerLR or PrfLR. In some 
countries, according to IEC rules, consent can only obtained from the patient. In these 
countries, if the patient is unable to give consent, their relatives and the patient’s own 
family doctor will be informed about the study. Consent from the patient will be 
obtained as soon as the patient is able to understand the study and sign the consent 
form. As this is an international study, the appropriate guidance and law will be 
followed for each country. 
If a protocol amendment is required, the ICD may need to be revised to reflect those 
changes. If the ICD is revised, it must be reviewed and approved by the appropriate 
IEC, and signed by all patients (or their representatives) subsequently enrolled in the 
study as well as those currently enrolled in the study. 
9.6.1 
Consent Procedure 
The person giving consent will be informed about the study by the Investigator or by 
a member of the research team to whom the Investigator has delegated the consent 
process. 
To provide all the necessary information, clinical study information and ICDs are 
quite lengthy. For this study, dependent on country specific regulations, an 
abbreviated initial section of the ICD will provide a short summary of key 
information, followed by the detailed information for those interested in receiving 
further information. 
The patient, PerLR or PrfLR must be given adequate time to consider their decision 
about entering the study. However, the requirement to initiate study treatment within 
48 hours of moderate to severe ARDS diagnosis will of necessity be a consideration. 
In all cases, the patient, PerLR or PrfLR will be asked to sign two copies of the ICD, 
which will then be countersigned by the Investigator or the member of the study team 
to whom obtaining consent has been delegated.  One copy of the document will be 
retained by the person giving consent (patient, PerLR or PrfLR). The second copy 
will be photocopied. The photocopy will be placed in the patient’s medical records 
and the original will be retained in the Investigator Site File. 
A similar procedure will be followed for retrospective patient informed consent, 
which will be an additional section at the end of the ICD (see Section 9.6.5). 
The terms of the consent and when it was obtained must be documented in the e-CRF 
system. 
The patient, PerLR or PrfLR will also be asked to give separate consent for a genetic 
sample to be taken. Consent for genetic sampling is not a prerequisite for study 
participation. 
9.6.2 
Patient Consent 
Whenever possible, informed consent will be obtained from the patient. Once the 
patient has been informed about the study, the patient will be given a copy of the ICD. 
After being given an adequate amount of time to consider the information, if the 
patient decides to enter the study, they will be asked to sign two copies of the ICD. 


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9.6.3 
Personal Legal Representative Consent 
If the patient is unable to give consent then informed consent will be sought from the 
patient’s PerLR. The PerLR may be a relative, partner or close friend. Any country-
specific guidance on who may act as a PerLR will be followed. 
Once the PerLR has been informed about the study, the PerLR will be given a copy of 
the ICD and will be asked to give an opinion as to whether the patient would object to 
taking part in the study. 
After being given an adequate amount of time to consider the information, if the 
PerLR decides that the patient would have no objection to participating in the study 
then the PerLR will be asked to sign two copies of the ICD. 
9.6.4 
Professional Legal Representative Consent 
If the patient is unable to give consent and no PerLR is available then a doctor at the 
investigational site who is not connected with the conduct of the study may act as a 
PrfLR. Any country-specific guidance on who may act as a PrfLR will be followed. 
After being informed about the study, the PrfLR will be given a copy of the ICD. If 
the PrfLR decides that the patient is suitable for entry into the study then the PrfLR 
will be asked to sign two copies of the ICD. 
9.6.5 
Retrospective Patient Informed Consent 
Patients for whom consent was given by a PerLR or a PrfLR will be informed of their 
participation in the study by the Investigator or by a member of the research team to 
whom the Investigator has delegated the consent process. This process will take place 
once the patient has regained the capacity to understand the details of the study. The 
timing of this process will thus vary between patients. However, every attempt to 
obtain retrospective consent must be made when the patient’s condition is appropriate. 
If a patient’s condition has precluded the re-consent process occurring by D360 
(12 months), then no further attempts will be made to re-consent the patient. 
Once informed, patients will be given an adequate amount of time to consider their 
decision to consent to continued participation in the study and to sign the re-consent 
section of the ICD. 
If the patient does not give retrospective consent then the patient will be asked if the 
data collected to that time point can be analysed. If the patient will not allow any of 
their data to be used, then the data collected from the patient to that time point will not 
be entered into the analyses and no further data will be collected; the patient will be 
considered as withdrawn and the reason for withdrawal will be ‘retrospective consent 
not given’. 
9.6.6 
Withdrawal of Consent 
Patients may withdraw or be withdrawn (by the PerLR or PrfLR) from the study at 
any time, for any reason and such a decision will not affect the ongoing care given to 
the patient. Data recorded up to the point of withdrawal will be included in the study 
analyses, unless consent for any use of the data has also been withdrawn. In this case, 
data entered in the e-CRF would not be deleted, but would not be used in subsequent 
analyses or reports. 
If a patient or PerLR/PrfLR requests termination of the administration of study drug 
during the treatment period, then the administration of study drug will be stopped but 
the patient will continue in the study and all follow-up assessments will be performed. 


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If a patient or a PerLR/PrfLR withdraws consent during the treatment period then the 
administration of study drug will be stopped and no further active study assessments 
will be performed from that point on. However, permission will be sought to access 
the patient’s medical records to obtain data relevant to the study (e.g., mortality, 
VFDs, etc.). 
If a patient or a PerLR/PrfLR withdraws consent after the treatment period then no 
further active study assessments will be performed from that point on. However, 
permission will be sought to access the patient’s medical records to obtain data 
relevant to the study (e.g., mortality, VFDs, etc.). 
9.7 
Protocol Approval and Amendment 
For the study to start, all required documentation must be approved by the IEC and 
Competent Authority, in accordance with local legal requirements. The Sponsor must 
ensure that all ethical and legal requirements have been met before the first patient is 
enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be 
written, receive approval from the appropriate personnel, and receive IEC/competent 
authority approval prior to implementation (if appropriate). 
Administrative changes (not affecting the patient benefit/risk ratio) may be made 
without the need for a formal amendment. All amendments will be distributed to all 
protocol recipients, with appropriate instructions. 
9.8 
Independent Data Monitoring Committee 
An IDMC will be established for the study. The IDMC and associated parties (CRO 
Pharmacovigilance, Data management, Sponsor as well as the CRO for IDMC 
management) will function under the terms of an IDMC Charter. The IDMC will 
comprise four members, including one independent biostatistician and three senior 
clinicians with significant experience in ARDS and who are not involved in the study. 
The duty of this IDMC is to protect the safety interests of patients and all others who 
may possibly be exposed to the study drug and to make recommendations to the 
Sponsor. The IDMC will review ongoing safety data in an unblinded manner. 
According to the current IDMC Charter, meetings are scheduled to take place after the 
data has been received for the last patient of approximately 30, 60, 200 and 300 
patients who either have completed 14 days in the study following their first dose of 
study medication or have been withdrawn for any reason (including death). The 
IDMC will not review efficacy data, other than how it relates to the safety of the 
therapy. From each meeting, the IDMC will make a blinded recommendation to the 
Sponsor regarding the study to continue without change, modify study or enrolment to 
be placed on hold, or study termination. The sponsor is obligated to inform the study 
sites, Ethics Committees and Competent Authorities of the IDMC recommendations 
according to country specific requirements 
 
9.9 
Steering Committee 
In addition to the IDMC, a separate and blinded Steering Committee of respected and 
experienced critical care personnel representing all participating countries will be 
established for this study. Members of the Steering Committee may also be 


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Investigators or Sub-investigators. Face-to-face meetings will be held as determined 
by need. Routine business will be conducted by email, post or teleconferencing. 
The Steering Committee will provide advice and support to the study in matters 
concerning: 
• 
Communicating with national sites (e.g., in the instance of recruitment or quality 
issues) 
• 
Oversight of the progress of the study 
• 
Informing and advising on all aspects of the study 
• 
Review and advice on any proposal for a co-enrolment study 
9.10 Duration of the Study 
For an individual patient, the maximum duration of the study will be up to 376 days, 
including up to 48 hours for screening, 6 days’ treatment and follow-up at 6 and 12 
months (D360 with a ±14-day window). 
The study will close when all patients have completed the 12-month extended follow-
up visit. 
9.11 Premature Termination of the Study 
The Sponsor reserves the right to stop the study at any time on the basis of new 
information regarding safety or efficacy (e.g., discovery of an unexpected, significant 
or unacceptable risk to the patients enrolled in the study), or if study progress is 
unsatisfactory (e.g., failure to enrol patients at an acceptable rate), or for other valid 
reasons (e.g., Sponsor decides to suspend or discontinue development of the drug). 
After such a decision is made, the Investigator must inform all on-study patients 
within 1 week. All delivered study materials must be collected and all e-CRF pages 
completed to the extent possible. 
9.12 Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator 
and members of their research team must not disclose any information without prior 
written approval from the Sponsor. 
The anonymity of participating patients must be maintained. Patients will be 
identified on the e-CRF and other documents submitted to the CRO by their patient 
number and/or birth date, not by name. Documents that identify the patient must not 
to be submitted to the CRO (e.g., the ICD) and must be maintained in confidence by 
the Investigator. 
9.13 Other Ethical and Regulatory Issues 
If a significant safety issue is identified, either from an individual case report or 
review of aggregate data, then the Sponsor will issue prompt notification to all parties 
– regulatory authorities, Investigators and IEC/ EC. 
A significant safety issue is one that has a significant impact on the course of the 
clinical study or programme (including the potential for suspension of the 
development programme or amendments to protocols) or warrants immediate update 
of informed consent. 


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9.14 Publication Policy 
Any manuscript, abstract or other publication or presentation of results or information 
arising in connection with the study (including any ancillary study involving study 
patients) must be prepared in conjunction with the study Sponsor and must be 
submitted to the Sponsor for review and comment at least 45 days prior to submission 
for publication or presentation. No single centre or groups of centres may publish 
individually. The Sponsor’s comments on the proposed publication shall be 
considered in good faith by the authors. The Sponsor may delay such submission by a 
maximum of 90 days if it reasonably believes that publication of results may 
compromise its intellectual property rights or may insist that such information or data 
is removed from the proposed publication. Publication of the results will not include 
confidential information without the permission of the Sponsor. 
The original e-CRF pages and all data generated during the study under this protocol 
will become the property of the Sponsor. 
The Sponsor may announce quality-assured summary data in order to comply with the 
requirements of financial regulatory authorities, while ensuring so far as possible that 
such announcements will not compromise the Investigators’ ability to publish the data 
in appropriate scientific forums. 
 


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10 REFERENCE LIST 
Bellingan G et al 2014 
The effect of intravenous interferon-beta-1a (fp-1201) on lung cd73 expression and on acute 
respiratory distress syndrome mortality: an open-label study. The Lancet Respiratory 
Medicine 2014, 2:98–107. 
ARDS Definition Task Force 2012 
Acute respiratory distress syndrome: the Berlin Definition  
JAMA. 2012;307(23):2526-2533.  
Bernard et al 1994 
The American-European Consensus Conference on moderate to severe ARDS Definitions, 
mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 
1994;149:818-824. 
Committee for Medicinal Products for Human Use 1994 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & 
Co; 1994: pp253-256. 
Committee for Medicinal Products for Human Use 2006 
Guideline on clinical investigation of medicinal products in the treatment of patients with 
acute respiratory distress syndrome. EMEA/CPMP/EWP/504/97 Rev1. 21 Sep 2006. 
Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00003553.pdf.  
Declaration of Helsinki 2013 
(as adopted by the 18th World Medical Assembly, 1964 and as revised by the 29th World 
Medical Assembly, Tokyo 1975, the 35th World Medical Assembly, Venice 1983, the 41st 
World Medical Assembly, Hong Kong 1989, and the 48th General Assembly, Somerset West, 
Republic of South Africa, 1996, 52nd WMA General Assembly, Edinburgh, Scotland, 
October 2000, 53rd WMA General Assembly, Washington DC, USA, October 2002, 55th 
WMA General Assembly, Tokyo, Japan, October 2004, 59th WMA General Assembly, Seoul, 
Republic of Korea, October 2008, 64th WMA General Assembly, Fortaleza, Brazil) October 
2013. 
Doyle et al 1995 
Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care 
Med 1995;152:1818-1824. 
Finkelstein et al 1999 
Combining mortality and longitudinal measures in clinical trials. Statist Med 1999;18:1341-
1354. 
Grissom et al 2010 
A modified sequential organ failure assessment score for critical care triage. Disaster Med 
Public Health Prep 2010;4:277-284. 
Holland et al 2014 
An official European Respiratory Society/American Thoracic Society technical standard: field 
walking tests in chronic respiratory disease. Singh European Respiratory Journal Dec 2014, 
44 (6) 1428-1446; DOI: 10.1183/09031936.00150314  
Kiss et al 2007 
Interferon-beta protects from acute lung injury via up-regulation of CD73. Eur J Immunol 
2007;37:3334-3338. 


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Knaus WA et al 1985 
APACHE II: a severity of disease classification system. Crit Care Med 1985;13:818–29. 
Phua et al 2009 
Has mortality from acute respiratory distress syndrome decreased over time? A systematic 
review. Am J Respir Crit Care Med 2009;179:220-227.  
Sloane et al 1992 
A multicenter registry of patients with acute respiratory distress syndrome. Physiology and 
outcome. Am Rev Respir Dis 1992;146:419-426. 
Van Elteren 1960 
On the combination of independent two-sample tests of Wilcoxon. B Int Statist Inst 
1960;37:351-361. 
Zilberberg et al 1998 
Acute lung injury in the medical ITU comorbid conditions, age, etiology, and hospital 
outcome. Am J Respir Crit Care Med 1998;157:1159-1164. 
 


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11 APPENDIX 1: GUIDANCE ON SUPPORTIVE CARE MEASURES 
11.1 Guidance on Supportive Care Measures 
Abbreviations used in Appendix 1 
APRV 
Airway pressure release ventilation 
ARDS 
Acute respiratory distress syndrome 
CPAP 
Continuous positive airway pressure 
CVP 
Central Venous Pressure  
e-CRF 
Electronic Case Report Form 
FiO2 
Fraction of inspired oxygen 
HFOV 
High-frequency oscillatory ventilation 
ICU 
Intensive Care Unit 
PaO2 
Arterial partial pressure of oxygen 
PBW 
Predicted body weight 
PEEP 
Positive end expiratory pressure 
Pplat 
Inspiratory plateau pressure 
PS 
Pressure support  
SBT 
Spontaneous breathing trial  
SpO2 
Peripheral capillary oxygen saturation  
Vt 
Tidal volume  
 
1. Introduction 
Patients treated in the FPCLI002 study will be managed with supportive care 
measures according to best practice and in line with guidance agreed locally by each 
intensive care unit (ICU) to ensure full buy-in by the ICU team. 
• 
Each participating ICU must be in agreement with the use of a lung-protective 
ventilation strategy incorporating a low tidal volume (Vt) strategy for ventilation 
based on predicted body weight (PBW). 
• 
Each participating ICU must give due consideration to the study guidance detailed 
below on all supportive measures. 
2. Prohibited Medications and Procedures 
There are no prohibited concomitant medications or procedures. 
The guidance detailed below on nutritional support, nitric oxide use, corticosteroid 
use, glucose management, neuromuscular blockers use and sedation should be 
followed. 
3. Ventilation Management 
Investigative sites must use a lung-protective ventilation approach incorporating a low 
Vt strategy based on PBW in line with the ARDS Network publication.(Ref: The Acute 
Respiratory Distress Syndrome Network 2000) The goal for ventilation of a patient with acute 


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respiratory distress syndrome (ARDS) is to maintain adequate gas exchange while 
minimising ventilator-induced lung injury and barotrauma. The ARDS Network 
conclusions reported in 2000 should be followed and are part of the ventilation 
strategy set out below under ventilator procedures. 
Non-conventional ventilation: Given the two recently published studies on high-
frequency oscillatory ventilation (HFOV) (Oscillate (Ref: Ferguson N D. et al 2013) and 
OSCAR (Ref: Young D et al 2013; the OSCAR Study Group)) mechanical ventilation using HFOV is 
discouraged as a first-line ventilation strategy but is allowed as a non-conventional 
ventilation strategy. However it should be noted that when using HFOV it is not 
possible to record some ventilation parameters as detailed in the study assessments. 
All the possible parameters should be recorded. 
3.1 
Ventilator Procedures 
ICUs should have a ventilator policy and this should be followed. In the absence of 
such a policy, the ARDS Network lung-protective lower Vt strategy is to be used in 
this study. This strategy was associated with lower mortality rates in three ARDS 
Network studies (ARMA (Ref: ARDS Network 1998), ALVEOLI (Ref: The National Heart, Lung and Blood 
Institute ARDS Clinical Trials Network 2004), and FACTT (Ref: The National Heart, Lung and Blood Institute Acute 
Respiratory Distress Syndrome (ARDS) Clinical Trials Network 2006)) and has been widely adopted. This 
strategy is detailed below:  
• 
Ventilation mode: Although volume-assist control mode was used in the ARDS 
Network study, any mode of ventilation capable of delivering the prescribed Vt 
(6 mL/kg PBW ±2 mL/kg) within the pressure limitation (plateau pressure 
limitation ≤30 cm of water) may be used, provided the Vt and airway pressure 
targets are monitored and adjusted appropriately. 
• 
During airway pressure release ventilation (APRV), Vt is defined as the sum of 
the volume that results from the ventilator pressure release and an estimation of 
the average spontaneous Vt. 
• 
Measurement and recording of inspiratory plateau pressure (Pplat) should be 
according to the ICU routine at the investigational site. Measurement and 
recording at intervals of at least 4 hours and after changes in Vt and positive end 
expiratory pressure (PEEP) is recommended. 
• 
If Pplat is ≥30 cmH2O, then Vt should be reduced to 5 mL/kg PBW and then to 4 
mL/kg PBW if necessary to decrease Pplat to ≤30 cmH2O. 
• 
If “severe dyspnoea” is seen (> 3 double breaths per minute or the airway pressure 
remains at or below the PEEP level during inspiration), then the Vt should be 
raised to 7 or 8 mL/kg PBW if Pplat remains <30 cmH2O. If Pplat exceeds 30 
cmH2O on 7 or 8 mL/kg PBW, then a lower Vt should be used and increased 
sedation should be considered. 
• 
If a pH < 7.15 is observed, Vt may be raised and the Pplat limit suspended (not 
required). 
• 
The oxygenation target is: arterial partial pressure of oxygen (PaO2) of 7.33–10.67 
kPa or peripheral capillary oxygen saturation (SpO2) of 88–95%. 
• 
The minimum PEEP that should be used is 5 cmH2O. 
• 
Within 5 minutes of consistent measurements that are below the oxygenation 
target range, the fraction of inspired oxygen (FiO2) or PEEP should be adjusted 
upwards. 


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• 
Within 30 minutes of consistent measurements above the oxygenation target 
range, the FiO2 or PEEP should be adjusted downwards. 
• 
In the absence of an ICU policy, Investigators should implement the strategy for 
PEEP as described in EXPRESS (Ref: Mercat A et al 2008) or the ALVEOLI 2004 (Ref: The 
National Heart, Lung and Blood Institute ARDS Clinical Trials Network 2004) as long as Vt and plateau 
airway pressures are maintained within target. 
• 
It is recommended to raise the ventilator respiratory rate incrementally up to 35 
breaths per minute (maximum set rate) if a pH <7.30 is observed. 
• 
No specific rules are set in this study about the ratio of the duration of inspiration 
to the duration of expiration (inspiration: expiration ratio) settings. 
• 
The use of bicarbonate is allowed in this study (it is neither encouraged nor 
discouraged) if a pH ≤7.30 is observed. 
3.2 
Extra-corporeal Membrane Oxygenation 
The use of extra-corporeal membrane oxygenation is allowed as a rescue therapy and 
its use should be recorded in the study e-CRF. 
3.3 
Weaning Procedures 
Where there is an ICU weaning policy on ventilation this should be followed. In the 
absence of a unit policy the guidelines below should be followed. 
• 
Patients should be assessed for the following weaning readiness criteria each day 
between 06:00 and 12:00. This assessment will NOT be performed within the first 
24 hours after randomisation. 
a) PaO2/FiO2 >300 after 1 hour with PEEP <10 and FiO2 <0.5 
b) Values of both PEEP and FiO2 ≤ values from previous day 
c) The patient is not receiving neuromuscular blocking agents 
d) The patient is exhibiting inspiratory efforts 
e) Systolic arterial pressure ≥90 mmHg without vasopressor support 
(≤5 µg/kg/min dopamine or dobutamine will not be considered 
vasopressor support in this context) 
• 
If criteria a–e are met, application of respiratory management as per protocol will 
be terminated and, in the treatment group, extra-corporeal carbon dioxide removal 
will be interrupted and vascular catheters removed. Clinicians will then be free to 
use any ventilation protocol they consider clinically appropriate. 
• 
A spontaneous breathing trial (SBT) procedure and assessment for unassisted 
breathing will be performed. The SBT will take place over up to 120 minutes of 
spontaneous breathing with FiO2 <0.5 using any of the following approaches: 
a) Pressure support (PS) <5 cmH2O, PEEP <5 cmH2O 
b) Continuous positive airway pressure (CPAP) <5 cmH2O 
c) T-piece 
d) Tracheotomy mask 
• 
Criteria for reporting a SBT as “successful” are: 
a) SpO2 ≥90% and/or PaO2 ≥60 mmHg 
b) Respiratory rate ≤35/min 
c) pH ≥7.30 
d) No respiratory distress (defined as ≥2 of the following): 


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o 
Heart rate ≥120% of the rate at 06:00 (≤5 min at ≥120% may be 
tolerated) 
o 
Marked use of accessory muscles 
o 
Abdominal paradox 
o 
Diaphoresis 
o 
Marked subjective dyspnoea  
If any of criteria a–d are not met, the SBT will be reported as “unsuccessful” and 
previous ventilator settings will be initiated or PS ≥10 cmH2O with PEEP and FiO2 = 
previous settings. The patient should be reassessed for weaning the following day. 
If all criteria a–d are met for the last 30 minutes of the trial, the SBT will be reported 
as “successful” and ventilation support will be removed. 
• 
Patients will be reported as “ventilator free” after two consecutive calendar days 
of “unassisted breathing”. “Unassisted breathing” will be defined as any of the 
following: 
a) 
Spontaneously breathing with face mask, nasal prong oxygen or room air 
b) 
T-piece breathing 
c) 
Tracheostomy mask breathing 
d) 
CPAP ≤5 without PS or intermittent mandatory ventilation assistance 
e) 
Use of CPAP or bi-level positive airway pressure solely for sleep apnoea 
management 
4. Fluid Management 
Fluid management will be unrestricted during episodes of shock. However, in patients 
not in shock, a conservative fluid approach should be adopted. If the ICU has a fluid 
balance policy for ventilated patients, this should be followed. If no policy exists, 
those patients not in shock should be managed with a conservative fluid management 
approach represented by a simplification of the algorithm utilised in the ARDS 
Network FACTT study (Ref: The National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome 
(ARDS) Clinical Trials Network 2006) (see below). 
4.1 
Conservative Fluid Management Algorithm 
This fluid management protocol captures the primary positive outcome of the FACTT 
(protocol 2001 (Ref: ARDS Network 2001) and report 2006 (Ref: The National Heart, Lung and Blood Institute 
Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network 2006)) study on increasing ventilator-
free days. If not already being used, this conservative fluid management approach 
should be initiated within 4 hours of study drug treatment being initiated and should 
be continued until the patient achieves unassisted breathing or D7, whichever occurs 
first. 
Fluid administration will be recorded daily while the patient is in ICU and will be 
noted in the study e-CRF as being positive, neutral or negative.  
This conservative fluid management protocol states that for a patient: 
a) 
Discontinue maintenance fluids. 
b) 
Continue medications and nutrition. 
c) 
Manage electrolytes and blood products as per usual practice. 
d) 
For shock, use any combination of fluid boluses (see footnote b of 
Table 8) and vasopressor(s) to achieve a mean arterial pressure of 
60 mmHg (or higher if clinically indicated) as quickly as possible. 


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Vasopressors should then be stopped as quickly as can be tolerated 
beginning 4 hours after blood pressure has stabilised. 
e) 
Withhold diuretic therapy in renal failure if feasible and until 12 hours 
after the last fluid bolus or vasopressor was given. Renal failure is defined 
as: dialysis dependence, OR oliguria with serum creatinine >3 mg/dL (265 
µmol/L ), OR serum creatinine 0–3 mg/dL (265 µmol/L) with urinary 
indices indicative of acute kidney injury 
Table 7 
Conservative Fluid Management Algorithm 
CVP 
(recommended), 
cmH2O 
PAOP 
(optional), 
cmH2O 
MAP ≥60 mmHg AND  
off vasopressors for ≥12 hours 
Average urine output <0.5 
mL/kg/h (PBW) 
Average urine output ≥0.5 
mL/kg/h (PBW) 
>8 
>12 
Furosemidea 
 
Reassess in 1 hour 
Furosemidea 
 
Reassess in 4 hours 
4–8 
8–12 
Give fluid bolus as fast as 
possibleb 
 
Reassess in 1 hour 
<4 
<8 
No intervention 
Reassess in 4 hours 
a Recommended furosemide dosing to begin with 20 mg bolus or 3 mg/h infusion or last known effective 
dose. Double each subsequent dose until goal achieved (oliguria reversal or intravascular pressure 
target) or maximum infusion rate of 24 mg/h or 160 mg bolus reached. Do not exceed 620 mg/d. Also, 
if patient has heart failure, consider treatment with dobutamine. 
b Recommended fluid bolus= 15 mL/kg (PBW) crystalloid (round to nearest 250 mL) or 1 unit packed 
red cells or 25 g albumin. 
Abbreviations: CVP=central venous pressure; MAP=mean arterial pressure; PAOP=pulmonary 
artery occlusion pressure; PBW=predicted body weight. 
5. Body Positioning  
The use of prone positioning is recommended in severe ARDS (PaO2/FiO2 <150 
mmHg) as per the PROSEVA study (Ref: PROSEVA Study Group 2013) and if used should be 
recorded in the e-CRF. 
6. Nutritional Support 
Nutritional support should be initiated as early as possible (total parenteral nutrition or 
enteral nutrition). 
7. Nitric Oxide 
The use of nitric oxide is not recommended; if used, this should be recorded in the 
study e-CRF. 
8. Corticosteroids 
The use of corticosteroids to treat ARDS or sepsis should be avoided; if used, this 
should be recorded in the study e-CRF. 
9. Glucose Management 
Maintaining blood glucose levels in a reasonable range is important. Each 
investigational site will use its own ICU protocol for glucose and insulin 


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administration. In the absence of a locally agreed ICU best practice protocol, the 
target should be to maintain blood glucose at 8–10 mMol/L (144–180 mg/dL) as per 
the control limb of the NICE-SUGAR study. (Ref: NICE-SUGAR Study Investigators 2009) 
10. Neuromuscular Blockers 
In line with the results of the ACURASYS study, (Ref: Papazian L et al 2010 for the ACURASYS study 
investigators) neuromuscular blockers can be given to patients with ARDS when their 
PaO2/FiO2 ratio is <120 with a PEEP ≥5 cmH2O. When given, neuromuscular 
blockers should be administered for a maximum of 48 hours. Otherwise, use 
neuromuscular blockers as clinically indicated and record in the e-CRF. 
11. Sedation 
The minimum sedation possible will be given; that is, no more sedation than the 
patient needs. Daily interruption of sedation to permit a detailed assessment of the 
patient should be considered as part of a weaning protocol, dependent on the 
individual patient’s condition. 
12. Prevention of Pneumonia 
Efforts to prevent ventilator-associated pneumonia, bacterial or pneumonia cause 
unspecified, and new nosocomial lung infections should be made by: 
a) 
Administration of a chlorhexidine oral rinse and chlorhexidine gel paste, as 
this can reduce the oral bacterial load. Several studies have shown that oral 
decontamination is an effective method of reducing ventilator-associated 
pneumonia 
b) 
Raising the head of the patient’s bed: elevation of the head of the bed to 30° 
is supported as a preventive strategy that lowers the risk of aspiration 
13. Deep Vein Thrombosis: Thrombosis Prevention  
Investigators should follow their local guidance for prevention of deep vein 
thrombosis. 
14. Stress Ulcer Prevention 
Investigators should follow their local guidance for prevention of stress ulcers. 
 
 


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11.2 Reference List 
 
ARDS Network 1998  
Prospective, randomized, multi-center trial of 12 ml/kg vs. 6 ml/kg tidal volume positive 
pressure ventilation for treatment of acute lung injury and acute respiratory distress syndrome 
(ARMA); ARMA Protocol. ARDS Network ARDSNet Study 01, Version III; September 11, 
1998. 
ARDS Network 2001  
Prospective, randomized, multi-center trial of pulmonary artery catheter (PAC) vs. central 
venous catheter (CVC) for management of acute lung injury (ALI) and acute respiratory distress 
syndrome (ARDS) and prospective, randomized, multi-center trial of “fluid conservative” vs. 
“fluid liberal” management of acute lung injury (ALI) and acute respiratory distress syndrome 
(ARDS). FACTT Protocol Study Version II; Footnote, Version IV ARDS Network ARDSNet 
Study 05; July 31, 2001. 
Ferguson N D. et al 2013 
High-Frequency Oscillation in Early Acute Respiratory Distress Syndrome for the OSCILLATE 
Trial Investigators and the Canadian Critical Care Trials Group 
N Engl J Med 2013; 368:795-805February 28, 2013DOI: 10.1056/NEJMoa1215554 
Mercat A et al 2008  
Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory 
distress syndrome, a randomized controlled trial. JAMA 2008;299:646-655. 
NICE-SUGAR Study Investigators 2009  
Intensive versus conventional glucose control in critically ill patients. N Engl J Med 
2009;360:1283-1297. 
Papazian L et al 2010; for the ACURASYS study investigators 
Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 
2010;363:1107-1116. 
PROSEVA Study Group 2013 
Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159-
2168. 
The Acute Respiratory Distress Syndrome Network 2000 
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung 
injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308. 
The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical 
Trials Network 2006 
Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl 
J Med 2006;354:2213-2224. 
The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network 2004 
Higher versus lower positive end-expiratory pressures in patients with the acute respiratory 
distress syndrome. N Engl J Med 2004;351:327-336. 
Young D et al 2013; the OSCAR Study Group 
High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med 
2013;368:806-813. 
 
 


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12 APPENDIX 2: GUIDELINES FOR THE SIX-MINUTE WALK TEST 
 
Holland et al 2014 
An official European Respiratory Society/American Thoracic Society technical standard: field 
walking tests in chronic respiratory disease. Singh European Respiratory Journal Dec 2014, 
44 (6) 1428-1446; DOI: 10.1183/09031936.00150314  
 
 


Reprinted from / An official European Respiratory Society/
American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease Anne E. Holland, Martijn A. Spruit, Thierry Troosters, 
Milo A. Puhan, Véronique Pepin, Didier Saey, Meredith C. McCormack, 
Brian W. Carlin, Frank C. Sciurba, Fabio Pitta, Jack Wanger, 
Neil MacIntyre, David A. Kaminsky, Bruce H. Culver, Susan M. Revill, 
Nidia A. Hernandes, Vasileios Andrianopoulos, Carlos Augusto Camillo, 
Katy E. Mitchell, Annemarie L. Lee, Catherine J. Hill and Sally J. Singh
V O L U M E  4 4  /  N U M B E R  6  /  D E C E M B E R  2 0 1 4
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An official European Respiratory Society/
American Thoracic Society technical
standard: field walking tests in chronic
respiratory disease
Anne E. Holland, Martijn A. Spruit, Thierry Troosters, Milo A. Puhan,
Ve´ronique Pepin, Didier Saey, Meredith C. McCormack, Brian W. Carlin,
Frank C. Sciurba, Fabio Pitta, Jack Wanger, Neil MacIntyre, David A. Kaminsky,
Bruce H. Culver, Susan M. Revill, Nidia A. Hernandes, Vasileios Andrianopoulos,
Carlos Augusto Camillo, Katy E. Mitchell, Annemarie L. Lee, Catherine J. Hill and
Sally J. Singh
Affiliations: For a full list of the authors’ affiliations please refer to the Acknowledgements.
Correspondence: Anne E. Holland, La Trobe University Clinical School, Alfred Health, Level 4, The Alfred
Centre, 99 Commercial Rd, Melbourne 3004, Australia. E-mail: a.holland@alfred.org.au
ABSTRACT
Field walking tests are commonly employed to evaluate exercise capacity, assess prognosis
and evaluate treatment response in chronic respiratory diseases. In recent years, there has been a wealth of
new literature pertinent to the conduct of the 6-min walk test (6MWT), and a growing evidence base
describing the incremental and endurance shuttle walk tests (ISWT and ESWT, respectively). The aim of
this document is to describe the standard operating procedures for the 6MWT, ISWT and ESWT, which can
be consistently employed by clinicians and researchers.
The Technical Standard was developed by a multidisciplinary and international group of clinicians and
researchers with expertise in the application of field walking tests. The procedures are underpinned by a
concurrent systematic review of literature relevant to measurement properties and test conduct in adults
with chronic respiratory disease.
Current data confirm that the 6MWT, ISWT and ESWT are valid, reliable and responsive to change with
some interventions. However, results are sensitive to small changes in methodology. It is important that two
tests are conducted for the 6MWT and ISWT.
This Technical Standard for field walking tests reflects current evidence regarding procedures that should
be used to achieve robust results.
@ERSpublications
Technical Standard document: standard operating procedures for the 6MWT, ISWT and ESWT in
chronic respiratory disease http://ow.ly/Bq2B9
Received: Aug 16 2014 | Accepted: Aug 31 2014
Support statement: The realisation of this Technical Standard would not have been possible without the financial support
of the European Respiratory Society and American Thoracic Society. Sally J. Singh is supported by the National Institute
for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East Midlands (CLAHRC
EM), and work took place at the University Hospitals of Leicester NHS Trust. Support was also provided by the NIHR
Leicester Respiratory Biomedical Research Unit. The views expressed are those of the authors and not necessarily those of
the NHS, the NIHR or the Dept of Health.
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
This article has supplementary material available from erj.ersjournals.com
Copyright !ERS 2014
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Overview
The aim of this Technical Standard is to document the standard operating procedures for the 6-min walk
test (6MWT), incremental shuttle walk test (ISWT) and endurance shuttle walk test (ESWT) in adults with
chronic respiratory disease. The testing procedures were developed by a multinational and multidisciplinary
group of experts in field exercise testing, informed by a systematic review of the measurement properties
and interpretation of the 6MWT, ISWT and ESWT in adults with chronic respiratory disease [1].
The key findings of the Technical Standard are as follows.
1) The 6-min walking distance (6MWD), ISWT and ESWT demonstrate good construct validity. Strong
relationships with measures of exercise performance and physical activity support their conceptualisation as
tests of functional exercise performance.
2) A lower 6MWD is strongly associated with increased risk of hospitalisation and mortality in people with
chronic respiratory disease, with a small number of studies suggesting a similar relationship for the ISWT.
3) The 6MWD, ISWT and ESWT exhibit good test–retest reliability; however, there is strong evidence of a
learning effect for the 6MWT and ISWT. Two tests should be performed when the 6MWT or ISWT are used
to measure change over time.
4) The 6MWD, ISWT and ESWT are responsive to treatment effects in people with chronic respiratory
disease; however, most studies have evaluated responsiveness to rehabilitation and fewer data are available
to confirm responsiveness to other interventions.
5) The 6MWD and ISWT elicit a peak oxygen uptake (V9O2peak) that is similar to that during a
cardiopulmonary exercise test (CPET). As a result, the contraindications and precautions for field testing
should be consistent with those used for a CPET.
6) The 6MWD is very sensitive to variations in methodology, including use of encouragement, provision of
supplemental oxygen, changes in track layout and length, and use of wheeled walkers. These factors should
be held constant on repeat testing.
7) The 6MWD is the primary outcome of the 6MWT.
8) The lowest arterial oxygen saturation measured by pulse oximetry (SpO2) recorded during a 6MWT has
emerged as an important marker of disease severity and prognosis; however, it may not be consistent with
end-test SpO2. Continuous pulse oximetry is recommended during the 6MWT, to ensure that the lowest
SpO2 is recorded.
9) Available evidence suggests a minimal important difference (MID) of 30 m for the 6MWD in adults with
chronic respiratory disease.
10) The primary outcome of the ISWT is distance, measured to the nearest 10 m.
11) The primary outcome of the ESWT is time, although distance has also been reported.
12) Application of reference equations for 6MWD or ISWT to an individual gives rise to substantial
variation in predicted values. If reference values are to be used, an equation generated and verified in a local
population should be applied where possible.
13) Testing procedures that are consistent across the 6MWT, ISWT and ESWT include test location and
staffing, patient assessment and preparation, use of oxygen and medications, indications for test cessation,
and quality assurance. These procedures are detailed in the Technical Standard.
Introduction
The 6MWT plays a key role in evaluating functional exercise capacity, assessing prognosis and evaluating
response to treatment across a wide range of respiratory diseases. Since publication of the previous
American Thoracic Society (ATS) statement on the 6MWT in 2002 [2], new information regarding the
6MWT has emerged in a range of areas, including methods of test performance and interpretation. This
increased body of knowledge has significant implications for the good conduct of the 6MWT in individuals
with chronic respiratory disease, in both research and clinical settings.
The last 10 years have also seen a growing body of evidence describing the uses and measurement properties
of the ISWT and the ESWT. Given the increasing uptake of these field tests in clinical practice, the scope of
the 2002 document has been expanded to include the ISWT and ESWT. While the use of other field tests has
also been reported in chronic respiratory disease (e.g. timed up and go, sit to stand test, 4-m gait speed test),
the committee considered that there were currently insufficient data to include them in this version of the
Technical Standard.
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The testing procedures outlined in this document are based on a systematic review of the literature
describing the use and properties of these field walking tests in adults with chronic respiratory disease,
including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), cystic fibrosis
(CF), bronchiectasis, asthma, pulmonary arterial hypertension (PAH) and pulmonary vascular disease [1].
As a consequence, these standards are not intended for application to children or to individuals who do not
have chronic respiratory disease. This Technical Standard provides guidance on the practical aspects of
conducting field walking tests in a safe, effective and reproducible manner. This document is not intended
to provide guidance regarding when or in which patients these tests should be performed. The measurement
properties of each field walking test are described individually. Standard operating procedures common to
all three tests are outlined and those specific to each test are described. A brief comparison of the three tests
is included. Finally, important differences between this document and the previous ATS statement on the
6MWT are highlighted.
Methods
An ad hoc Task Force was assembled to develop technical standards for the performance of the 6MWT,
ISWT and ESWT based upon a systematic review of the evidence [1]. Co-chairs were selected by the
Pulmonary Rehabilitation Assembly and Proficiency Standards Committee of the ATS and the
Rehabilitation and Chronic Care Assembly and Allied Respiratory Professionals Assembly of the European
Respiratory Society (ERS), then approved by the leadership of both societies. Members of the Task Force
were selected by the co-chairs on the basis of their expertise in application of field walking tests in research
and/or clinical practice. All potential conflicts of interest were disclosed and managed according to the policies
and procedures for joint ATS/ERS projects. Drafts of this document were prepared by two members (Anne E.
Holland and Sally J. Singh), with all authors providing comment and suggestions for the final document.
The methods checklist is presented in table 1.
The systematic review which informs this document addressed seven questions relevant to the measurement
properties, performance, clinical utility, reporting, monitoring, reference equations and interpretation for
field walking tests in chronic respiratory disease. Full details are provided in a companion paper [1].
The 6MWT: measurement properties important to test conduct
The 6MWT is a self-paced test of walking capacity. Patients are asked to walk as far as possible in 6 min
along a flat corridor. The distance in metres is recorded. Standardised instructions and encouragement are
commonly given during the test [2].
Validity of 6MWD
There is a large body of data demonstrating construct and criterion validity for the 6MWD in individuals
with chronic respiratory disease [1]. Relationships are strongest with measures of maximal exercise
TABLE 1 Methods checklist
Yes
No
Panel assembly
Included experts for relevant clinical and nonclinical disciplines
X
Included individual who represents the views of patients and society at large
X
Included methodologist with appropriate expertise
X
Literature review
Performed in collaboration with a librarian
X
Searched multiple electronic databases
X
Reviewed reference lists of retrieved studies
X
Evidence synthesis
Applied pre-specified inclusion and exclusion criteria
X
Evaluated included studies for sources of bias
X
Explicitly summarised benefits and harms
X
Used PRISMA1 to report systematic review
X
Used GRADE to describe quality of evidence
X
Generation of recommendations
Used GRADE to rate the strength of recommendations
NA
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; GRADE: Grading of
Recommendations Assessment, Development and Evaluation; NA: not applicable.
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performance and physical activity (correlation coefficients 0.4–0.93). Relationships between 6MWD and
respiratory function (forced expiratory volume in 1 s (FEV1), forced vital capacity and diffusing capacity
of the lung for carbon monoxide (DLCO)) (correlation coefficients 0.31–0.55) or health-related quality of
life (HRQoL) (correlation coefficients 0.03–0.65) are of weak to moderate strength across all disease
groups examined.
Direct comparisons of the physiological demands of the 6MWT and CPET show that although measures of
peak exercise performance (V9O2peak and heart rate (HR) peak) are similar between the tests, the 6MWT has
substantially lower ventilatory requirements (peak carbon dioxide production, peak ventilation and
respiratory exchange ratio) [3–8], which may contribute to its tolerability in adults with chronic respiratory
disease. Overall, these data lend support to the conceptualisation of the 6MWT as a test of functional
exercise capacity.
Reliability and learning effect for 6MWD
The 6MWD is a reliable measure in people with chronic respiratory disease, with excellent intra-class
correlation coefficients (ICCs) (range 0.82–0.99) [1]. There are no discernible differences in reliability
across groups with different chronic respiratory diseases. Despite its excellent reliability, there is strong
evidence of a learning effect for the 6MWD when two or more tests are conducted. 13 studies in patients
with COPD show a pooled mean improvement on the second 6MWT of 26.3 m [1]. This estimate does not
change when including only the subgroup of studies where the two tests are conducted within 24 h
(26.1 m). The largest study to address this issue (n51514) reported a 95% confidence interval for the
learning effect of 24–29 m [9]. There is some variability across individuals: the proportion of participants
who walked further on the second 6MWT ranged from 50% to 87% across studies. Fewer data are available
in other chronic respiratory diseases, although the available studies tend to support a learning effect across
all chronic respiratory diseases [1]. Whether the learning effect is equally significant for individuals who
have previously performed multiple 6MWTs is difficult to establish, as few data are available. If the tests are
repeated 3 months later, the learning effect appears to persist in individuals with COPD; however, it may be
smaller in magnitude [10].
The effect of learning on the 6MWD is large enough to be clinically important when the 6MWT is used to
evaluate response to treatment or change over time. In these situations, two 6MWTs should be performed
and the best 6MWD recorded. Use of two 6MWDs may also decrease the sample size requirements for
clinical trials, due to reduced variability in the pre- and post-intervention measures [11]. Where the 6MWD
is used as a one-off measure to stage disease or assess risk (e.g. likelihood of hospitalisation or mortality),
the magnitude of the learning effect may be less important and one test may be sufficient. However,
clinicians should be mindful of the learning effect if the 6MWD is approaching pre-defined thresholds on
which treatment decisions may be based [12, 13]; in this situation, repeat testing should be considered. One
test may also be sufficient for patients who have recently performed the test, where the learning effect is
smaller (e.g. end of pulmonary rehabilitation) [10].
Relationship of 6MWD to clinical outcomes
The 6MWD has a strong relationship to important clinical outcomes in individuals with chronic respiratory
disease. A shorter 6MWD was associated with increased mortality in 13 (93%) out of the 14 COPD studies
reviewed [1]. Associations were less consistent in ILD (four (50%) out of eight studies) and PAH (six (66%)
out of nine studies) [1]. There is less evidence for the association of 6MWD with hospitalisation, but all
studies in which it was evaluated (n53, COPD and ILD) found a statistically significant relationship [1]. It
was outside the scope of this document to identify thresholds for 6MWD to categorise patients according to
their risk for these outcomes.
Methodological factors affecting test performance
The 6MWD is highly sensitive to changes in methodology (table 2). Given the impact of encouragement on
6MWD [33] and the use of encouraged tests in the generation of reference equations [1], it is recommended
that standardised phrases of encouragement are used (see later section on the testing protocol for 6MWT).
Provision of supplemental oxygen [26–29], method for carrying the supplemental oxygen [31, 32] and use
of wheeled walkers [20–25] also have an important impact on 6MWD. These factors must be kept constant
on repeat testing. The 6MWD generated using an externally paced treadmill is substantially lower than in a
hallway [14, 15], which is probably the result of the poor walking efficiency during treadmill walking in
subjects unaccustomed to this activity. Externally paced treadmill testing is not recommended. Track layout
and length may also affect performance on the test, especially when very short track lengths are used [19];
these factors should be kept constant where within-subject comparison of 6MWD on subsequent occasions
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is required. For track lengths of .15 m, differences may be small enough such that tests on different track
layouts can still be used for risk stratification [1]; however, more data are needed to confirm this.
Monitoring and reporting for 6MWT
Safety
Complications associated with the performance of the 6MWT are unusual. We were unable to find
published reports of complications associated with performance of the 6MWT in clinical trials. Only two
articles have specifically addressed the issue of complications during the 6MWT. In 741 patients attending
an outpatient pulmonary rehabilitation programme who completed the 6MWT in accordance with a
standardised protocol, including continuous monitoring of oxyhaemoglobin saturation (SpO2) and HR,
adverse events were noted in 43 (6%) of patients [35]. The most common adverse event was oxygen
desaturation ,80%, upon which the test was terminated by the operator (35 out of 43); chest pain (one out
of 43) and tachycardia (one out of 43) were also recorded. No long-term adverse sequelae from these events
were reported. In the remaining tests the patients developed intolerable symptoms and the test was
discontinued, which would be expected during the 6MWT and is not considered a complication. A second
study in ILD (n519) showed that desaturation to ,80% occurred in 58% of participants during the 6MWT
[36]. Concurrent ECG monitoring showed no clinically significant arrhythmias that needed treatment,
although atrial tachycardia occurred in one case.
Measurements
The 6MWD is the primary outcome of the 6MWT, given its excellent reliability and validity, as well as its
strong relationship to important clinical outcomes. The 6MWD should be reported for every test in metres
or feet. However, other outcomes have been reported, such as SpO2, HR responses, symptoms of dyspnoea
and fatigue and 6-min walk work (6MWD6body weight).
Oxyhaemoglobin saturation
Oxygen desaturation during a 6MWT provides information regarding exercise-induced desaturation,
disease severity and disease progress. Exercise-induced desaturation is associated with impaired daily
TABLE 2 Effect of methodological variations on 6-min walking distance (6MWD)
Variation in methodology
Studies n
First author [ref.]
Effect on 6MWD
Hallway versus treadmill
2
STEVENS [14]
DE ALMEIDA [15]
13–20% less on treadmill
Indoors versus outdoors
1
BROOKS [16]
4 m (1%) more outside
Circular versus straight track
2
BANSAL [17]
SCIURBA [18]
13–19 m (3–5%) more on circular track
Track length
2
SCIURBA [18]
BEEKMAN [19]
No statistically significant difference in 6MWD
from tracks of 15–121 m
50 m more on 30-m track compared to 10-m track
Wheeled walking aid versus no aid
6
GUPTA [20]
HONEYMAN [21]
PROBST [22]
ROOMI [23]
SOLWAY [24]
VAES [25]
Weighted mean 6.2% more with wheeled walker
Range 2–46 m more with wheeled walker
83 m more with modern draisine compared
to wheeled walker
With versus without oxygen
4
DAVIDSON [26]
FUJIMOTO [27]
ROOYACKERS [28]
JOLLY [29]
12–59 m more with oxygen
Oxygen versus compressed air
2
JOLLY [29]
MCDONALD [30]
17–109 m more with oxygen
Carry oxygen versus oxygen in
wheeled cart
1
CRISAFULLI [31]
23 m more with wheeled cart
Patient carries oxygen versus tester
carries oxygen
1
WOODCOCK [32]
24 m versus 35 m improvement
Encouragement
1
GUYATT [33]
30.5 m more with encouragement
Instructions
1
WEIR [34]
53 m further when asked to walk as ‘‘fast’’ as
possible, rather than as ‘‘far’’ as possible
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physical activity, faster FEV1 decline and worse prognosis [37, 38], which supports its clinical importance.
The 6MWT is more sensitive for identifying exercise-induced desaturation than cycle testing [39].
Measurements of SpO2 during the 6MWT are reliable [1], provided that an adequate pulse signal is obtained.
However, change in SpO2 may be more variable in people with systemic sclerosis-associated ILD (SSc-ILD)
than in other lung conditions (ICCs ranging 0.24–0.64 in SSc-ILD, compared to 0.80–0.97 in CF and
COPD) [1], perhaps due to cutaneous involvement in SSc-ILD. The 6MWT may be safe without
continuous monitoring of SpO2 [36]. However, constant monitoring of SpO2 during the 6MWT is needed to
obtain an accurate measure of exercise-induced desaturation, as the lowest SpO2 often does not occur at the
end of the test [40, 41].
A number of novel desaturation indices have been proposed in patients with ILD, with the aim of
improving the ability of the 6MWT to predict mortality. These include the distance–saturation product
[42–45], the desaturation area [46] and the desaturation–distance ratio [47]. As only a small number of
studies are available, the utility of these measures has not been confirmed and they are not routinely
collected during the 6MWT.
Heart rate
The resting and end-test HR are often recorded during the 6MWT. Limited data are available regarding the
reliability of HR measures during the 6MWT; however, change in HR recorded on the pulse oximeter
appears reliable (ICCs 0.62–0.87) [9, 48]. No studies have compared the HR obtained from pulse oximetry
to that obtained with other methods (e.g. frequency meter). Other measures of HR response include HR
recovery (HRR), which is the reduction in HR with rest that occurs after the 6MWT is concluded. A
reduced HRR during the first minute after the 6MWT has been associated with poor outcomes, including
increased mortality, in ILD [49] and PAH [50, 51]. However, there is not a universally accepted cut-off for
HRR that is applicable across chronic respiratory diseases.
Dyspnoea
Dyspnoea may be an important determinant of the 6MWD in patients with chronic respiratory disease [52–55],
where it reflects both the physiology of exercise limitation [56, 57] and the impact of exercise limitation on
daily life [58]. Dyspnoea scores collected during the 6MWT exhibit good reliability, with the modified Borg
dyspnoea scale [59] (ICCs 0.59–0.92) showing greater reliability than the 15-count dyspnoea scale (ICC 0.66)
and visual analogue scale for dyspnoea (coefficient of variation 0.22) [1]; however, few studies have investigated
these latter measures.
Subjective fatigue
Fatigue is a common feature in patients with chronic respiratory diseases, both as a local muscle
phenomenon and general fatigue. This is reflected during the 6MWT, where COPD patients experienced
more fatigue compared to healthy elderly subjects [60]. Patient-reported fatigue is commonly measured at
the beginning and end of the 6MWT using the Borg scale [59], which exhibits moderate reliability [9, 61].
Fatigue measured during the 6MWT using the Borg scale is associated with lower 6MWT, slower gait speed,
more severe airflow obstruction, more dyspnoea on exertion and lower HRQoL [1]. Notably, low-frequency
muscle fatigue in the quadriceps is seldom found with the 6MWT, although low-frequency fatigue in distal
leg muscles has been reported to be greater in COPD patients compared with controls [62].
6-min walk work
The 6-min walk work is the product of 6MWD and body weight, which may provide a better estimation of
the work required to perform the test than distance alone. The 6MWD6weight product correlates more
strongly with DLCO and V9O2peak than 6MWD alone [63, 64]. To date, no studies have investigated the
sensitivity of 6MWD6weight product to change over time. Additional studies are needed to better
characterise the utility of the 6-min walk work in adults with respiratory disease.
In summary, the 6MWD is the primary outcome of the 6MWT and should be recorded on every test. The
SpO2 and HR should be measured continuously during the 6MWT, to ensure that the lowest SpO2 and the
end-test HR are recorded. Care should be taken that obtaining these measures does not affect performance.
Current data indicate that the 6MWT has an excellent safety profile when the test is stopped if SpO2 falls to
,80%; few data are available to define the safety profile if desaturation to ,80% is permitted. Dyspnoea
and subjective fatigue should be measured before and after the 6MWT.
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Identifying meaningful change in 6MWD
Minimal important difference for the 6MWD
Over the past 10 years, a number of new estimates of the MID for 6MWD have been published. Our
systematic review [1] identified 11 studies, in COPD (six studies), ILD (three studies) and PAH (two
studies). The majority of MID estimates from these studies are based on distribution-based methods (using
statistical properties of the measure), rather than anchor-based methods (where change in 6MWD is related
to another clinically important marker of change). Most values were generated for individuals with COPD
participating in a rehabilitation programme rather than pharmacotherapy. The median estimate across all
studies was 30 m [1]. There is currently little evidence to suggest that the MID varies according to patient
characteristics, including the type of chronic lung disease or the baseline 6MWD. Most MID estimates were
generated using group mean data and are best used to interpret group mean changes in 6MWD [65–67].
However, studies that derived the MID using methodologies that are applicable to individuals reported
similar MID estimates [68, 69]. More studies are required to explore the magnitude of important changes in
6MWD with different interventions and to establish the MID in other chronic respiratory diseases.
In summary, the available evidence suggests a MID of 30 m for adult patients with chronic respiratory
disease. There is some variability across studies and methods to determine the MID; however, based on the
large evidence base now available, we can be confident that the MID lies between 25 and 33 m.
Responsiveness of the 6MWD
Few studies have been explicitly designed to assess the responsiveness of 6MWD to treatment effects, but a
large number of randomised trials provide insights in this area. We chose the Cochrane reviews on exercise
interventions for COPD [70, 71] and ILD [72] and the Cochrane review on endothelin receptor antagonists
in PAH [73] to investigate the responsiveness of 6MWD to interventions of known efficacy. The meta-
analyses for 6MWD showed highly statistically significant improvements in 6MWD, with effects between 34
and 78 m and effect sizes between 0.38 and 1.07 [1]. The standardised response means (mean change/
standard deviation of change) ranged from 0.2 to 1.2 [1]. The 6MWD therefore appears to be responsive to
treatment effects in patients with COPD, ILD and PAH. It should be noted that most of these values have
been generated from rehabilitation-based studies.
Reference equations for 6MWD
The systematic review identified 16 published studies from 1998 to 2013 that included 6MWD prediction
equations from healthy adults [1]. One additional study has been published since the systematic review [74].
These studies were conducted using a wide variety of populations and methodologies. Track lengths ranged
from 20 to 50 m and the number of tests ranged from one to four. Application of these equations to an
individual gives rise to substantial variation in the predicted distance.
Factors that may affect the 6MWD in healthy adults, and therefore the predicted distance, include
methodology for 6MWT, percentage of peak HR achieved, height, age, sex, weight and perhaps race/
ethnicity. The utility of % predicted values in assessing clinically meaningful change in 6MWD over time
has not been investigated.
Due to the wide variation in predicted 6MWD generated by different equations, reference equations
generated and verified in a local population should be applied where possible. A summary of reference
equations can be found in the accompanying systematic review [1].
The ISWT and ESWT: measurement properties important to test conduct
Validity of the ISWT and ESWT
The ISWT is an externally paced maximal exercise test; the speed of walking is controlled by a series of
pre-recorded signals. The speed of walking increases until the participant can no longer continue. The
maximum duration of the test is 20 min.
Given the progressive nature of the ISWT, a strong relationship with performance on laboratory-based tests
might be anticipated. Seven studies in COPD and one in lung cancer show that the V9O2peak, estimated
V9O2peak, peak work and distance measured on ISWT show moderate to strong correlations with measures
of maximal exercise performance on CPET [1], with no difference in measured oxygen uptake (V9O2)
between the tests [6, 75, 76]. HILL et al. [6] performed a minute-by-minute analysis, and both the ISWT
and CPET demonstrated a linear response in V9O2peak, suggesting that the two tests provoke a similar
cardiopulmonary response. In summary, the current literature suggests that the ISWT is a valid measure of
cardiopulmonary exercise capacity in COPD and provokes a similar physiological response to a CPET.
More evidence in other disease populations is required.
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The ESWT is a derivative of the ISWT, where patients walk for as long as possible at a predetermined
percentage of maximum walking performance as assessed by the ISWT [77]. To set the speed for the ESWT,
the ISWT must have been completed previously. The ESWT has been shown to elicit similar end-test HR
and dyspnoea responses compared to a treadmill endurance test at the same intensity [77].
Reliability and learning effect for ISWT
Only a handful of studies have reported the reliability of the ISWT, with most data in COPD. One study
documented an ICC of 0.88 (95% CI 0.83–0.92) [78]. Another study reported an ICC of 0.89 [79]. These
two studies suggest that the association between test–retest walk distances is strong, with the majority
of variability being attributable to between-subject differences. More studies are needed to confirm
these findings.
There is a small but statistically significant difference between the first two ISWTs performed (mean
differences of 20 and 25 m for tests performed on the same day, and 23.5 m for tests performed on different
days) [6, 80, 81]. The effect of learning on the ISWT is large enough to be clinically important when
evaluating change over time. It is recommended that two ISWTs be performed and the best distance
recorded. It remains to be established whether one test would be sufficient where the ISWT is used as a one-
off measure to stage disease or assess risk (e.g. likelihood of hospitalisation or mortality). Whether one test
is sufficient if the test has previously been conducted, similar to the 6MWT, is still unclear. It is common to
repeat the test once after an intervention, but whether this underestimates the impact of the intervention
remains to be established. The reliability of the test in chronic respiratory diseases other than COPD has not
been explored.
Reliability and learning effect for ESWT
Three studies have examined the reliability of the ESWT, all in COPD [6, 81, 82]. The differences between
tests repeated on the same day were generally small and statistically nonsignificant (pooled mean difference
+26 s). Two tests do not appear to be necessary, although it is acknowledged that the number of studies is
limited. Measurements of HR, SpO2 and modified Borg dyspnoea scale appear to repeat well during the test [1].
The reliability of the ESWT in other chronic respiratory diseases has not been examined.
Relationship of ISWT and ESWT to clinical outcomes
A small number of studies show that the ISWT is a significant predictor of survival and re-admission in
people with COPD, with a lower distance predicting a greater risk of admission [83–85]. The relationship of
ESWT to these outcomes is unknown.
Methodological factors affecting ISWT and ESWT performance
Unlike the 6MWT, the track for the ISWT and the ESWT is fixed, and alterations of the course have not
been studied. The effect of encouragement has not been directly observed, but the external pacing of the
tests may make it difficult to override the test protocol. The impact of supplemental oxygen is influenced by
the mode of delivery. If patients are required to support a cylinder independently, oxygen supplementation
confers little advantage in walking distance compared to air walking conditions [86], but if the oxygen
(or heliox) is carried by a clinician/researcher, the benefit is magnified [87]. Accordingly, if supplemental
oxygen is to be used during testing, the same approach should be taken for repeat testing, with the device
and the flow rate remaining constant.
Monitoring and reporting for ISWT and ESWT
Safety
Adverse events have not been directly studied or reported in association with either the ISWT or the ESWT.
We were unable to find any literature describing complications of conducting the shuttle tests. To date,
there is no clear guidance on the value of monitoring SpO2 and the level to which this may fall in any
individual has yet to be described. However, consensus suggests that the ISWT and the ESWT should be
discontinued if SpO2 falls below 80%. The test has been reported in patients with cardiac disease [88–90]
with no adverse events; to date the test has not been used for patients with PAH.
Measurements
The primary outcome of the ISWT is distance, reported as an accumulation of 10-m lengths. The minimum
distance is 0 m if patients fail to complete the first 10 m, and the maximum is 1020 m. The ESWT, like all
endurance tests, is reported as time (minutes and seconds); although it can be expressed as distance
completed, this is less commonly reported for endurance tests in the literature. The speed that the
participant walks is chosen from 16 available speeds (1.78–6.00 km?h-1), with the speed calculated from the
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performance on the ISWT. Additional outcomes have been reported; these include SpO2, HR responses,
dyspnoea, fatigue and the reason for terminating the test.
Identifying meaningful change in ISWT and ESWT
Minimal important difference for the ISWT
The MID for the ISWT has been described in one paper that was specifically designed to assess this
threshold [91] and confirmed within a second paper [92]. Both studies used a similar approach, with a
preference-based anchor method using rehabilitation as the intervention. The original paper described that
a change of 47.5 m (approximately five shuttles) was associated with feeling ‘‘slightly better’’, while a change
of 78.7 m (approximately eight shuttles) was associated with the next rating (‘‘better’’). The authors
concluded that the MID for the ISWT was 47.5 m. More studies are required, exploring different
interventions and different approaches, to describe the MID in COPD. The MID for other chronic
respiratory diseases has not been explored.
Minimal important difference for the ESWT
The MID for the ESWT in patients receiving pulmonary rehabilitation or bronchodilation has been
estimated using a distribution-based approach and anchor-based method (change in ESWT time and
distance was related to patients’ perception of change from baseline) [93]. Bronchodilation data indicated
that a change of 65 s (95% CI 45–85 s) or 85 m (95% CI 60–115 m), representing 13–15% of baseline, was
associated with a one-point change on the Likert rating scale and thus likely to be perceivable to patients. An
estimate of the MID could not be obtained from the pulmonary rehabilitation data, although preliminary
data suggest this is in the region of 180 s [93]. It is possible that the MID may be context or intervention
specific, although to date this has not been shown for 6MWD.
Responsiveness of the shuttle walk tests
Despite the ISWT being employed in a number of studies, only eight studies were explicitly designed to
evaluate the responsiveness to treatment of the ISWT and/or ESWT [86, 94–100]. These studies suggest that
the ISWT and ESWT are both responsive. The standardised response means (mean change/standard
deviation of change) range from 0.72 to 1.55 for the ISWT and from 0.52 to 1.27 for the ESWT [1].
Reference equations for ISWT and ESWT
Three papers have described reference values for the ISWT, two from South America [101, 102] and one
from the UK [103]. There is a need for more data, including diversity in the country of origin. Existing data
suggest that age, sex and body mass index are important variables. Data from a single centre in the UK [1]
included measures of strength (quadriceps maximum voluntary contraction) and physical activity (Duke
Physical Activity Status Index and a physical activity monitor), in an attempt to further explain the
variability; however, these additions did not improve the reference equation.
To date there has been no attempt to identify reference equations for the ESWT.
Selecting a field walking test
It is beyond the scope of this Technical Standard to recommend one field test over another. The systematic
review underpinning this document did not address the question of the relative merits of each test.
However, some general considerations that may influence test selection are outlined here.
Field walking tests may be performed to identify the individual’s exercise capacity (peak exercise capacity,
functional exercise capacity or endurance), factors limiting exercise performance (dyspnoea, subjective
fatigue, musculoskeletal limitations) and often their response to an intervention. The field tests can also be
used to identify a threshold to predict survival and the likelihood of a hospital readmission, with a more
extensive body of evidence reporting use of 6MWD rather than ISWT or ESWT for this purpose [1].
Prescription of exercise intensity for pulmonary rehabilitation, using the established principles of exercise
training, may also be a consideration. The uses of the 6MWT and the ISWT/ESWT have been reported in all
of these circumstances [1]. Practical considerations include whether sufficient space is available. If the test of
choice is the 6MWT then the test should be conducted as recommended along a course at least 30 m in
length; if this space is not available then consideration should be given to using the ISWT/ESWT. Both the
6MWT and ISWT require two tests to be performed prior to an intervention [1] and thus the time taken to
conduct each test is comparable.
The 6MWT and ISWT/ESWT offer quite different protocols: the 6MWT is self-paced, and the shuttle
tests are externally paced. Although both tests generally provoke a V9O2 similar to that seen on a CPET
[6, 75, 104–106], the precise pattern of response may be different for the externally paced tests (ISWT/ESWT)
compared to a self-paced test (6MWT). The response of the ISWT mirrors the physiological response
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observed in an incremental laboratory-based test, with an incremental increase in V9O2 over time, whereas
the self-paced 6MWT shows a steady-state V9O2 profile after the third minute [3, 75, 104]. Because of the
similarity in response of the ISWT and CPET, prescribing an exercise regimen as a percentage of peak
performance on a field walking test may be easier with the ISWT than the 6MWT, because of the
incremental nature of the test. Responses to the ESWT show a significantly more rapid rise in V9O2 and
ventilation than during the 6MWT, but similar end-test values [95]. The V9O2peak on ESWT does not
differ significantly when compared to the ISWT and 6MWT [6]. The physiological responses to each test
are reported in more detail in the systematic review [1].
The comparative sensitivity of field walking tests has been examined in small studies that have looked at
rehabilitation or bronchodilation as the intervention, predominantly in COPD. PEPIN et al. [95] observed an
enhanced response in the ESWT compared to the 6MWT after an acute administration of a bronchodilator,
with standardised response means of 0.66 and 0.42, respectively. Similarly, EATON et al. [98] reported that,
after a course of pulmonary rehabilitation, the magnitude of the change was proportionally greater on the
ESWT than the 6MWT (92% versus 17%). The ESWT has also proven to be more responsive than
the 6MWT in a randomised trial of an exercise intervention for COPD [107]. These results suggest that the ESWT
may be more sensitive to change than the 6MWT, following bronchodilation or pulmonary rehabilitation.
Given
the
differing
protocols,
physiological
patterns
of
response,
measurement
properties
and
circumstances in which field walking tests are applied, the choice of test should be carefully considered.
Regardless of the test selected, robust results can only be obtained with careful attention to testing
procedures as described in the following sections.
Test procedures applicable to all field walking tests
Equipment
The equipment required to conduct a field walking test is listed in table 3.
Test location and staffing
The test should be conducted along a quiet course, physiotherapy gym or dedicated exercise testing room. A
comfortable temperature is important and air conditioning should be available if needed. Testing should be
performed in a location where a rapid, appropriate response to an emergency is possible. The appropriate
location of a crash cart should be determined by the physician supervising the facility. Supplies that must be
available include oxygen, sublingual nitroglycerine and salbutamol (metered dose inhaler or nebuliser). A
telephone or other means of calling for help should be available in case of emergency.
The assessor performing the test should be certified in cardiopulmonary resuscitation with a minimum of
Basic Life Support certification. Training, experience and certification in related healthcare fields are also
desirable. A certified individual should be readily available to respond if needed. Physicians are not required
to be present during all tests. The physician ordering the test or a supervising laboratory physician may
decide whether physician attendance at a specific test is required.
Patient assessment
Given that all three field-based exercise tests can elicit a V9O2peak and peak HR that are similar to the CPET
[1], absolute and relative contraindications for exercise testing should be consistent with recommendations
for maximal exercise testing (table 4) [108]. Patients with any of these findings should be referred to the
physician ordering or supervising the test for individual clinical assessment and a decision about the
conduct of the test. Stable exertional angina is not an absolute contraindication for field walking tests, but
patients with these symptoms should perform the test after using their anti-angina medication, and rescue
TABLE 3 Equipment required for conduct of field walking tests
At least one chair, positioned at one end of the walking course
A validated scale to measure dyspnoea and subjective fatigue
Sphygmomanometer for blood pressure measurement
Pulse oximeter
Stopwatch
Pre-measured marks along the track/corridor
Access to oxygen and telephone in case of an emergency
An emergency plan
Portable supplemental oxygen if required by patient to perform exercise test
Clipboard with reporting sheet and pen
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nitrate medication should be readily available. All comorbidities and medication use should be recorded
prior to the test.
Patient preparation
Patients should wear comfortable clothing and appropriate shoes for walking. Patients should use their
usual walking aids during the test and this should be documented on the assessment form. Patients should
not have exercised vigorously within 2 h of beginning the test but should have taken their usual
medications. All subsequent testing occasions should occur at about the same time of day to minimise intra-
day variability, including variability in self-paced tests (6MWT) associated with bronchodilator use [109]. A
warm-up is not permitted prior to commencing the test, neither is a shortened version of the test. If
respiratory function tests are to be performed on the same day, this should occur prior to exercise testing, to
avoid the confounding effects of exercise on these measures. The patients should then rest for at least
15 min before commencing an exercise test.
Use of oxygen
If a patient is on long-term oxygen therapy, oxygen should be given at their standard flow rate or as directed
by a physician or a protocol. For any test where the outcome is distance, oxygen flow should be held
constant throughout the test. If the purpose of the exercise test is to compare distance walked between tests,
any subsequent test should be performed using the same oxygen conditions, in order to make a valid
comparison between testing occasions. If oxygen supplementation is needed during the walks and serial
tests are planned, then oxygen should be delivered in the same manner (flow rate and delivery device) for all
subsequent walks. If the flow rate must be increased for subsequent visits due to worsening gas exchange,
this should be noted on the worksheet and considered during interpretation of any changes in performance.
The type of oxygen delivery device should also be noted on the report: for instance, whether the subject
carried liquid oxygen or pushed or pulled an oxygen tank, and whether the delivery was pulsed or
continuous. Assessors should avoid transportation of the oxygen source where possible; however, if the
subject is not able to control/carry/manage their own oxygen cylinder, the assessor should try to walk
slightly behind the subject to avoid setting the walking pace. It should be clearly documented how the
assessor has assisted with the transport of the oxygen, so any subsequent walk tests with the same subject
can be performed in the same manner. Oxygen is not to be titrated during any of the tests where distance is
a measured outcome. If oxygen titration is desired, this should be done during a separate test.
TABLE 4 Absolute and relative contraindications for field walking tests
Absolute
Relative
Acute myocardial infarction (3–5 days)
Unstable angina
Uncontrolled arrhythmias causing symptoms or
haemodynamic compromise
Syncope
Active endocarditis
Acute myocarditis or pericarditis
Symptomatic severe aortic stenosis
Uncontrolled heart failure
Acute pulmonary embolus or pulmonary infarction
Thrombosis of lower extremities
Suspected dissecting aneurysm
Uncontrolled asthma
Pulmonary oedema
Room air SpO2 at rest f85%#
Acute respiratory failure
Acute noncardiopulmonary disorder that may
affect exercise performance or be aggravated
by exercise (i.e. infection, renal failure,
thyrotoxicosis)
Mental impairment leading to inability to cooperate
Left main coronary stenosis or its equivalent
Moderate stenotic valvular heart disease
Severe untreated arterial hypertension at rest
(200 mmHg systolic, 120 mmHg diastolic)
Tachyarrhythmias or bradyarrhythmias
High-degree atrioventricular block
Hypertrophic cardiomyopathy
Significant pulmonary hypertension
Advanced or complicated pregnancy
Electrolyte abnormalities
Orthopaedic impairment that prevents walking
SpO2: arterial oxygen saturation measured by pulse oximetry. #: exercise patient with supplemental oxygen.
Reproduced from [108] with permission from the publisher.
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Medications
Patients should be instructed to take all usual medications. The type of medication, dose and number of
hours it was taken before the test should be noted. Significant improvement in the distance walked or the
dyspnoea scale after administration of bronchodilators has been demonstrated in patients with COPD
[93–96], although this may be small and clinically insignificant for the 6MWT [95, 110].
Measurements
Patients should rest in a chair, located near the starting position, before the test starts. Absolute and
relative contraindications should be checked for prior to test commencement (table 4). The following
measurements should be obtained at rest: SpO2 and HR from pulse oximetry, baseline dyspnoea and fatigue
using a reproducible scale, and systemic blood pressure, if not recently documented [108].
Immediately prior to the test
The assessor should provide standardised instructions, either verbally for the 6MWT (table 5) or from the
ISWT or ESWT audio recording. The patient should be positioned at the starting line. For the 6MWT, the
timer should be started as soon as the patient starts to walk. The recorded instructions of the ISWT and
ESWT will prompt the individual to start.
A pulse oximeter should be used for continuous measurement of SpO2 and HR. The assessor should not
‘‘pace’’ the patient during the test, but should walk behind such that measures of nadir SpO2 and end-test
HR can be recorded without influencing the patient’s movement. The assessor should ensure that the probe
is placed such that a quality signal is obtained.
Immediately on test cessation
The SpO2 and pulse rate should be recorded from the oximeter, and the patient should be asked to rate their
dyspnoea and subjective fatigue on the standardised scale. In addition, it is important to understand the reason
for test termination/limitation, so patients should be asked why they could not walk any further. It is common
for patients to report either dyspnoea or leg fatigue as the primary reason for a restricted performance.
Reasons for the assessor to stop an exercise test
In some individuals, profound desaturation (SpO2 ,80%) may occur during a walking-based exercise test.
Use of a 6MWT protocol that directs test cessation when SpO2 falls to ,80% is associated with an extremely
low rate of adverse events [35]; this has not been reported for the ISWT or ESWT. Few data are available to
determine the risk if the test is not stopped when SpO2 falls below 80%. Ceasing a test when SpO2 falls to
,80% is also consistent with the recommendations for incremental exercise testing [108]. If SpO2 recovers
to o85% during the 6MWT, the patient may be asked to recommence walking.
Other reasons for test cessation include chest pain, intolerable dyspnoea, leg cramps, staggering,
diaphoresis, and a pale or ashen appearance. If a test is stopped for any of these reasons, the patient should
sit or lie supine as appropriate. The following should be obtained based on the judgment of the assessor:
blood pressure, pulse rate, SpO2 and a physician evaluation. Oxygen should be administered as appropriate.
Test repetition
To establish a stable baseline for the 6MWT and ISWT so that change over time can be detected, two tests
must be completed. These can be performed on the same day but there must be an interval between tests of
at least 30 min and measures of HR and SpO2 must have returned to baseline prior to the second test.
Quality assurance
Consistency of testing procedures and conditions is critical to ensure that results are of good quality. It is
important that all assessors are familiar with the test procedures, as the test requires clear processes to be followed.
TABLE 5 Standardised instructions for the 6-min walk test
The aim of this test is to walk as far as possible for 6 minutes. You will walk along this hallway between the
markers, as many times as you can in 6 minutes.
I will let you know as each minute goes past, and then at 6 minutes I will ask you to stop where you are.
6 minutes is a long time to walk, so you will be exerting yourself. You are permitted to slow down, to stop,
and to rest as necessary, but please resume walking as soon as you are able.
Remember that the objective is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog.
Do you have any questions?
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For the ISWT and ESWT, the assessor must be able to walk at exactly the first speed of walking to pace the
patient; this is particularly important for patients with a higher functional capacity where their natural speed
of walking is much faster than the very slow pace required on the first level of the ISWT. All assessors should
have their performance peer reviewed to ensure that performance of the tests is in accordance with the
Technical Standard. Ideally, quality assurance testing should require the assessor to conduct the test on
participants with a range of functional exercise capacity.
It must be ensured that the pulse oximeter is operating according to the manufacturer’s instructions
and that the track is accurately measured. The effects of any changes in testing scenario (e.g. location,
equipment) should be evaluated to assess their effect on test outcomes. Any changes in procedures should
be reviewed and approved by the programme director. Consistent documentation must be ensured for every
test and a regular audit should be considered, to ensure that important procedures have been followed (e.g.
recording of appropriate physiological signals at baseline and end-test, documentation of nadir SpO2, end-
test HR and 6MWD, consistent use of oxygen, appropriate test repetition).
Testing protocol for 6MWT
Course
The 6MWT should be performed along a flat, straight course with a hard surface with little pedestrian
traffic. It is recommended that the walking course be 30 m or more in length, to be consistent with the
courses on which reference equations have been generated [1]. The ends of the course should be marked
such that they are easily visible to patients.
Conduct
The patient should be encouraged every 60 s using the standard phrases (table 6). Other words of
encouragement and other nonverbal prompts should not be used. If the patient stops walking during the
test, the timer must not be stopped. The patient should be allowed to rest while sitting or standing, as they
prefer. While the patient is stopped, standardised encouragement should be provided every 30 s (table 6).
The time that the patient stopped and the time that walking is recommenced should be recorded.
Recording performance of the 6MWT
The primary outcome to be reported is 6MWD. The number of laps and any additional distance covered
(the number of metres or feet in the final partial lap) should be recorded. The total distance walked is
calculated, rounding to the nearest metre or foot. If the patient stopped during the test, the total time
stopped, the number of stops and the average walking speed over the 6 min are also reported [111]. In
patients who cannot walk for 6 min, this may provide alternative metrics for detecting change over time
[111] and may facilitate exercise prescription [112]. It is optional to report the 6MWD as a percentage of
predicted. If the % predicted 6MWD is reported, the reference equations used should be stated. Lowest
SpO2, end-test HR and symptom scores obtained before and after the test should also be reported. A sample
recording form can be found in the online supplementary material (table S1).
Testing protocol for ISWT
Course
The course is 10 m in length and is identified for the patient by two cones with an inset of 0.5 m from either
end (fig. 1), thus avoiding abrupt changes in direction [113].
At the beginning of the test the instructions are played to the patient from an audio recording (table 7).
Once the instructions have been played, and it is confirmed that the patient has understood the task, the
TABLE 6 Standardised encouragement for the 6-min walk test
1 min
You are doing well. You have 5 minutes to go.
2 min
Keep up the good work. You have 4 minutes to go.
3 min
You are doing well. You are halfway.
4 min
Keep up the good work. You have only 2 minutes left.
5 min
You are doing well. You have only 1 minute to go.
6 min
Please stop where you are.
If the patient stops during the test, every
30 s once SpO2 is o85%
Please resume walking whenever you feel able.
SpO2: arterial oxygen saturation measured by pulse oximetry.
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patient is positioned at one end of the course in preparation to start the test. The speed at which the patient
should walk is directed by an audio signal and cannot be overridden. There is a triple bleep indicating the
test has started: at this point the participant commences walking and the timer is activated.
Conduct of the test
It is important for the assessor to watch the patient but also to ensure they keep count of the number of
lengths as the subject completes them, throughout the duration of the test. It is advisable to time the
performance as an additional measure, to confirm manual recording of the number of shuttles completed.
As the speed of walking increases every minute, indicated by a triple bleep [113], the patient should be
advised: ‘‘You now need to increase your speed of walking.’’ During the test, only one verbal cue can
be used to encourage the patient to pick up their speed: ‘‘You need to increase your speed to keep up with
the test.’’
Termination of the test
The test is terminated when either 1) the patient indicates that they are unable to continue, 2) the operator
determines that the patient is not fit to continue, or 3) the operator assesses that the patient was unable to
sustain the speed and cover the distance to the cone prior to the beep sounding [113].
Operator termination of the test
The operator will be required to terminate the test if the patient fails to reach the cone/marker in the time
allowed [113]. This is defined as the patient being .0.5 m away from the cone when the bleep sounds on a
second successive 10-m length. When the patient is just outside the 0.5-m marker they are advised to
increase their speed of walking; if the patient fails to do so then the test is terminated and the distance recorded.
The test should be discontinued by the operator if SpO2 falls below 80% as described in the ATS/American
College of Chest Physicians (ACCP) statement on cardiopulmonary exercise testing [108].
TABLE 7 Incremental and endurance shuttle walk test instructions
Incremental shuttle walk test instructions
The object of the progressive shuttle walking test is to walk as long as possible, there and back along the
10-metre course, keeping to the speed indicated by the bleeps on the audio recording. You will hear
these bleeps at regular intervals.
You should walk at a steady pace, aiming to turn around the cone at one end of the course when you hear
the first bleep, and at the other end when you hear the next. At first, your walking speed will be very
slow, but you will need to speed up at the end of each minute. Your aim should be to follow the set
rhythm for as long as you can. Each single bleep signals the end of a shuttle and each triple bleep
signals an increase in walking speed. You should stop walking only when you become too breathless to
maintain the required speed or can no longer keep up with the set pace.
The test is maximal and progressive. In other words, it is easier at the start and harder at the end. The
walking speed for the first minute is very slow. You have 20 seconds to complete each 10-metre shuttle,
so don’t go too fast. The test will start in 15 seconds, so get ready at the start now. Level one starts with
a triple bleep after the 4-second countdown.
Endurance shuttle walk test instructions
Walking test level (1 to 16). The instructions below are repeated for all 16 levels.
The walking speed for the first 2 minutes is fairly slow, so don’t go too fast. The test will start in
10 seconds so get ready at the start now. The test starts with a triple bleep after a 4-second countdown.
At the next triple bleep increase your walking speed.
9 m
FIGURE 1 Course layout for the
incremental and endurance shuttle
walk tests. Cones are inset 0.5 m from
either end to avoid abrupt changes in
direction.
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Participant termination of the test
The patient may terminate the test if they are unable to continue. In respiratory disease, the most common
reason for terminating the test is excessive dyspnoea; however, other reasons may include fatigue
(commonly leg fatigue) or pain (knee/hip/low back pain).
Recording performance of the test
The assessor should calculate the distance walked, in metres, including the last 10-m length that was
completed, and record this on the form available (see online supplementary material table S2).
Testing protocol for ESWT
Course
The test is conducted along the same course as described for the ISWT (fig. 1) [113].
Conduct of the test
Unlike the ISWT, the ESWT is not incremental and is performed at a constant speed, but there is a warm-
up period of ,1.5 min [77]. At this point, there are standardised instructions for the participant played
from the audio recording, advising the individual that at the next bleep the speed of walking will increase
(table 7). This is the speed at which the test is performed. It is important to pre-define the speed at which
the test is going to be conducted. This can be calculated from the ISWT: the speed may be taken from a
pre-defined percentage of peak performance on the ISWT (e.g. 70–85% estimated V9O2peak) [114] or a
percentage of the peak speed achieved [115]. Once the instructions have been played to the patient, they
should be directed to one end of the course. A triple bleep indicates that the test has started [77]. The initial
stages of the test are at a slower speed and are a warm-up for the participant. After the warm-up period, the
speed of walking increases; this is advised on the audio recording at the end of the warm-up period. The
timer is started at the end of the warm-up period. Participants are then paced for the first two shuttles.
During the test, only one verbal cue can be used to encourage the patient to pick up their speed: ‘‘You need
to increase your speed to keep up with the test.’’
Termination of the ESWT
The procedure to terminate the test is as described for the ISWT [113].
Recording performance of the test
It is conventional for endurance performance to be recorded as time (in seconds). It is important that the
speed of walking and time are recorded. A sample scoring sheet is included in the online supplementary
material (table S2).
Key changes in this updated Technical Standard
Absolute and relative contraindications for field walking tests
Research published since 2002 has shown that, in adults with moderate chronic respiratory disease, the
6MWT and ISWT elicit a V9O2peak that is comparable to that on CPET [3–6, 8]. As a result, the absolute and
relative contraindications for CPET have been adopted for field walking tests of exercise capacity.
Continuous measurement of SpO2
New data show both the importance of nadir SpO2 during the 6MWT as a marker of prognosis [38, 46, 116–119]
and that end-test SpO2 frequently does not reflect this important value [40, 41]. These factors, together with
improvements in pulse oximetry technology in managing motion artefact, have made it feasible and desirable to
measure SpO2 continuously during field walking tests.
6MWT repetition
There are now consistent and compelling data showing a learning effect for the 6MWD [1, 9]. As a result, it
is recommended that two 6MWTs are performed when the test is used to measure change over time.
Addition of the ISWT and ESWT
The ISWT and ESWT have emerged as robust and useful tests of exercise capacity in chronic respiratory
disease [1]. The standard operating procedures for these tests are described here for the first time.
Common testing procedures for field walking tests
Testing procedures, such as test staffing, patient assessment, patient preparation, use of oxygen and
medications, and quality assurance, are now consistent across the three field walking tests described in this
Technical Standard.
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Acknowledgements
The authors’ affiliations are as follows. Anne E. Holland: Dept of Physiotherapy, La Trobe University, Melbourne,
Australia, Dept of Physiotherapy, Alfred Health, Melbourne, Australia, and Institute for Breathing and Sleep, Austin
Health, Melbourne, Australia; Martijn A. Spruit: Dept of Research and Education, CIRO+ Centre of Expertise for Chronic
Organ Failure, Horn, The Netherlands, and REVAL – Rehabilitation Research Center, BIOMED – Biomedical Research
Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Thierry Troosters and
Carlos Augusto Camillo: Faculty of Kinesiology and Rehabilitation Sciences, Dept of Rehabilitation Sciences, Katholieke
Universiteit Leuven, Leuven, Belgium; Milo A. Puhan: Institute for Social and Preventive Medicine, University of Zurich,
Zurich, Switzerland; Ve´ronique Pepin: Axe maladies chroniques, Centre de recherche de l’Hoˆpital du Sacre´-Coeur de
Montre´al, Montreal, QC, Canada, and Dept of Exercise Science, Faculty of Arts and Science, Concordia University,
Montreal, QC, Canada; Didier Saey: Centre de recherche, Institut Universitaire de cardiologie et de pneumologie de
Que´bec, Que´bec, QC, Canada, and Faculte´ de me´decine, Universite´ Laval, Que´bec, QC, Canada; Meredith C. McCormack:
Johns Hopkins University, Pulmonary and Critical Care Medicine, Baltimore, MD, USA; Brian W. Carlin: Drexel University
School of Medicine, Pittsburgh, PA, USA, and Sleep Medicine and Lung Health Consultants, Pittsburgh, PA, USA;
Frank C. Sciurba: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Fabio Pitta and Nidia A. Hernandes:
Laboratory of Research in Respiratory Physiotherapy, Dept of Physiotherapy, Universidade Estadual de Londrina, Londrina,
Brazil; Jack Wanger: ATS Proficiency Standards for Pulmonary Function Laboratories Committee, Rochester, MN, USA;
Neil MacIntyre: Duke University, Durham, NC, USA; David A. Kaminsky: University of Vermont College of Medicine,
Burlington, VT, USA; Bruce H. Culver: Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA,
USA; Susan M. Revill: Clinical Diagnostix Ltd, Derby, UK; Vasileios Andrianopoulos: Dept of Research and Education,
CIRO+ Centre of Expertise for Chronic Organ Failure, Horn, The Netherlands; Katy E. Mitchell: Centre for Exercise and
Rehabilitation Science, University Hospitals of Leicester NHS Trust, Leicester, UK; Annemarie L. Lee: Dept of
Physiotherapy, Alfred Health, Melbourne, Australia, and Institute for Breathing and Sleep, Austin Health, Melbourne,
Australia; Catherine J. Hill: Institute for Breathing and Sleep, Austin Health, Melbourne, Australia, and Dept of
Physiotherapy, Austin Health, Melbourne, Australia; Sally J. Singh: Centre for Exercise and Rehabilitation Science,
University Hospitals of Leicester NHS Trust, Leicester, UK.
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ERS/ATS TECHNICAL STANDARD | A.E. HOLLAND ET AL.
DOI: 10.1183/09031936.00150314
1446
Faron Pharmaceuticals Ltd  
Protocol Number: FPCLI002
Clinical Study Protocol 
CONFIDENTIAL
Final Version 6.0
111 of 111
9Aug2017

SAP_001.pdf: 
 
COVER PAGE FOR STATISTICAL ANALYSIS PLAN  
 
Official Study Title:  A Phase III Double-blind, Randomised, Parallel-Group Comparison of the 
Efficacy and Safety of FP-1201-lyo (Recombinant Human Interferon Beta-1a) and Placebo in the 
Treatment of Patients with Moderate or Severe Acute Respiratory Distress Syndrome 
 
Unique Protocol ID: FPCLI002 (INTEREST Study)  
 
Date of the Statistical Analysis Plan: 19 April 2018 
 
NCT Number: NCT02622724 
 
 


Statistical Analysis Plan 
 
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Faron Pharmaceuticals Ltd   
Protocol: FPCLI002 - INTEREST 
 
Statistical Analysis Plan:    
A Phase III Double-blind, Randomised, Parallel-Group Comparison of 
the Efficacy and Safety of FP-1201-lyo (Recombinant Human Interferon Beta-1a) 
and Placebo in the Treatment of Patients with Moderate or Severe Acute 
Respiratory Distress Syndrome 
 
 
Sponsor: 
Faron Pharmaceuticals Ltd 
 
 
Joukohaisenkatu 6 
FIN-20520 Turku 
Finland 
 
 
 
  
Author & 
Qualifications 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Document Date: 
19th April 2018 
Version/Status: 
1.3 
Final  
 
 
 
 
 
 
 
 




Statistical Analysis Plan 
 
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AUTHORISATION  
Position  
Name 
Signature 
 Date 
(dd/mon/yyyy) 
Medical Director 
Faron Pharmaceuticals Ltd 
 
 
  
 
 
 
  
Statistical Consultant 
Data Magik Ltd.  
 
 
  
 
DOCUMENT HISTORY 
Created: 6NOV2015 with Microsoft Office 2010 (Windows 7 Operating System) 
Current SOPs: Data Magik Ltd –  2017 & 2018 
Version 
Date 
Author 
Section/Page Amendment 
1 Draft 
6NOV2015 
 
Original draft 
1 Draft 
23DEC2015 
 Review against final protocol 
1 Draft 
24JUN2016 
Review 
2 Draft 
25OCT2016 
 
 
Draft incorporating RK/MM comments 
3 Final 
Draft 
22FEB2017 
 
 
Final draft incorporating RK comments 
4 Final 
Draft 
6AUG2017 
 
 
 
Final draft incorporating Sponsor and 
RK comments, & accepting track 
changes as appropriate. Data derivations 
moved from Section 5.9.4 to Appendix 
4. SAP now following protocol version 
5. 
1 Final 
4JAN2018 
 
 
 
Updated following release of protocol 
amendment 5 (Protocol version 6). The 
main report will now be produced 
following long term follow up at Day 90 
database lock. Addendum reports will 
be produced following the lock of long 
term and extended long term database 
locks at Day 180 and Day 360, 
respectively.  
1.1 Final 12MAR2018 
 
Updated following final review by 
Sponsor & Professor Ville Pettilä 
1.2 Final 11APR2018 
 
 
Finalised after blinded review 
1.3 Final 19APR2018 
 
 
Updated Fig1, Table 3 and paragraph 3, 
Section 4.1 & Table 1, 3 not doses not 4 


Statistical Analysis Plan 
 
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CONTENTS. 
1. INTRODUCTION 
4 
2. OBJECTIVES 
5 
3. STUDY DESIGN 
5 
4. ANALYSIS SETS 
7 
5. STUDY METHODS 
10 
6. STATISTICAL METHODS 
30 
7. PRESENTATION 
42 
8. REFERENCES 
57 
9. FINALISATION OF STATISTICAL ANALYSIS PLAN 
58 
10. APPENDICES TO BE INCLUDED IN THE STATISTICAL REPORT 
58 
 
 
 
 
APPENDIX 1 TABLE SHELLS 
 
APPENDIX 2 FIGURE SHELLS 
 
APPENDIX 3 SUPPORTING LISTINGS 
 
APPENDIX 4 DATA DERIVATIONS 
 
APPENDIX 5  LONG TERM FOLLOW UP - DAY 180 OUTPUTS FOR  
 
 
ADDENDUM REPORT 
 
APPENDIX 6 EXTENDED LONG TERM FOLLOW UP - DAY 360 OUTPUTS FOR  
 
 
ADDENDUM REPORT 
 
 
 
 
 
 
 


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1. Introduction 
 
This is a phase III clinical study to investigate the efficacy and safety of FP-1201-lyo in patients 
with moderate or severe acute respiratory distress syndrome (ARDS).  
 
FP-1201-lyo is a lyophilisate for solution for injection of interferon beta-1a (IFN) and is 
administered intravenously. Recombinant human IFN beta-1a is an approved treatment for 
patients with relapsing-remitting multiple sclerosis. 
 
ARDS is a life threatening clinical disorder which follows a variety of severe lung insults such as  
pneumonia, aspiration of gastric contents, non-pulmonary sepsis and major trauma. It is 
characterised by injury to the endothelial barriers and alveolar epithelium of the lung with acute 
inflammation and protein-rich pulmonary oedema leading to acute respiratory failure. 
 
Mortality rates across all severities range from approximately 20% to 40% but can be higher 
when associated with dysfunction in other organs. There are currently no approved 
pharmacological therapies for ARDS. Treatment is limited to supportive care. 
 
This document describes in detail the framework for the analysis and reporting of all data 
obtained from this study prior to finalising the database and unblinding. Any changes made in the 
course of the evaluation and analysis of these data performed after the locking and unblinding the 
database will be documented and fully justified in the final integrated clinical report. 
 
A single analysis at the conclusion of the study is planned with no formal interim investigations 
planned other than specified safety data reviews performed by an Independent Data Monitoring 
Committee (IDMC). 
 
The Safety data reviews are performed at regular intervals and specific details of the 
requirements for these evaluations are documented in a separate Charter (see INTEREST Study 
IDMC Charter v1 0_16Oct2015 and INTEREST Study IDMC Charter_V 2.0 01Mar2018).  
 
The main analysis itself is to be undertaken when all patient data collected up to 3 months post 
treatment is available (Day 90 or earlier in the event of withdrawal). However, subsequent 
supplemental follow-up analyses are planned after completion of a further 3 and 6 months 
observations to 6 months and 12 months post treatment (Day 180 and Day 360, respectively). 
These results will be added as addendums to the main Clinical Study Report. But, all efficacy and 
safety data available at Day 90 will also be analysed and reported in the main CSR, including all 
available data up to Day 180 and/or Day 360 where applicable. 
 
This statistical analysis plan is based on FPCLI002 Protocol FINAL v 6.0 29Aug2017 and is in 
line with ICH E8 and E9 guidelines (Ref 1, 2). 
 
 
 
 


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2. Objectives 
 
The primary objective is to investigate the efficacy of FP-1201-lyo through improvement of the 
clinical course and outcome at Day 28. Efficacy is based on a composite measure of both survival 
and the need for mechanical ventilation (VFDsurv) in patients with moderate or severe ARDS. 
 
Further objectives concern investigation of Safety, Secondary Short term efficacy and Long term 
efficacy, Pharmacodynamics including immunogenicity, as well as Pharmacoeconomics. 
 
Safety of FP-1201-lyo is investigated through patient assessment and adverse event reporting 
 
Secondary efficacy objectives, assessed during the Short Term Follow Up period, include the 
assessment of mortality (all causes) at Day 28, with further ICU based efficacy evaluations of 
Organ failure, Renal support, Vasoactive support and Mechanical ventilation (including 
pulmonary function through gas exchange PaO2/FiO2 ratio) followed by Time spent in in 
intensive care unit (ICU) and Overall time spent in hospital. 
 
Long term efficacy objectives, assessed during the Long Term and Extended Follow Up periods, 
include: investigation of survival (through Mortality Day 90, 180 and 360), requirement for 
mechanical ventilation (through Ventilation free survival), Quality of life (through EQ-5D-3L) 
and Organ functioning (through respiratory (FEV-1) and neurological (six minute walk test 
(6MWT)).  
 
Pharmacodynamics objectives assessed during Short Term Follow Up period include the 
investigation of impact of FP-1201-lyo response through myxovirus resistance protein A (MxA), 
CD73 biomarker, Potential Inflammatory Markers (PIMs) and on neutralising antibodies to IFN 
beta-1a. 
 
The Pharmacoeconomic value of FP-1201-lyo will be investigated through the total costs of 
standard treatment and care services used. These will be determined by application of unit costs 
to the key secondary efficacy outcome variables (Organ failure, Renal support, Vasoactive 
support, Mechanical ventilation and Stay in ICU/hospital). 
 
A full description is provided in the protocol. 
 
 
3. Study Design 
 
This is a multicentre, Phase III, double-blind, randomised, parallel-group comparison study of the 
efficacy and safety of FP-1201-lyo (10ug) compared with placebo in approximately 300 adult 
patients diagnosed with moderate or severe ARDS (see Figure 1). 
 
After a careful screening process the aim is to obtain at least 272 evaluable patients for the 
assessment of efficacy. 
 


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Study centres are identified from Western Europe, with no more than 30 patients recruited from 
each. Patients are randomised to either FP-1201-lyo (10ug) or Placebo control in an allocation 
ratio of 1:1.  
 
A stratified randomisation procedure is administered according to the Severity of the ARDS 
diagnosis (Moderate/Severe) and Country of investigational site. This enables control of the two 
factors which may impact the magnitude of the treatment effect.    
 
Following satisfactory eligibility evaluations and successful randomisation, treatment consists of 
6 doses of FP-1201-lyo 10 µg or Placebo control. Treatment is administered intravenously as a 
bolus, once per day, over 6 consecutive days. In order to be effective it is considered that 
administration of first dose must be within 48 hours of confirmed Moderate or Severe ARDS 
diagnosis. 
 
Patients are assessed daily while in the Intensive Care Unit (ICU) for up to a maximum of 28 
days. This is called the Short Term Follow Up period. A complete set of evaluations are 
performed at the time of release from the ICU.  
 
After leaving ICU (Day 28 or earlier), patients receive follow-up care with additional 
assessments performed at Day 90, 180 and 360. These are called the Long Term (Day 90, Day 
180) and Extended Follow Up (Day 360) periods. Throughout (and indeed subsequently if 
required) the procedure for patient care follows normal hospital practice. 
 
The schedule for all efficacy and safety assessments performed are outlined in Section 5 and 
summarised in Table 2.  
   
No formal interim analyses are planned although an Independent Data Monitoring Committee 
(IDMC) will review on-going safety. Specifically all adverse events including any classified as 
serious will be reviewed on an unblinded basis. The IDMC will make recommendations to the 
Sponsor. The constitution, evaluation, recommendations and actual process details are given in a 
separate IDMC charter. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1 – Study Design 
 
 
 
 
 
 
FP-1201- 
lyo 10 µg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
-48 h 
pre-dose on D1          D1–D6 
D7–D28 
D90c 
D180 
D360 
Visit 
Screening 
Randomisation 
 
Double-
blind 
treatment 
period 
Short-
term FU 
Long-term FU 
Extended 
FU 
 
Baseline 
includes pre-dose on D1a 
Daily assessments up to 
D28 while in ICUb  
 
 
End of Study 
 
 
   CSR  
Addendum 
to CSR 
Addendum to 
CSR 
 
a 
Not more than 48 hours may elapse between confirmation of moderate or severe ARDS during 
screening and administration of the first dose of study drug on D1. Randomisation can occur 
during screening or pre-dose on D1. 
b 
Assessments are described in the Schedule of Procedures in Table 2 or the patient’s last day in the 
ICU. These will be done on D28 or earlier, according to the clinical progress of the patient. If a 
patient leaves the ICU before D28, their survival status and other endpoints must be assessed on 
D28 (see schedule in Table 2). 
c 
Can be visit or telephone contact. 
Abbreviations: CSR=Clinical Study Report; D=day; FU=follow-up; ICU=intensive care unit. 
 
 
4. Analysis Sets   
 
Three analysis sets (or subject populations) will be evaluated: The Full Analysis Set (FAS), Per 
Protocol Set (PPS) and the Safety Set (SS). 
 
The Full Analysis Set (FAS) will consist of all randomised and treated patients who receive one 
or more doses and who provide post baseline data. Patients who receive the wrong treatment 
according to the randomisation schedule will be analysed according to the treatment that was 
assigned and not the treatment they actually received. This 'as randomised' population will be 
used for the analysis of the primary efficacy endpoint but a supporting 'as treated' population 
(sensitivity) analysis may also be included if sufficient patients are administered the 'wrong' 
treatment. 
 
The Per Protocol Set (PPS) will consist of patients from the FAS but excluding those with major 
protocol deviations considered to be violations according to Section 4.1 below. A list of all 


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relevant situations which constitute major protocol violations and constitute reasons for exclusion 
from the PPS are specified in Section 4.1. 
 
Patients who are to be included in and excluded from the PPS will be identified and listed 
following a Blind Data Review meeting prior to the database lock and unblinding at Day 90. 
 
Statistical analyses for the primary and secondary endpoints will be performed using both the 
FAS and PPS (where appropriate). Although the FAS is considered of primary importance, the 
PPS will enable evaluation of the sensitivity and robustness of the estimates of the magnitude of 
the treatment effect 
 
All other evaluations will involve the FAS population (i.e.: Demographic and baseline 
characteristics, Pharmacodynamics, Pharmacoeconomics). 
 
The Safety Set (SS) will consist of all patients who receive at least one dose of study drug. All 
safety and tolerability evaluations will be based on this analysis set. Patients who receive the 
wrong treatment according to the randomisation schedule will be analysed according to the 
treatment actually received. 
 
The SS population will be applied to all safety and tolerability assessments and analyses 
 
Administration of the 'wrong' treatment applies to any of the 6 vials administered over the 6 day 
period. If a placebo randomised patient therefore receives at least one vial of active treatment 
they will be classified as actually treated with FP-1201-lyo. If a treated patient is however given 
one or more placebo vials they will still be classified as treated with FP-1201-lyo as long as one 
vial was correctly administered.   
 
4.1 Protocol Deviations Considered to be Violations 
 
Subject specific protocol deviations are defined and entered by Investigators, or CRAs, in the 
eCRF, and are graded as either minor or major.  
 
 
But Violations are those protocol deviations defined by the Sponsor as being clinically important 
and may be in whole, or in part, a subset of the eCRF deviations. Any deviation considered by the 
Sponsor to be a ‘violation’ will lead to that patient being excluded from the PPS population. 
Table 1 defines these protocol deviations. To ensure that none of these deviations have been 
omitted, i.e. not captured by the Investigators and/or CRAs, Data Magik Ltd will 
programmatically interrogate the clinical study database and extract a listing of the events 
displayed in Table 1 below.  
 
Furthermore, following the completion of PPD takeover from Gaea of the study management, all 
deviations in the eCRF database are being transferred and recorded in the PPD CTMS deviation 
tracker (except for Italian patients, who have not consented themselves). Deviations from these 
Italian patients will be tracked by the Sponsor using a compatible file to the PPD tracker. Prior to 
the Day 90 database lock, the deviations will be signed off by the Investigators, exported and sent 
to DML, and combined with the listing tracker produced from the DML database interrogation 


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process described above. This combined tracker report showing all deviations will be assessed by 
the Sponsor, study Medical Monitor and Data Magik Ltd statistical team at the population 
assignment meeting, and patients to be excluded from the PPS will be identified prior to the Day 
90 database lock. 
 
If patients fail to meet one or more of these criteria they will be excluded from the PPS. 
 
Table 1: Protocol Deviations Considered to be Violations 
 
Potential Violations 
Detail/Criteria 
Reason 
Delayed or Incomplete 
treatment 
Failure to treat within 
first 48 hours of 
diagnosis or receive 
less than 3 doses* 
IMP needs to be taken within 48 hours 
of diagnosis and at least 4 doses are 
deemed necessary for clinical 
effectiveness 
Mis- Dosing 
Patient is given 
incorrect vials leading 
to ‘mixed’ treatments 
May receive different treatment to the 
one assigned, or a combination of both 
treatments 
Inclusion criteria 
Failed one or more 
inclusion criterion 
Data changed after dosing had 
commenced 
Exclusion criteria 
Failed one or more 
exclusion criteria 
Data changed after dosing had 
commenced 
Eligibility 
Failed one or more 
eligibility criteria 
Data changed after dosing had 
commenced 
 
 
 
Temperature excursion 
IMP must be stored at  
2 – 8 ºC** 
Active ingredient may be affected by 
temperature excursion.  
 
 
 
Other reasons 
Any Major Deviation 
considered by the 
Sponsor and Medical 
Monitor that might 
influence the 
effectiveness of the 
active compound  
To ensure that the PPS contains only 
subject data which has not been 
‘clinically’ compromised. Reasons for 
this decision will be recorded in a 
comments column on the assignment 
population spreadsheet during the 
population assignment meeting. 
*Patients who die during the dosing period will not be excluded from the PPS. 
** Individual temperature deviations outside 2-8 may have been accepted and the IMP considered valid for use based 
on IMP stability data. Those patients who have received an IMP with an temperature excursion, but accepted by the 
Sponsor, are not classified as Protocol Violations. 
 
Consent:  
Full details of the consent procedures are given in Section 9.6 of the protocol. In summary, 
whenever possible informed consent will be obtained from the patient. When this is not 
immediately possible due to the patient’s condition, the informed consent can be given by a: 
PerLR: Personal Legal Representative (e.g. relative, partner or close friend) 
PrfLR: Professional  Legal Representative (e.g. doctor not involved in the study) 
Note: A separate consent will also be requested for patient’s genetic sampling. 


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After PerLR  or PrfLR, Investigators will attempt to obtain retrospective consent until Day 360, 
unless the patient’s condition has precluded this (e.g. in case of death). If the patient refuses to 
give retrospective consent and the reason for withdrawal is ‘retrospective consent not given’ then 
all data for this patient will be removed from any analyses population group. 
Withdrawal of consent: Patients may withdraw or be withdrawn (by the PerLR or PrfLR) from 
the study at any time and, any data collected up to the time of withdrawal can be included, unless 
consent for any use of the data has also been withdrawn. If not specified otherwise, data will be 
used up until the time of withdrawal. 
Patient data excluded from any or all analysis populations because of a withdrawal of consent 
will also be reported in the population assignment record. 
 
   
5. Study Methods  
 
The subject assessments performed during both the Short Term and Long Term/Extended Follow 
Up periods together with the timetable of events are summarised using only details relevant to the 
analyses provided. Precise details of all assessments performed on each study day are given in 
Section 6 of the protocol. 
 
5.1 Schedule 
 
The timetable of events are summarised in Table 2. 
 
 
 
 
 


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Table 2 Study Timetable and Assessment Overview (See protocol for full details)  
 
  
 
 
Screen
-ing 
period 
Double-blind treatment 
period 
Days 1-6 
Short-term follow-up until D28 or 
discharge from ICU (whichever is earlier) 
Long-term 
follow-up 
Extended 
follow-up 
Baseline period 
 
D7–D28 
Procedure 
48 ha 
D1 
pre-
dose 
D1  
D2–D6 
D7–D14 
D15–
D27 
Last day 
in ICUb 
D28c 
D90d 
+14 days 
D180 
+14 days 
D360     
+14 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Demographic details 
X 
 
 
 
 
 
 
 
 
 
 
Documentation of chest X-ray or 
CT scan 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xe  
 
 
 
 
 
 
 
 
 
Randomisation 
Xf 
 
 
 
 
 
 
 
 
 
Administration of study drug 
 
 
X 
X 
 
 
 
 
 
 
 
Survival 
 
 
 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
On mechanical ventilation? (Y/N) 
 
 
 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
In ICU/in hospital? (Y/N) 
 
 
 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
SOFA 
 
X 
 
X 
X 
D21 
X 
X o 
 
 
 
GCS (for SOFA and APACHE II) 
X 
X 
 
X 
X 
D21 
X 
X o 
 
 
 
APACHE II 
X g 
 
 
 
 
 
 
 
 
 
 
Renal and vasoactive support? 
(Y/N) 
 
X 
 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
 
 
 


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Screen
-ing 
period 
Double-blind treatment 
period 
Days 1-6 
Short-term follow-up until D28 or 
discharge from ICU (whichever is earlier) 
Long-term 
follow-up 
Extended 
follow-up 
Baseline period 
 
D7–D28 
Procedure 
48 ha 
D1 
pre-
dose 
D1  
D2–D6 
D7–D14 
D15–
D27 
Last day 
in ICUb 
D28c 
D90d 
+14 days 
D180 
+14 days 
D360     
+14 days 
Blood sample: IFN beta-1a 
neutralising antibodies 
 
Xh 
 
 
 
 
X 
X 
 
 
 
Blood sample: MxA 
 
Xh 
 
X 
X  
 
 
 
 
 
 
EQ-5D-3L, FEV1 and 6MWT  
 
EQ-
5D-3Li 
 
 
 
 
 
 
 
X 
X 
PaO2/FiO2  
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Blood sample: CD73 and PIM 
 
Xh 
 
X 
X 
 
 
 
 
 
 
Pharmacoeconomics 
 
 
 
 
 
 
X 
X 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
X o 
 
 
 
Vital signs 
Xj 
X 
 
X 
X 
X 
X 
X o 
 
 
 
ECG 
 
X 
 
 
D7 
 
 
 
 
X 
X 
Haematology, chemistry, 
urinalysisk 
Xj 
X 
 
X 
X 
X 
X 
X o 
 
 
 
Pregnancy test in women of 
childbearing potential 
X 
 
 
 
 
 
 
 
 
 
 
Previous and concomitant 
medications and therapies 
Xl 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -X 
 
 
 
Adverse events 
Xm 
X - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - X 
Xn 
Xn 
Xn 
Blood sample: genetic analysis 
(requires separate consent) 
X - - - - - - - - - - - - - 1 sample at any time while in ICU - - - - - - - - -X 
 


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a No more than 48 hours may elapse between confirmation of moderate or severe ARDS and administration of the first dose of study drug. 
b These assessments will be done on the day the patient leaves the ICU, which will either be on D28 or earlier, according to the clinical progress of the patient. If 
the patient is still in the ICU on D28, the next visit or telephone contact will be at D90. If a patient leaves the ICU before D28, the survival status and other 
endpoints must be assessed on D28. 
c D28 procedures apply for patients leaving the ICU before D28 and for patients withdrawing from the study before D28. For patients withdrawing from the study 
before D28 a sample should be taken for neutralising antibodies on the day they leave the ICU. 
d D90 can either be a visit or telephone contact. 
e Reconfirm inclusion/exclusion criteria before dosing, including that patient requires mechanical ventilation and is in the ICU (patients requiring ECMO after 
randomisation but before the first dose of IMP may still be included). 
f Randomise after consent obtained and once eligibility criteria confirmed. 
g Within 24 hours of ICU admission 
h Within 1hour pre-dose. 
i Baseline EQ-5D-3L to be obtained from relatives and checked later with patient. 
j For APACHE II scoring. 
k Samples should be taken in the morning between 04:00 and 10:00. 
l Medicines and therapies in previous month. 
m Adverse events will be recorded after informed consent is obtained. 
n  Deaths are reported as SAE 
0 if it is possible to be performed by the investigator 
Abbreviations: APACHE II=Acute Physiology and Chronic Health Evaluation; CD=cluster of differentiation; CT=computerised tomography; D=study day; 
ECG=electrocardiogram; ECMO=extra-corporeal membrane oxygenation; EQ-5D-3L=EuroQol 5-Dimensions 3-Levels questionnaire; FEV1=forced 
expiratory volume in 1 second; GCS=Glasgow Coma Scale; ICU=intensive care unit; IFN=interferon; MxA=myxovirus resistance protein A; PaO2/FiO2=partial 
pressure of oxygen/fraction of inspired oxygen; PIM=potential inflammatory marker; SOFA=Sequential Organ Failure Assessment; 6MWT=6-minute walk test;. 
 


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5.2 Patient Status And Baseline Characteristic Assessments Prior To Treatment Start 
 
Study specific patient eligibility assessments required prior to recruitment are recorded during 
Screening and/or at Pre-Dosing on Day 1 (Baseline). 
 
5.2.1 Admission 
 
At Admission to the ICU they include details of: Status including Intubation, Renal support, 
Body position and any required Vasoactive infused drug treatment. 
 
These are then supported by a combined assessment of Acute physiology and Chronic health to 
derive an APACHE II score (0-71) to additionally classify the severity of the condition. 
 
Demographics (Age, Race, Sex) are then supplemented with details of the Disease diagnosis and 
Aetiology supported by Imaging (Chest X-ray / CT scan) and Ventilation evidence (Gas 
exchange variables). Aetiology is categorised as: Pancreatitis, Trauma/Burns, Sepsis, Multiple 
Transfusion, Aspiration, Pneumonia or Other. If the cause is Sepsis then the site of infection is 
noted. 
 
Following satisfactory completion of all the Inclusion/Exclusion criteria details (including a 
negative pregnancy test for females) Medical history (including any relevant previous and 
ongoing medical conditions) is recorded together with Prior medications (taken in the last 30 
days but stopped before signing Informed consent) and a complete Physical examination (with 
predicted body weight). 
 
Ongoing medications are recorded as Concomitant Medications (classified as either Bolus or 
Infusion) and reported accordingly if started prior to treatment dosing (Day 1). Any medication 
given with or after the first injection of study drug is also classified as a concomitant treatment. 
 
Prior to the start of dosing on Day 1 the Patient status and Inclusion/Exclusion criteria are 
confirmed and all Medications are updated.  
 
A series of Baseline safety assessments are then performed. These include: Safety laboratory tests 
(Biochemistry, Haematology, Urinalysis), Vital signs, 12 Lead ECG and Ventilation (Gas 
exchange). Specific variables measured are listed in section 5.8.  
 
Baseline efficacy assessments performed are: the System Organ Failure SOFA score and Quality 
of Life (EQ-5D-3L) assessment. Details of the specific variable items measured are given in 
section 5.3.3.5 and 5.4.2 respectively.  
 
Pre-dose blood samples are taken for pharmacodynamic baseline assessment. These include: 
Myxovirus Resistance Protein A (MxA), CD 73 biomarker, Potential Inflammatory Markers 
(PIMs). Also a sample for Anti Drug Antibodies (ADA) and Neutralising Antibodies (NAbs) to 
Interferon Beta-1a assessment will be taken. A tier based approach for the NAbs analyses will be 
used where NAbs will be assessed only if ADAs exists. 
 


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If all the study specific inclusion criteria are met then the patient is eligible for entry into the 
study. Screen failures are retained in the database, but only the patient screening number and 
reason for exclusion will be listed in the report.  
 
5.2.2 Randomisation 
 
Randomisation details, including details of the severity of the ARDS condition and any change in 
the condition are recorded on Day 1 of dosing. Drug compliance is not measured but a record of 
the daily infusion of the Study IMP (material number, date and time of administration) is 
maintained on Days 1-6. These data will be categorically summarised and individual details 
listed. Details of the construction (including block size) and application of the randomisation will 
be described in the Statistical Report. The severity of ARDS reported at Day 1 dosing will be 
used to assign patients to their respective groups (i.e. Moderate or Severe), irrespective of the 
stratification selected in the IWRS system. 
 
5.3 Efficacy Assessments - Short Term Follow Up 
 
Daily assessments are performed in the ICU for the evaluation of treatment benefit. This is the 
Short Term Follow Up period (Day 1 to Day 28).  
 
Efficacy related assessments are predominantly performed as part of the Patient Status evaluation 
(see Section 5.3.1). 
 
From these observations both primary and secondary efficacy endpoints to the end of the Short 
Term Follow Up period Day 28 can be derived. They include: Mortality (All causes), Mortality in 
ICU, Mortality in hospital, Days free of organ failure, of renal support, of vasoactive support and 
of mechanical ventilation together with the Number of ICU care free days and the Number of 
days in hospital. A combination of Mortality and the Need for mechanical ventilation is used to 
determine the primary efficacy outcome of the treatment (see Section 5.3.2). 
 
Further efficacy evaluations involve assessment of the impact on body organs as a whole through 
the Sequential Organ Failure Assessment (SOFA) and individually through the need for 
Vasoactive support, Ventilation performance and Fluid balance and these are recorded separately 
(see Section 5.3.3). 
 
The end of the Short Term Follow Up may be less than Day 28 if the patient is Discharged from 
the ICU or Withdrawn from the study. In either event a complete set of assessments identical to 
those performed daily and at the conclusion of the Short Term Follow Up (Day 28). 
 
Further assessments following discharge from the ICU are then performed at Long Term and 
Extended Follow Up on Day 90 and Day 180 and Day 360 respectively (see Section 5.4). 
 
5.3.1 Patient Status Assessments 
 
The Patient Status assessments are performed on Days 1 (Pre-dose) then daily on Days 2 - 28 
(Day 28 In or Out of ICU). At each visit patient details recorded are: Alive/Dead, Location of 


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death (ICU/Hospital), Date of death, Location if alive (ICU/Hospital), Requirement for 
mechanical ventilation, On renal support and Relative change in condition from yesterday.   
 
 
At selected visits (Day 1 (Pre-dose), Day 27 - 28), Body positioning (except Day 28 if already 
left ICU), Vasoactive support and Concomitant medications and Other therapies are recorded. 
 
Prior to Day 28 in the event of withdrawal an Early Termination is completed. In the event of 
discharge from the ICU a Last Day in ICU form is completed. Each includes a complete set of 
Patient Status evaluations. 
 
In addition, at Day 28 patients who have been externally transferred and are no longer in the ICU 
complete details of the Total number of days spent free of Mechanical ventilation, free of Organ 
failure (SOFA score=0), free of Renal support and free of Vasoactive support. Totals for the 
entire short term follow up period are derived (see Section 5.9.4, Appendix 4). In addition, the 
total number of days spent in the ICU and the Hospital environment are also similarly derived.   
 
5.3.2 Primary Efficacy - Ventilation Free Survival (VFDsurv) 
 
The primary endpoint for treatment benefit includes Mortality and the Number of days free of 
Mechanical ventilation within 28 days among survivors as a composite measure (VFDsurv). 
 
Mortality is patient death by Day 28. Ventilator-free days (VFDs) correspond to those days when 
unassisted breathing (UAB) is possible for a complete calendar day. For the initiation of the VFD 
count at least two consecutive calendar days of UAB are required. 
 
The definition of UAB is given in the protocol and the actual VFDsurv and VFD scoring 
mechanisms are described in Section 5.9.4, Appendix 4. 
 
5.3.3. Secondary Efficacy 
 
Secondary efficacy assessments include: Mortality (All causes), Mortality in ICU, Mortality in 
hospital, Days free of Organ failure, of Renal support, of Vasoactive support and of Mechanical 
ventilation together with the Number of ICU care free days and the Number of days in hospital. 
 
Additionally, Organ failure (SOFA score) and individual organ assessment through Vasoactive 
support, Ventilation performance and Fluid balance are also assessed. 
 
5.3.3.1 Mortality Evaluations 
 
Mortality is primarily assessed in the hospital at Day 28. All details are obtained from the daily 
assessment of Patient Status. Mortality is categorised as: Mortality (All causes), Mortality in ICU 
and Mortality in hospital.  
 
The Mortality rate will be a proportion derived from the number of deaths up to Day 28 divided 
by the total number of eligible patients in the FAS patient population. The Mortality rate in the 


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ICU and Mortality rate in the hospital will be similarly calculated based on the location of the 
death. 
 
Investigators  are required to confirm mortality using the ‘Death report’ section of the eCRF. In 
the event of missing or insufficient information then patients are assumed alive and still 'at risk' at 
the time of assessment. 
 
5.3.3.2 Days Free Of Mechanical Ventilation Evaluations 
 
The Total number of days free of Mechanical ventilation is derived from the Patient Status report 
recorded on each day during the 28 day period. Patients who die during this period will be 
assigned a value of zero. Defined rules are specified in Section 5.9.4, Appendix 4.  
 
The definition used by site staff for unassisted breathing (UAB) and 'being ventilator free for the 
whole of the calendar day' as recorded in the CRF is given in the protocol. 
 
This variable is not the same as the calculated Ventilation Free Days (VFD) endpoint which 
contributes to the VFDsurv primary efficacy endpoint as it requires 2 consecutive calendar days 
of UAB. If there are fewer than 2 consecutive days of UAB then VFD is assigned the value zero. 
 
5.3.3.3. Days Free Of Organ Failure, Renal Support, Vasoactive Support Evaluations 
 
Patient assessment of Organ failure, Renal support and Vasoactive support is also recorded daily 
in the Patient Status record. 
 
The Number of days free of Organ failure, Renal support and Vasoactive support is derived from 
this information using defined rules and algorithms specified in Section 5.9.4. Patients who die 
during this period will be assigned a value of zero. 
 
A patient will be defined as being free of organ failure when the SOFA score is zero. However, 
as organ failure is only assessed at Day 21 and Day 28 after Day 14 a scoring scheme will be 
used to derive the total number of days.  
 
This is:   
If Day 21 and Day 28 are both zero then 50% of the days between Day 14 and Day 21 and 100% 
of the days between Day 21 and Day 28 will be assumed to be zero.  
If Day 21 is non-zero and Day 28 is zero than 100% of the days between Day 14 and Day 21 will 
be assumed to be non-zero and 50% of the days between Day 21 and Day 28 will be assumed to 
be zero.  
Finally if Day 21 is zero and Day 28 is non-zero then 50% of the days between Day 14 and Day 
21 will be assumed to be zero and 100% of the days between Day 21 and Day 28 will be assumed 
to be non-zero (also see Section 5.9.4.2, Appendix 4).  
 
The need for Renal support or for Vasoactive support is defined in the protocol. 
 
 
 


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5.3.3.4. Length Of ICU 'Care Free' Stay/Hospital Stay  
 
Patient stay in the ICU and Hospital setting is also recorded daily in the Patient Status record. 
The Number of ICU care free days and the Number of days in hospital is derived from this 
information using defined rules and algorithms specified in Section 5.9.4, Appendix 4. Again 
patients who die during this period will be assigned a value of zero. 
 
 
5.3.3.5 Sequential Organ Failure Assessment (SOFA) 
 
Organ failure status is assessed using the SOFA score. This assesses six organ systems and the 
score ranges from 0-24 with a score of zero indicating no organ failure (see Protocol for the 
scoring mechanism).  
 
The scores are based on the worst daily values recorded for: Hypotension/Use of vasopressors 
(Cardiovascular score), PaO2/FiO2 (Respiratory score), Platelets (Coagulation score), Bilirubin 
(Hepatic score), Creatinine (Renal score) and Glasgow Coma Scale (GCS) (CNS score). 
 
The SOFA score is assessed pre-dose on Day 1, then daily up to Day 14 and then at Day 21 and 
Day 28 In or Out of the ICU or at withdrawal (Early Termination).  
 
The Last observation performed whether at Day 28 or earlier will be derived. 
 
The change from baseline (Day 1 Pre-dose) will be calculated. 
 
The values for each contributing variable in the scoring mechanism are recorded by the site staff 
in Patient Status record of the EDC system and the total scores are derived programmatically 
according to the algorithm specified in the protocol. 
 
5.3.3.6. Individual Organ Assessments  
 
A number of separate assessments are performed to assess the functioning of individual body 
organs including: Cardiovascular, Pulmonary and Renal. 
 
5.3.3.6.1 Cardiovascular Function 
 
The need for Vasoactive support is recorded daily in the Patient Status (Days 1 (Pre-dose) then 
daily on Days 2 - 28 (Day 28 In or Out of ICU) at the Medications update and specific details are 
recorded in the Concomitant infusion vasoactive medications record. 
 
The Last observation performed whether at Day 28 or earlier will be derived. 
 
The Number of days free of Vasoactive support is derived from this information using defined 
rules and algorithms specified in Section 5.9.4, Appendix 4. 
 
 
 


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5.3.3.6.2 Pulmonary Function  
 
Ventilation assessments are recorded daily (Days 1 (Pre-dose) then daily on Days 2 - 28 (Day 28 
In or Out of ICU).  
Gas exchange measurements are performed. Measures include: Fraction inspired oxygen (FiO2), 
Partial pressure arterial oxygen (PaO2), PaO2/FiO2 ratio, PEEP together with a Baro-trauma 
classification (Yes/No). The PaO2/FiO2 ratio change from baseline will used to assess pulmonary 
function.  
 
The Last observation performed whether at Day 28 or earlier will be derived. 
 
The change from baseline (Day 1 Pre-dose) will be calculated. However, Fraction inspired 
oxygen (FiO2), Partial pressure arterial oxygen (PaO2), PaO2/FiO2 ratio and PEEP may be 
measured at Day 1 dosing and, in this case, these values will be utilised for the change from 
baseline calculations.  
 
Additional measurements of Peak inspiratory pressure, Plateau pressure, Mean airway pressure, 
Respiratory rate and Tidal volume are collected at Screening and Day 1 (Pre-dose) only. 
 
At Day 1 Pre-dose and also at Day 28 (In or Out of ICU or earlier in the event of Early 
Termination) the severity status of ARDS will be classified as Mild (except Pre-dose/Day 1 
dosing), Moderate, Severe or Death (Table 3) and numerically rated from 1-4 respectively.  
 
Improvement is defined as a decrease in the severity score at the Last observation performed 
(Day 28 or earlier if withdrawn), No change is a zero change score and Worsening an increase in 
the severity score.  
 
Both the Severity status and Change score (from Investigator CRF Day 1 dosing) classifications 
will be categorically summarised, and post Day 1 classifications will be calculated as follows: 
  
Table 3: ARDS Severity Classification Post Day 1 
 
ARDS 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 
 
 
 
 


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5.3.3.6.3 Renal Function  
 
Fluids are monitored on a daily basis with the total input and output recorded (Day 1-28 / Last 
Day in ICU) and Fluid balance calculated (Input-Output). 
 
The Last observation performed whether at Day 28 or earlier will be derived. 
 
The change from baseline (Day 1 Pre-dose) will be calculated. 
 
5.3.3.7 Information from Externally Transferred Patients  
 
Observations recorded by site staff for patients who are externally transferred between Day 7 and 
Day 28 include: Total number of days spent in an ICU/Hospital, free of mechanical ventilation, 
free of organ failure, free of renal support or free of vasoactive support plus death date. 
 
As this is a subset of patients these will only be numerically summarised. However, these data 
may contribute to the 'Days free' or 'Days spent' variable derivations and survival indicator (see 
Section 5.9.4, Appendix 4). 
 
5.3.3.8 Other Observations In The ICU 
 
Other observations recorded during Days 1-28 include Concomitant medications taken and any 
notable Procedures, Interventions, Surgeries sand Diagnostics. These data will be categorically 
summarised and listed respectively. 
 
5.4 Efficacy Evaluations - Long Term/Extended Follow Up    
 
Long term follow up is performed first at Day 90 and then Day 180 after discharge from the ICU. 
This is followed by a further Extended follow up at Day 360. In the event of Early termination 
(on or before Day 28) no Long term follow up is performed.  
 
Efficacy is assessed through Patient status assessments performed at Day 90, Day 180 and Day 
360 with Respiratory and Neurological functioning and Quality of life (EQ-5D-3L) assessed at 
Day 180 and Day 360. 
 
5.4.1 Patient Status Assessments 
 
The Patient Status assessment records: Alive/Dead, Location of death (ICU/Hospital), Date of 
death, Location if alive (ICU/Hospital), Requirement for assisted ventilation at Day 90, 180 and 
360 in a similar manner to those performed during Short Term Follow Up in the ICU. 
 
These data will be categorically summarised. 
 
 
 
 
 


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5.4.2 Quality Of Life Evaluations 
 
General assessment of health is performed through a quality of life questionnaire (QOL). The 
EuroQol 5-Dimensions 3-Levels questionnaire (EQ-5D-3L) is administered at Day 1 Pre-dose, 
Day 180 and Day 360. 
 
An EQ VAS score (ranging from 0-100) is measured (0= Worst imaginable health state, 100= 
Best imaginable health state) together with sub scores for Mobility, Self-care, Usual Activities, 
Pain/Discomfort and Anxiety/Depression. Each sub score ranges from 1 to 3 with 1 representing 
the best case and 3 the worst case. 
 
The change from baseline (Day 1 Pre-dose) will be derived. 
 
5.4.3. Respiratory and Neurological Assessments 
 
5.4.3.1 Respiratory Function  
 
Respiration through the FEV-1 test is only assessed at Day 180 and Day 360 (and only if able to 
attend the hospital). This is a general test of pulmonary function. The FEV-1 is the volume 
exhaled as % of Forced Vital Capacity in 1 second. 
 
Baseline measurement is not appropriate. These data will be numerically summarised. 
 
5.4.3.2 Neurological Function  
 
The Six-minute Walk Test (6MWT) is performed at Day 180 and Day 360. It evaluates global 
and integrated responses of all systems involved during exercise, including the pulmonary and 
cardiovascular systems, systemic circulation, peripheral circulation, blood and neuromuscular 
units and muscle metabolism.  
 
The distance travelled over the 6 minute period on a flat, hard surface is recorded together with 
other potentially contributing factors. (Specific details of the procedure are given in the protocol 
Appendix II). 
 
The test itself is performed according to the Respiratory Society/American Thoracic Society 
guidelines (Ref 11). The guidelines recommend that each test should be performed twice and the 
best result should be used. According to these guidelines this is usually the second result as it 
includes a 'learning effect'.  
 
Details are recorded Pre-test, during the test and also post test for both Test One and Test Two. 
 
Pre-test evaluations assess the Overall patient suitability to undergo the test (Absolute/Relative 
contraindications, ECG findings, Medication prescribed, Co morbidities present), Vital signs 
(Walking limitations, Systolic/Diastolic blood pressure, Heart rate, Oxygen required with flow 
rate and Peripheral capillary oxygen saturation(Sp02) and any other debilitating Symptoms 
(Dyspnoea and Fatigue as measured by the modified Borg scale (0-10)). 
 


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During the test the number of stops made by the patient and those requested by the Assessor are 
recorded. 
 
After each test the Vital signs and any debilitating Symptoms are again recorded together with 
the Total distance walked (m) and the conditions under which the test was undertaken.  
 
The Total distance walked (m) during Test One and Test Two on Day 180 and Day 360 will be 
numerically summarised together with the furthest distance walked during Tests One or Test 
Two. During this study, many patients have only performed the test once. Therefore, when only 
the first result is available this will also be used as the best result. 
 
 
Baseline measurement is not appropriate. All other data will be numerically/categorically 
summarised as appropriate. 
 
5.4.4 Study Completion / Unblinding 
 
After completion of the Short Term Follow Up period and as part of the Long Term/Extended 
Follow Up assessment period the completion of a Study Completion form is mandated at the end 
of study Day 180 or Day 360. Either the date of Withdrawal (if before Day 180 or Between Day 
180 and Day 360) is recorded or the date of the End of Long Term Follow Up or Extended 
Follow Up is given. 
 
All details of the reason for termination (including the primary reason) are given: Screen Failure, 
Protocol Violation, Non-Compliance, Lost to Follow-up, Retrospective Consent Not Given, 
Other Withdrawal of Consent, Investigator Decision, Death, Adverse Event (Non-Serious), 
Serious Adverse Event (Non-Fatal) or Other. 
 
Any Unblinding performed (Yes/No) with Date of unblinding and Reasons are also recorded. 
 
5.4.5 Exploratory Efficacy - Ventilation Free Survival At Day 90 
 
A protocol defined (Section 3.2.4) exploratory assessment of efficacy Ventilation Free Survival 
at Day 90 will be summarised. As daily assessments are not performed between completion of 
the Short Term Follow Up (Day 28) and Day 90, VFDsurv at Day 90 will be categorically 
classified as Dead, Alive-On Ventilator, Alive-Breathing Unassisted and summarised. 
 
5.4.6 Secondary Efficacy - Mortality At Day 90  
 
Mortality (All causes) up to Day 90 will be derived from the recorded Date of Death (recorded as 
part of the Patient Status).  
 
Investigators  are also required to confirm mortality using the ‘Death report’ section of the eCRF. 
In the event of missing information, then patients are assumed alive and still 'at risk' at the time of 
assessment. 
 
The cause of death detailed in the Death Report will be categorically summarised. 


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The date of death will also be used to produce Kaplan-Meier estimates and these will be 
displayed in plots to assess survival curves and median survival times. The number of patients ‘at 
risk’ at each assessment time will be superimposed. Information from the date of randomisation 
and for the entire follow up period will be taken into account. Patients who withdraw, are lost to 
follow-up, or are alive without the event occurring since the last follow-up will be considered 
right censored. 
 
Mortality up to Day 180 and Day 360 will be evaluated as part of the Long Term and Extended 
Long Term Follow up assessments, respectively, and included as addendum reports (see Section 
6.1.6 and 6.1.7). 
 
5.5 Pharmacoeconomic Evaluations 
 
The total cost of treatment and care whilst patients are confined in the ICU (up to Day 28) will be 
derived from key individual patient efficacy measures and assigned unit costs for each measure. 
    
UK Unit costs are considered representative and are given in Table 4. 
  
Specific efficacy measures used are: Days free of organ failure, Days free of renal support, Days 
free of vasoactive support, Days free of mechanical ventilation, Number of ICU-free days, 
Number of days spent in hospital. 
 
Individual patient need for these services will be determined in terms of days of use (subtracted 
from 28 for 'days free' or actual for 'days spent') and these will be multiplied by the daily costs to 
derive a total cost burden for each service and overall services.  
 
Table 4: Treatment And Care Costs Per Patient in the UK 
 
Support Service 
Unit 
Cost (£) 
 
 
 
Organ Failure Support (SOFA) 
Per Day 
TBC 
Renal Support 
Per Day 
TBC 
Mechanical Ventilation 
Per Day 
TBC 
Vasoactive Support 
Per Day 
TBC 
 
 
 
Stay In ICU 
Per Day 
TBC 
Stay In Hospital 
Per Day 
TBC 
TBC: To Be Confirmed 
 
The unit costs per patient will be provided to DML by the Sponsor prior to analysis, and will be 
based on the most current (2018) financial data available in the UK. Data for other countries may 
be displayed at a later date. 
 
These data will be numerically summarised overall patients by Treatment group (FP-1201-
lyo/Placebo) and Severity of ARDS (Moderate/Severe). However, to expedite the finalisation of 


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the Day 90 CSR, these summaries will be presented with the Day 180 and/or Day 360 long-term 
follow up reports and not at Day 90. 
 
5.6 Pharmacodynamic Including Immunological Evaluations 
 
Blood samples are taken on a number of occasions during confinement in the ICU during the 
Short Term Follow Up (Day 1-Day 28) to assess a range of Pharmacodynamic effects. 
 
 
5.6.1 Anti Drug Antibodies (ADA) and Neutralising Antibodies to Interferon Beta-1a (NAb) 
 
The immunological response to FP-1201-lyo is assessed through monitoring of neutralising 
antibodies to IFN beta-1a on Day 1 Pre-dose and at Day 28, the Last day in ICU or Early 
termination (if earlier). NAb can interfere with the biological and clinical response to treatment. 
Anti-Drug Antibodies (ADAs) are determined first and if present, the NAbs are also determined. 
In case a fit for purpose ADA assay for FP-1201-lyo cannot be established, only the NAb assay 
will be done. 
 
The Last observation performed whether Day 28, Last Day in ICU or Early termination will be 
derived. 
   
The Positive/Negative classifications will be categorically summarised. 
 
5.6.2 Myxovirus Resistance Protein A (MxA) 
 
MxA are interferon-induced GTPases and mediate an antiviral response to a broad range of 
viruses. MxA activity is one of the best markers for IFN beta bioactivity and is often used to 
monitor the IFN beta treatment in Multiple Sclerosis patients. MxA levels are thus induced by the 
IFN beta treatment and possibly by the underlying disease. This response is measured on Day 1 
Pre-dose and daily thereafter until Day 14 in the ICU. 
 
The Last observation performed whether Day 14 or earlier will be derived. 
 
The change from baseline (Day 1 Pre-dose) will be calculated. 
 
5.6.3 Biomarkers - CD73  
 
CD73 is an ecto-5’-nucletidase controlling the dephosphorylation of adenosinemonophosphate 
(AMP) to adenosine. The key rationale of FP-1201-lyo (IFN beta-1a) treatment is that FP-1201-
lyo is a potent inducer of CD73 expression. Thus, the FP-1201-lyo treatment induces the CD73 
expression on cell surfaces resulting in increased adenosine levels and the subsequent restoration 
of the endothelial barrier function. CD73 levels are assessed at Day 1 Pre-dose and daily 
thereafter until Day 14 in the ICU. 
 
The Last observation performed whether Day 14 or earlier will be derived. 
 
The change from baseline (Day 1 Pre-dose) will be calculated. 


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5.6.4 Biomarkers For Inflammation (PIM) 
 
Cytokines, chemokines and growth factors are secreted by several different cell types to stimulate 
or dampen the immune response during the different stages of infection or trauma. These 
biomarkers of inflammation are measured on Day 1 Pre-dose and daily thereafter until Day 14 in 
the ICU and could provide information on the disease severity and progression and also on 
treatment response. Specifically, PIM samples will be analysed from serum using the Bio-Rad 
multiplex kit Bio-Plex Pro™ Human Cytokine 27-plex Assay for the assessment of the following 
27 potential biomarkers: FGF basic, Eotaxin, G-CSF, GM-CSF, IFN-γ, IL-1β, IL-1ra, IL-2, IL-( 4 
-10), IL-12(p70), IL-13, IL-15, IL-17, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, PDGF-BB, 
RANTES, TNF-α, VEGF. 
 
 
The Last observation performed whether Day 14 or earlier will be derived. 
 
The change from baseline (Day 1 Pre-dose) will be calculated. 
 
Summary of PIM results will be included in the D90 CSR, but the  full analyses, which will be of 
an exploratory nature, will be reported separately at Day 180 and/or Day 360. 
 
5.7 Pharmacogenetic Evaluations 
 
A blood sample for pharmacogenetic analysis is obtained during the study.  
Each DNA sample extracted from the patient blood samples will be subjected to targeted 
resequencing of six genes (NT5E, IFNAR1, IFNAR2, MCM2, ANGPT2, RASSF3). For this, a 
custom amplicon panel, AmpliSeq, was designed and produced by Illumina. The amplicon panel 
covers the whole gene region (exons, introns and UTRs) and 3 kb up- and down-stream. The raw 
data obtained will be subjected to quality control and preprocessing steps before subsequent 
mapping to a human reference sequence. Mapped reads will undergo variant calling (SNPs and 
indels) to identify and annotate the variants found in the samples. Based on the metadata 
produced, the samples may then be divided into groups to study which variants (if any) are 
enriched in a particular group of samples. Further, the annotation utilizing publicly available data 
sources provides predictions on the possible impact a variant has on the protein structure, levels 
and functions.  
 
The final exploratory genetic analyses are still to be decided and a separate SAP describing these 
analyses will be produced and the results will be reported at Day 360, for the patients who have 
given genetic informed consent.  
 
 
5.8 Safety Evaluation Endpoints 
 
Subject safety is monitored throughout the period of confinement in the ICU (Short Term Follow 
Up: Day 1-28). Specific evaluations include: Vital signs, 12-lead ECG, Physical examination, 
Adverse events and Laboratory safety tests (Biochemistry, Haematology, Urinalysis). Specific 
timings of assessments are specified but unscheduled recordings may be performed as necessary. 


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As part of the Long/Extended Term Follow Up period thereafter safety is assessed as part of the 
ongoing standard of patient care (Day 90, 180 and 360). In addition to a Patient Status assessment 
any notable Adverse events are recorded. 
 
Detailed descriptions and definitions of all safety variables are described in the protocol. 
 
 
5.8.1 Vital Signs 
 
Vital signs are recorded at Day 1 (Pre-dose), then at selected visits (Day 2 - 28 (In/Out of ICU), 
Last day in ICU) and in the event of withdrawal, at Early Termination. The Last observation 
performed will be derived and identified. 
 
On each occasion measurements involve recordings of: Blood pressure (systolic/diastolic), Mean 
arterial pressure, Heart rate and Body temperature and Total respiratory rate. Procedural details 
are given in the protocol.   
 
The change from baseline (Day 1 Pre-dose) will be calculated. 
 
5.8.2 Twelve Lead ECGs  
 
Twelve Lead digital ECG recordings are performed at Day 1 (Pre-dose) then on Day 7. 
 
On each occasion measurements involve recordings of: Ventricular rate, PR, PQ Interval, QRS 
Duration, QTc and Categorised Normal/Abnormal result. Procedural details are given in the 
protocol.  
 
The change from baseline (Day 1 Pre-dose) will be calculated. 
 
ECGs are also performed on Days 180 and 360 prior to the Six-minute walk tests to ensure 
patient safety during that evaluation. The ECG data from these visits will be listed only. 
 
5.8.3 Physical Examination 
 
Physical examinations are recorded at Day 1 (Pre-dose), then at the Last day in ICU and Day 28 
(Out of ICU) and in the event of withdrawal, at Early Termination. The Last observation 
performed will be derived and identified. 
 
This includes the major body systems: General appearance, Ear, nose and throat, Eyes, 
Respiratory, abdomen, Urogenital, Musculoskeletal, Neurological, Lymph nodes and Skin. 
 
At screening Height is also measured to enable calculation of the Predicted body weight (PBW: 
For men: 50 + 0.91(height in cm – 152.4, For women: 45.5 + 0.91(height in cm – 152.4). 
 
 
 


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5.8.4 Adverse Events (AEs) 
 
Adverse events are defined as any untoward medical occurrence subsequent to administration of 
an investigational product that does not necessarily have a causal relationship with the treatment. 
(For a full definition refer to the protocol).  
 
AE collection starts from signing the Informed Consent and continues until the end of the D28. 
AEs possibly related to the study drug (by investigator) and/or leading to death are collected until 
the end of Extended Follow Up period (Day 360). AEs will be categorised according to those that 
occur during the period of confinement in the ICU (up to Day 28) and those that occur thereafter 
during the Long Term/Extended Follow Up period. 
 
Adverse events starting on or after the first treatment dose are defined as Treatment Emergent 
Adverse Events (TEAEs). Any event starting before the first dose of study drug on Day 1 will be 
identified as a Pre-Treatment Sign or Symptom (PTSS). Any event starting before the first dose 
of study drug on Day 1 but subsequently worsening will also be defined as a TEAE. 
 
All events will be coded using the MedDRA dictionary. The actual description of the AE will be 
matched, as closely as possible, with the Lower Level Term (LLT) in the dictionary.  
 
Related AEs are any AE reported as possibly related or related to the study drug according to the 
investigator. Any events with missing relationship to study drug will be tabulated as related. AE 
intensity is reported as mild, moderate or severe. Any events with missing intensity will be 
tabulated as severe. If a subject has an AE which changes in severity this will be recorded as a 
separate event. Serious adverse events (SAEs) are classified as described in the protocol. If a 
subject has more than one AE and at least one is considered drug-related, the subject will be 
included as having a drug-related AE. Similarly, if a subject has more than one AE and at least 
one is considered severe, then the subject will be included as having a severe AE.  
 
All SAEs are reported and then processed separately according to standard pharmacovigilance 
practice.   
 
Patient survival is assessed as part of the regular Patient Status assessment. The location at the 
time of death (ICU or hospital) is recorded. All deaths are recorded as AEs and SAEs up to and 
including Day 360.  
 
As part of the Death report (Day 180 or Day 360) the cause of death is categorised as: Acute 
Coronary Syndromes, Arrhythmia, Brainstem Death, Bleeding, Cardiac Failure, Cerebral Event, 
Multiple Organ Failure, Pulmonary Embolus, Respiratory Failure, Sepsis, Withdrawal of 
Treatment (e.g. removal of mechanical ventilation) or Other. 
 
5.8.5 Laboratory Safety 
 
Laboratory safety assessments (haematology and chemistry and urinalysis) are performed at Day 
1 (Pre-dose), then at daily during intensive care (Day 2 - 28 (In/Out Of ICU), Last day in ICU) 
and in the event of withdrawal, at Early Termination. The Last observation performed will be 


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identified and derived. Additional laboratory assessments may be performed if required 
(Unscheduled). 
 
All laboratory results are obtained from the hospital local laboratory. In view of the variability 
between the participating laboratories with respect to assays performed, units used and normal 
ranges applied the actual numerical values will only be used to determine within patient changes 
at the time of assessment.    
 
However, the laboratory values will also be classified by the Investigator as Out of range (Not 
clinically significant), Out of range (Clinically significant) or Out of range (Clinically significant 
and an Adverse event).  
 
The specific Haematology laboratory variables measured are: Haemoglobin, Haematocrit, 
Erythrocytes, MCV, Platelets, Leucocytes and Differential counts of: Neutrophils, Eosinophils, 
Basophils, Lymphocytes, Monocytes. 
 
The specific Biochemistry laboratory variables measured are: Albumin, Creatine kinase, 
Creatinine, Glucose, Triglycerides, Urea, Bilirubin, Total protein, Alkaline phosphatase, AST, 
ALT, Lactate, Sodium, Potassium, Bicarbonate, Calcium (total calcium corrected for albumin 
level) and Chloride.  
 
Variables for Urinalysis are: pH, Protein, Glucose, Ketones, Bilirubin and Blood.  
 
5.9 Data Definitions And Conventions 
 
Details of how all the available data are managed under particular situations are specified. This is 
to ensure consistency within the analysis and reporting. Aspects of data definition and 
conventions, data derivations and strategies in particular circumstances are detailed.  
 
 
5.9.1 Definition Of Baseline 
 
The baseline assessment is considered to be the Day 1 Pre-dose unless the assessment is only 
performed at Screening.   
 
In the event of the site needing to repeat the Screening Safety laboratory tests the last available 
'valid' pre-dose assessment will be entered in the EDC system and used in all cases as the 
baseline value. 
 
5.9.2 Conventions For Assessment Visits 
 
During confinement in the ICU for up to the required 28 days all visit assessments are performed 
on a daily basis and therefore as scheduled. Therefore, there is no requirement to allow for 'Visit 
Windows'. 
 


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However as subsequent follow up at Day 90, 180 and 360 could occur after discharge from 
hospital there is the potential to miss the target date. The acceptable margin of +14 days is 
permitted for D90 and D180 assessments, and r 14 for D360 assessments. 
 
Given the margin permitted these data will be presented according to the visit section they were 
completed in the CRF. Therefore, there is no requirement for programmatically re-slotting results 
due to the visit 'windows'.   
 
In the event of any Unscheduled assessments, for example in the case of additional Safety 
laboratory assessments or Vital signs associated with non-protocol clinical visits or obtained in 
the course of investigating or managing AEs) these will only be included in the report listings. 
They will not be included in the construction of the report summaries or analyses.  
 
As only the most relevant laboratory assessment is reported on a daily basis in the EDC system 
there is no requirement for evaluation of the applicability of any Unscheduled assessments in 
relation to identifying and using the first valid observation for a given assessment time. 
Unscheduled assessments will however be presented in listings. Invalid laboratory values from 
haemolysed, mishandled, insufficient quantities, or other conditions for samples therefore will 
not be entered into the EDC or used.  
 
5.9.3 Conventions For Managing Unblinded Data 
 
In the event of unbinding, all patient data (with the exception of safety data) will be reviewed as 
part of the Blind Data Review to assess the potential impact and biasing of the statistical analysis 
before inclusion. All such data will be included in listings and flagged appropriately.  
 
5.9.4 Data Derivations 
 
Data Derivations, Section 5.9.4 is presented in Appendix 4. 
 
5.9.5 Strategy For Assessing Sources Of Variability 
 
Both the Country and Severity of ARDS are considered major sources of variability and 
potentially influencing factors on the magnitude of the treatment effect. Both are included as 
strata in the randomisation process. All analyses will include these as factors in statistical models 
or classification strata for hypothesis tests in order to ensure the precision of estimates obtained. 
 
Recruitment of patients to individual sites within each of the countries is likely to be highly 
variable. However, although the process of pooling of patients within country should produce a 
more uniform distribution this will be monitored. In the event of low recruitment in some 
countries then country pooling strategies may need to be investigated in order to minimise 
variability. Decisions regarding pooling will take place at the Blind Review.  
 
The impact of patient variability on the Severity of ARDS (Moderate, Severe) will also be 
explored. 
 


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As the adjustment for covariates increases the precision of estimates in proportion to correlation 
with outcome measure, demographic and other baseline patient data will also be assessed as 
additional sources of potential variability. Identified variables will be included in the statistical 
models to evaluate the sensitivity and robustness of the magnitude of the treatment effects 
determined in the main analyses.   
 
Sources of variability will be assessed at the Blind Data Review prior to database lock at Day 90 
and subsequent unblinding. These will include but not limited to the following baseline variables: 
age, race, sex, Apache score, SOFA score, disease diagnosis, aetiology (including 
presence/absence of shock), country, PaO2/FiO2 ratio, plateau pressure, tidal volume, PEEP, 
mode of ventilation, respiratory rate, vasoactive drug use, renal support,  patient position, co-
morbidities from MH coding, season (quarter), study stage, arterial pressure, arterial pH, weight 
(BMI), renal/liver biochemistry (creatinine, CK, AST, ALT). If other variables are assessed 
during the blinded review, these will be described in the Day 90 statistical analysis report. 
 
 
5.9.6 Strategy For Missing Data  
 
No biases resulting from missing data are anticipated and, as a consequence No imputation of any 
missing values at any of the assessments performed is planned.  
 
However, to allow for patient attrition or any changes to the scheduled patient assessments as a 
consequence of the treatment response a 'Last observation performed' assessment will be derived 
for specific Short term efficacy (Ventilation assessment, System Organ Failure (SOFA), 
Cardiovascular, Pulmonary and Renal function), Pharmacodynamic (IFNß ADA & Nab, MxA, 
CD73, PIM) and Safety variables (Vital signs and Laboratory assessments). This approach will 
use the last available non-missing post baseline value. 
 
 
6. Statistical Methods  
 
6.1 General Considerations 
 
All data derivations, manipulations and reporting procedures will use SAS v9.4 in a Windows 7 
operating system environment.  
 
For all evaluations, data will be described and analysed according to Treatment group (FP-1201-
lyo/Placebo), Severity of ARDS (Moderate/Severe) and Country (1-8) and where appropriate 
Assessment period (Screening, Day 1 Pre-Dose, Short Term Follow Up (Day 1-28 ICU based), 
Long Term Follow Up (Day 90, Day 180) and Extended Follow Up (Day 360)) will be included. 
In addition, other endpoints summarising overall response are derived and analysed (e.g.: 
VFDsurv - the survival plus days free from mechanical ventilation composite). 
 
All the data collected are to be summarised, and the descriptive statistics produced will account 
for the nature and distribution of the data collected. For continuous variables, data will be 
presented as number (n), mean, median, standard deviation, and range. For discrete variables data 


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will be presented as frequencies and proportions (as appropriate) and the denominator will be the 
number of patients available in the relevant population.  
 
6.1.1 Null Hypothesis 
 
The Null Hypothesis throughout the investigations is that there is no difference between 
treatment (FP-1201-lyo) and placebo (Control).  
 
That is: H0: μ1 = μ2, where H0 = the null hypothesis, μ1 = the mean/proportion of treatment group 
1, and μ2 = the mean/proportion of treatment group 2. 
 
Each hypothesis test or statistical model therefore constructed compares the obtained results with 
the distribution under the null hypothesis and assesses the likelihood that chance or random 
processes alone were responsible.  
 
Two tailed directionality (H0: μ1 ^= μ2: Treatment superior or Placebo superior) is to be assessed.  
 
The primary efficacy endpoint is considered to be a composite, Ventilation Free Survival 
(VFDsurv). This comprises of Mortality and Number of ventilation free days.  
 
6.1.2 Sample Size And Power Estimation 
 
Sample size and power estimations were performed at the outset to determine the required size of 
this investigation. These were detailed in the protocol (see Section 8.10). 
 
It was decided that a total of 272 evaluable patients would be required to demonstrate a clinically 
relevant difference between the active treatment and placebo control with a two-tailed 
significance level of 0.05 and 90% power using a non- parametric test comparison (Mann–
Whitney U-test). PASS software (Version 11; NCSS LLC, Kaysville, UT, USA) was used for all 
calculations. 
 
The clinically relevant difference at the end of the Short Term Follow Up (Day 28) was 
comprised of:   
 
- 
A mortality rate of 30% in the placebo control group and 15% in the FP-1201-lyo  
group. 
- 
20% of patients who survive in the placebo control group have zero ventilator-free days. 
- 
A mean difference of 3.0 days in ventilator-free days (FP-1201-lyo - Placebo control) 
(VFD=0 with deaths assigned Score=0). 
 
Calculations assumed multinomial distributions and an overall attrition rate of 9% (5% drop-out, 
4% non evaluable). This resulted in a recruitment requirement of 300 patients.  
 
However, the attrition rate will be monitored during the course of the investigation. If it proves to 
be in excess of 9% then recruitment process will continue until 272 evaluable patients are 
available.   
 
 
 


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6.1.3 Multiplicity Of Testing 
 
In view of the number of statistical tests employed to assess the secondary efficacy endpoints 
measured, a hierarchical approach will be employed which ranks the endpoints in order of 
importance to control for the multiplicity of testing. 
 
The pre-specified hierarchy for the secondary endpoints is: 
 
 
1. Mortality (All-cause) at Day 28 
 
2. Mortality in ICU at Day 28 
 
3. Mortality in hospital at Day 28 
4. Overall Mortality at Day 360 
 
 
The process will involve declaring statistical significance down to the first non-significant 
endpoint (based on a two-sided significance level of 0.05). However, all p-values will be 
presented and those that are ≤0.05 but below a non-significant endpoint in the hierarchy will be 
considered as nominally significant but not formally significant. 
 
Mortality during the follow up period (Day 90, 180 and 360) is considered secondary and 
included as part of the Kaplan-Meier survival analysis. 
 
All other statistical hypothesis testing applied and p-values generated during the exploratory or 
safety evaluations will only be used as indicators of potential interest or concern requiring 
clinical expert commentary. 
 
A two-sided significance level of 5% (0.05) will be used throughout, although in line with 
standard practice this may be relaxed to 10% when investigating potential model interactions. 
 
6.1.4 Interim Analyses 
 
A single analysis at the conclusion of the investigation is intended. No interim analyses will be 
performed. However, in order to monitor patient safety a Sponsor-Independent Data Monitoring 
Committee (IDMC) was formed and regularly convened according to the requirements of the 
IDMC Charter to assess the accumulating data.  
 
The safety data provided to the IDMC will be unblinded by a study Independent Statistician to 
enable identification of treatment group and simplify the medical review process.     
 
IDMC data summaries and listings required for review purposes are given in the IDMC Charter. 
 
The primary analysis is considered to be once all patients have completed Day 90 (or earlier in 
the event of withdrawal). Once these data become available the evaluation of the efficacy 
endpoints that relate to the Short Term Follow Up at 28 days and the Long Term Follow Up at 
Day 90, together with all available safety will reported. Efficacy endpoints associated with later 
time points (Day 180 and Day 360) will be analysed subsequently and any accumulating safety 
data re-presented where appropriate.  
 


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6.1.5 Blind Data Review 
 
Prior to the Day 90 database lock and unblinding a blinded review of the entire data up to Day 90 
(and any available post Day 90 data) will be performed. 
 
This will serve several purposes. It will enable identification of questionable values, potential 
outlier patients and potential missing data which may require ratification. It will enable 
identification of potential sources of variability (see Section 5.9.5) and it will enable assessment 
of the structure of the table shells. Patient populations will then be assigned by the Sponsor 
according to the definitions in Section 4 of this SAP. 
 
For evaluation of the suitability of the table shells a 'dummy' randomisation will be used which 
has a known structure to prevent mistaking for the actual randomisation code. 
 
 
6.1.6 Long Term and Extended Follow Up Periods (Day 180, Day 360) Addendum Reports 
 
All data collected up to and including the first 3 months follow up (Short Term Follow Up (Day 
1-28 in ICU), Long Term Follow Up (Day 90) together with the primary analyses will be 
included in the main clinical study report (CSR).  
 
However, all patients will be followed up for another 3 months (Long term Follow Up (Day 180, 
i.e. Day 90 – Day 180)) and then a further 6 months (Extended Follow Up (Day 360, i.e. Day 180 
– Day 360).  Assessments performed at Day 180 and Day 360 will include:  Patient Status 
(including Mortality at Day 360), Quality of life, Respiratory functioning (FEV-1), Neurological 
functioning (6MWT), Patient Completion, Unblinding, Additional AEs and Death reporting. All 
are considered efficacy variables, except any additional AE reports, and as such will involve 
patients from the FAS population.  Medications, deviations and comments data will also be 
followed up after the Day 90 visit at both Day 180 and Day 360. 
 
Separate or addendums to existing tables and listings will be generated. However, all available 
data up to and including Day 360 will be presented with the main report at Day 90 and Day 180 
addendum report. 
 
Details of the outputs required (including summary tables, analyses and listings) are given in 
Section 7.4. 
 
6.1.7 Pharmacogenetic Evaluations 
 
The potential influence of patient genotype on the treatment outcome will be performed and 
reported separately to the main analysis through a specific pharmacogenetic evaluation. 
The final genetic analyses are to be decided and those results will be reported separately at Day 
360. 
 
 
 
 


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6.2 Statistical Analyses 
 
6.2.1 Overall Study Patient Group 
 
Basic information regarding the sample of patients obtained to represent the ARDS population 
will be summarised. This includes: Disposition, Major Protocol Violations and Deviations, 
Patient Status and Baseline Characteristic Assessments Prior to Treatment Start, and 
Randomisation.  Details are given in Section 7.2.1 
 
6.2.2 Baseline Treatment Group Comparability 
 
No formal statistical comparisons of the treatment groups at baseline will be performed as this 
serves only to assess the randomisation procedure. A descriptive clinical evaluation of the 
representativeness of this population sample will be described in the Clinical Study Report 
(CSR). 
 
 
6.2.3 Efficacy Assessments - Short Term Follow Up 
 
Assessments performed during Days 1 to 28 during confinement in the ICU are considered of 
critical importance. 
 
6.2.3.1 Patient Status Assessments  
 
All Patient Status assessments performed on Days 1 (Pre-dose) then daily on Days 2 - 28 (Day 28 
In or Out of ICU), at Early Termination or Last Day in ICU will be summarised (See Section 
7.2.3.1). 
 
6.2.3.2 Primary Efficacy Analysis - Ventilation Free Survival (VFDsurv) 
 
Ventilation Free Survival (VFDsurv) is a composite measure of Mortality and the Number of 
days free of Mechanical ventilation (VFD) within 28 days among survivors. The Ventilation Free 
Days (VFD) count requires two consecutive calendar days of unassisted breathing (UAB) and the 
precise definition is given in Section 5.9.4.1. 
 
The combination of time to event measure (mortality) with a longitudinal measure (VFD) follows 
methodology for scoring and analysis proposed by Finkelstein and Schoenfeld (Ref 3).  
 
According to the scoring scheme definition and derivation rules described, higher scores indicate 
better response with the possible integer scores range from -1 to 28.  
 
VFDsurv scores derived will be numerically summarised (excluding means and standard 
deviations) according to Treatment group (FP-1201-lyo/Placebo), Severity of ARDS 
(Moderate/Severe) and Overall according to the FAS population. Separate supporting summaries 
by Country will also be included. 
 


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A non-parametric analysis will be performed as the data distribution is non normal and negatively 
skewed. This will involve a generalised Wilcoxon rank sum based stratification test which 
assigns ranks within strata and compares two treatments within strata (Van Elteren hypothesis 
test) (Ref 4). The Treatment groups are (FP-1201-lyo/Placebo) with stratification variables 
Severity of ARDS (Moderate/Severe) and Country (1-8). Statistical significance (p-values) 
obtained will be displayed with the numerical summaries.  
 
The analysis will primarily use the FAS population but this will be repeated using the PPS group 
as supporting information. 
 
Summary statistics only will be presented for severity of ARDS subgroups and by country, but 
will not include non-parametric analysis p-values.  
 
Other baseline characteristic variables potentially contributing to sources of variability may be 
included in further sensitivity analyses and these will be investigated during the blinded review as 
described in Section 5.9.5. 
 
 
6.2.4 Secondary Efficacy Analysis 
 
Other efficacy variables analysed include: Mortality rates, Days free of Mechanical ventilation 
(actual days not VFD calculated days), Days free of Organ Failure, Renal Support And 
Vasoactive Support, Length Of ICU 'Care Free' Stay/Hospital Stay, Sequential Organ Failure 
Assessment (SOFA) and Other Individual Organ Assessments 
 
6.2.4.1 Mortality Analysis 
 
The Mortality rate is principally assessed during the Short Term Follow Up in the hospital at Day 
28. However, the mortality rates occurring within the ICU and in the hospital will be calculated 
separately using the location of the death. The Overall mortality rate irrespective of location will 
be analysed. 
 
The observed Mortality rates (with 95% Confidence Intervals (Clopper Pearson)) for each 
Treatment group (FP-1201-lyo and Placebo) and the Treatment difference (FP-1201-lyo - 
Placebo) will be displayed using categorical summarises (Alive/Dead) according to Severity of 
ARDS (Moderate/Severe) and Overall according to the FAS population. Separate supporting 
summaries by Country will be included. 
 
The binary mortality endpoint outcome (Alive/Dead) will be modelled using logistic regression 
applied (Ref 6) to the FAS population. The model will include Treatment group (FP-1201-
lyo/Placebo), Severity of ARDS (Moderate/Severe) and Country (1-8) as factors.  
 
Homogeneity of treatment effect will be assessed by calculating ORs and associated confidence 
intervals by ARDS severity and by country and displaying these in a Forest Plot (log scale). 
 
The analysis will primarily use the FAS population but this will be repeated using the PPS group 
as supporting information. 


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Other baseline characteristic variables potentially contributing to sources of variability may be 
included in further sensitivity analyses.  
 
6.2.4.2 Days Free Of Mechanical Ventilation Analysis 
 
The actual Total number of days free of mechanical ventilation (not the derived VFD scores 
which require additional conditions of UAB to be met) will be numerically summarised 
(excluding means and standard deviations) according to Treatment group (FP-1201-lyo/Placebo), 
Severity of ARDS (Moderate/Severe) and Overall. Separate supporting summaries by Country 
will be included. 
 
These endpoints will be analysed using the same methods as for the primary efficacy variable, 
VFDsurv, using the Van Elteren hypothesis test as the distribution is likely to be non-normal and 
negatively skewed by patients who are assigned scores of zero (0) in the event of death.  
 
6.2.4.3 Days Free Of Organ Failure, Renal Support And Vasoactive Support Analysis 
 
Totals derived will be numerically summarised and analysed as described in Section 6.2.4.2 
above. 
 
6.2.4.4 Length Of ICU 'Care Free' Stay/Hospital Stay Analysis 
 
Totals derived will be numerically summarised and analysed as described in Section 6.2.4.2 
above. 
 
6.2.4.5 Sequential Organ Failure Assessment (SOFA) Analysis 
 
Total scores and Change from baseline scores (Day 1 Pre-dose) assessed daily up to Day 14 and 
then at Day 21 and Day 28 (In or Out of the ICU) or Early Termination, together with the derived 
Last observation performed will be numerically summarised according to Treatment group (FP-
1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall using the FAS population. 
Separate supporting summaries by Country will be included. 
 
The contributing Cardiovascular, Respiratory, Coagulation, Hepatic, Renal and CNS organ sub 
scores will be similarly presented. 
 
The Total SOFA score at the Last observation performed will be analysed using an Analysis Of 
Covariance (ANCOVA) model (Ref 8) this will use change from baseline as the response 
variable and will include Treatment group (FP-1201-lyo/Placebo), Severity of ARDS 
(Moderate/Severe) and Country (1-8) as fixed effect factors. The Baseline value will also be used 
as a covariate term in the model. 
 
Model assumptions of normality and constant variance will be investigated and if necessary an 
alternative model or data transformation will be substituted. 
 


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Model estimates (LS means and a 95% confidence interval for the treatment difference) will be 
presented. Homogeneity of treatment effect will be assessed by obtaining the difference in LS 
means together with 95% confidence intervals for the categories of ARDS severity using the 
ANCOVA model with the addition of a treatment by ARDS severity interaction term and 
displaying these in a Forest Plot. 
 
Sub scores will not be analysed. 
 
6.2.4.6 Individual Organ Assessments Analysis 
 
6.2.4.6.1 Cardiovascular Function 
 
Vasoactive support assessments recorded daily (Days 1 (Pre-dose) then daily on Days 2 - 28 (Day 
28 In or Out of ICU) will be will be categorically summarised (Yes/No) with the derived Last 
observation performed, by Treatment group (FP-1201-lyo/Placebo), Severity of ARDS 
(Moderate/Severe) and Overall for each assessment time using the FAS population.  
 
6.2.4.6.2 Pulmonary Function  
 
Ventilation assessments recorded daily (Day 1 (Pre-dose/Day 1 dosing) then daily on Days 2 - 28 
(Day 28 In or Out of ICU) will be numerically summarised (with the derived Last observation 
performed) using the actual values and change from baseline values by Treatment group (FP-
1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall for each assessment time 
using the FAS population. Separate supporting summaries by Country will be included. 
 
Each of the gas exchange variables measured will be reported but the PaO2/FiO2 ratio change 
from baseline will used to assess pulmonary function. 
 
In addition, an Analysis of Covariance (ANCOVA) model, similar to the Total SOFA scores in 
Section 6.2.4.5 will include the PaO2/FiO2 ratio change from baseline value as the response 
variable at the Last observation performed assessment time.  
 
Homogeneity of treatment effect will be assessed as for the SOFA score. 
 
The Severity status and Change score classifications derived over the period of confinement 
within the ICU will be categorically summarised according Treatment group (FP-1201-
lyo/Placebo), Severity of ARDS (Moderate/Severe) and overall using the FAS population.  
 
The derived overall Change score classification (Improved, No Change, Worsened) will be 
analysed using the Cochran-Mantel-Haenszel hypothesis test including Severity of ARDS and 
Country as stratification variables. Statistical significance (p-value) overall will be displayed with 
the categorical summaries. Summary counts will be presented by severity of ARDS 
(Moderate/Severe). 
 
 
 
 


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6.2.4.6.3 Renal Function  
 
Fluid balance monitored at Baseline (Days 1 (Pre-dose) and then daily on Days 2 - 28 (Day 28 In 
or Out of ICU) will be numerically summarised (with the derived Last observation performed) 
using the actual values and change from baseline values by Treatment group (FP-1201-
lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall for each assessment time using 
the FAS population.  
 
 
 
 
6.2.4.7 Information from Externally Transferred Patients  
 
Observations recorded by site staff for patients who are externally transferred between Day 7 and 
Day 28 will be numerically summarised as this is applies to only a subset of patients.  
 
These data will be added to the 'Days free' endpoint scores and 'Length of stay' variables as 
appropriate for specific patients according to derivations specified in Section 5.9.4, Appendix 4.  
 
6.2.4.8 Other Observations In The ICU 
 
Other notable Procedures, Interventions, Surgeries and Diagnostics which are recorded as free 
text during confinement in the ICU will be listed.   
 
6.2.5 Efficacy Evaluations - Long Term/Extended Follow Up    
 
Assessments performed at Day 90 and Day 180 are considered Long term follow up and those at 
Day 360 an Extended follow up. These will only involve the FAS population.  
 
6.2.5.1 Patient Status Analyses   
  
The Patient Status assessments of efficacy performed at Day 90, 180 and 360 will be 
categorically summarised by Treatment group and Severity of ARDS and Overall using the FAS 
population. 
 
Details include: Alive/Dead, Location of death (ICU/Hospital), Date of death, Location if alive 
(ICU/Hospital) and Requirement for assisted ventilation. All are summarised and listed. 
 
6.2.5.2 Quality Of Life Questionnaire Analyses 
 
The EQ-5D-3L is performed at Day 1 Pre-dose, Day 180 and Day 360. The EQ VAS score and 
sub scores will be numerically summarised for actual values and change from baseline by 
Treatment group (FP-1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall for 
each assessment time using the FAS population only, although this sample will exclude any 
patients who did not survive to Day 180 or Day 360. Separate supporting summaries by Country 
will not be included. 
 


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The EQ VAS score will be analysed using an Analysis Of Covariance (ANCOVA) model as 
described for Total SOFA scores in Section 6.2.5.5. A separate analysis will be performed at each 
assessment time (Day 180 and Day 360) although p-values for inferential purposes will not be 
presented.  
 
Sub scores will not be analysed. 
 
 
6.2.5.3 Respiratory And Neurological Function Assessment 
 
6.2.5.3.1 Respiratory Function (FEV-1) Analyses 
 
FEV-1 measured at Day 180 and Day 360 will be numerically summarised using actual values by 
Treatment group (FP-1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall for 
each assessment time using the FAS population only. Again this group will only include 
survivors at the time of assessment. Separate supporting summaries by Country will not be 
included. 
 
The FEV-1 will be analysed using an ANCOVA model (as for the Total SOFA scores in Section 
6.2.5.5 but excluding the baseline covariate).   
 
6.2.5.3.2 Neurological Function (6MWT) Analyses 
 
6MWT distances recorded at both Day 180 and Day 360 will be numerically summarised using 
actual values by Treatment group (FP-1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) 
and Overall for each of the performed tests (Test One/Test Two). They will also be summarised 
according to the furthest distance walked during Test One or Test Two as recommended by the 
6MWT guidelines (Ref 11). Separate summaries by Country will not be included. 
 
These will involve patients from the FAS population who survive up to the time of assessment.  
 
In line with the guidelines the furthest distance walked during the two tests will be analysed using 
an ANCOVA model (similar to the Total SOFA scores in Section 6.2.5.5 excluding the baseline 
covariate). As described in Section 5.4.3.2, in cases where only one result is collected this will 
also be used as the best result (furthest distance walked). The value of inclusion of additional Pre-
Test covariates such as Walking limitations, Supplemental Oxygen use, SP02, Dyspnoea or 
Fatigue will be explored. 
 
In addition, the distance walked during Test One will also be performed as a supplemental 
analysis in case there is a disproportionate number of patients across the two treatment groups 
who refuse or who are unable to perform the second test and which may lead to inconsistent 
inclusion of a possible 'learning effect'. 
 
As the 6MWT is likely to only be performed in what is effectively a selective subgroup of 
patients (i.e.: those who survive) the results will be assessed in conjunction with the mortality 
rates in the two treatment groups. The LS mean and the 95% confidence interval for the treatment 
difference in those LS means will therefore only be presented Overall. 


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All other measures will only be summarised.  
 
6.2.5.4 Study Completion / Unblinding 
 
Long term and Extended follow up completion details reported at Day 180 and Day 360 
respectively will be categorically summarised by Treatment group, Severity of ARDS and 
Overall for the FAS population according to whether the Patient has withdrawn (Yes/No) and the 
Primary Reason for termination. All other reasons will be listed. 
 
A supporting Unbinding (Yes/No) categorical summary will be provided and all details listed. 
 
6.2.5.5 Ventilation Free Survival At Day 90 Analyses 
 
Ventilation Free Survival at Day 90 will be classified as Dead, Alive-On Ventilator or Alive-
Breathing Unassisted and summarised according to Treatment group (FP-1201-lyo/Placebo), 
Severity of ARDS (Moderate/Severe) and Overall. Separate supporting summaries by Country 
will be included.  
 
A Cochran-Mantel-Haenszel hypothesis test including the stratification levels will be used to 
compare the two treatment groups. Statistical significance (p-values) obtained for the Overall 
group will be displayed with the categorical summaries. 
 
6.2.5.6 Mortality At Day 90  
 
Overall mortality through to Day 90 (and subsequently to Day 180 and Day 360) will be 
displayed using Kaplan Meier survival plots and analysed using the logrank test.  
 
Kaplan Meier product limit estimators of survival, together with median survival times (with 
95% confidence intervals) for each treatment group will be presented.  
 
The distributions will be compared for differences in rates between the two treatment groups (FP-
1201-lyo/Placebo) with the stratified logrank hypothesis test (stratified by ARDS severity and 
country). The adjusted hazard ratio, obtained by fitting a Cox PH model containing both ARDS 
severity and country as factors in the model will be presented with 95% confidence intervals 
 
Sensitivity analysis may be performed to assess the impact of censoring in the event of missing 
data due to withdrawal due to adverse events, efficacy, investigator decision or loss to follow up 
and also due to withdrawal of consent (as detailed on the Day 180/Day 360 Patient Status CRF 
page). 
 
Homogeneity of treatment effect will be assessed by obtaining hazard ratios and associated 
confidence intervals by ARDS severity and by country and displaying these in a Forest Plot (log 
scale) using the Cox PH model with the addition of treatment by ARDS severity and treatment by 
country interaction terms. 
 


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Mortality at Day 180 and Day 360 will be similarly assessed as part of the Addendums for the 
Long Term and Extended Follow Up Reports, respectively (see Section 6.4).  
 
6.2.6 Pharmacoeconomic Analysis 
 
Numerical summaries of overall costs and according to cost item for the UK will be by Treatment 
group (FP-1201-lyo/Placebo) and Severity of ARDS (Moderate/Severe) using the FAS 
population. NB: Separate summaries by other countries may be included later. 
 
A cost-effectiveness analysis (Ref 9) to compare treatment with FP-1201-lyo to standard care 
(Placebo control) will involve an Analysis Of Variance (ANOVA) model.  The total individual 
patient cost of treatment whilst in the ICU will be the response variable and Treatment group (FP-
1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Country (if available) will be 
included (without interactions) as fixed effect factors.  
 
The total cost will be logarithmically transformed prior to analysis as the data distribution is 
likely to be truncated and positively skewed. The model fit and assumptions (particularly 
residuals) will be carefully assessed to ensure that the model is adequate and therefore provides 
reliable estimates. 
 
Resulting model parameters for Treatment (FP-1201-lyo and Placebo) will be back transformed 
(exponentiated) to obtain geometric mean estimates (including 95%CI) of the total cost of each 
treatment and similar transformation of the treatment difference (FP-1201-lyo - Placebo) will 
allow expression of the difference in costs as a ratio (FP-1201-lyo relative to Placebo (%)) with 
95% confidence limits.  
 
In the event of model failure a non-parametric bootstrap procedure (Ref 10) will be substituted 
which involves repeated resampling from the available data to obtain estimates of the mean 
treatment costs together with 95% confidence intervals (using 2.5 and 97.5 percentiles from the 
resulting distribution).  
 
A supplemental Incremental Cost Effectiveness Ratio (ICER) plot may also be presented for each 
Treatment group using the primary efficacy endpoint (VFDsurv) vs total cost of treatment for 
each individual patient. 
   
This quadrant plot will identify both increasing and decreasing utility of the treatment cost with 
those of treatment efficacy 
 
As discussed, these summaries will be presented with the Day 180 and/or Day 360 long-term 
follow up reports. 
 
 
6.2.7 Pharmacodynamic Endpoints Including Immunological Markers Analysis 
 
IFN Beta-1a ADA and NAb is measured at Day 1 Pre-dose and at Day 28 (or Early Termination 
or last day in ICU), MxA, CD73 and other biomarkers such as PIMs are measured on Day 1 Pre-
dose and then daily until Day 14 in the ICU. These will be summarised categorically or 


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numerically (with the derived Last observation performed) according to Treatment group (FP-
1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall using binary classifications 
(Positive/Negative) or the actual values and change from baseline for the FAS population 
depending on the type of variable. Separate supporting summaries by Country will be included.  
 
For the categorical variable, the observed proportions with 95% Confidence Intervals (Clopper 
Pearson) at Day 28 (or Early Termination) will be analysed and displayed. The binary 
classification will involve the Cochran-Mantel-Haenszel hypothesis test with Severity of ARDS 
and Country as stratification variables.  
 
For numeric variables the change from baseline at the Last observation performed will be used 
for the purpose of analysis. This will involve an Analysis Of Covariance (ANCOVA) model as 
for the Total SOFA scores in Section 6.5.5 and will include change from baseline value as the 
response variable.  
 
As the PIMs biomarkers are considered exploratory, further sensitivity analyses may also be 
performed and the results will also be presented and justified in any supporting statistical reports. 
 
6.3 Safety Evaluations 
 
Specific evaluations include: Vital signs, Twelve lead ECG, Physical examination, Adverse 
events and Laboratory safety tests (Biochemistry, Haematology, Urinalysis). Interval or 
Categorical data summaries (as appropriate) for the SS population will be used to assist clinical 
evaluation. No formal statistical analyses will be performed. All safety summaries will be 
presented according to Treatment group and Severity of ARDS (Moderate/Severe) but there will 
be no grouping by Country. Details are given in Section 7.3. 
 
6.4 Addendums Long Term and Extended Follow Up Efficacy And Safety Reports  
 
Data collected at Days 180 and 360 encompassing the Long Term and Extended Follow Up 
periods (Day 90 to Day 180, and Day 180 to Day 360, respectively) will be summarised 
separately and issued as addendums to the Clinical Study Report (CSR). Details are given in 
Section 7.4. Table shells are given in Appendix 5 and Appendix 6.  
 
 
 
7. Presentation 
 
7.1 General Information 
 
All data described in Section 5 and 6 will be presented in tables, figures and listings. Detailed 
‘shells’ to accompany this section are located in Appendix 1 to 6. 
 
All tables will be displayed as courier new font size 8pt, in a landscape orientated A4 Word 
document. Solid lines will be provided beneath all column headings and after the last row of data. 
Each summary table will be supported by individual subject data listings (Section 7.5). 


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All demographic and safety data summaries will be produced for the FAS and SS populations 
respectively according to Treatment group (FP-1201-lyo, Placebo).  
 
Efficacy, Pharmacodynamic and Pharmacoeconomic data analyses and summaries will be 
produced for the FAS population according to Treatment group (FP-1201-lyo, Placebo), Severity 
of ARDS (Moderate/Severe) and Country (1-8). The denominator for all categorical data 
summaries will be the number of patients available in the population.  
 
Graphical displays will be provided according to Treatment group (FP-1201-lyo, Placebo) 
Overall and by Severity of ARDS (Moderate/Severe).  
 
A Consort diagram will be used to classify the number of patients enrolled: Assessed for 
eligibility, Excluded/Included, Randomised, Treated, Followed up after ICU confinement and 
Analysed (by population) overall patients and by Treatment group and according to Severity of 
ARDS (Table 14.1).  
 
The following described tables, figures and listings will be included in the statistical report.  
Note: All listings will be output with the original Day 90 report, and the Day 180 and Day 360 
addendums including all relevant additional data, e.g. adverse events and medications reported 
after Day 90, together with any other additional safety and efficacy data. Tables and figures will 
be output for the main report once 300 patients have completed short term follow up at Day 28, 
and long term follow up at Day 90. Additional tables and figures will be output after locking long 
term follow up data at Day 180, and subsequently after locking data reported at the extended long 
term follow up at Day 360. The Day 180 and Day 360 report addendums will be displayed 
according to Appendix 5 and Appendix 6 table shells.   
 
7.2 Output Formats 
 
7.2.1 Overall Study Patient Group 
 
7.2.1.1 Disposition 
 
Overall study disposition details at Day 90 will be summarised by Treatment group (FP-1201-
lyo/Placebo), Severity of ARDS (Moderate/Severe) and Country (1-8) and Overall for all patients 
considered for inclusion. This categorical summary will include details of the number of patients 
Screened, Randomized no medication, Randomized, Treated in the ICU (Day 1-28), Completed 
the Short Term Follow Up Day 7, Short Term Follow Up Day 14, Short Term Follow Up Last 
Day in ICU, Short Term Follow Up Day 28 and Long Term Follow Up (Day 90) and also the 
numbers actually assigned to each of the analysis sets. Additionally, all available data will be 
used to indicate the number and percentage of patients who have completed Day 180 and/or Day 
360 at this time. Supporting listings will detail the reasons for screen failure (Tables 14.1.1). 
Tables 14.1.1 will be re-presented both on completion of the long term visit at Day 180 
(including all available Day 360 data), and subsequently for the extended long term visit at Day 
360 in the Addendum Day 180 and Day 360 reports. 
 


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The number of patients completing each of the study periods, with all reasons for discontinuation, 
will also be displayed.  
 
The disposition will also include information on the proportion of patients who Completed 
treatment (Days 1-6 of dosing) and those who Discontinued treatment (Less than 6 and also less 
than 4 days dosing) in the Day 90 report (Table 14.1.2), together will all available discontinuation 
data for patients who have reached or would have reached Day 180 and/or Day 360. This table 
will be re-presented in the Day 180 Addendum report and include the number and percentage of 
subjects who completed Long Term Follow Up at Day 180 and those who discontinued before 
Day 180 with reasons for discontinuation together will all available patient 
completion/discontinuation data at Day 360. This summary will be repeated by country (Tables 
14.1.2). Tables 14.1.2 will be represented once all Day 360 data has been locked. 
 
Additionally, any potential Investigator unblinding details or death reports recorded at Days 180 
or 360 will be listed separately in the respective Addendum reports.  
 
Furthermore, study informed consent and genetic sampling informed consent and associated 
dates and times are listed by treatment group and subject.  
 
7.2.1.2 Protocol Deviations, Violations And Investigator Comments  
 
Listing 16.2.1.4 will display all protocol deviations recorded in the eCRF and which were then 
subsequently transferred to the PPD CTMS tracker (which also contains site specific deviations), 
together with a similar tracker to be supplied by the Sponsor from Italian sites. The listing will 
identify country, site, patient, treatment group, description and date of the deviation, relevant 
Visit   name, any action taken and, ‘if relevant’ whether the deviation was considered significant 
(yes/no) and the source (PPD, Faron, DML). The Sponsor, study MM and Data Magik Ltd 
statistical team will review these combined trackers and additional listing sets produced by Data 
Magik Ltd as described in Section 4.1. Table 14.1.3 summarises the assignment of each patient to 
their population group (Screen failure, RNM, PPS, FAS, safety).  
 
Investigator comments will be listed by treatment group and subject. 
 
 
7.2.1.3 Patient Status And Baseline Characteristic Assessments Prior To Treatment Start  
 
Assessments performed on Admission to the ICU, including time from admission to first dose of 
IMP, time from intubation and mechanical ventilation to first dose of IMP, and patient status 
(requiring renal support, in the prone position, receiving vasoactive drugs), are summarised 
according to Treatment group (FP-1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and 
Overall according to the FAS population. Separate supporting summaries by Country will be 
included (Tables 14.1.4). 
 
Demographics (Age, Race, Sex, APACHE II score) (Tables 14.1.5), plus Disease diagnosis and 
Aetiology (Tables 14.1.6 and 14.1.7) are similarly summarised using the FAS population, 
together with all Medical history past conditions (Table 14.1.8.1) and Medical history ongoing 
conditions (Table 14.1.8.2).  


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Medical history is classified using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology matching verbatim reported text to the Lower Level Term according to System 
Organ Class (SOC) and Preferred Term (PT). Prior and concomitant medications will be 
similarly summarised using the World Health Organization Drug Dictionary coding system 
(WHODD) according to ATC levels 2 and 4. 
 
Prior medications are those taken in the last 30 days but stopped before signing Informed consent 
and before injection of the first dose of treatment (Table 14.1.9). Concomitant medications 
(classified as either Infusion or Bolus) (Tables 14.1.10.1 and 14.1.10.2) are those starting 
between Screening and Day 28, or start before the first dose of study IMP but then continue after 
this point. Concomitant vasoactive medications are recorded separately and will be summarised 
(Table 14.1.11) and indicated in the supporting listings. Tables 14.1.10.1, 14.1.10.2 and 14.1.11 
will be re-presented in the Addendum report at Day 180 and Day 360, and will include any 
additional medication reported after Day 90, and Day 180, respectively. 
 
Details of pregnancy testing for woman of childbearing potential will be presented in a summary 
table according to Treatment group (FP-1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) 
and Overall according to the FAS population (Table 14.1.12). 
 
Inclusion and exclusion criteria will be defined in Part 1 and individual patient responses listed in 
Part 2 of Table 14.1.13, by severity and country according to the FAS population. 
 
Physical examination at Screening will be presented as the number and percentage of patients for 
each body system categorised by the Investigator as ‘normal, abnormal NCS, abnormal CS, or 
not done’ according to Treatment group (FP-1201-lyo/Placebo), Severity of ARDS 
(Moderate/Severe) and Overall according to the FAS population (Table 14.1.14). 
 
Patient status on Day 1 Pre-Dose will be summarised in a similar manner to the physical 
examination summary (Table 14.1.15).  
 
All other assessments (efficacy, safety, pharmacodynamics) performed at Baseline (Screening 
and/or Day 1 Pre-dose) which are subsequently repeated during treatment and follow up will be 
summarised and reported with the appropriate data collected over time. 
 
7.2.1.4 Randomisation 
 
Randomisation, Severity of the ARDS condition, Changes in the condition and Individual daily 
infusion details during Days 1-6 will be summarised according to Treatment group. The 
scheduled treatment and actual treatment received with any 'miss' randomisations and the 
assigned analysis set will also be indicated. The record of the daily infusion of the Study IMP 
(material number, date and time of administration) maintained on Days 1-6 will also be included. 
 
Details of any unblinding (reported at Day 180 and Day 360 follow up assessments) will be 
included in the addendum reports (Table 14.1.16). 
 
 


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7.2.2 Baseline Treatment Group Comparability 
 
Group comparability will be discussed in the final Clinical Study Report (CSR). 
 
7.2.3 Efficacy Assessments - Short Term Follow Up 
 
7.2.3.1 Patient Status Assessments  
 
All Patient Status assessments performed will be summarised according to Treatment group (FP-
1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall (Tables 14.2.1).  
 
Patients no longer in ICU (Externally Transferred Patients) will also be separately summarised. 
 
7.2.3.2 Primary Efficacy Analysis - Ventilation Free Survival (VFDsurv) 
 
VFDsurv scores derived will be numerically summarised (excluding means and standard 
deviations) according to Treatment group (FP-1201-lyo/Placebo), Severity of ARDS 
(Moderate/Severe) and Overall. Statistical significance overall (Van Elteren p-values) will be 
displayed with the numerical summaries. Both FAS and PPS group analyses will be given (Table 
14.2.2.1.1). Table 14.2.2.1.1 will also display secondary efficacy variables in the same manner, 
including Ventilation Free Days (VFD), Days Free of Organ Failure, Days Free of Renal Support, 
Days Free of Vasoactive Support, Days Free of Mechanical Ventilation, Number Of ICU Care 
Free Days, Number of ICU days and Number of Days In Hospital. 
A frequency distribution (Table 14.2.2.2), together with Box and Whisker plots (Figures 14.2.1) 
of the VFDsurv scores will be presented by Treatment group and by Severity of ARDS for both 
FAS and PPS populations. 
 
7.2.4 Secondary Efficacy Analysis 
 
7.2.4.1 Mortality Analysis  
 
Observed Mortality rates (Day 28, Overall, In ICU, In Hospital) with 95% Confidence Intervals 
(Clopper Pearson) will be displayed using categorical summarises (Alive/Dead) for each 
Treatment group (FP-1201-lyo and Placebo), Severity of ARDS (Moderate/Severe) and Overall 
(Tables 14.2.3.1, Figures 14.2.2). 
 
Adjusted odds ratio estimate (including a 95% confidence interval) for the treatment effects will 
be displayed (in summary table (Table 14.2.3.2) and graphically (Figures 14.2.3)). Both FAS and 
PPS group analyses will be given for the mortality analysis. 
 
Homogeneity of treatment effect will be assessed by calculating ORs and associated confidence 
intervals by ARDS severity and by country and displaying these in a Forest Plot (log scale) 
(Figure 14.2.3.3). 
 
 
 
 


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7.2.4.2 Days Free Of Mechanical Ventilation Analysis 
 
Total number of days free of mechanical ventilation (not derived VFDsurv scores) will be 
numerically summarised (excluding means and standard deviations) according to Treatment 
group (FP-1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall. Statistical 
significance (Van Elteren p-values) obtained will be displayed with the summaries (Table 
14.2.2.1.1, Figure 14.2.4.1). Days free of mechanical ventilation will be also displayed as a 
frequency plot over 28 days by treatment group overall (Figure 14.2.4.2). 
 
7.2.4.3 Days Free Of Organ Failure, Renal Support And Vasoactive Support Analysis 
 
Totals derived will be presented as described in Section 7.2.4.2 above (Table 14.2.2.1.1, Figures 
14.2.5.1 – 14.2.5.3). 
 
7.2.4.4 Length Of ICU 'Care Free' Stay/Hospital Stay Analysis 
 
Totals derived will be presented as described in Section 7.2.4.2 above (Table 14.2.2.1.1, Figures 
14.2.6.1 – 14.2.6.2). 
 
7.2.4.5 Sequential Organ Failure Assessment (SOFA) Analysis 
 
Total scores and Change from baseline scores will be numerically summarised according to 
Treatment group (FP-1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall for 
all patients and by country (Tables 14.2.4.1). 
 
Contributing Cardiovascular, Respiratory, Coagulation, Hepatic, Renal and CNS organ sub 
scores will be similarly presented for all patients (Tables 14.2.4.2). 
 
ANCOVA analysis of the Total SOFA score at the Last observation performed will be similarly 
presented (in summary Table 14.2.4.3) and graphically (Figure 14.2.7.1) with model estimates 
(LS means and a 95% confidence interval for the difference). 
 
Homogeneity of treatment effect will be assessed by obtaining the difference in LS means 
together with 95% confidence intervals for the categories of ARDS severity using the ANCOVA 
model with the addition of a treatment by ARDS severity interaction term and displaying these in 
a Forest Plot (Figure 14.2.7.2). 
 
 
7.2.4.6 Individual Organ Assessment Analysis 
 
7.2.4.6.1 Cardiovascular Function 
 
Vasoactive support assessments will be categorically summarised (Yes/No) with the derived Last 
observation performed, by Treatment group (FP-1201-lyo/Placebo), Severity of ARDS 
(Moderate/Severe) and Overall for each assessment time and by country (Tables 14.2.5). 
 
 


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7.2.4.6.2 Pulmonary Function  
 
Ventilation assessments will be numerically summarised (with the derived Last observation 
performed) using the actual values and change from baseline values by Treatment group (FP-
1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall for each assessment time 
and by country (Tables 14.2.6.1 – 14.2.6.9). These include: Fraction inspired oxygen (FiO2), 
Partial pressure arterial oxygen (PaO2), PEEP (cm H2O), Peak inspiratory pressure (cm H2O), 
Plateau pressure (cm H2O), Mean airway pressure (cm H2O), Respiratory rate (bpm) and Tidal 
volume (mL). 
 
ANCOVA estimates (LS means and a 95% confidence interval for the treatment difference) for 
the PaO2/FiO2 ratio change from baseline analysis will be similarly presented and by country 
(Table 14.2.6.10, Figure 14.2.8) for the FAS population. 
 
Any evidence of Barotrauma will be categorically summarised (Yes/No) with the derived Last 
observation performed, by Treatment group (FP-1201-lyo/Placebo), Severity of ARDS 
(Moderate/Severe) and Overall for each assessment time and by country (Tables 14.2.6.11). 
 
The Severity status (mild/moderate/severe/death) and Change score classifications will also be 
categorically summarised. The Change score CMH analysis, statistical significance (p-values) 
will be included (Tables 14.2.6.12). 
 
7.2.4.6.3 Renal Function  
 
Fluid balance monitored will be numerically summarised (with the derived Last observation 
performed) using the actual values and change from baseline values by Treatment group (FP-
1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and Overall for each assessment time 
and by country (Fluid input, Tables 14.2.7.1; Fluid output, Tables 14.2.7.2; Fluid Balance, Tables 
14.2.7.3). 
 
7.2.4.7 Information from Externally Transferred Patients  
 
Observations recorded by site staff for patients who are externally transferred between Day 7 and 
Day 28 will be numerically summarised (Tables 14.2.8). 
 
7.2.4.8 Other Observations In The ICU 
 
Other notable Procedures, Interventions, Surgeries and Diagnostics will be listed (Table 14.2.9).   
 
7.2.5 Efficacy Evaluations - Long Term/Extended Follow Up    
 
7.2.5.1 Patient Status Analyses   
  
The Patient Status assessments of efficacy performed at Day 90 will be categorically summarised 
by Treatment group and Severity of ARDS and Overall (Tables 14.2.10.1). 
 


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Details include: Alive/Dead, Location of death (ICU/Hospital), Date of death, Location if alive 
(ICU/Hospital) and Requirement for assisted ventilation. All are summarised and listed. 
 
Similarly, the patient status assessments of efficacy performed at Long Term Day 180 Follow Up 
and Extended Long Term Day 360 follow up will be presented in the Day 180 and Day 360 
Addendum reports (Tables 14.2.10.2 and 14.2.10.3, respectively). 
 
 
7.2.5.2 Quality Of Life Questionnaire Analyses 
 
Quality of life questionnaire analyses will only be carried out at Baseline, Long Term Follow Up 
Day 180 and Extended Long Term Follow Up Day 360. Therefore, these results will only be 
presented in the Day 180 and Day 360 Addendum reports as appropriate. 
 
The EQ-5D-3L VAS score and sub scores will be numerically summarised for actual values and 
change from baseline by Treatment group (FP-1201-lyo/Placebo), Severity of ARDS 
(Moderate/Severe) and Overall for each assessment time (Tables 14.2.11.1 and 14.2.11.3, Day 
180 and Day 360, respectively). 
 
EQ VAS score analysis will be similarly presented (in summary table and graphically) with 
model estimates (LS means and a 95% confidence interval for the difference in change from 
baseline values) (Tables 14.2.11.2 and 14.2.11.4, Figures 14.2.9.1 and 14.2.9.2, Day 180 and Day 
360, respectively).  
 
7.2.5.3 Respiratory And Neurological Function Assessment 
Respiratory and Neurological function assessments are carried out at Baseline, Long Term 
Follow Up Day 180 and Extended Long Term Follow Up Day 360. Therefore, these results will 
only be presented in the Day 180 and Day 360 Addendum reports as appropriate. Table shells are 
displayed in Appendix 5 and 6 for Day 180 and Day 360, respectively. 
 
7.2.5.3.1 Respiratory Function (FEV-1) Analyses 
 
FEV-1 will be numerically summarised using actual values at Day 180 and Day 360 (Table 
14.2.12.1 and 14.2.12.3, respectively). ANOVA parameter estimates (LS  means and a 95% 
confidence interval) will be presented for each treatment group Overall and according to Severity 
of ARDS at each assessment time (Day 180, Table 14.2.12.2; Figure 14.2.10.1; Day 360, Table 
14.2.12.4, Figure 14.2.10.2). 
 
7.2.5.3.2 Neurological Function (6MWT) Analyses 
 
Pre-test, During test and Post test evaluations will be summarised for each Test performed (Test 
One/Test Two) on Day 180 (pre-test: Tables 14.2.13.1-2, 14.2.14.1-2, 14.2.15.1-2, 14.2.16.1-2; 
during: Table 14.2.17.1-2; after: Table 14.2.19.1-2) and Day 360 (Tables (pre-test: Tables 
14.2.13.3-4, 14.2.14.3-4, 14.2.15.3-4, 14.2.16.3-4; during: Table 14.2.17.3-4; after: Table 
14.2.19.3-4)).  
 


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6MWT distances (Furthest distance walked (Test One/Two), Test One only) will be numerically 
summarised using actual values. ANOVA parameter estimates (LS means and 95% confidence 
interval) for the overall treatment difference will be presented (in summary table and graphically) 
for maximum distance walked and distance walked in test one on Day 180 (Tables 14.2.20.1-2, 
Figures 14.2.11.1-2) and Day 360 (Tables 14.2.20.3-4, Figures 14.2.11.3-4). 
 
 
7.2.5.4 Study Completion / Unblinding 
 
Long term (Day 180) and Extended follow up (Day 360) completion details will be categorically 
summarised according to Withdrawal (Yes/No) and the Primary Reason, and presented in the 
Day 180 and Day 360 Addendum reports, respectively (Tables 14.2.21.1 and 14.2.21.2). All other 
reasons will be listed. 
 
A supporting Unbinding (Yes/No) categorical summary will be provided and all details listed. 
 
7.2.5.5 Ventilation Free Survival At Day 90 Analyses 
 
Categorical summaries including the number and percentage of patient deaths, alive but on a 
ventilator and breathing unassisted by Treatment group (FP-1201-lyo/Placebo), Severity of 
ARDS (Moderate/Severe) and Overall will be presented with CMH test statistical significance (p-
values) obtained overall at Day 90 (Tables 14.2.22).  
 
7.2.5.6 Mortality - Day 90 Report 
 
The observed mortality is investigated using Kaplan Meier survival plots, Logrank test and Cox's 
PH model. A summary table showing the number and percentage of deaths/survivors, together 
with survival (number of days) statistics: median, lower and upper quartiles and the range will be 
presented overall and by country for each severity and overall by treatment (Table 14.2.23.1.1).  
Summaries of product limit estimators of survival and median survival times (with 95% 
confidence interval) and Logrank statistics will be displayed at Day 90 and include all available 
patient data up to Day 360 (Tables 14.2.23.2.1, Figure 14.2.12.1).  Adjusted Hazard ratios (with 
95% confidence interval) will also be presented (Tables 14.2.23.2.1, overall and according to 
Severity and Country.  
 
Similar summaries and analyses will be carried out for the long term and extended follow-up 
periods at Day 180 and Day 360 including any additional available data collected since the Day 
90 and Day 180 reports, respectively (Day 180: Tables 14.2.23.1.2 and 14.2.23.2.2, Figure 
14.2.12.2; Day 360: Tables 14.2.23.1.3 and 14.2.23.2.3, Figure 14.2.12.3). 
 
7.2.6 Pharmacoeconomic Analysis 
 
Numerical summaries of overall costs and according to cost item will be presented together with 
ANCOVA analysis of logarithmically transformed costs. Numeric summaries will display actual 
values by Treatment group (FP-1201-lyo/Placebo), Severity of ARDS (Moderate/Severe) and 
Overall for the UK and by country if other country data become available (Tables 14.2.24.1, 


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Figures 14.2.13.1 and 14.2.13.2). Parameter estimates will also be presented after back 
transformation to obtain geometric mean estimates overall (Table 14.2.24.2). 
 
A supplemental Incremental Cost Effectiveness Ratio (ICER) plot may also be presented for each 
Treatment group using the primary efficacy endpoint (VFDsurv) vs total cost of treatment for 
each individual patient (Figure 14.2.13.3). 
 
As discussed, these summaries will be presented with the Day 180 and/or Day 360 long-term 
follow up reports to expedite the publication Day 90 statistical and clinical study reports. 
 
7.2.7 Pharmacodynamic Endpoints Including Immunological Markers Analysis 
 
IFN Beta-1a ADA (BAb)  and NAb will be summarised categorically (using Positive/Negative 
classification) displaying the observed proportions with 95% Confidence Intervals (Clopper 
Pearson) (Tables 14.2.25.1.1 and 14.2.25.2, Figures 14.2.14) with an overall p-value (CMH). 
Titre values for BAb will be listed only. For the numeric biomarker variables: MxA, CD73 and 
other biomarkers such as PIMs, these will be summarised using the actual values and change 
from baseline (with the derived Last observation performed) (Tables 14.2.25.2). ANCOVA 
estimates (LS means and a 95% confidence interval for the treatment difference) will be 
presented for all numeric biomarker variables (Tables 14.2.25.3).   
 
Both sets of summaries will be displayed by Treatment group (FP-1201-lyo/Placebo), Severity of 
ARDS (Moderate/Severe) and Overall by assessment. 
 
These variables will also be displayed graphically (Figures 14.2.15 to 14.2.17). 
 
7.3 Safety Evaluations 
 
Specific evaluations include: Adverse events, Vital signs, Twelve lead ECG, Physical 
examination, and Laboratory safety tests (Biochemistry, Haematology, Urinalysis). All safety 
summaries will be presented according to Treatment group and Severity of ARDS 
(Moderate/Severe) but there will be no grouping by Country. 
 
7.3.1 Adverse Events (AEs)  
 
AEs will be presented according to the coded System Organ Class (SOC) and Preferred Term 
(PT), by Treatment group for the entire study period (Overall-irrespective of whether in ICU) and 
also according to when the events occurred (during Short Term Follow Up, Days 1-28 and Day 
90, or during Long Term (Day 180)/Extended Follow Up (Day 360)). All AEs reported up to Day 
90 will be included in the main study report. Adverse events reported between Day 90 and Day 
180 will be included in the cumulative AE tables presented in the Day 180 Addendum report, 
which will also include all previously reported AEs. Similarly, adverse events reported between 
Day 180 and Day 360 will be included in cumulative AE tables presented in the Day 360 
Addendum report. Additionally, any available AE data reported between long term follow up at 
Day 90 and long term follow up at Day 180, and long term follow up at Day 180 and extended 
long term follow up at Day 360 will also be included in the Day 90 main report and Day 180 long 
term follow up addendum reports, as described below. 


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The overview summary will display the number and percentage of patients, with any adverse 
event, PTSS and Treatment Emergent Adverse Events (TEAEs). Additionally, the table will 
include the number of TEAEs classed as drug-related (probably related, possibly related), TEAE 
intensity (mild, moderate, severe), those leading to discontinuation and TEAEs considered 
serious and Deaths. This table will be produced in the main report at Day 90 for: All AEs up to 
Day 90 (Table 14.3.1.1.1); short term follow-up, Day 1-28 (Table 14.3.1.1.2); long term follow-
up, Day 28 – Day 90 (Table 14.3.1.1.3); and all available data for short and long term follow up 
to Day 180 (Table 14.3.1.1.4); and all available data for short, long term and extended follow up 
to Day 360 (Table 14.3.1.1.5). Tables 14.3.1.1.4 and 14.3.1.1.5 will be updated with any 
additional data and re-presented in the Day 180 and Day 360 addendum reports. 
 
Similarly, the number and percentage of patients of each TEAE will also be summarised for each 
Treatment group and overall both alphabetically by SOC and PT (Tables 14.3.1.2) by period and 
according to event frequency (Table 14.3.1.3) as for the ‘overall’ tables. Tables 14.3.1.2.4 and 
14.3.1.3.4 (Day 180) and Tables 14.3.1.2.5 and 14.3.1.3.5 (Day 360) will be updated with any 
additional data and re-presented in the Day 180 and Day 360 addendum reports. Similarly, the 
number (and percentage) of subjects for each PTSS will also be summarised alphabetically for 
each treatment group and overall (Table 14.3.1.4) in the main Day 90 report. 
 
7.3.1.1 Treatment Emergent Adverse Events According To Relationship and Intensity   
 
The number of patients, percentage of each TEAE event classified as Related (probably 
related/possibly related) to study drug will be summarised by Treatment group and overall by 
SOC and PT (Tables 14.3.1.5), together with the number and percentage of patients classified 
according to intensity (mild, moderate, severe) (Tables 14.3.1.6).  
 
Related TEAE Table 14.3.1.5.2 (Day 180) and Table 14.3.1.5.3 (Day 360) will be updated with 
any additional data and re-presented in the Day 180 and Day 360 addendum reports. Similarly, 
AE event intensity tables for Day 180 (Tables 14.3.1.6.1.2, 14.3.1.6.2.2, 14.3.1.6.3.2) and Day 
360 (Tables 14.3.1.6.1.3, 14.3.1.6.2.3, 14.3.1.6.3.3) will be presented in the Day 90 report with 
all available data and be re-presented and updated with any additional data in the Day 180 and 
Day 360 addendum reports. 
 
7.3.1.2 Serious Treatment Emergent Adverse Events  
 
Serious TEAEs will be presented according to the coded System Organ Class (SOC) and 
Preferred Term (PT), by Treatment group for the entire study period (Overall) and also according 
to when the events occurred (during Short Days Term Follow Up 1-28 in ICU) or during Long 
Term/Extended Follow Up). 
 
Serious TEAEs will also be listed by Treatment group and patient, indicating the name of the AE, 
PT and SOC, together with details of the start and end dates and times, event duration (hours) and 
maximum intensity. Additionally, the relation to study drug, action taken, outcome and the time 
between the first dose of study drug and the start of the serious TEAE will also be displayed 
(Table 14.3.1.7.1).  
 


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The number and percentage of patients of each SAE will also be summarised for each Treatment 
group and overall both alphabetically by SOC and PT (Tables 14.3.1.7.2) by period and 
according to event frequency (Table 14.3.1.7.3) as for the ‘overall’ tables. Table 14.3.1.7.2.4 
(Day 180) and Table 14.3.1.7.2.5 (Day 360) will be updated with any additional data and re-
presented in the Day 180 and Day 360 addendum reports. 
 
7.3.1.3 Discontinuations Due To Treatment Emergent Adverse Events 
 
Similar tables to that for serious TEAEs will be produced for all discontinuations due to TEAEs 
to Day 90 (Tables 14.3.1.8.1.1 and 14.3.1.8.2.1), Day 180 (Tables 14.3.1.8.1.2 and 14.3.1.8.2.2) 
and Day 360 (Tables 14.3.1.8.1.3 and 14.3.1.8.2.3). 
 
7.3.1.4 Deaths 
 
Similar tables to that for serious TEAEs will be produced for deaths to Day 90 (Tables 
14.3.1.9.1.1 and 14.3.1.9.2.1), Day 180 (Tables 14.3.1.9.1.2 and 14.3.1.9.2.2) and Day 360 
(Tables 14.3.1.9.1.3 and 14.3.1.9.2.3). 
 
A supporting categorical summary will also be presented using other collected data. These 
include: Time of death after randomisation (days), Location (ICU or hospital) at the Time of 
death (Patient Status (i.e.: partly a repeat of Patient Status data in section 6.6.1)) and Cause of 
death (Death Report at Day 180 or Day 360) (Table 14.3.1.10). 
 
7.3.2 Vital Signs 
 
Vital signs are recorded at Day 1 (Pre-dose), then at selected visits (Day 2 - 28 (In/Out Of ICU), 
Last day in ICU) and in the event of withdrawal, at Early Termination. The Last observation 
performed is also derived. 
 
Blood pressure (systolic/diastolic), Mean arterial pressure, Heart rate, Body temperature and total 
respiratory rate measured will be summarised numerically for each Treatment group and Severity 
of ARDS (Moderate/Severe) at each assessment time (i.e.: Each Day in ICU and including Last 
observation performed) using the actual values and change from baseline (Tables 14.3.2).  
 
7.3.3 Twelve Lead ECG  
 
ECG are recorded are performed at Day 1 (Pre-dose) then on Day 7. Ventricular rate, PR, PQ 
Interval, QRS Duration and QTc will be summarised numerically for each Treatment group and 
Severity of ARDS at both assessment times (Day in ICU) using the actual values and change 
from baseline (Tables 14.3.3.1).  
 
A categorical summary will be used for the overall Normal/Abnormal NCS/Abnormal CS result 
(Table 14.3.3.2). 
 
 
 
 


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7.3.4 Physical Examination 
 
The Physical examination findings will be displayed as categorical summaries at each assessment 
time.  
 
Physical examinations are performed at Screening, then at the Last day in ICU and Day 28 (Out 
of ICU) or Early Termination. The Last observation performed is derived.  Major body systems: 
General appearance, Ear, nose and throat, Eyes, Respiratory, Abdomen, Urogenital, 
Musculoskeletal, Neurological, Lymph nodes and Skin will be categorically summarised for each 
Treatment group and overall and Severity of ARDS at each assessment time (Day in ICU) 
(Tables 14.3.4).  
 
Predicted body weight at screening will be summarised with other demographics. 
  
7.3.5 Laboratory Assessments 
 
Laboratory assessments are performed at Day 1 (Pre-dose) and Day 2 - 28 (In/Out Of ICU), Last 
day in ICU) or at Early Termination. The Last observation performed is derived. Actual values 
and within patient Change from baseline (for numeric variables) for all haematology, chemistry 
and urinalysis will only be listed with patients identified by Treatment group, Severity of ARDS, 
Country and Investigational site for each assessment time using the Safety population.  
 
Laboratory values are also classified by the Investigator as Out of range (Not clinically 
significant), Out of range (Clinically significant) or Out of range (Clinically significant and an 
Adverse event). Categorical summaries for these data will be pooled over all sites and identified 
according to Treatment group but not by Severity of ARDS or by Country. These summary tables 
will also contain Normal and Not Done (including missing) categories for comparative purposes 
(Tables 14.3.5.1.1, Haematology; Tables 14.3.5.2.1, Biochemistry; Urinalysis, Tables 14.3.5.3.1). 
 
Source laboratory normal ranges for these classifications will also be presented as listings for 
each of the Investigational sites. 
 
Shift tables displaying the overall change from baseline (Day 1 Pre-dose) in these categorical 
classifications (Out of range (Not clinically significant), Out of range (Clinically significant) or 
Out of range (Clinically significant and an Adverse event)) will be provided according to 
Treatment group for each laboratory variable relating the Last observation performed during the 
28 day period in the ICU. These shift tables will also contain Normal and Not Done (including 
missing) categories for comparative purposes (Tables 14.3.5.4.1, Haematology; Tables 
14.3.5.5.1, Biochemistry; Urinalysis, Tables 14.3.5.6.1). 
 
Supporting listings for all the laboratory variables for each patient and each assessment time will 
include the actual values, clinical classification and any comments on the clinical significance of 
findings. Patient identifiers of Treatment group, Severity of ARDS, Country and Investigational 
site will be included. Additional (Unscheduled) laboratory assessments performed will only be 
listed. 
 
 


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7.4 Addendums Long Term (Day 180) & Extended Follow Up (Day 360) 
Efficacy And Safety Report  
 
Data collected at Day 180 (Day 90 to Day 180) encompassing the long term follow up and Day 
360 encompassing the Extended Follow Up period (Day 180 to Day 360) will be summarised 
separately and issued as an addendum to the Clinical Study Report (CSR). However, where 
appropriate any available safety data will be presented in the main report at Day 90 and/or Day 
180 addendum report. 
 
But, new table summaries will be generated and separate statistical analyses performed with the 
additional information available where appropriate. This applies to: Patient Status (+Mortality 
rate Day 180/360), Quality of life (EQ-5D-3L), Respiratory functioning (FEV-1) and 
Neurological functioning (6MWT).  
 
The Overall survival rate (Time to Death) analysis will also be updated and relevant tables and 
figures regenerated.  
 
Other specific table summaries relating to previously reported data will be regenerated after 
updating the database. This applies to: Patient Completion and Unblinding details plus all AEs 
and Death reports. 
 
Table shells for the long term and extended follow up periods are given in Appendix 5 and 6, 
respectively. 
 
7.5 Graphical Presentations 
Key findings identified in summary and analysis tables will be presented graphically. A complete 
list with template shells are given in Appendix 2. 
 
Template type 1 will present individual treatment estimates for FP-1201-lyo and placebo. Type 2 
will present FP-1201-lyo - placebo differences or FP-1201-lyo / placebo ratios. Variability (95% 
CI) of all estimates will be indicated.    
 
7.6 Data Listings 
 
All data presented in summary tables will be supported by specific referenced data listings. These 
will identify the Patient number, Investigator site, Country id, Treatment, Visit/Day/Dose number 
and provide actual data and/or derived data as appropriate.  
 
The following listings will be included in the Day 90 report only: 
 
Listing 16.2.1.6: ICU Admission  
Listing 16.2.1.8: Demographics  
Listing 16.2.1.9 APACHE II Scores 
Listing 16.2.1.10: Disease Diagnosis 
Listing 16.2.1.11: Medical History 
Listing 16.2.1.12: Prior Medications 
Listing 16.2.1.16: Pregnancy Test 


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Listing 16.2.1.17.1: Inclusion Criteria – Part 1 
Listing 16.2.1.17.2: Inclusion Criteria – Part 2 
Listing 16.2.1.18.1: Exclusion Criteria - Part 1 
Listing 16.2.1.18.2: Exclusion Criteria - Part 2 
Listing 16.2.1.19: X-Ray Selected 
Listing 16.2.1.20: Eligibility Criteria 
Listing 16.2.1.21: Randomisation 
Listing 16.2.1.22: Drug Administration 
Listing 16.2.2.2: Externally Transferred Patients - Day 28 No Longer in ICU 
Listing 16.2.2.3: Patient  Status Score Derivations 
Listing 16.2.2.4: SOFA 
Listing 16.2.2.5: Ventilation Parameters 
Listing 16.2.2.6: Fluid Balance 
Listing 16.2.2.15.1: Blood Sampling for Biomarkers - IFNß BAb and NAb 
Listing 16.2.2.15.2: Blood Sampling for Biomarkers – MxA 
Listing 16.2.2.15.3: Blood Sampling for Biomarkers - CD73 
Listing 16.2.2.15.4: Blood Sampling for Biomarkers – PIMs 
Listing 16.2.3.3: Electrocardiogram (Safety Population) 
Listing 16.2.3.4: Physical Examination at Screening 
Listing 16.2.3.5: Physical Examination Changes 
 
 
The following listings will be included in the Day 90 report and subsequently updated and 
presented again in the Day 180 and 360 addendums: 
 
Listing 16.2.1.1.3: Patient Disposition (All Patients) - Death Reports  
Listing 16.2.1.4: Deviations Day 90 Report ((All Patients)) 
Listing 16.2.1.5: Comments 
Listing 16.2.1.7: Visit Dates 
Listing 16.2.1.13: Infusion Concomitant Medications - Parts 1 – 2 
Listing 16.2.1.14: Bolus Concomitant Medications - Parts 1 – 2 
Listing 16.2.1.15: Vasoactive Medications 
Listing 16.2.2.1.1: Patient Status - Deaths (Safety Population) 
Listing 16.2.2.1.2: Patient Status - Ventilation, Renal and Vasoactive Support  
Listing 16.2.2.7: Procedures, Interventions, Surgeries and Diagnostics 
Listing 16.2.3.1: Adverse Events Listing (Safety Population) 
Listing 16.2.3.6.1: Laboratory Values – Haemotology (for unscheduled visits only) 
Listing 16.2.3.6.2: Laboratory Values – Chemistry (for unscheduled visits only) 
Listing 16.2.3.6.3: Laboratory Values – Urinalysis (for unscheduled visits only) 
 
The following listings supporting data collected only at Days 180 and 360 will be included in the 
addendum reports only: 
 
Listing 16.2.1.1.1: Patient Disposition (All Patients) - Completion and Withdrawal Day 180 
Listing 16.2.1.1.2: Patient Disposition (All Patients) - Completion and Withdrawal Day 360 
Listing 16.2.2.8: EQ-5D-3L Assessment 
Listing 16.2.2.9: FEV 


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Listing 16.2.2.10: Investigator's Evaluation Form for 6MWT 
Listing 16.2.2.11: 6MWT Concomitant Medications 
Listing 16.2.2.12: 6MWT Comorbidities 
Listing 16.2.2.13.1: 6MWT Pre First Test Recordings 
Listing 16.2.2.13.2: 6MWT During the First Test Recordings 
Listing 16.2.2.13.3: 6MWT After the First Test Recordings 
Listing 16.2.2.14.1: 6MWT Pre Second Test Recordings 
Listing 16.2.2.14.2: 6MWT During the Second Test Recordings 
Listing 16.2.2.14.3: 6MWT After the Second Test Recordings 
 
Listings will be created according to the ICH guidelines, as appropriate for the data collected. 
 
 
8. References 
 
1-ICHE9 “Statistical Principles For Clinical Trials” February 1998. 
 
2-ICHE8 “General Considerations For Clinical Trials” July 1997. 
 
3-Scoring Mechanism and Analysis 
Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical 
trials. Statist Med 1999;18:1341-1354 
 
4-Generalised Wilcoxon rank sum - non parametric test for ordered categorical  
Van Elteren PH. On the combination of independent two-sample tests of Wilcoxon. B Int Statist 
Inst 1960;37:351-361. 
 
5-Poisson Regression 
JS. Long, J. Freese "Regression Models for Categorical Dependent Variables Using Stata", 
Second Edition 2006. 
 
6-Logistic regression 
CYJ Penga, KL Leea & GM. Ingersolla. "An Introduction to Logistic Regression Analysis and 
Reporting" The Journal of Educational Research Volume 96, Issue 1, 2002 
 
7-Kaplan-Meier / Logrank 
Altman, DG, (1991) Practical Statistics for Medical Research: London, Chapman and Hall 
 
8-ANCOVA 
Frison L1, Pocock SJ. Repeated measures in clinical trials: analysis using mean summary 
statistics and its implications for design. Stat Med. 1992 Sep 30;11(13):1685-704. 
 
9-Cost Effectiveness Analysis 
Mannings WG, Mullahy J. Estimating log models: to transform or not to transform? J Health 
Econ. 2001; 20:461-94. 


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10-Bootstrap Estimates 
 
Cassell  DL. Bootstrap Mania!: Re-Sampling the SAS® Way Paper 268 SAS Global Forum 2010 
 
11-6MWT Guidelines 
Holland et al An official European Respiratory Society/American Thoracic Society technical 
standard: field walking tests in chronic respiratory disease. Singh European Respiratory Journal 
Dec 2014, 44 (6) 1428-1446 
 
 
9. Finalisation of Statistical Analysis Plan 
 
The statistical analysis plan, and all relevant table, figures and listing ‘shells’ will be finalised 
before database lock – Day 90 CSR. 
 
 
10. Appendices to be Included in the Statistical Report 
 
1. Summary tables 
2. Figures 
3. Listings supporting summary tables  
4. Data derivations – contains rules for deriving efficacy variables when required 
5. Long Term Follow Up Day 180 = Summary tables, figures and supporting listing 
    (Addendum  to report) 
6. Extended Long Term Follow Up Day 360 = Summary tables, figures and supporting listing   
    (Addendum  to report)