Clinical trial NCT03212690
Conditions: Acute Lung Injury
Keywords: mechanical ventilation echocardiography right ventricular function Ang (1-7) Ang II Renin-angiotensin system
Sponsor: GlaxoSmithKline
Start date: 2018-06-11; Completion date: 2019-07-08
Enrollment: 57 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess whether circulating Angiotensin (Ang) II and Ang (1-7) levels are associated with right ventricular (RV) dysfunction in mechanically ventilated subjects. It is also designed to further characterize the subject population for severity of RV dysfunction. This study will investigate the association of renin-angiotensin system (RAS) peptides and markers of RV function, as measured by echocardiography, in subjects requiring acute mechanical ventilation. Maximum 150 subjects will be enrolled for the study and they will be evaluated over three days period using standard of care investigations, including trans-thoracic echocardiography (TTE) and/or trans-esophageal echocardiography (TOE) echocardiography. The maximum total duration of this study for subjects is 28 days.

Detailed description:

Arms: arm 1: Subjects receiving invasive mechanical ventilation (Duration of ventilation \<=48 hours) will be evaluated using standard care investigations.
Interventions: intervention 1: Local standard of care intervention 2: Mechanical ventilation
Intervention descriptions: intervention 1: Local standard of care will include fluid resuscitation, use of vasopressor drugs and renal support. intervention 2: Mechanical ventilation will be based on volume-assist control mode, with a target tidal volume of 6-8 milliliter per kg (mL/kg) and a target plateau pressure of 30 centimeter of water (cmH2O).

Protocol documents:
Prot_001.pdf: 
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TITLE PAGE
Protocol Title: Study to elucidate the association of the Renin-angiotensin system and 
right ventricular function in mechanically ventilated patients
Protocol Number: 205821 – Amendment 3
Short Title: Study of Renin-angiotensin system in mechanically ventilated patients
Compound Number: Non-Compound Specific 
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual.
Approval Date: 27-FEB-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Protocol Amendment 3
27-Feb-2019
Protocol Amendment 2
27-Nov-2017
Protocol Amendment 1
02-Jun-2017
Original Protocol
26-Apr-2017
The Summary of Changes tables for Protocol Amendment 1 (02-Jun-2017) and Protocol 
Amendment 2 (27-Nov-2017) are in Section 12.6 (Appendix 6).
Amendment 3 (27-FEB-2019)
Overall Rationale for the Amendment:  The primary reason for the protocol 
amendment is to increase the duration that a participant may be mechanically ventilated, 
before they are included in the study – from ≤24 hours to ≤48 hours.  This change has 
been made to assist enrolment of participants into the study, but the sponsor considers 
that it will not impact the objectives of the study.  Additionally, minor clarifications have 
been made.
In the table below, in the column ‘Description of Change’, new text is shown in bold and 
deleted text has been striked through.
Section # and Name
Description of Change
Brief Rationale
Sponsor Signatory
Andy Fowler
Discovery Medicine Physician, 
Respiratory Therapy Area
Aili Lazaar, MD,
Discovery Medicine
Clinical Pharmacology and 
Experimental Medicine
Sponsor signatory change due 
to change in study personnel.
2. Schedule of activities –
Simplified acute physiology 
score (SAPS II)
SAPS II score to be taken 
within approximately 24 hours 
of admission to intensive care. 
Not at time of intubation.
To align the protocol with 
standard of care.
 
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Section # and Name
Description of Change
Brief Rationale
2. Schedule of activities
Echocardiogram
First echocardiogram must be 
completed within 24 48 hours 
of starting mechanical 
ventilation (but ≤24 hours, 
whenever possible)
To align the protocol with the 
revised inclusion criteria – that 
a participant may be 
mechanically ventilated for 
≤48 hours before inclusion in 
the study.
5. Study Design –  
5.1 Overall study design
The initial echocardiogram will 
take place within 24 48 hours 
of mechanical ventilation (but 
≤24 hours, whenever 
possible).
Figure 1 updated to show up 
to 48 hours from mechanical 
ventilation to inclusion.
To align the protocol with the 
revised inclusion criteria – that 
a participant may be 
mechanically ventilated for 
≤48 hours before inclusion in 
the study.
6. Study Population
6.1 Inclusion Criteria
Inclusion 2
2. Participants who are 
receiving invasive mechanical 
ventilation (duration of 
ventilation ≤24 ≤48 hours, but 
≤24 hours, whenever 
possible).
To increase the duration that a 
participant may be mechanically 
ventilated, before they are 
included in the study – from 
≤24 hours to ≤48 hours.  This 
change has been made to 
assist enrolment of participants 
into the study.
6. Study Population
6.2 Exclusion Criteria
Investigator will make every 
effort to ensure that the 
following exclusion criteria 3 to 
10 are met; however, in some 
instances it may not be 
possible to assess all of these 
criteria within the 24 48-hour 
window.  
To align the protocol with the 
revised inclusion criteria – that 
a participant may be 
mechanically ventilated for 
≤48 hours before inclusion in 
the study.
9.2 Pharmacodynamics
9.2.1 Echocardiograms
The first echocardiogram must 
be undertaken within 24
48 hours of the start of 
mechanical ventilation (but 
within 24 hours, whenever 
possible)
To align the protocol with the 
revised inclusion criteria – that 
a participant may be 
mechanically ventilated for 
≤48 hours before inclusion in 
the study.
9.5 Participant Status
9.5.1 SAPS II
The SAPS II score will be 
measured at screening only 
and is comprised of the 
following components:
Removed timing of SAPS II
score, because this is described 
more accurately in the 
Schedule of Activities 
(Section 2).
 
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Section # and Name
Description of Change
Brief Rationale
9.7.1 Serious Adverse 
Events (SAE)
Although no investigational 
product will be given, SAEs 
will be recorded, as follows:  
SAEs relating to study 
procedures; and SAEs 
related to GlaxoSmithKline 
(GSK) medication used as 
co-medication. 
This ensures that any SAEs 
relating to study procedures or 
any GSK medication used as 
co-medication, are captured.
Clarification made in the SAE 
section, but no change in the 
guidance.
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE..........................3
1.
SYNOPSIS.....................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SOA).............................................................10
3.
INTRODUCTION..........................................................................................13
3.1.
Study Rationale .................................................................................13
3.2.
Background........................................................................................13
3.3.
Benefit/Risk Assessment ...................................................................14
3.3.1.
Risk Assessment .................................................................14
3.3.2.
Benefit Assessment .............................................................15
3.3.3.
Overall Benefit:Risk Conclusion...........................................15
4.
OBJECTIVES AND ENDPOINTS.................................................................16
5.
STUDY DESIGN...........................................................................................19
5.1.
Overall Design ...................................................................................19
5.2.
Number of Participants ......................................................................19
5.3.
Participant and Study Completion......................................................20
5.4.
Scientific Rationale for Study Design.................................................20
5.5.
Dose Justification...............................................................................20
6.
STUDY POPULATION .................................................................................20
6.1.
Inclusion Criteria................................................................................20
6.2.
Exclusion Criteria...............................................................................21
6.3.
Lifestyle Restrictions..........................................................................22
6.4.
Screen Failures..................................................................................22
7.
TREATMENTS .............................................................................................22
7.1.
Concomitant Therapy ........................................................................22
8.
DISCONTINUATION CRITERIA ..................................................................23
8.1.
Discontinuation of Study Treatment...................................................23
8.2.
Withdrawal from the Study.................................................................23
9.
STUDY ASSESSMENTS AND PROCEDURES...........................................23
9.1.
Demographic/Medical History Assessments......................................24
9.2.
Pharmacodynamics ...........................................................................24
9.2.1.
Echocardiograms.................................................................24
9.2.2.
Electrical Impedance Tomography (EIT)..............................25
9.3.
Ventilator Settings..............................................................................25
9.4.
Lung Function....................................................................................25
9.5.
Participant Status...............................................................................26
9.5.1.
SAPS II ................................................................................26
 
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9.5.2.
Sequential Organ Failure Assessment (SOFA) score..........26
9.5.3.
Disease diagnosis................................................................27
9.5.4.
General management status................................................27
9.6.
Additional Clinical assessments.........................................................28
9.7.
Adverse Events..................................................................................28
9.7.1.
Serious Adverse Events (SAE)............................................28
9.7.2.
Time Period and Frequency for Collecting SAE 
Information...........................................................................28
9.7.3.
Method of Detecting SAEs...................................................29
9.7.4.
Follow-up of SAEs ...............................................................29
9.7.5.
Regulatory Reporting Requirements for SAEs.....................29
9.8.
Safety Assessments ..........................................................................29
9.8.1.
Vital Signs............................................................................29
9.8.2.
Clinical Laboratory Assessments.........................................29
9.9.
Biomarkers.........................................................................................30
10. STATISTICAL CONSIDERATIONS..............................................................30
10.1. Sample Size Determination ...............................................................30
10.2. Populations for Analyses ...................................................................33
10.3. Statistical Analyses............................................................................34
10.3.1.
Pharmacodynamic Analyses................................................34
10.3.2.
Safety Analyses...................................................................35
10.3.3.
Interim Analyses ..................................................................35
11. REFERENCES.............................................................................................40
12. APPENDICES ..............................................................................................42
12.1. Appendix 1: Abbreviations and Trademarks ......................................42
12.2. Appendix 2: Clinical Laboratory Tests ...............................................44
12.3. Appendix 3: Study Governance Considerations ................................45
12.3.1.
Ethical Considerations .........................................................45
12.3.2.
Financial Disclosure.............................................................45
12.3.3.
Informed Consent Process ..................................................45
12.4. Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting..............................50
12.5. Appendix 5: Assumptions for sample size calculations......................55
12.5.1.
Distribution of Ang II ............................................................55
12.5.2.
Definition of outcome: an objective measure of right 
ventricular (RV) dysfunction.................................................56
12.5.3.
"Success" and "futility" criteria .............................................58
12.5.4.
Assumptions for simulated datasets ....................................59
12.5.5.
Analysis of simulated data ...................................................60
12.5.6.
Metrics for operating characteristics ....................................61
12.6. Appendix 6: Protocol Amendment History .........................................62
 
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1.
SYNOPSIS
Protocol Title: Study to elucidate the association of the Renin-angiotensin system and 
right ventricular function in mechanically ventilated patients
Short Title: Study of Renin-angiotensin system in mechanically ventilated patients
Rationale:
Right ventricular (RV) dysfunction may result from increased RV afterload secondary to 
increased pulmonary vascular resistance in patients with severe respiratory failure,
including acute respiratory distress syndrome (ARDS). RV dysfunction, particularly 
severe dysfunction [acute cor pulmonale (ACP)], has been associated with worse 
outcomes in critically ill patients, including patients with ARDS. Increased mortality has 
been associated with RV dilatation and increased pulmonary artery pressures [termed 
pulmonary circulatory dysfunction (PCD)]. The Renin-angiotensin system (RAS) is a key 
regulator of vascular tone in the pulmonary vasculature and Angiotensin II (Ang II) in 
particular drives both vasoconstriction and vascular remodelling in human diseases such 
as pulmonary arterial hypertension. RAS peptides such as Ang II and Ang(1-7) may play 
a role in the observed changes in pulmonary vasoconstriction in patients with severe 
respiratory failure with consequent adverse effects on the right ventricle. This study is 
designed to assess whether circulating Ang II and Ang(1-7) levels are associated with RV 
dysfunction in mechanically ventilated patients. It is also designed to further characterise 
the patient population, including severity of RV dysfunction.  
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the association between 
plasma Ang II levels and RV function 
in mechanically ventilated 
participants. 

Ang II levels 

Echocardiographic measures: 
Ratio of right ventricular to left 
ventricular end-diastolic area
Paradoxical septal motion
Pulmonary arterial systolic pressure 
(PASP) estimated from 
transtricuspid pressure and right 
atrial pressure or inferior vena cava 
(IVC) diameter (whichever is 
available)
Up to and including Day 3 of observation
 
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Objectives
Endpoints
Secondary

To define the incidence of ACP and 
PCD in mechanically ventilated 
participants.

Presence of PCD, ACP (severe PCD) 
and severe ACP 
Up to and including Day 3 of observation

To evaluate the association between 
plasma Ang(1-7) levels, Ang 
II/Ang(1-7) ratio and RV function in 
mechanically ventilated participants.

Ang(1-7) levels 

Ang II/Ang(1-7) ratio 

Echocardiographic measures:
Ratio of right ventricular to left 
ventricular end-diastolic area
Paradoxical septal motion
PASP estimated from transtricuspid 
pressure and right atrial pressure or 
IVC diameter (whichever is 
available)
Up to and including Day 3 of observation
Overall Design:
This study will investigate the association of RAS peptides and markers of RV function,
as measured by echocardiography, in participants requiring acute mechanical ventilation. 
It is a low interventional study without an investigational product. Participants will be 
evaluated over a 3-day period using standard of care investigations, including 
transthoracic echocardiography (TTE) and/or transesophageal echocardiography (TOE). 
Three separate echocardiographs over three consecutive days will be undertaken, and at 
the same time point blood samples will be taken for assessment of RAS peptides to allow 
the association with right ventricular function to be assessed.  
Number of Participants:
A total of approximately 150 participants are planned to be included.
Treatment Groups and Duration:
There are no treatment groups as no investigational product will be administered.
The total duration of this study for participants is 28 days. The study period is 3 days and 
health outcomes will be recorded daily for up to 28 days. Health outcomes will not be 
recorded beyond hospital discharge. 
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Study Period
Notes
Screening1
Day 
1
Day 
2
Day 
3
Up to day 
28
Start of mechanical 
ventilation  
X
Inclusion/exclusion 
criteria
X
Reason for intubation (underlying diagnosis 
e.g. sepsis, pneumonia) to be collected 
where possible.
Informed consent 
(ICF)
X
Consent process will be followed as outlined 
in Informed Consent Process (Section 
12.3.3)
Demography
X
If it is not possible to collect at screening can 
be collected at any point during the study.
Height and weight 
X
Collected for the purposes of evaluating BMI. 
Clinical estimates are acceptable if direct 
measurement is not possible.
Medical history 
X
If possible to collect, includes medication and 
cardiovascular risk factors. If it is not possible 
to collect at screening can be collected at any 
point during the study.
Diagnosis of 
pulmonary 
circulatory 
dysfunction (PCD)
and acute cor 
pulmonale (ACP) 
X
X
X
As per echocardiographic output.
Participant status 
X
X
X
X
Intubation status, proned status; diagnosis of 
acute respiratory distress syndrome (ARDS)
including severity at time of diagnosis (if 
available). Post screening status to be 
assessed at the same time point as 
echocardiogram (1 hour).
Participant 
management
X
X
X
X
Management with extracorporeal membrane
oxygenation (ECMO) and extracorporeal CO2
(ECCO2R) removal. Post screening status to 
be assessed at the same time point as 
echocardiogram (1 hour).
Simplified acute 
physiology score 
(SAPS II)
X
To be taken within approximately 24 hours of 
admission into the intensive care unit, as per 
standard of care.
 
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Procedure
Study Period
Notes
Screening1
Day 
1
Day 
2
Day 
3
Up to day 
28
Sequential Organ 
Failure (SOFA)
score
X
X
X
X
Echocardiogram
X
X
X
Transthoracic echocardiogram (TTE) and/or 
transoesophageal echocardiogram (TOE). 
First echocardiogram must be completed 
within 48 hours of starting mechanical 
ventilation (but ≤24 hours, whenever 
possible); the following echocardiograms will 
be undertaken as per standard of care 24 
hours apart (± 2 hours) on subsequent 
consecutive days (Day 2 and 3).
Vital signs
X3
X
X
X
Blood pressure (mean arterial, systolic and 
diastolic), heart rate, body temperature to 
match echocardiogram time points (± 30 
minutes)2.
Laboratory 
assessments
X
X
X
X
Clinical chemistry and haematology.
Ventilator settings 
X3
X
X
X
Includes tidal volume, respiratory rates, static 
respiratory compliance, level of positive end 
expiratory pressure (PEEP), peak and 
plateau ventilator pressures, mean airway 
pressure and driving pressure. 
Measurements to be taken at intubation and 
at the time of each echocardiogram (± 30 
mins)2.
Lung function and 
blood gas measures 
X3
X
X
X
Oxygen saturation(SaO2) via pulse oximetry. 
Arterial Blood Gases (ABGs) measuring 
partial pressure of oxygen and carbon 
dioxide (PaO2 and PaCO2).4 Oxygen 
requirement (FiO2) should be documented at 
the same time point. 
pH, lactate and bicarbonate levels and base 
excess or deficit when available should also 
be documented when ABGs are assessed. 
Measurements to be taken at intubation and 
at the time of each echocardiogram (± 30 
mins)2.
Electrical 
Impendance 
Tomography
X
X
X
X
Measurements to be taken at intubation and 
at the time of each echocardiogram when 
available (±2 hours)2.
 
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Procedure
Study Period
Notes
Screening1
Day 
1
Day 
2
Day 
3
Up to day 
28
Serious Adverse 
Event (SAE) Review
<=======================>
SAEs will only be collected during the 3-day
observation period or until participant 
withdrawal, whichever is sooner.  
Concomitant 
medication review
<=======================>
Only specified prescription medication 
(name, start and end dates required) as 
described in Section 7.1. Vasopressor use to 
be documented for each time point of 
echocardiography.
Intensive Care Unit 
(ICU) length of stay
<=======================>
Will be recorded daily up to 28 days.
Ventilator free days
<=======================>
Will be recorded daily up to 28 days; 
however, follow up is not necessary beyond 
hospital discharge.
In hospital mortality
<=======================>
Will be recorded daily up to 28 days; 
however, follow up is not necessary beyond 
hospital discharge.
Biomarkers 
Blood sample for 
renin-angiotensin 
system (RAS) 
biomarkers
X
X
X
Blood samples to be taken at the same time 
as echocardiography (± 30 mins)2.
Blood sample for 
biomarkers
X
X
X
Blood samples to be taken at the same time 
as echocardiography (± 30 mins)2.
1.
Screening may be considered part of Day 1.
2.
When multiple measurements are to be taken at the same time in relation to echocardiography, blood 
sampling for RAS peptides should be given priority. Other measurements (e.g. ventilator settings) to be
prioritized as per investigator for patient care.
3.
Will be recorded at the time of intubation if available.
4.
Where available, a blood sample is required for arterial blood gases (ABGs) for PaO2/FiO2 and oxygenation 
index. A FiO2 measurement should be assessed at the same time point as ABGs are taken for PaO2.
Any changes in the timing or addition of time points for any planned study assessments 
must be documented and approved by the relevant study team member and then archived 
in the sponsor and site study files, but will not constitute a protocol amendment. The 
Independent Ethics Committees (IEC) will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the ICF.
 
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3.
INTRODUCTION
3.1.
Study Rationale
Right ventricular (RV) dysfunction may result from increased RV afterload secondary to 
increased pulmonary vascular resistance in patients with severe respiratory failure 
including acute respiratory distress syndrome (ARDS). RV dysfunction, particularly 
severe dysfunction [acute cor pulmonale (ACP)], has been associated with worse 
outcomes in critically ill patients including patients with ARDS [Boissier 2013; 
Mekontso-Dessap 2016]. Patients with changes in RV size and pulmonary artery 
pressures [termed pulmonary circulatory dysfunction (PCD)] have also been observed to 
have an increased mortality with particularly high mortality in those patients with ACP 
(designated as severe PCD in this study) [Bull 2010, Boissier 2013]. The renin-
angiotensin system (RAS) is a key regulator of vascular tone in the pulmonary 
vasculature and Angiotensin II (Ang II) in particular is thought to play a role in both 
vasoconstriction and vascular remodelling in human diseases such as pulmonary arterial 
hypertension. RAS peptides such as Ang II and Ang(1-7) may play a role in the observed 
changes in pulmonary vasoconstriction in patients with severe respiratory failure. This 
study is designed to assess whether circulating Ang II and Ang(1-7) levels are associated 
with RV dysfunction in mechanically ventilated patients. It is also designed to further 
characterise the patient population including the severity of RV dysfunction.  
3.2.
Background
Increased pulmonary vascular resistance (PVR) is a common finding in patients with 
severe respiratory failure [Zapol 1977; Bull 2010]. There is evidence of worse outcomes
for patients with increased PVR. PVR has been observed to fall in survivors, whilst 
remaining elevated in patients who died [Zapol 1977]. PVR may often lead to pulmonary 
hypertension and increased RV afterload, a frequent complication of ARDS [Ware 2000]. 
The acutely increased after-load of the RV causes RV dilatation, impaired RV function, 
and reduced cardiac output. Worse outcomes, including increased mortality, have been 
observed in patients with ARDS and RV dysfunction [Bull 2010; Boissier 2013]. In a 
study of 752 patients, hospital mortality in ARDS patients with ACP was 48% (compared 
with 42% in non ACP patients), rising to 57% with severe ACP [Mekontso-Dessap
2016]. Patients with ACP exhibit a higher incidence of shock, increased heart rates and 
lower arterial pressures. 
The mechanism for increased RV afterload in patients with respiratory failure is multi-
factorial and may result from pulmonary vasoconstriction, micro-embolism and/or 
endothelial dysfunction in addition to the direct effects of mechanical ventilation. 
Pulmonary vasoconstriction may be mediator induced and the RAS is a key regulator of 
vascular tone in the pulmonary vasculature. Ang II in particular drives both acute 
vasoconstriction and vascular remodelling in human diseases including pulmonary 
arterial hypertension. Ang(1-7) appears to be a counter-regulatory peptide in the RAS, 
associated with vasodilation, anti-proliferative and anti-inflammatory activity, and 
reduced vascular leak. Specifically, the RAS regulates pulmonary vascular tone with an 
increase in the Ang II/Ang(1-7) ratio, driving increased PVR with subsequent deleterious 
effects on RV function. Therefore, whilst other effects e.g. mechanical ventilation may 
 
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affect pulmonary vascular resistance, in some patients with respiratory failure, activation 
of the RAS may contribute to pulmonary vascular and consequently RV dysfunction. 
Attenuation of RAS-mediated vasoconstriction, without compromising the normo-
adaptive pulmonary vascular response, may improve pulmonary blood flow, cardiac 
output, ventilation/perfusion matching and reduce afterload which should ultimately 
improve outcomes in mechanically ventilated patients. RAS mediated vasoconstriction 
might be improved through the dual action of angiotensin converting enzyme (ACE2) by 
simultaneously reducing Ang II and forming Ang(1-7). Thus, increasing the total amount 
of active enzyme may be beneficial in the treatment of RV dysfunction in patients with 
severe respiratory failure [Tom 2001; Idell 1987; Santos 2003; Wenz 2000].
Data exploring the RAS status and its association with acute changes in pulmonary 
hemodynamics and worsening RV function is limited in patients with severe respiratory 
failure, including in those who are mechanically ventilated. This study is designed to test 
the hypothesis that an association exists between RAS peptides, primarily plasma Ang II 
and Ang(1-7) levels, and RV function in mechanically ventilated patients. The hypothesis 
will be tested by assessing the plasma levels of RAS peptides and RV function as 
measured by echocardiography assessing RV size, sepal kinetics and degree of 
pulmonary hypertension as measured by pulmonary arterial systolic pressure (PASP). A 
secondary aim of the study is to further characterise this population to inform future 
interventional studies, by assessing the incidence and severity of RV dysfunction, and 
assessing the variability of key echocardiographic parameters including RV size and 
PASP as well as RAS peptide levels in mechanically ventilated patients.  An exploratory 
aim of the study is to consider regional lung ventilation and perfusion assessed by global 
inhomogeneity index, which may improve understanding of venitilation/perfusion
matching in patients undergoing mechanical ventilation with changes in pulmonary 
vascular resistance.    
3.3.
Benefit/Risk Assessment
3.3.1.
Risk Assessment
There is no investigational product administered in this study. 
This is a low interventional study without administration of an investigational product. 
All procedures with the exception of 3 blood draws are standard of care in the involved 
centres, including TTE/TOE assessments. Therefore, there is a limited extra risk to the 
participants beyond standard of care.
 
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Potential Risk of 
Clinical Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Study Procedures (if applicable)
Phlebotomy for 
biomarkers: Bruising, 
irritation or redness at 
the site of blood draw 
Blood samples will be 
collected for assessment of 
RAS peptides and other 
biomarkers of relevance 
Careful blood draw to 
minimise bruising, irritation 
and redness; samples may be 
collected from central or 
arterial line already in place. 
3.3.2.
Benefit Assessment
There is no benefit to the individual participant from being included as part of the study.  
3.3.3.
Overall Benefit:Risk Conclusion
Although individual participants will not benefit, the information derived from the study 
will inform future interventions in an area of high unmet medical need. Given the limited 
additional procedures beyond standard of care (3 blood draws) there is limited extra risk 
to the participants beyond standard of care. Consequently, given the potential future 
benefit to critically unwell participants, the small additional risk of the blood draws is 
considered justified. 
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the association between 
plasma Ang II levels and RV function 
in mechanically ventilated 
participants.

Ang II levels 

Echocardiographic measures: 

Ratio of right ventricular to left 
ventricular end-diastolic area

Paradoxical septal motion

PASP estimated from transtricuspid 
pressure and right atrial pressure or 
IVC diameter (whichever is 
available)
Up to and including Day 3 of observation
Secondary 

To define the incidence of ACP and 
PCD in mechanically ventilated 
participants.

Presence of PCD, ACP (severe PCD) 
and severe ACP 
Up to and including Day 3 of observation

To evaluate the association between 
plasma Ang(1-7) levels, 
AngII/Ang(1-7) ratio and RV function 
in mechanically ventilated participants.

Ang(1-7) levels

Ang II/Ang(1-7) ratio 

Echocardiographic measures:

Ratio of right ventricular to left
ventricular end-diastolic area

Paradoxical septal motion 

PASP estimated from transtricuspid 
pressure and right atrial pressure or 
IVC diameter (whichever is 
available)
Up to and including Day 3 of observation
 
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Objectives
Endpoints
Exploratory 

To evaluate the association between 
plasma Ang II and Ang(1-7) levels and 
other measures of right ventricular 
function in mechanically ventilated 
participants. 

Ang II, Ang(1-7) levels  

Echocardiographic measures:

Paradoxical septal motion (systolic 
eccentricity index)

Maximal velocity of s wave (tissue 
Doppler imaging) at the tricuspid 
annulus 

Fractional area contraction (end 
diastolic area minus end systolic 
area normalised to end diastolic 
area)

Acceleration time of RV ejection 
flow

Mean acceleration of RV ejection 
flow (maximum velocity/
acceleration time) at end-expiration 
and end-inspiration

Inferior vena cava diameter at 
end-expiration

Respiratory variations of RV 
velocity time integral (end-
expiration minus end-inspiration
normalised to end-expiration)

Tricuspid annular plane systolic 
excursion (TAPSE) 
Up to and including Day 3 of observation

To evaluate the association between 
plasma Ang II and Ang(1-7) levels and 
other measures of cardiac function and 
pulmonary hemodynamics in 
mechanically ventilated participants. 

Ang II and Ang(1-7)

Central venous pressure (if available)

Mean arterial pressure

Echocardiographic measures:

Respiratory variations of diameter of 
superior vena cava

Cardiac output (pulsed wave 
Doppler, left ventricle (LV) outflow 
track) 

LV ejection fraction 

LV Velocity (E’) tissue doppler 
imaging (TDI) of annulus 

LV early to late ventricular filling 
velocities (E/A)
Up to and including Day 3 of observation
 
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Objectives
Endpoints

To characterise disease severity by 
clinical assessment.

Oxygen saturation (SpO2) via pulse 
oximetry 

pH of arterial blood gases

PaO2/FiO2 ratio

PaCO2

Peak and plateau ventilator pressure

PEEP

Oxygenation index

Static respiratory system compliance

Mean airway pressure

Driving pressure (plateau pressure –
total PEEP)

Clinical Safety labs

Vital Signs 
Up to and including Day 3 of observation

To characterise levels of organ 
dysfunction.
Sequential Organ Failure Assessment 
(SOFA) score
Up to and including Day 3 of observation

To assess the association of cardiac 
and inflammatory biomarkers and RV 
function.

PCD and ACP status

Biomarkers: for example, cardiac 
biomarkers (B-type natriuretic peptide 
(BNP)) or inflammatory biomarkers 
(cytokines such as IL-6, IL-8 and 
sTNFR1) may be analysed as sample 
availability allows
Up to and including Day 3 of observation

To evaluate the association between 
additional markers of the RAS system 
(if samples permit) and 
primary/secondary or exploratory 
endpoints.
Markers could include but are not limited 
to: Ang(1-5) in relation to primary, 
secondary or exploratory endpoints if 
sufficient sample is available
Up to and including Day 3 of observation

To characterize health outcome 
measures.

Duration of intubation

Length of hospital stay 

ICU length of stay 

Ventilator free days 

In ICU and hospital mortality 
Up to 28 days after first echocardiogram

To assess lung ventilation and 
perfusion distribution (in selected site 
only).

Lung regional ventilation and perfusion
with global inhomogeneity (GI) index
Up to and including Day 3 of observation
 
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5.
STUDY DESIGN
5.1.
Overall Design
This study will investigate the association of RAS peptides and markers of RV function 
in participants requiring acute mechanical ventilation. This is a low interventional study 
without an investigational product. Participants will be evaluated over a 3-day period 
using standard of care investigations, including TTE and/or TOE echocardiography. 
Additional investigations will be limited to blood samples for RAS peptides and cardiac
biomarkers (inflammatory markers if samples allow).
Participants will be enrolled in the study following intubation and mechanical ventilation. 
The initial echocardiogram will take place within 48 hours of mechanical ventilation (but 
≤24 hours, whenever possible); this will be considered Day 1. Participants will be 
assessed every 24 hours for a further two days with daily echocardiography to monitor 
right and left ventricular function. Time 0 h for the study will be defined as the start of 
the first echocardiogram. Blood samples for RAS peptides will be collected at the time of 
the echocardiogram on each day. Additional parameters (including ventilator settings and
arterial blood gases) will be collected at the time of intubation and daily as per standard 
of care. Daily assessment of mechanical ventilation and mortality will continue until 
hospital discharge or 28 days whichever is sooner.
Figure 1
Study Schematic
5.2.
Number of Participants
Up to a maximum of 150 participants may be enrolled.  
If participants prematurely discontinue the study, additional replacement participants may 
be recruited at the discretion of the Sponsor in consultation with the investigator.
 
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5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed Day 3 
assessments as shown in the SoA. If participants are extubated after the first 
echocardiogram and prior to the second/third echocardiogram he/she will remain in the 
study and be followed using echocardiography if conducted as per standard of care. In the 
event that further echocardiographs are undertaken, RAS peptide sampling will continue 
as per SoA. 
Participants enrolled but not undergoing any echocardiograms will be considered 
withdrawn from the study.  
The end of the study is defined as the date of last scheduled assessment of the last 
participant in the trial.
5.4.
Scientific Rationale for Study Design
This study is designed to test the hypothesis that an association exists between RAS 
peptides, primarily plasma Ang II and Ang(1-7) levels, and RV function in mechanically 
ventilated participants. Therefore, this a prospective study to collect blood samples to 
assess RAS peptide levels and RV function as measured by echocardiography.
5.5.
Dose Justification
Not applicable as there is no investigational product. 
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
1. Male or female participant must be 18 to 80 years of age inclusive, at the time of 
enrolment. 
2. Participants who are receiving invasive mechanical ventilation (duration of 
ventilation ≤48 hours, but ≤24 hours, whenever possible).
Weight
3. Body mass index within the range 18.0 – 38.0kg/m2 (inclusive). Clinical estimate of 
height and weight is acceptable.
Informed Consent
4. Capable of giving signed informed consent as described in Section 12.3.3 (Appendix
3) which includes compliance with the requirements and restrictions listed in the ICF 
 
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and in this protocol. If participants are not capable of giving signed informed consent 
an emergency consent procedure will be followed as detailed in Section 12.3.3
(Appendix 3).
In France, a subject will be eligible for inclusion in this study only if either affiliated 
to or a beneficiary of a social security category.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Participants who are moribund or whose clinical condition is deteriorating rapidly or 
any participant for whom the investigator does not consider there is a reasonable 
expectation that they will be able to complete the 3 days of observation in the study.
2. Participants undergoing elective surgery. 
Investigator will make every effort to ensure that the following exclusion criteria 3 to 10
are met; however, in some instances it may not be possible to assess all these criteria 
within the 48-hour window.  In this case, a participant can be included, and investigator 
will obtain the information when available.
3. COPD requiring long term oxygen treatment or home mechanical ventilation.
4. Documented pre-existing chronic pulmonary hypertension.
5. Massive pulmonary embolism (defined by pulmonary embolism with systemic 
hypotension (defined as a systolic arterial pressure <90 mmHg or a drop in systolic 
arterial pressure of at least 40 mmHg for at least 15 min which is not caused by new 
onset arrhythmias) or shock (manifested by evidence of tissue hypoperfusion and 
hypoxia, including an altered level of consciousness, oliguria, or cool, clammy 
extremities)).
6. Pulmonary vasculitis or pulmonary haemorrhage including diffuse alveolar 
haemorrhage.
7. Lung transplantation within last 6 months.
8. Cardiopulmonary arrest during concurrent illness.
Concomitant Therapy
9. Any use of RAS modulators including ACE type 1 inhibitors, Renin inhibitors and 
Angiotensin Receptor Blockers within 4 days or 5.5 half-lives, whichever is longer.
If unable to obtain medication history at time of enrolment, participant is allowed to be 
included. 
Other Exclusions
10. Do not resuscitate status.
 
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6.3.
Lifestyle Restrictions
No restrictions are required.
6.4.
Screen Failures
Screen failures are defined as participants who consent (or are consented on behalf of) to 
participate in the clinical study, but are not subsequently enrolled in the study.  A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details and
eligibility criteria.
Individuals who do not meet the criteria for participation in this study (screen failures) 
may not be rescreened. 
7.
TREATMENTS
No investigational product will be administered. Treatments will be based on local 
standard of care including fluid resuscitation, use of vasopressor drugs and renal support. 
Vasopressor use and renal replacement therapy will be documented.
Mechanical ventilation will be applied based on local practice: in the volume-assist 
control mode, with a target tidal volume of 6–8 ml/kg (predicted body weight) and a 
target plateau pressure (Pplat) of <30 cmH2O. Respiratory rate can be increased in case of 
high arterial carbon dioxide partial pressure (PaCO2) level, while avoiding intrinsic 
PEEP. Level of PEEP is left to the discretion of the frontline intensivist.
The use of prone position and use of inhaled nitric oxide is left to the discretion of the 
attending physician but should be documented in the Case Report Form (CRF).
7.1.
Concomitant Therapy
Any prescription medication or vaccine (if known) that the participant is receiving at the 
time of enrolment or receives during the study must be recorded. Specifically collect any 
medication that may affect the RAS, cardiovascular or pulmonary homeostasis including 
but not limited to vasopressors, diuretics, beta blockers, steroids, induction agents such as 
Propofol, and inhaled nitric oxide. 
The date and time of inhaled nitric oxide and vasopressor use must be recorded. 
The following do not need to be documented: medication doses, administration of fluids 
or electrolyte infusions and nutrition.  
 
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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Not applicable as there is no study treatment.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
request by their LAR, or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons.

If a participant withdraws from the study or the LAR requests that the 
participant is withdrawn after consenting, no additional blood samples 
will be taken. Samples already taken but not sent to central laboratory 
can be destroyed at patient or LAR’s request. The investigator must 
document this in the site study records. If the participant withdraws 
consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.

Participants who are withdrawn may be replaced. 
9.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the parameters of each planned study assessment.  Participants will be
evaluated using standard of care investigations including parameters derived from 
ventilator readings, arterial blood gases, safety laboratory measures, and 
echocardiographic readings (TTE and/or TOE). Additional daily blood samples will be 
collected on Days 1, 2 and 3 to assess RAS peptides and other biomarkers which are not 
part of the standard of care. Health outcomes will also be measured including mortality, 
ICU status and ventilator free days up to a maximum of 28 days.
Detailed procedures for obtaining each assessment are provided in the Study Reference 
Manual (SRM). Whenever vital signs, lung function, ventilator settings, echocardiogram 
and blood draws are scheduled for the same nominal time, the assessments should occur 
in the following order: echocardiogram, blood draws, vital signs, ventilator settings, lung
function. The timing of the assessments should allow the blood draw to occur at the exact 
nominal time. Time 0h will be defined as the start of the first echocardiogram.

Study procedures and their timing are summarized in the schedule of assessments 
(SoA; Section 2).

Protocol waivers or exemptions are not allowed. Adherence to the study design 
requirements, including those specified in the SoA, is essential and required for 
study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
 
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log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study for the purpose of meeting the objectives will not exceed 30 mL.  This does 
not include any standard of care assessments.

A single repeat of a sample may be taken for technical reasons as long as they are 
within the timelines defined in the SoA. 
9.1.
Demographic/Medical History Assessments
The following demographic parameters will be captured: year of birth and gender. If it is 
not possible to collect at screening can be collected at any point during the study.
Medical and medication history including cardiovascular risk will be collected. If it is not 
possible to collect at screening can be collected at any point during the study.
Height and weight will be collected at screening. Clinical estimates are acceptable if 
direct measurement is not possible.
9.2.
Pharmacodynamics
9.2.1.
Echocardiograms
As per standard of care, TTE will be conducted on all participants with TOE 
measurements undertaken in those participants in whom adequate windows cannot be 
obtained via the transthoracic route. The first echocardiogram must be undertaken within 
48 hours of the start of mechanical ventilation (but within 24 hours, whenever possible),
with subsequent echocardiograms approximately 24 hours apart on Day 2 and Day 3. As 
previously described [Mekontso-Dessap 2016], echocardiography will be undertaken by 
trained operators in the field of advanced critical care echocardiography and in the case 
of TOE will be performed using a multiplane oesophageal probe. Images will be stored in 
a digital format at site and a computer assisted consensual interpretation will be 
performed off line by at least two trained senior investigators (see SRM for further details 
on echocardiography standards).
Variables that will be recorded from TTE and/or TOE, as data permit, include:

Ratio of right ventricular to left ventricular end-diastolic area

Paradoxical septal motion (systolic eccentricity index) 

PASP (estimated from transtricuspid pressure gradient and right atrial pressure or 
IVC diameter (whichever is available))

Maximal velocity of s wave (tissue Doppler imaging) at the tricuspid annulus
 
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
Fractional area contraction: End Diastolic Area minus End Systolic Area normalised 
to End Diastolic Area 

Acceleration time of RV ejection flow (Tacc)

Mean acceleration of RV ejection flow (maximum velocity/ acceleration time) at 
end-expiration and end-inspiration 

Inferior vena cava diameter at end expiration

Respiratory variations of RV velocity time integral (end-expiration minus             
end-inspiration / end-expiration)

Tricuspid annular plane systolic excursion

Respiratory variations of superior vena cava diameter

Cardiac output (pulsed wave Doppler, LV outflow track) 

LV ejection fraction 

LV Velocity (E’) tissue doppler imaging (TDI) of annulus 

LV Early to late ventricular filling velocities (E/A)
9.2.2.
Electrical Impedance Tomography (EIT)
The Global Inhomogeneity (GI) index will be measured based on electrical impendence 
(Enlight, Timpel, Brazil) to assess lung regional and/or perfusion in centres where 
measurements are taken routinely. Measurements will be taken daily at time of 
echocardiography for up to three days. The GI index will be measured according to the 
methods set out by Zhao 2009.
9.3.
Ventilator Settings
Measurements will include tidal volume, respiratory rates, respiratory static compliance 
of the respiratory system, level of total PEEP, peak and plateau ventilator pressures, mean 
airway pressure and driving pressure.
9.4.
Lung Function
Measurements will include oxygen saturation (SpO2) via pulse oximetry and Partial 
pressure of oxygen and carbon dioxide in arterial blood (PaO2 and PaCO2). The pH, 
lactate and bicarbonate levels of ABGs will also be documented when ABGs are assessed
as well as the base excess/deficit if available. Oxygen requirement (FiO2) will be
collected and documented at the same time as ABG collection.
 
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9.5.
Participant Status
9.5.1.
SAPS II
The SAPS II score is comprised of the following components: 

Age

Heart Rate

Systolic Blood Pressure

Temperature

Mechanical Ventilation or Continuous Positive Airway Pressure

PaO2

FiO2

Urine Output

Blood Urea Nitrogen

Sodium

Potassium

Bicarbonate

Bilirubin

White Blood Cell

Chronic Diseases

Type of Admission

Glasgow Coma Score (GCS)
If the patient is sedated at the time of assessment, an estimated GCS prior to sedation will 
be used instead.
More information is provided in the SRM.
9.5.2.
Sequential Organ Failure Assessment (SOFA) score
The SOFA score is made up of the following components:

PaO2/FiO2 (mmHg)

Mean Arterial Pressure or administration of vasopressors required

Bilirubin

Platelets

Creatinine (or urine output)
 
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Due to the difficulties in accurately scoring Glasgow coma score in sedated patients, the 
neurologic system will not be included.
More information is provided in the SRM.
9.5.3.
Disease diagnosis
Diagnosis of ARDS, PCD and ACP.

ACP is defined as a dilated RV in the mid-esophagus longitudinal view or apical 4-
chamber view [end-diastolic RV / left ventricle (LV) area ratio (0.6)] associated 
with the presence of a septal dyskinesia in the (transgastric) short-axis view of the 
heart.

Severe ACP is defined as severely dilated RV (end-diastolic RV / LV area ratio ≥1) 
with septal dyskinesia. Septal dyskinesia will be particularly sought at end-systole, 
while analysing loops in slow motion.

PCD is defined as moderate dysfunction (PASP [>40 mmHg] or a dilated RV end-
diastolic RV / left ventricle (LV) area ratio [≥0.6] but without septal dyskinesia). In 
case of the inability of measuring transtricuspid pressure gradient, pulmonary 
hypertension will be defined as a Tacc below 100 ms.

ARDS is defined as per the Berlin definition (Ranieri 2012):
Timing 
Within 1 week of a known clinical insult or new or worsening 
respiratory symptoms
Chest imaging
Bilateral opacities—not fully explained by effusions, lobar/lung 
collapse, or nodules
Origin of edema
Respiratory failure not fully explained by cardiac failure or fluid 
overload
Need objective assessment (eg, echocardiography) to exclude 
hydrostatic edema if no risk factor present
Oxygenation
      Mild
200 mm Hg _<  PaO2/FIO2 _ ≤ 300 mm Hg with PEEP or  CPAP 
≥_5 cm H2Oc
      Moderate
100 mm Hg <_ PaO2/FIO2  ≤_ 200 mm Hg with PEEP _5 cm H2O
      Severe
PaO2/FIO2 ≤_ 100 mm Hg with PEEP ≥_5 cm H2O
9.5.4.
General management status
The following measurements of general management status will be recorded at the time 
of echocardiogram for each of the three study days:

Proned status

Intubation status

Management with extracorporeal membrane oxygenation (ECMO) 

Management with extracorporeal CO2 (ECCO2R) removal
 
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9.6.
Additional Clinical assessments
The following data will be collected for up to a maximum of 28 days:

Mortality

ICU status

Ventilator free days
Date and time of any concomitant surgery will also be recorded.
9.7.
Adverse Events
Safety assessments will be conducted as part of standard of care and include serious 
adverse event collection, safety laboratory assessments, and vital signs. More information 
will be provided in the SRM.
9.7.1.
Serious Adverse Events (SAE)
The definitions of an adverse event (AE) or SAE can be found in Appendix 4.
Although no investigational product will be given, SAEs will be recorded, as follows:  
SAEs relating to study procedures; and SAEs related to GlaxoSmithKline (GSK) 
medication used as co-medication. 
This ensures that any SAEs relating to study procedures or any GSK medication used as 
co-medication are captured.
AEs (other than SAEs, as described above) will not be captured in the study.
The investigator is responsible for the detection and documentation of events meeting the
criteria and definition of an SAE, as provided in this protocol. During the study when
there is a safety evaluation, the investigator or site staff will be responsible for detecting,
documenting and reporting SAEs, as detailed in both this section of the protocol and in
the SAE section of the study reference manual.
9.7.2.
Time Period and Frequency for Collecting SAE Information

All SAEs will be collected over the 3 days of study period from the time of 
enrolment.

All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 4. 
The investigator will submit any updated SAE data to the sponsor within 24 hours 
of it being available.

Investigators are not obligated to actively seek SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study procedure or GSK medication, the investigator 
must promptly notify the sponsor.
 
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
The method of recording, evaluating, and assessing causality of SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 
4.
9.7.3.
Method of Detecting SAEs
SAEs will be detected by the medical team. 
9.7.4.
Follow-up of SAEs
After the initial SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is discharged from ICU or up 
to 28 days (whichever is sooner).
9.7.5.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of any GSK product or study 
procedure. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IEC, and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.
9.8.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2) as per 
standard of care.
9.8.1.
Vital Signs

Systolic and diastolic and mean arterial blood pressure and heart rate will be 
assessed.

Blood pressure and heart measurements will be assessed (supine if possible) with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.
9.8.2.
Clinical Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency. 
 
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9.9.
Biomarkers
The following samples are required and will be collected from all participants in this 
study as specified in the SoA

The levels of Ang II and Ang(1-7) will be analysed in plasma. Additional 
components of the RAS [e.g. Ang(1-5)] may be evaluated from the same blood 
sample to better understand the correlation of the RAS to RV function if samples 
allow. 

Collection of samples for other biomarker research is also part of this study. For 
example cardiac biomarkers (eg. BNP) and other biomarkers (eg. Inflammatory 
markers or lung injury markers) may be evaluated if sample availability allows.

Samples will be stored to assess future biomarkers of interest in lung injury 
pathophysiology as sample availability allows.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
Up to 150 participants may be enrolled in the study (as described in Section 5.2). The 
sample size is deemed to be sufficient to evaluate the secondary objectives of the study. 
In particular, the sample size of 150 participants would provide a precision of ±5 
percentage points (defined as the half-width of the 95% Wald confidence interval) around 
a point estimate for ACP incidence (based on an estimated incidence rate of 10%).
The primary analysis (association between Ang II and RV function measured by PASP 
and RV size ratio) will be evaluated after ~50 participants have been enrolled in the 
study. If results are inconclusive, then a second analysis after ~100 participants will be 
carried out. Full details of the assumptions and simulations used to determine the sample 
size are given in Section 12.5.
In the event of a conclusion of "success" or "inconclusive" at an interim analysis, only the 
decision to continue with the study will be communicated with the study sites, to mitigate 
against the possibility of the nature of the interim conclusion influencing the data 
collection process and introducing bias into the later interim and final analysis results. In 
the event of a "futility" decision, recruitment to the study will be halted.
Simulations were carried out to evaluate the operating characteristics of the 
success/futility criteria (described Section 10.3.3) at the primary analysis timepoint (i.e. 
after 50 participants have completed their assessments), under a range of scenarios 
describing the correlation between Ang II and the two endpoints of PASP and RV size 
ratio. The main results from these simulations are as follows:

In the case of there being no relationship between Ang II and either of the 
endpoints, the decision-making criteria will return a conclusion of "futility" 99.1% 
of the time.
 
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
In the case of there being a strong relationship (defined as a correlation of 0.6) 
between Ang II and both of the endpoints, the mean difference in probabilities of 
RV dysfunction between the two reference values will be 33.9%, and the decision-
making criteria will return a conclusion of "success" 74.7% of the time (with 
"inconclusive" being returned the remaining 25.3% of the time).

When the relationship between Ang II and the endpoints is less clear, there is a 
greater likelihood of returning an inconclusive result and continuing the study up to 
the backup interim analysis at 100 participants.

The conclusions returned by the decision-making criteria are more sensitive to Ang 
II's correlation with RV size ratio than to its correlation with PASP. For example, 
when the correlation between Ang II and RV size ratio is reduced from 0.6 to 0.3, 
the decision-making criteria return "success" only 12.6% of the time and the mean 
difference in probabilities of RV dysfunction is 22.5%. Conversely, if the 
correlation between Ang II and PASP is reduced from 0.6 to 0.3, the decision-
making criteria will return "success" 30.1% of the time and the mean difference in 
probabilities of RV dysfunction is only reduced to 26.9%.
A full description of the simulation methods is given in Appendix 5 (Section 12.5) and a 
summary of the results from all the scenarios simulated is given in Table 1.
 
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Table 1
Operating characteristics of decision-making criteria at the primary 
interim analysis (N = 50) under a range of scenarios regarding the 
relationship between Ang II and the two endpoints PASP and RV 
size ratio
a) Probabilities of returning conclusions of success, futility and inconclusive, by scenario
Correlations between Ang II and
Probability of reaching a conclusion of
(%)
PASP
RV size ratio
Success
Futility
Inconclusive
Extreme null scenario: no correlation between Ang II and either component of RV 
dysfunction
0.0
0.0
0.0
99.1
0.9
Extreme positive scenario: strong correlation between Ang II and both components of RV 
dysfunction
0.6
0.6
74.7
0.0
25.3
"Middling" scenario: weak correlation between Ang II and both components of RV 
dysfunction
0.3
0.3
0.6
49.3
50.1
Mixture scenarios (I): Ang II correlated more strongly with PASP than with RV size ratio
0.3
0.0
0.0
92.6
7.4
0.6
0.0
0.6
60.9
38.5
0.6
0.3
12.6
10.9
76.5
Mixture scenarios (II): Ang II correlated more strongly with RV size ratio than with 
PASP
0.0
0.3
0.2
81.3
18.5
0.0
0.6
12.6
12.5
74.9
0.3
0.6
30.1
2.1
67.8
Other assumptions in the simulation: N = 50 participants; correlations between PASP and RV size = 0.5.
For each scenario, results are based on 1000 simulated study datasets, each analysed using a MCMC 
simulation with 3 chains of 1000 iterations (after a burn-in of 1000 iterations) each.
b) Mean difference in predicted probability of RV dysfunction, PASP and RV size ratio 
between estimated pre-dose and post-dose Ang II reference values, by scenario
Correlations between Ang II and
Mean difference between predicted values
PASP
RV size ratio
P (RV 
dysfunction) 
%
PASP 
(mmHg)
RV size 
ratio
Extreme null scenario: no correlation between Ang II and either component of RV 
dysfunction
0.0
0.0
0.3
0.0
0.00
Extreme positive scenario: strong correlation between Ang II and both components of RV 
dysfunction
 
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Correlations between Ang II and
Mean difference between predicted values
PASP
RV size ratio
P (RV 
dysfunction) 
%
PASP 
(mmHg)
RV size 
ratio
0.6
0.6
33.9
5.7
0.11
"Middling" scenario: weak correlation between Ang II and both components of RV 
dysfunction
0.3
0.3
14.9
2.8
0.05
Mixture scenarios (I): Ang II correlated more strongly with PASP than with RV size ratio
0.3
0.0
6.1
2.9
0.00
0.6
0.0
13.2
5.6
0.00
0.6
0.3
22.5
5.6
0.05
Mixture scenarios (II): Ang II correlated more strongly with RV size ratio than with 
PASP
0.0
0.3
9.1
0.0
0.05
0.0
0.6
22.5
0.0
0.11
0.3
0.6
26.9
2.9
0.11
Other assumptions in the simulation: N = 50 participants; correlations between PASP and RV size = 0.5.
For each scenario, results are based on 1000 simulated study datasets, each analysed using a MCMC 
simulation with 3 chains of 1000 iterations (after a burn-in of 1000 iterations) each.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Completed
All participants for whom PASP, RV size ratio, Ang II and Ang(1-7)
data have been recorded for all three study days. For the purpose of 
evaluating ACP incidence, participants who have ACP either on entry or 
occurring during the study period will also be included in this 
population, even if they subsequently do not have three days’ worth of 
study assessments, provided consent is not withdrawn.
Evaluable
All participants for whom PASP, RV size ratio, Ang II and Ang(1-7)
data have been recorded for at least one study time point.
Safety
All participants for whom at least one echocardiograph and/or blood 
sample has been taken.
 
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10.3.
Statistical Analyses
10.3.1.
Pharmacodynamic Analyses
Endpoint
Statistical Analysis Methods
Primary
The association of Ang II with RV function (measured by PASP and RV 
size ratio) will be modelled using a Bayesian repeated measures mixed 
effects linear regression model, where PASP and RV size ratio are joint
response variables, and including subject as a random effect and 
log(Ang II), age and sex as fixed effects. The model will be used to 
make a probabilistic prediction of PASP and RV size ratio for two 
reference values of Ang II, and hence an estimate for the probability of 
RV dysfunction (defined as PASP > 40 mmHg or RV size ratio > 0.6, 
following Boissier 2013) for the two given Ang II levels will be 
obtained using mean values for the other continuous covariates and 
averaging over all levels of class effects for categorical covariates.
The above modelling may use a modified Ang II value (modification 
based on the corresponding Ang(1-7) result to account for potential 
inhibitory interactions); details to be provided in the reporting and 
analysis plan (RAP).
The primary analysis will use the Evaluable population.
Secondary
Association of Ang(1-7) with RV function (measured by PASP and RV 
size ratio) and of Ang II/Ang(1-7) with RV function (measured by 
PASP and RV size ratio) will both be modelled as per the primary 
analysis described above. These analyses will be done using the 
Evaluable population.
A model including both Ang II and Ang(1-7) as co-predictors of RV 
function may also be built, to explore the relationship between RV 
function and the envisaged dual action of angiotensin converting 
enzyme (ACE)2 effecting a reduction in Ang II together with a 
simultaneous increase in Ang(1-7).
Incidence of PCD and ACP during the three days of the study period 
and prevalence of pre-existing PCD/ ACP on entry to the study will be 
reported with 95% confidence intervals. This analysis will be done using 
the Completed population (which includes a clause to include 
participants who have an onset of PCD/ ACP but are subsequently 
withdrawn from the study before all three days' worth of data are 
collected without withdrawing consent).
The distribution of PASP, RV size ratio and other measurements of RV 
function in mechanically ventilated participants will be assessed via a 
combination of descriptive summary tables and outputs from the 
statistical modelling.
Exploratory
Will be described in the reporting and analysis plan
 
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Given that the hypothesis to this study is that RAS-mediated pulmonary vasoconstriction 
may be reduced through the dual action of ACE2 by simultaneously reducing Ang II and 
forming Ang(1-7) (see Section 3.2), an important secondary analysis will be to explore 
the joint effect of both Ang II and Ang(1-7) as related to RV dysfunction. That is to say, 
in addition to exploring the individual hypotheses that Ang II is deleterious to RV 
function and that Ang(1-7) is beneficial, a model will be developed that integrates the 
combined effects of these two mediators, since the expected effect of treatment with 
ACE2 is that both will change. Several models may be analysed in order to explore the 
exact nature of the relationship between the dual action of changes in Ang II and Ang(1-
7) and the probability of RV dysfunction as measured by PASP and RV size ratio.
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. Safety data will be
presented in tabular and/or graphical format and summarised descriptively according to
GSK’s Integrated Data Standards Library (IDSL) standards.
10.3.3.
Interim Analyses
Two interim analyses are planned during the course of this study, both of which will 
provide an opportunity to stop the study for futility (close study to future recruitment but 
allow existing participants to complete the study as planned). A third interim analysis 
may optionally be performed if the second is inconclusive. The primary analysis of the 
association between Ang II and RV function (measured by PASP and RV size ratio) will 
be performed at each interim analysis, and will be used for the purposes of decision-
making. The results of these analyses are to be considered "rules of thumb" and may be 
overridden by other considerations such as an observed association between the 
secondary RAS biomarkers and measurements of RV (dys)function that is strong enough 
to warrant further investigation. The interim analysis may be postponed if there is 
insufficient coverage in the first 25 participants of Ang II values to make an interpolative 
prediction of RV (dys)function for the two pre-specified reference values (see below).
RV function will be measured using PASP and RV size ratio. The general principle 
underlying all the analyses of RV function and RAS peptide biomarkers will be:

Model the joint distribution of PASP and RV size ratio as a function of the RAS 
peptide(s) in question (together with confounding variables also included as 
covariates)

Choose reference values of the RAS peptide(s) in question and estimate a 
posterior distribution of PASP and RV size ratio for those given values, and

Use the posterior distribution to determine the probability of RV dysfunction
(for a future individual participant), defined (following the definition of 
moderate/severe pulmonary circulatory disease given in Figure 2 of Boissier
2013) as:
o
PASP > 40 mmHg
o
RV size ratio > 0.6
 
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The advantage of this method is that all the information on the continuous scales of PASP 
and RV size ratio is maintained throughout the modelling process, and that dichotomising 
participants into binary categories takes place at the end after the modelling has been 
done.
In order to evaluate the estimated effect of administering rhACE2 on RV outcomes (via 
its effect on the RAS peptides), predictions for the probability of RV dysfunction will be 
calculated for specific, pre-determined values of RAS peptide measurements that 
represent reasonable estimates for each RAS peptide both before and after dosing with 
rhACE2 in this patient population. These values will be hereafter referred to as reference 
values. Reference values for the RAS peptides will be defined based on available 
observed data from an investigator sponsored study (NCT01884051) (where RAS 
peptides were observed both before and after dosing with rhACE2) and will be calculated 
using the geometric mean of the observed pre-dose values (for the first reference value, 
hereafter referred to as the pre-dose reference) and the geometric mean of the observed 2 
hours post-dose values (for the second reference value, hereafter referred to as the post-
dose reference). (Note: the terminology "pre-dose" and "post-dose" should not be taken 
to imply that investigational product is used in this study; these values should be taken as 
being borrowed from that interventional study. Furthermore, the term "reference values" 
in this context should not be interpreted as upper or lower limits to the normal range. 
They represent the best guess available for a patient's typical experience before and after 
rhACE2 administration that may reasonably relate to a change in pulmonary 
haemodynamics.)
In the case that an assessment of inconclusive or futile conclusions based on Ang II at an 
interim analysis Ang 1-7 and the ratio of Ang II:Ang1-7 (and/or other peptides of the 
RAS as possible) will be evaluated and may lead to continuation of the study. In all the 
results from the simulation exercises described in this section, Ang II was taken to be the 
analyte in question for the purpose of evaluating the operating characteristics of the 
decision-making criteria, had they been strictly applied, with no fallback on the analyses 
of other RAS peptides. Additionally, for the sake of simplicity, only one measurement 
per participant was assumed (rather than three repeated measurements). This represents 
the worst case scenario (in terms of independence of samples) where all measurements 
within the same participant are perfectly correlated with each other.
At the time of writing, the reference values for Ang II were as follows (based on the two 
available observations of sufficient quality from the aforementioned investigator 
sponsored study (NCT01884051).

Pre-dose reference value: 55.4 pg/ml

Post-dose reference value 7.1 pg/ml
For the purposes of evaluating sample size considerations, these were the reference 
values for Ang II that were used in the assumptions underlying the simulations. An initial 
set of reference values for all RAS peptides measured in this study will be agreed before 
the first subject enters the study, and will be detailed in the RAP.
 
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The first interim analysis will take place after approximately 25 evaluable participants 
have completed the 3 day observational part of the study. The primary analysis of the 
association between Ang II and RV function will be performed and a probabilistic 
prediction for the difference in probability of RV dysfunction associated with a change in 
Ang II from the pre-dose reference value to the post-dose reference value will be 
obtained. If the median estimate of this difference is positive (i.e. probability of RV 
dysfunction at the pre-dose reference value is lower than that at the post-dose reference 
value) then additional follow-on analyses of the association of the other RAS biomarkers 
with RV (dys)function will be conducted. If similar conclusions are drawn from these 
analyses, then the study may be stopped for futility. If an association between another 
RAS biomarker and RV (dys)function is observed in the absence of an association 
between Ang II and RV (dys)function, then this biomarker may be substituted in place of 
Ang II as the primary endpoint for subsequent analyses.
As part of the sample size simulations (see Section 10.1), the operating characteristics of 
the first interim analysis were assessed to evaluate the probability of falsely declaring 
futility after approximately 25 participants when the study would have gone on to show 
success after 150 participants. None of the simulations, in any of the scenarios returned a 
futility result after 25 participants that would have gone on to be a success after 150 
participants. Full results are given in Table 2.
 
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Table 2
Proportion of simulated studies returning conclusion of futility at N
under a range of scenarios regarding the relationship between Ang 
II and the two endpoints PASP and RV size ratio
Correlations between Ang II and
Probability 
(%) of 
futility at 
N=25
Probability 
(%) of 
futility at 
N=25 
followed by 
success at 
N=150
Probability 
(%) of 
futility at 
N=25 
followed by 
inconclusive
at N=150
PASP
RV size ratio
Extreme null scenario: no correlation between Ang II and either component of RV 
dysfunction
0.0
0.0
49.7
0.0
0.0
Extreme positive scenario: strong correlation between Ang II and both components of RV 
dysfunction
0.6
0.6
0.0
0.0
0.0
"Middling" scenario: weak correlation between Ang II and both components of RV 
dysfunction
0.3
0.3
4.6
0.0
1.4
Mixture scenarios (I): Ang II correlated more strongly with PASP than with RV size ratio
0.3
0.0
23.3
0.0
0.1
0.6
0.0
8.3
0.0
1.0
0.6
0.3
0.4
0.0
0.4
Mixture scenarios (II): Ang II correlated more strongly with RV size ratio than with 
PASP
0.0
0.3
13.4
0.0
0.0
0.0
0.6
1.2
0.0
1.2
0.3
0.6
0.1
0.0
0.1
Other assumptions in the simulation: N = 50 participants; correlations between PASP and RV size = 0.5.
For each scenario, results are based on 1000 simulated study datasets, each analysed using a MCMC 
simulation with 3 chains of 1000 iterations (after a burn-in of 1000 iterations) each.
The second interim analysis will take place after approximately 50 evaluable participants 
have completed the 3-day observational part of the. This interim analysis will be used as 
the main go/no-go decision-making point as to whether to continue gathering data on 
biomarkers and other background information and to start internal GSK preparations for 
future interventional studies. The primary analysis of the association between RV 
(dys)function and Ang II will be performed and a probabilistic prediction for the 
difference in the probability of RV dysfunction associated with a change in Ang II from 
the pre-dose reference value to the post-dose reference value will be obtained (as at the 
first interim analysis). The absolute difference between these probabilities will then be 
calculated as and conclusions made as follows:
 
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
If the absolute difference between P(RV dysfunction at the pre-dose reference 
value and P(RV dysfunction at the post-dose reference value) ≤ 15%, then the 
study may be stopped for futility.

If the absolute difference between P(RV dysfunction at the pre-dose reference 
value and P(RV dysfunction at the post-dose reference value) ≥ 30%, then the 
study may continue, collecting biomarker data up to a maximum of 150 
participants, and GSK may begin enabling activities to prepare for a future 
interventional study.

If the absolute difference lies somewhere between these values (i.e. between 15 
and 30%), then a decision will be made by the Sponsor in conjunction with the 
investigator as to whether or not to continue based on observed associations 
between the secondary RAS biomarkers and RV (dys)function in addition to the 
primary analysis. A further interim analysis after 100 participants may 
additionally be performed in this case.
Recruitment will continue whilst the interim analyses are being performed.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
 
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11.
REFERENCES
Boissier F, Katsahian S, Razazi K, Thille AW, Roche-Campo F, Leon R, et al. 
Prevalence and prognosis of cor pulmonale during protective ventilation for acute 
respiratory distress syndrome. Intensive Care Med. 2013 Oct;39(10):1725-1733. 
Bull TM, Clark B, McFann K, Moss M; National Institutes of Health/National Heart, 
Lung, and Blood Institute ARDS Network. Pulmonary vascular dysfunction is associated 
with poor outcomes in patients with acute lung injury. Am J Respir Crit Care Med. 2010 
Nov 1;182(9):1123-1128 
Idell S, Kueppers, F, Lippmann, M, Rosen, H, Niederman, M, Fein, A. ACE elevated in 
ARDS BAL. Angiotensin converting enzyme in bronchoalveolar lavage in ARDS. Chest, 
1987; 91:52-56.
Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, 
Humphries SE, Hill MR, Laurent GJ. Angiotensin converting enzyme insertion/deletion 
polymorphism is associated with susceptibility and outcome in acute respiratory distress 
syndrome. Am J Respir Crit Care Med. 2002 Sep 1; 166(5):646-650.
Mekontso-Dessap A, Boissier F, Charron C, Bégot E, Repessé X, Legras A, Brun-
Buisson C, Vignon P, Vieillard-Baron A. Acute cor pulmonale during protective 
ventilation for acute respiratory distress syndrome: prevalence, predictors, and clinical 
impact. Intensive Care Med. 2016 May; 42(5):862-870. 
Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, 
Camporota L, Slutsky AS (ARDS Definition Task Force). Acute respiratory distress 
syndrome: the Berlin Definition. JAMA. 2012; 307(23):2526-33. 
Santos RAS, Simoes e Silva, AC, Maric, C, Silva, DMR, machado, RP, de Buhr, 
I,Heringer-Walther, S, Pinheiro, SVB, Lopes, MT, Bader, M, Mendes, EP, Soares 
Lemos,V, Campagnole-Santos, MJ, Schultheiss, H-P, Speth, R and Walther, T. ANG (1-
7) as the agonist of mas. ‘Angiotensin (1-7) is an endogenous ligand for the G-protein 
coupled receptor Mas’ Proc. Natl. Acad. Sci. USA. 2003; 100:8258-8263.
Tom B, de Vries R, Saxena PR, Danser AH. Bradykinin potentiation by angiotensin-(1-7) 
and ACE inhibitors correlates with ACE C- and N-domain blockade. Hypertension. 2001 
Jul; 38(1):95-99.
Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 
May 4; 342(18):1334-49.
Wenz M, Hoffmann, B, Bohlender, J, Kaczmarczyk, G. ANG II elevated in 
ARDS.Anfgiotensin II formation and endothelin clearance in ARDS participants in 
supine and prone positions. Intensive Care Med. 2000; 26:292-298.
Zapol WM, Snider MT: Pulmonary hypertension in severe acute respiratory failure. N 
Engl J Med 1977, 296: 476–480.
 
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Zhao Z1, Möller K, Steinmann D, Frerichs I, Guttmann J. Evaluation of an electrical 
impedance tomography-based Global Inhomogeneity Index for pulmonary ventilation 
distribution.Intensive Care Med. 2009 Nov;35(11):1900-6
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
ABG
Arterial Blood Gases 
ACP
Acute Cor Pulmonale
ACE
Angiotensin Converting Enzyme
rhACE2
Recombinant Human Angiotensin 
Converting Enzyme 2
AE
Adverse Event 
Ang
Angiotensin
ARDS
Acute Respiratory Distress Syndrome
CRF
Case Report Form
CO2
Carbon Dioxide 
CONSORT
Consolidated Standards of Reporting Trials
cmH2O
Centimeter of Water
E’
LV Velocity
FiO2
Oxygen Requirement
GCS
Glasgow Coma Score
GI
Global Inhomogeneity
GSK
GlaxoSmithKline
h
Hour
ICF
Informed Consent Form 
ICU
Intensive Care Unit
IDSL
Integrated Data Standards Library 
IEC
Independent Ethics Committee 
IRB
Institutional Review Board
IVC
Inferior Vena Cava
Kg/m2
Kilogram/Square Meter
LAR
Legally Acceptable Representative 
LV
Left Ventricle 
Mins
Minutes
mL
Milliliter
mmHg
Millimeter of Mercury
ms
Millisecond
PaCO2
Partial Pressure of Carbon Dioxide
PaO2
Partial Pressure of Oxygen 
PASP
Pulmonary Arterial Systolic Pressure 
PCD
Pulmonary Circulatory Dysfunction
PEEP
Positive End Expiratory Pressure
Pg/ml
Picograms per millilitre
Pplat
Target Plateau Pressure 
PI
Principle Investigator 
PVR
Pulmonary Vascular Resistance
RAP
Reporting and Analysis Plan
RAS
Renin Angiotensin System
 
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RV
Right Ventriculum
SAE
Serious Adverse Event
SAPS 
Simplified Acute Physiology Score
SaO2
Oxygen Saturation
SoA
Schedule of Assessments 
SOFA
Sequential Organ Failure Assessment
SRM
Study Reference Manual 
SUSAR
Suspected Unexpected Serious Adverse 
Reactions
TAPSE
Tricuspid Annular Plane Systolic 
Excursion
TDI
Tissue Doppler Imaging 
TOE
Transesophageal echocardiography
TTE
Transthoracic echocardiography
SpO2
Oxygen Saturation
Trademark Information
Trademarks of the GlaxoSmithKline group 
of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the local laboratory.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 3
Protocol-Required Safety Laboratory Assessments
Collected as per standard of care  
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
WBC (absolute)
Haemoglobin
Haematocrit
Clinical 
Chemistry
BUN
Potassium
Total bilirubin
Creatinine
Sodium
Troponin I or T
Chloride
Total CO2
 
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12.3.
Appendix 3: Study Governance Considerations
12.3.1.
Ethical Considerations
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki

This study will be conducted in accordance with the protocol and with:
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
Applicable ICH Good Clinical Practice (GCP) Guidelines
Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IEC by the investigator and 
reviewed and approved by the IEC before the study is initiated. 

Any amendments to the protocol will require IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 

The investigator will be responsible for the following:
Providing written summaries of the status of the study to the IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IEC
Notifying the IEC of SAE or other significant safety findings as required by IEC 
procedures
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
12.3.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
12.3.3.
Informed Consent Process
Given participants may be mechanically ventilated upon enrolment, obtaining informed 
consent directly from the participants may not always be feasible. Therefore, participants
may be enrolled in three ways:
 
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1.
Participant is enrolled by signing the informed consent
If the participant is capable of understanding and signing the informed consent prior to 
enrolment, the below points will apply:

The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.
2.
Participant is enrolled by his/her LAR 
If the participant is unable to provide informed consent, best efforts will be undertaken by 
the investigator or delegate to obtain consent from a LAR prior to enrolment.  If consent 
is obtained from a LAR, the following points will apply:

Best efforts will be undertaken to obtain written consent from a LAR; however,
if only oral LAR consent is feasible, participants can be enrolled on LAR’s oral 
consent and a written LAR consent will be sought as soon as possible thereafter.

The investigator has responsibility for applying local laws in the matter of who 
has the capacity to consent and who qualifies as a LAR of a potential subject.

A LAR is defined as an individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical trial.

LAR can be a member of the participant’s family, next-of-kin or trusted person 
previously designated by the participant.

As soon as is practically possible following a participant regaining capacity, 
participants will be asked to provide informed consent to remain in the study.  If 
they decline, then they will be withdrawn from the study. The subjects will 
decide if they want to allow samples already collected to be used or request for 
them to be discarded if not yet analysed.  
3.
Participant is enrolled upon emergency consent process
If the participant in unable to provide informed consent and the LAR cannot be reached 
when the study selection criteria are fulfilled, the investigator will be able to enrol the 
participant according to the emergency consent process, and the following points will 
apply.

The emergency consent process is indicated in last resort (article L1122-1-2 of 
French Public Health code) as per the following arguments: the urgency and 
gravity of the situation has mandated invasive mechanical ventilation and 
intensive care admission; the use of echocardiography for hemodynamic 
monitoring is routine in the participating centres in this situation.
 
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
As soon as it is practically possible following a participant regaining capacity, 
participants will be asked to provide informed consent to remain in the study.  If 
they decline, then they will be withdrawn from the study. The participants will 
decide if they want to allow samples already collected to be used or request for 
them to be discarded if not yet analysed.  
Documentation of Informed consent process
The management of the informed consent process will be documented in the medical 
source document.  This will include which process was used to obtain consent. 
The following should be noted in regard to the informed consent process: 

If consent is provided by LAR, name, time and date of LAR and name of the 
personnel at site that collected this information 
If consent is not obtained the time and date of attempt(s) must be collected along with the 
name(s) of LAR and personnel at site that attempted contact. Participants/LAR must be 
informed that their participation is voluntary. Participants and/or LAR will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IEC or study centre. 
A copy of the signed ICF(s) must be provided to the participant or the participant’s LAR.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IEC members, and by inspectors from regulatory 
authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicentre studies only in their entirety and not as 
 
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individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Study information from this protocol will be posted on publicly available clinical 
trial registers before enrolment of subjects begins.

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator will 
be provided reasonable access to statistical tables, figures, and relevant reports and 
will have the opportunity to review the complete study results at a GSK site or 
other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results. 
The investigator is encouraged to share the summary results with the study subjects, 
as appropriate.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
Data Quality Assurance 

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
 
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unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor. 
Source Documents 

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.
Study and Site Closure 
GSK or its designee reserves the right to close the study site(s) or terminate the study at 
any time for any reason at the sole discretion of GSK. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment*, whether or not considered related to 
the study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
*Although there is no “study treatment” in this study, AE/SAE definitions still apply to 
reports of serious adverse events explicitly attributed to GSK products or to study 
procedures.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of concomitant 
GSK product. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
 
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Events NOT Meeting the AE Definition 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
 
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A SAE is defined as any untoward medical occurrence that:
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
Recording SAE
SAE Recording

When a SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study procedure, 
GSK product and each occurrence of each SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.
 
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Assessment of Causality

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each SAE, the investigator must document in the medical notes that he/she has 
reviewed the SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. New or updated information will be recorded in 
the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next Section).
 
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SAE Reporting to GSK via Electronic Data Collection Tool

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to study procedure or GSK product (causality) within 72 
hours of SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next Section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.
 
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12.5.
Appendix 5: Assumptions for sample size calculations
12.5.1.
Distribution of Ang II
For the purposes of these sample size calculations, Ang II was chosen as the primary 
explanatory variable. This choice is based on the a priori belief that lowering Ang II is 
associated with improvements in RV outcomes. Similar modelling approaches can be 
applied to other RAS biomarkers, in particular Ang(1-7) (the other component of the dual 
action of Angiotensin Converting Enzyme (ACE)2); indeed these will be applied in the 
final analysis. However, for the purposes of defining sensible decision criteria, and 
assessing whether the proposed sample size of 50 participants (for the primary interim 
analysis) is suitable for purpose, only Ang II is considered in these simulations.
The assumptions underlying the distribution of Ang II in the participant population are as 
follows:

Ang II follows log-normal distribution with mean and standard deviation as observed 
in 42 participants of the previous ARDS study (ACE114622; baseline 
measurements)

Geometric mean of 16.1 pg/ml.

Standard deviation of log(Ang II) is 1.74; equivalent to 5.7-fold change in 
Ang II.

Implies that ~⅔ of population will be in the range (2.8, 92.1) (one SD 
below mean to one SD above mean)
Figure 2
Distribution of observed Ang II in study ACE116422 with super-
imposed normal distribution curve
 
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12.5.2.
Definition of outcome: an objective measure of right ventricular 
(RV) dysfunction
Following the definition of moderate pulmonary circulatory dysfunction (PCD) presented 
by Boissier 2013, quantitative criteria for an objective measurement of right ventricular 
(RV) dysfunction were set out as follows:

A participant is defined as having right ventricular (RV) dysfunction if one of the 
following two criteria is true:

pulmonary arterial systolic pressure (PASP) > 40 mmHg

ratio of the right ventricular to the left ventricular end-diastolic areas 
(hereafter referred to as RV size ratio) > 0.6
These two criteria can be represented on a 2-dimensional plane divided into two regions 
representing "no RV dysfunction" and "RV dysfunction" (Figure 3a).
However, rather than dichotomising participants into those with and those without RV 
dysfunction based on individual measurements (Figure 3b), the two component 
variables, PASP and RV size ratio, will be modelled as bivariate continuous outcomes, 
with Angiotensin II (Ang-II) level as a continuous predictor variable. The joint posterior 
distribution of PASP and RV size ratio for given reference levels of Ang-II will be 
calculated based on the observed data, and a posterior probability of the mean PASP and 
mean RV jointly lying in the "RV dysfunction" region of the plane calculated from these 
posterior distributions (Figure 3c).
 
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Figure 3
Illustration of the process of modelling the joint distribution of PASP 
and RV size ratio and obtaining a predicted probability of RV 
dysfunction for given Ang II levels
a) The criteria used for defining RV dysfunction 
are represented as a plane divided into two 
regions. Points (representing participant data) 
lying in the green region are categorised as not 
having RV dysfunction ("normal"), points lying 
in the grey region are categorised as having RV 
dysfunction ("dysfunctional").
b) Illustrative mock data showing simulated 
values of the two component variables RV 
dysfunction (PASP and RV size ratio, represented 
on the x and y axes) and their relationship to  Ang 
II values (represented by colour). It is possible to 
dichotomise participants into those with RV 
dysfunction and those with normal RV function at 
this stage; this is not the approach proposed here.
 
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c) Illustration of posterior prediction regions for 
the two component variables of RV dysfunction 
for two reference values of Ang II.  Instead of 
modelling the association of Ang II with the 
dichotomised RV dysfunction response variable 
(and losing the information from the continuous 
variables), a Bayesian linear regression model is 
fitted with PASP and RV size ratio as bivariate 
outcome variables and Ang II as the explanatory 
variable. Prediction regions and the probability of 
RV dysfunction (defined as the weighted 
proportion of the prediction region being within 
the grey region of the plane) are calculated for 
two reference Ang II values. The absolute 
difference between these two probabilities is then 
calculated. If this difference is ≥30%, then the 
relationship between Ang II and RV dysfunction 
is considered strong enough for there to be 
potential for the action of ACE2 on Ang II to be 
of clinical benefit and further study to be 
conducted ("success"). If the difference is ≤15%, 
then the relationship is considered too weak to 
warrant further inquiry ("futile"). The reference 
values are derived as the geometric mean of the 
observed Ang II values at pre-dose and at 2 hours 
post rhACE2 dose in the investigator sponsored 
study (NCT01884051).
12.5.3.
"Success" and "futility" criteria
Criteria for "success" (that is to say, the strength of association between Ang II and RV 
dysfunction required to confirm potential for the effect of rhACE2 on Ang II to yield 
clinical benefits, warranting further study) and "futility" (an association too weak to 
justify continuing development) are based on posterior predictive regions for PASP and 
RV size ratio for two given Ang II values. These reference values are the geometric mean 
of observed pre-dose and 2 hours’ post-dose Ang II values from an investigator-
sponsored study (NCT01884051), and represent the best estimate for a typical "before 
rhACE2" and "after rhACE2" measurement. The reference values used in this simulation 
are based on the two participants in that study for which, at the time of writing, data of 
sufficient reliability were available, and were derived as follows:

Pre-dose Ang II: 55.4 pg/ml (geometric mean of 121.3 and 25.3 pg/ml)

Post-dose Ang II: 7.1 pg/ml (geometric mean of 16.3 and 3.1 pg/ml)
"Success" and "futility" criteria are derived using the predicted probabilities of RV 
dysfunction for a hypothetical future participant with the reference values listed above. 
The predicted probability of RV dysfunction for a given Ang II value is defined as the 
proportion of the posterior joint predicted region of PASP and RV size ratio (weighted by 
density) that satisfies the criteria for RV dysfunction (i.e. what portion of the prediction 
region lies in the grey zone in Figure 3). The absolute difference between the two 
 
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probabilities is then calculated and compared with the following criteria for success or 
futility (for N = 50, 100 and 150):

"Success": P(RV dysfunction when Ang II = 55.4) - P(RV dysfunction 
when Ang II = 7.1) ≥ 30%

"Futile": P(RV dysfunction when Ang II = 55.4) - P(RV dysfunction when 
Ang II = 7.1) ≤ 15%
The results are deemed "inconclusive" otherwise.
For N = 25, a conclusion of futile was returned if the difference between P (RV 
dysfunction when Ang II = 55.4) and P (RV dysfunction when Ang II = 7.1) was 
negative. A result of inconclusive was returned otherwise.
12.5.4.
Assumptions for simulated datasets
A simulation was carried out to assess the operating characteristics of the above success 
and futility criteria, given reasonable assumptions for the distributions of PASP, RV size 
and Ang II, and the three pairwise correlations between them.
The assumptions for the distributions of these variables are as follows:

Ang II is log-normally distributed, with mean(log(Ang II)) = 2.78 and 
SD(log(Ang II)) = 1.74 (as described above)

PASP is normally distributed, with mean(PASP) = 38 mmHg and 
SD(PASP) = 8 mmHg

RV size ratio is normally distributed, with mean(RV size ratio) = 0.61 and 
SD(RV size ratio) = 0.15
The assumed pairwise correlations between these three variables were as follows:

The correlation between PASP and RV size ratio (the two outcome 
variables) was assumed to be 0.5

Three different scenarios each for the correlation between PASP and 
log(Ang II), and between RV size ratio and log(Ang II) were considered 
(for a total of nine scenarios in all): zero, 0.3 and 0.6. This was to test the 
operating characteristics for a wide variety of scenarios ranging from "no 
association whatsoever" (both correlations zero) to "Ang II strongly 
correlated with both components of RV dysfunction" (both correlations 
0.6).
A single simulated study dataset consisted of 50 values for Ang II, PASP and RV size, 
drawn from a multi-variate normal distribution with the above characteristics.
For each of the nine scenarios, a total of 1000 study datasets were generated and 
analysed, which was the maximum that was feasible given computational constraints.
 
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12.5.5.
Analysis of simulated data
For each individual study dataset that was generated, the relationship between Ang II (as 
the explanatory variable) and the joint bivariate distribution of PASP and RV size ratio 
(the outcome variables) was analysed using a Bayesian multivariate linear regression 
model. Estimates for the posterior distributions of coefficients in the model were obtained 
using an MCMC simulation (using Gibbs sampling) running three chains of 2000 
iterations each. The first 1000 iterations of each chain were discarded (the "burn-in") and 
the posterior distributions estimated from the 3000 remaining iterations (1000 from each 
chain).
The multivariate normal model was specified as follows:



















,
~
2
1
2
1
i
i
i
i
MVNormal
y
y


where yij represents the observed value for the ith subject and the jth outcome (i.e. j=1
representing PASP and j=2 representing RV size ratio), µij represents the expected value 
for the ith subject and the jth outcome (j=1 and j=2 as above), and Σ represents a 2×2 
variance-covariance matrix for the two outcome variables. The expected values, µij, are 
modelled as follows:
i
j
j
ij
x





where αj is the intercept term for the jth outcome (i.e. PASP or RV size), βj represents the 
slope coefficient for log(Ang II) in the model, and xi represents the observed log(Ang II) 
value for the ith subject. For simplicity the simulations have no additional covariates (e.g. 
age, sex), and do not take into account multiple observations in the same participant (i.e. 
they represent the extreme worst case scenario where there is perfect within-participant 
correlation of all variables).
Uninformative prior distributions are assigned for α, β, and σ as follows:

α is assigned a bivariate normal distribution with mean zero (for both 
outcomes), large variances (for both outcomes) and zero covariance 
(between the two outcomes),

β is assigned a bivariate normal distribution with the same specifications 
as for α,

Τ, defined as the inverse of Σ, is assigned an uninformative Wishart prior 
distribution: T ~ Wishart(R, df) where:







001
.0
0
0
001
.0
R
and df=3.
 
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12.5.6.
Metrics for operating characteristics
For each scenario, 1000 simulated datasets of 150 participants each were generated and 
analysed according to the above modelling process, and the following metrics were 
calculated for the first 25, 50, 100 and the whole 150-participant dataset using the 1000 
results so generated:

the proportion of studies returning "success" results

the proportion of studies returning "futile" results

the proportion of studies returning “inconclusive” results

the mean absolute difference in predicted P(RV dysfunction) between the 
two reference Ang II values

the mean difference in predicted PASP between the two reference Ang II 
values

the mean difference in predicted RV size ratio between the two reference 
Ang II values
Results are summarised for the nine scenarios and presented in the main body of the 
protocol (Section 10.1 and Section 10.3.3).
 
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12.6.
Appendix 6: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents.
Protocol Amendment 2 (27-Nov-2017)
Overall Rationale for the Amendment: In this amendment, an exploratory outcome and 
emergency consent have been added. In addition, clarification was added throughout the 
protocol. 
Section # and Name
Description of Change
Brief Rationale
2. Schedule of Assessments
Added Sequential Organ 
Failure (SOFA) score
Clarification that SOFA will be 
calculated on a daily basis. All 
components needed to 
calculate the score were 
already being collected. 
2. Schedule of Assessments
The following language was 
added in Footnote 2 of 
Schedule of Assessments:
Other measurements (e.g. 
ventilator settings) to be 
prioritized as per investigator 
for patient care. 
The timing of exploratory 
outcomes can be prioritized by 
investigators in the best interest 
of patients as part of standard 
of care. 
2. Schedule of Assessments
A note was added that SAPS 
II will only be measured at 
screening.
The timing of the assessment 
was clarified.
2. Schedule of Assessments
4. Objectives and Endpoints
9.5.5 General management 
status
Added Participant 
Management which includes 
use of ECMO and ECCO2R. 
Sites have recently included 
use of ECMO and ECCO2R as 
part of patient’s standard 
management. The use needs to 
be documented in case of
interaction with outcomes.
2. Schedule of Assessments
4. Objectives and Endpoints 
9.3 Ventilator settings
Static compliance was added 
as a measurement that will be 
collected with other ventilator 
settings. 
It had previously been missed; 
static compliance is a standard 
measure read from the 
ventilator.
2. Schedule of assessments
4. Objectives and Endpoints
9.4 Lung Function
pH and base excess were 
added as measurements that 
will be collected with other 
lung function measurements.  
These measurements had 
previously been missed.

pH is a standard measure 
automatically calculated 
from blood gas analysis. 

Base excess is a standard 
blood gas analysis. 
Depending on the base 
status of the patient a base 
 
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Section # and Name
Description of Change
Brief Rationale
excess result may be 
collected rather than base 
deficit.
2. Schedule of Assessments
4. Objectives and Endpoints
9.9 Biomarkers
12.2 Appendix 2: Clinical 
Laboratory Tests
Troponin I or T was removed 
from the schedule of 
assessments, objectives and 
endpoints and biomarker 
sections and added to Table 
3. Protocol required safety 
laboratory assessments.
Troponin I or T was removed as 
a test performed by GSK and 
will be performed as a safety 
lab by sites when taken as 
standard of care.
4. Objectives and Endpoints 
Systolic eccentricity index was 
moved from Primary to 
exploratory endpoint. 
The primary analysis will use 
the binary outcome of 
paradoxical septal motion. 
Systolic eccentricity index is a 
continuous variable and was 
included in the primary endpoint 
in error. This will now be 
analysed separately as an 
exploratory outcome.
4. Objectives and Endpoints
9.2.2 Electrical Impedance 
Tomography (EIT) 
New exploratory objective was 
added. 
EIT assesses lung ventilation 
and perfusion. Understanding 
regional ventilation/perfusion 
may be of importance in 
understanding the role of the 
RAS in ventilation/perfusion 
matching in severe respiratory 
failure.
4. Objectives and Endpoints
9.2.1 Echocardiograms 
It was added that the inferior 
vena cava diameter will be 
taken at end-expiration.
The formula for calculating 
Respiratory variations of RV 
velocity time integral was 
added for completeness. The 
formula is (end-expiration 
minus end-inspiration / end-
expiration).
Values that will be recorded 
from the echocardiograms were 
further defined for clarity.
9.1 Demographic/Medical 
History Assessments
Clarification was added that 
demographic and medical 
history assessments could be 
collected at any point in the 
study if it is not possible at 
screening. 
Whilst important to collect this 
data where possible, 
sometimes it is extremely
challenging to collect in the 
acute care setting.
 
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Section # and Name
Description of Change
Brief Rationale
9.5.2 SAPS II
It was clarified that an 
estimated GCS can be used if 
a patient is sedated at the 
time of assessment 
When a patient is sedated the 
GCS cannot be calculated, 
therefore an estimate prior to 
sedation must be used (where 
available).
9.5.3 Disease Diagnosis
ARDS Definition was added.
The definition was missing from 
previous version.  
9.5.3 Disease Diagnosis
PCD definition clarified
Definition was previously 
missing > and ≥ for PASP and 
RV size respectively.  
9.6 Additional clinical 
assessments
It was defined that date and 
time of only concomitant 
surgery will be recorded.
To clarify that only concomitant 
surgery needs to be recorded. 
9.9 Biomarkers
Troponin I or T was removed 
as a test performed by GSK 
and will be performed by sites 
when taken as standard of 
care.
Clarified that samples will be 
stored, and other biomarkers 
may be assessed eg. BNP 
and eg. Inflammatory 
markers/lung injury markers.
Troponin I or T cannot be 
measured at GSK.
To clarify other biomarkers may 
be tested and samples will be 
stored. 
10.3.1 Pharmacodynamics 
Analyses
Statistical analysis (PD) 
wording updated to clarify the 
rationale for additional RAS 
peptide analyses.
The biological effects of the 
RAS are complex and effects of 
peptides beyond Ang II (peptide 
to be assessed in primary 
analysis) may be observed e.g. 
Ang 1-7.
12.2 Appendix 2: Clinical 
Laboratory Tests
It was clarified that the safety 
assessments in Table 3 will be 
as per standard of care.
To ensure assessments are 
only completed as per standard 
of care 
12.3.3 Informed consent 
process
The option to enrol a 
participant with emergency 
consent was added.
To ensure the consenting 
process is appropriate for the 
participant population.
Throughout 
Deleted mention of 
Institutional Review Board 
(IRB) throughout.
This protocol does not require 
submission to an IRB due to 
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Protocol Amendment 1 (02-Jun-2017)
Overall Rationale for the Amendment: Protocol was amended to remove the option for 
participants to be included without informed consent and to change errors in the previous 
version.
Section # and Name
Description of Change
Brief Rationale
2. Schedule of 
Assessments 
And
9.1 Demography and 
Medical History 
Assessments
Height & Weight assessment 
were added as they were 
missed from the prior version. 
Prior version mentioned these parameters 
only under the inclusion criteria, but 
missed them in Section 2 and Section 9.1.
2. Schedule of 
Assessments
Assessments of Diagnosis of 
PCD & ACP were removed 
from Participant status and 
added as a separate line. 
To provide more clarity on the time points 
of these assessments. 
9.5.1 SAPS II
Glasgow Coma scale was 
removed from the 
components defined for the 
SAPS II score.
It was incorrectly included in the prior 
version. 
12.3.3 
Informed consent 
process and 6.1 
inclusion criteria 
Removed the option for 
participants to be included 
without informed consent.  
It was decided participants must have a 
signed informed consent by their legally 
acceptable representative prior to 
enrolment. 
 
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SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205821
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study to elucidate the 
association of the Renin-angiotensin system and right 
ventricular function in mechanically ventilated patients
Compound Number 
:
GSK2586881
Effective Date 
:
30-JUL-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205821.

The final RAP has been written with the knowledge that the study / project had been 
terminated early and describes the agreed strategy of only reporting the primary and 
secondary outcomes.

This RAP will be provided to the study team members to convey the content of the 
SAC deliverable.

This RAP also captures additional clarifications / details to the Critical components 
version (e.g. clarifies the algorithm for choosing between TTE and TOE results per 
variable)
RAP Author(s):
Approver
Date
Approval Method
12-JUL-2019
e-mail (archived in 
Pharma TMF)
Director (Respiratory Biostatistics)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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RAP Team Review Confirmations:
Approver
Date
Review 
Confirmation 
Method
30-JUL-2019
e-mail (archived in 
Pharma TMF)
Lead Programmer (Development Biostatistics)
(MD)
15-JUL-2019
e-mail (archived in 
Pharma TMF)
Project Physician Lead (Discovery Medicine
Clinical Pharmacology and Experimental 
Medicine)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
30-JUL-2019
e-signature 
(PharmaTMF)
Director (Respiratory, Clinical Statistics)
29-JUL-2019
e-signature 
(PharmaTMF)
Programming Manager (Clinical Programming)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
5.1.
Study Treatment & Sub-group Display Descriptors.....................................14
5.2.
Baseline Definitions ....................................................................................14
5.3.
Examination of Covariates, Other Strata and Subgroups............................14
5.3.1.
Covariates and Other Strata ........................................................14
5.3.2.
Examination of Subgroups...........................................................14
5.4.
Multiple Comparisons and Multiplicity .........................................................15
5.5.
Display order of Echocardiography endpoints (source: SI.CV)....................16
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Study Population Analyses........................................18
7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES........................................19
7.1.
Primary Pharmacodynamic/Biomarker Analyses.........................................19
7.1.1.
Endpoint / Variables.....................................................................19
7.1.2.
Summary Measure ......................................................................19
7.1.3.
Population of Interest...................................................................20
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................20
7.1.5.
Statistical Analyses / Methods .....................................................20
7.1.5.1.
Statistical Methodology Specification..........................25
7.2.
Secondary Efficacy Analyses......................................................................26
7.2.1.
Endpoint / Variables.....................................................................26
7.2.2.
Summary Measure ......................................................................26
7.2.3.
Population of Interest...................................................................27
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................27
7.2.5.
Statistical Analyses / Methods .....................................................28
7.2.5.1.
Supportive Models to the Primary analysis, 
using other RAS peptides in place of Ang II................28
7.2.5.2.
Combined model of the joint association of Ang 
II and Ang (1-7) with RV function................................28
 
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7.2.5.3.
Analysis of disease incidence within the 
mechanically ventilated population .............................31
7.3.
Exploratory Efficacy Analyses.....................................................................32
8.
SAFETY ANALYSES .............................................................................................33
8.1.
Adverse Events Analyses ...........................................................................33
8.2.
Clinical Laboratory and Other Safety Analyses ...........................................33
9.
REFERENCES.......................................................................................................34
10. APPENDICES........................................................................................................35
10.1.
Appendix 1: Protocol Deviation Management and Definitions for 
Evaluable Population ..................................................................................35
10.1.1.
Exclusions from Evaluable Population .........................................35
10.2.
Appendix 2: Schedule of Activities ..............................................................36
10.2.1.
Protocol Defined Schedule of Events...........................................36
10.3.
Appendix 3: Assessment Windows .............................................................39
10.3.1.
Definitions of Assessment Windows for Analyses........................39
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................40
10.4.1.
Study Phases ..............................................................................40
10.4.1.1.
Study Phases for Concomitant Medication .................40
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................41
10.5.1.
Reporting Process .......................................................................41
10.5.2.
Reporting Standards....................................................................41
10.6.
Appendix 6: Derived and Transformed Data ...............................................43
10.6.1.
General........................................................................................43
10.6.2.
Study Population..........................................................................43
10.6.3.
Pharmacodynamic / Biomarker....................................................43
10.6.4.
Reason for Intubation ..................................................................44
10.6.5.
Oxygenation Index (OI)................................................................45
10.6.6.
Echocardiogram (Choosing between TTE and TOE results 
for subsequent statistical analyses) .............................................45
10.6.7.
Sequential Organ Failure Assessment (SOFA) score ..................49
10.6.8.
Oxygen Saturation.......................................................................51
10.6.9.
Calculation of PaO2 / FiO2 and SpO2 / FiO2...............................51
10.6.10. Construction of ARDATA.ALLCVTS.............................................51
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................63
10.7.1.
Premature Withdrawals................................................................63
10.7.2.
Handling of Missing Data.............................................................63
10.7.2.1.
Handling of Missing and Partial Dates/Times..............63
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................65
10.8.1.
Laboratory Values........................................................................65
10.8.2.
Vital Signs....................................................................................66
10.9.
Appendix 9: Abbreviations & Trade Marks ..................................................67
10.9.1.
Abbreviations...............................................................................67
10.9.2.
Trademarks .................................................................................68
10.10. Appendix 10: List of Data Displays..............................................................69
10.10.1. Data Display Numbering..............................................................69
10.10.2. Mock Example Shell Referencing ................................................69
10.10.3. Deliverables.................................................................................69
10.10.4. Study Population Tables..............................................................70
 
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10.10.5. Safety Tables...............................................................................73
10.10.6. Pharmacodynamic and Biomarker Tables....................................75
10.10.7. Pharmacodynamic and Biomarker Figures ..................................77
10.10.8. Statistical Modelling Tables .........................................................79
10.10.9. Statistical Modelling Figures ........................................................84
10.10.10.ICH Listings .................................................................................88
10.10.11.Non-ICH Listings..........................................................................90
10.11. Appendix 11: Example Mock Shells for Data Displays ................................92
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 205821.
The study was terminated early and the agreed reporting strategy is to only produce 
outputs to support the primary and secondary objectives/endpoints. Selected A&R 
datasets containing the exploratory endpoints may still be produced to enable future 
access requests and analyses of such endpoints.
Note: All data displays (Tables, Figures & Listings) will use the term “Subject” which 
reflects CDISC and GSK Data Display Standards terminology, rather than the term 
“Participant” (although the terms are interchangeable in this RAP document and its 
associated datasets/outputs). 
Revision Chronology:
2016N294782_00
26-APR-2017
Original
2016N294782_01
02-JUN-2017
Amendment 1
2016N294782_02
27-NOV-2017
Amendment 2
2016N294782_03
27-FEB-2019
Amendment 3
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Except for the planned modelling of the Ang II / Ang(1-7) ratio there were no changes or 
deviations to the originally planned statistical analysis specified in the protocol 
amendment 3 (27-FEB-2019).
The protocol originally stated that the ratio of Ang II / Ang(1-7) would be derived for 
each participant and formally modelled using the same approach as the primary endpoint. 
However, the statistical model fitting will not take place. Modelling the ratio does not 
adequately represent aspects of the underlying biology. For example if a participants Ang 
II and Ang(1-7) values were both 10 pg/mL and another’s were both 10000 pg/mL their 
derived ratios would be identical (one). Modelling a simple ratio naïvely implies the same 
significance and biological effect for each participant, even though they are at completely 
different places on the underlying concentration response curves. The additional 
approach to jointly analyzing Ang II and Ang (1-7) described in the protocol (and in 
Section 7.2.5.1) will now be the sole approach to modelling Ang II / Ang(1-7) ratios. 
Note: The simple summary statistics for the Ang II / Ang(1-7) ratios will still be 
produced because they capture information about enzyme activity.
Protocol amendment #3 (27-FEB-2019) increases the duration that a participant may be 
mechanically ventilated, before they are included in the study – from ≤24 hours to ≤48 
hours. This change has been made to assist enrolment of participants into the study, but 
the sponsor considers that it will not impact the objectives of the study. Informal checks 
may be made by the study statistician to confirm this assumption (e.g. visual comparisons 
 
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of results grouped by protocol version enrolled under). Any such checks would not be 
formally documented/reported unless a difference was apparent in which case the likely 
approach would be to perform additional sensitivity analyses with appropriate 
adjustments to the original output(s) to account for the protocol version.
At the time of writing the Critical Components RAP recruitment was going to commence 
under Protocol Amendment #1 and switch to amendment #2 as soon as possible. The 
initial set of subjects enrolled under amendment #1 have a reduced number of endpoints 
available because amendment #2 added the following endpoints: 
CRF form
Questions / Endpoint
Participant 
Status
Is the patient being managed with extracoporeal membrane 
oxygenation?
Is the patient being managed with extracorporeal CO2 (ECCO2R) 
removal?
What is the GI index?
LAB ABGS
PH
Base excess 
The critical components RAP indicated sites may re-consent subjects recruited under 
protocol amendment #1 and enter any new data into the eCRF and suggested an approach 
for imputing missing data. However, the missing data approach described in the critical 
components RAP may not be appropriate to the individual subject’s circumstances and so 
the default will now be to leave any data as missing/not applicable. Only 2x subjects were 
recruited under protocol amendment #1 (
and 
) so the impact of leaving their 
data missing/not applicable is unlikely to be influential on the outcome, and following the 
early termination decision these exploratory endpoints are not going to be analyzed 
further.
2.2.
Study Objective(s) and Endpoint(s)
Exploratory objectives/endpoints have been included for completeness, but due to the 
early termination of the study will not be analysed further (unless they naturally form part 
of an output related to a primary or secondary objective, in which case they may be 
included on a case by case basis).
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the association between 
plasma Ang II levels and RV function 
in mechanically ventilated participants.

Ang II levels

Echocardiographic measures:

Ratio of right ventricular to left ventricular end-
diastolic area
 
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Objectives
Endpoints

Paradoxical septal motion

Pulmonary arterial systolic pressure (PASP) 
estimated from transtricuspid pressure and right atrial 
pressure or inferior vena cava (IVC) diameter 
(whichever is available)
Up to and including Day 3 of observation
Secondary Objectives
Secondary Endpoints

To define the incidence of ACP and 
PCD in mechanically ventilated 
participants.

Presence of PCD, ACP (severe PCD) and severe ACP 
Up to and including Day 3 of observation

To evaluate the association between 
plasma Ang(1-7) levels, Ang II/ Ang(1-
7) ratio and RV function in 
mechanically ventilated participants.

Ang(1-7) levels 

Ang II/ Ang(1-7) ratio 

Echocardiographic measures:

Ratio of right ventricular to left ventricular end-
diastolic area

Paradoxical septal motion

PASP estimated from transtricuspid pressure and 
right atrial pressure or IVC diameter (whichever is 
available)
Up to and including Day 3 of observation
Exploratory Objectives
Exploratory Endpoints

To evaluate the association 
between plasma Ang II and Ang(1-
7) levels and other measures of 
right ventricular function in 
mechanically ventilated
participants. 

Ang II, Ang(1-7) levels  

Echocardiographic measures:

Paradoxical septal motion (systolic eccentricity index)

Maximal velocity of s wave (tissue Doppler imaging) 
at the tricuspid annulus 

Fractional area contraction (end diastolic area minus 
end systolic area normalised to end diastolic area)

Acceleration time of RV ejection flow

Mean acceleration of RV ejection flow (maximum 
velocity/ acceleration time) at end-expiration and 
end-inspiration 

Inferior vena cava (IVC) diameter at 
end-expiration (if available)

Respiratory variations of RV velocity time integral 
(end-expiration minus end-inspiration normalised to 
end-expiration) 

Tricuspid annular plane systolic excursion (TAPSE) 
Up to and including Day 3 of observation
Note: “Mean acceleration of RV ejection flow at end 
expiration” is omitted from the list of exploratory 
endpoints in the protocol but is collected as part of the 
study and may be analysed in the same manner as the 
above exploratory endpoints

To evaluate the association between
plasma Ang II and Ang(1-7) levels and 
other measures of cardiac function 
and pulmonary hemodynamics in 
mechanically ventilated participants. 

Ang II and Ang(1-7)

Central venous pressure (if available)

Mean arterial pressure

Echocardiographic measures:
 
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Objectives
Endpoints

Respiratory variations of diameter of superior vena 
cava

Cardiac output (pulsed wave Doppler, left ventricle 
(LV) outflow track) 

LV ejection fraction

LV Velocity (E’) tissue doppler imaging (TDI) of 
annulus 

LV early to late ventricular filling velocities (E/A)
Up to and including Day 3 of observation

To characterise disease severity by 
clinical assessment.

Oxygen saturation (SpO2) via pulse oximetry 

pH of arterial blood gases

PaO2/FiO2 ratio

PaCO2

Peak and plateau ventilator pressure

PEEP

Oxygenation index

Static respiratory system compliance

Mean airway pressure 

Driving pressure (plateau pressure – total PEEP)

Clinical Safety labs

Vital Signs 
Up to and including Day 3 of observation

To characterise levels of organ 
dysfunction.
Sequential Organ Failure Assessment (SOFA) score
Up to and including Day 3 of observation 

To assess the association of cardiac 
and inflammatory biomarkers and RV 
function.

PCD and ACP status 

Biomarkers: for example, cardiac biomarkers (B-type 
natriuretic peptide (BNP)) or inflammatory biomarkers 
(cytokines such as IL-6, IL-8 and sTNFR1) may be 
analysed as sample availability allows
Up to and including Day 3 of observation

To evaluate the association between 
additional markers of the RAS system 
(if samples permit) and 
primary/secondary or exploratory 
endpoints.
Markers could include but are not limited to: Ang(1-5) in 
relation to primary, secondary or exploratory endpoints if 
sufficient sample is available
Up to and including Day 3 of observation

To characterize health outcome 
measures.

Duration of intubation

Length of hospital stay 

ICU length of stay 

Ventilator free days 

In ICU and hospital mortality 
Up to 28 days after first echocardiogram

To assess lung ventilation and 
perfusion distribution (in selected site 
only).

Lung regional ventilation and perfusion with global 
inhomogeneity (GI) index 
Up to and including Day 3 of observation
 
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2.3.
Study Design
Overview of Study Design and Key Features
Note: Protocol Amendment #3 extends allowable duration from <24h to <48h (start of mechanical ventilation)
Start of mechanical 
ventilation via
endotrachealtube
<24h
Day 1
Day 2
Day 3
•Echocardiograms(24h apart)
•Lung function measurements and ventilator settings
•Blood draw for RAS peptide and biomarkers (+/-30min of echocardiograms)
Standard of care assessments
Design Features

"Low-interventional" study

No investigational product will be administered

A maximum of 150 participants are anticipated to be enrolled

Participants enrolled following intubation and mechanical ventilation

Participants evaluated over a 3-day period using standard-of-care 
investigations, including TTE and/or TOE echocardiography

Additional investigations limited to blood samples for RAS peptides 
and other disease biomarkers

Purpose is to investigate the association of RAS peptides with 
indicators of right ventricular (RV) function in participants requiring 
acute mechanical ventilation
Dosing

Not applicable
Treatment 
Assignment

Not applicable
Interim Analysis

Due to the early termination of the study no interim analysis will take 
place.
2.4.
Statistical Hypotheses / Statistical Analyses
This study is designed to test the hypothesis that an association exists between RAS 
peptides, primarily plasma Ang II and Ang(1-7) levels, and RV function in mechanically 
ventilated patients. No formal statistical hypotheses are being tested in this exploratory 
study.
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
Table 1
Interim analyses
None of the planned interim analyses will take place in study 205821 due to the 
decision to terminate the study early.
The original interim analysis strategy was going to examine data at

IA1: Approximately 25 evaluable subjects (Note: This was scheduled for Jan 
2019 but delayed due to technical issues with the assay for RAS peptides and 
the study was terminated before the RAS data became available)

IA2: Approximately 50 evaluable subjects.

IA3 (Optional): Approximately 100 evaluable subjects
3.2.
Final Analyses
The final planned analyses will be performed after the completion of the following 
sequential steps:
1.
All subjects have completed the study as defined in the protocol (i.e. after the last 
participant has completed their 28-day follow-up).
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
Protocol deviation reviews have taken place (See Section 4.1)
(Note: as there is no randomisation and no treatment intervention, the usual steps 
pertaining to unblinding and release of randomisation codes do not apply.)
4.
ANALYSIS POPULATIONS
Population1
Definition / Criteria
Analyses Evaluated
Screened
All participants who have been screened.

To aid construction 
of Consort diagram 
in any publication
Enrolled
All participants who had passed screening and 
who had appropriate informed consent (via any of 
the processes described in the protocol).

Summary of Subject 
Status and Reason 
for Study Withdrawal

Summary of Study 
Populations

Summary of 
Exclusions from the 
 
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Population1
Definition / Criteria
Analyses Evaluated
Safety/Completed/ 
Evaluable 
Populations
Safety
All participants for whom at least one 
echocardiograph and/or blood sample has been 
taken, and who did not retrospectively withdraw 
the consent.

Study population 
(excl. specific tables 
mentioned below)

Safety
Evaluable
All participants for whom PASP, RV size ratio, Ang 
II and Ang(1-7) data have been recorded for at 
least one study time point, and who did not 
retrospectively withdraw the consent (and who still 
had at least one study time point of data remaining 
after accounting for any prohibited concomitant 
medications (for example but not limited to renin 
inhibitors, ARBs or ACE inhibitors) – See Section 
10.1.1).

Pharmacodynamic/ 
Biomarker (excl. 
disease diagnosis 
status)
Evaluable with 
Prohibited Con 
Meds
All participants in the Evaluable population plus 
any participants who were excluded from the 
Evaluable population because of prohibited 
concomitant medications (for example but not 
limited to renin inhibitors, ARBs or ACE inhibitors)

Sensitivity for 
Primary analysis 
(conditional on 
number of prohibited 
con meds)
Completed2
All participants for whom PASP, RV size ratio, Ang 
II, and Ang(1-7) data have been recorded for all 
three study days. 

Disease diagnosis 
status
At Risk
For the purpose of evaluating ACP/PCD and 
ARDS incidence rates the participants who satisfy
1) PASP and RV size ratio recorded for 
all three study days (regardless of the 
Ang II and Ang(1-7) status) 
and/or 
2) databased ACP/PCD and/or ARDS 
assessment during the study period 
(even if they do not have three days’ 
worth of study assessments for the 
above echo outcomes)
provided consent is not withdrawn.

Disease diagnosis 
status
NOTES : 
1.
Please refer to Section 10.10: List of Data Displays which details the population to be used for each display being 
generated.
2.
Modifications to the Completed population listed in study protocol to assist with production of summary and 
incidence rate calculations for ACP/PCD status (include creating a new population “At Risk” to be used with 
selected incidence rate displays that is independent of the RAS biomarker availability). The remaining completed 
population is not formally used, but will provide feasibility information (i.e. could we measure items reliably in the 
“real world” of the ICU)
 
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4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the current version of the Protocol Deviation Management Plan.
1. Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
2. This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
No study treatment is being administered in this study. However, GSK’s standard SAS 
macro reporting tools will still assign each participant a set of treatment variables (“No 
treatment”). There will not be any treatment comparisons. Tables and Figures will only 
be presented with a single “No Treatment” column unless they are presented by covariate 
groupings or subgroups as described in Section 5.3 below.
5.2.
Baseline Definitions
At present, no analyses involving a change from baseline are planned since there is no 
treatment intervention. However, for each endpoint the Baseline will be defined as the 
earliest evaluable timepoint (if a baseline is required).
5.3.
Examination of Covariates, Other Strata and Subgroups
5.3.1.
Covariates and Other Strata
The set of potential covariates and other strata that may be used in descriptive summaries 
and statistical analyses, some of which may also be used for subgroup analyses are large.
To facilitate flexible model building and analyses a A&R dataset(s) of potential covariate 
and grouping variables should be constructed (called ARDATA.ALLCVTS). It would be 
expected to contain three records per participant (Study Day 1, Day 2 and Day 3 values 
for time-varying covariates), with subject-level covariates repeated across the three 
records (a flagging variable should also be created to subset the main dataset to extract 
one record per subject if analyses only involve subject-level covariates); an illustrative 
example is shown below
Subject
Visit
SUBJLEV
AGE
SEX
SAPSII
ARDSX
ARDSI
…
Day 1
1
35
M
12
N
N
…
Day 2
0
35
M
12
N
N
…
Day 3
0
35
M
12
N
N
…
Day 1
1
43
F
16
Y
N
…
Day 2
0
43
F
16
Y
Y
…
Day 3
0
43
F
16
Y
Y
…
Day 1…
1
54…
M…
7…
N…
N…
…
Guidance for its construction/algorithms are given in Section 10.6.10.
5.3.2.
Examination of Subgroups
The following list of subgroups may be used in descriptive summaries and statistical 
analyses. Additional subgroups of clinical interest may also be considered based on items 
in ARDATA.ALLCVTS.
 
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
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to producing the final version of the planned output.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Subgroup
[ARDATA.ALLCVTS Variable]
Categories 
ARDS Status [ARDSX]
ARDS, No ARDS(diagnosed at any time in the study)
Any PCD or ACP [PCDACPX & 
PCDACPI]
Yes; No (where Yes = Participant had disease state of PCD or ACP)
Group can be applied across all study visits [PCDACPX] or to specific 
days [PCDACPI]
No PCD or ACP [NORVDYSX & 
NORVDYSI]
Yes; No (where Yes = Participant did not have a disease state of PCD 
or ACP)
Group can be applied across all study visits [NORVDYSX] or to 
specific days [NORVDYSI]
PCD [PCDX & PCDI]
Yes; No (where Yes implies the worst diagnosis received was 
Moderate PCD across all study visits [PCDX variable] and Yes implies 
the worst diagnosis received on the corresponding study day was 
Moderate PCD [PCDI variable])
ACP [ACPX & ACPI]
Yes; No (where Yes implies the worst diagnosis received was Non-
severe ACP across all study visits [ACPX variable] and Yes implies the 
worst diagnosis received on the corresponding study day was Non-
severe ACP [ACPI variable])
Severe ACP [SEVACPX & 
SEVACPI]
Yes; No (where Yes implies the worst diagnosis received was Severe 
ACP across all study visits [SEVACPX variable] and Yes implies the 
worst diagnosis received on the corresponding study day was Severe 
ACP [SEVACPI variable])
ARDS and No PCD or ACP 
[ARDNOX]
Yes; No (where Yes implies participant received an ARDS diagnosis 
but never had PCD or ACP at any time in the study)
ARDS and PCD [ARDPCDX]
Yes; No (where Yes implies participant received an ARDS diagnosis 
but the worst case diagnosis was Moderate PCD at any time in the 
study)
ARDS and ACP [ARDACPX]
Yes; No (where Yes implies participant received an ARDS diagnosis 
but the worst case diagnosis was Non-severe ACP at any time in the 
study)
ARDS and Severe ACP 
[ARDSACPX]
Yes; No (where Yes implies participant received an ARDS diagnosis 
and the worst case diagnosis was Severe ACP at any time in the 
study)
5.4.
Multiple Comparisons and Multiplicity
No adjustments for multiplicity will be made.
 
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5.5.
Display order of Echocardiography endpoints (source: 
SI.CV)
Whenever multiple Echocardiography endpoints (found in the CV dataset) are required 
within the same Table/Listing/Figure and the display ordering is not explicitly stated the 
following display ordering should be apply:
Priority Order of 
presentation
CVTSTCD
Description 
(Note: the actual label/text would be taken from 
dataset manager at the time of reporting)
1 (1st in T/L/F)
AH001CAL
Pulmonary Artery Systolic Pressure
NA
AH001
Pulmonary Artery Systolic Pressure (eCRF)
2
AK001
Ratio of RV to LV End-Diastolic Area
3
AK002
Paradoxical Septal Motion
4
AK015
Have PCD or ACP
5
AK016
Severity of PCD or ACP
6
AK003
Systolic Eccentricity Index
7
AK006
Max Velocity S Wave at Tricuspid Annulus
8
AK007
Fractional Area Contraction
9
AK008
Acc Time of RV Ejection Flow (Tacc)
10
TAPSE
Tricuspid Annular Plane Systol Excursion
11
AK004
Transtricuspid Pressure Gradient (TPG)
12
AK009
Mean Acc of RV Ejection Flow at End Exp
13
AK010
Mean Acc of RV Ejec Flow at End Exp-Insp
14
AK005
IVC Diameter at End Expiration
15
AK011
Respiratory Variations of RV VTI
16
AK012
Respiratory Variations of SVC Diameter
17
CARDOUT
Cardiac Output (CO)
18
LVEJ
Left Ventricular Ejection Fraction
19
AK013
LV Velocity (E') Tissue of Annulus
20
AK014
LV Early to Late Filling Velocities
21
ERATRIAP
Estimated Right Atrial Pressure
22
AI001
Measured Right Atrial Pressure
23
RAP
Right Atrial Pressure
24
AD003
Central Venous Pressure (CVP)
NA
AH001src
<Do not display; variable used to track source of 
PASP> 
Note: Only display AH001CAL but label it using the AH001 label text (this is because the auto derived eCRF value 
for PASP; supplied as AH001; may not capture all data cases reliably and so will be re-calculated)
 
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5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.5
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Enrolled population, unless otherwise 
specified.
Study population analyses including analyses of participant disposition, protocol 
deviations, demographic and baseline characteristics, and prior and concomitant 
medications will be based on GSK Core Data Standards.  Details of the planned displays
are presented in Appendix 10: List of Data Displays.
Note: Local French law prohibits the collection of Race information, so the race/ethnicity
variables would be blank in the datasets and displays.
 
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7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES
7.1.
Primary Pharmacodynamic/Biomarker Analyses
7.1.1.
Endpoint / Variables
The following variables may be included in the statistical model:

Independent variable of interest:
o
Ang II on Study Days 1, 2 and 3 (after any imputations)

Dependent (bivariate) variable of interest:
o
PASP on Study Days 1, 2 and 3
o
RV size ratio on Study Days 1, 2 and 3

Potential covariates (to be explored, order listed indicates expected importance):
o
Centre
o
Age at screening
o
Sex
o
Use of vasopressors on Study Days 1, 2 and 3
o
PEEP on Study Days 1, 2 and 3
o
Proning status on Study Days 1, 2 and 3
o
BMI at screening
o
Concurrent use of inhaled nitric oxide on Study Days 1, 2 and 3
o
Mean airway pressure on Study Days 1, 2 and 3
o
Tidal Volume on Study Days 1, 2 and 3
o
ECMO on Study Days 1, 2 and 3
o
ECCO2R on Study Days 1, 2 and 3
o
SAPS II at screening
o
PaO2/FiO2 on Study Days 1, 2 and 3
Additionally, the presence/absence of paradoxical septal motion on Study Days 1, 2 and 3 
may be assessed on an informal visual basis.
Note: Since the study was terminated early there may not be sufficient information in the 
collected data to explore covariate analyses and the covariate exploration process may not 
take place at all.
7.1.2.
Summary Measure
The posterior predictive probability of RV dysfunction in a hypothetical individual for a 
pre-determined “pre-dose” Ang II value,
The posterior predictive probability of RV dysfunction in a hypothetical individual for a 
pre-determined “post-dose” Ang II value, and
The difference between the above two probabilities.
 
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7.1.3.
Population of Interest 
The primary pharmacodynamic analyses will be based on the Evaluable population, 
unless otherwise specified.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent events which may lead to missing data for all variables (such as death) would 
not impact the primary analysis since the planned modelling assumes no lag between 
RAS peptide concentrations and effect on RV dysfunction (i.e. RAS concentrations on 
day 1 are not used to predict RV dysfunction on day 2 and if death occurs between day 1 
and day 2 this will not impact the planned modelling). 
Intercurrent events such as taking a non-permitted con med may require exclusion of post 
medication data if the con med had the potential to confound the true relationship 
between RAS peptide and RV dysfunction. 
Intercurrent events that result in missing data for one or more of the variables required for 
the primary analysis (e.g. ECHO view not suitable, lost RAS sample) will result in the 
exclusion of the impacted timepoint as there is not sufficient information to postulate a 
suitable imputation model.
7.1.5.
Statistical Analyses / Methods
The purpose of the primary analysis is to evaluate the association of biomarkers of the 
Renin Angiotensin System (RAS), specifically Ang II but secondarily Ang(1-7) with 
measures of RV function (specifically PASP and RV size ratio in the primary model, and 
also paradoxical septal motion on a more informal visual basis), whilst taking into 
account any observable variables that may confound the relationship between the two 
concepts.
RV function will be measured using PASP and RV size ratio. The general principle 
underlying all the analyses of RV function and RAS peptide biomarkers will be:

model the joint distribution of PASP and RV size ratio as a function of the RAS 
peptide(s) in question (together with confounding variables also included as 
covariates),

choose reference values of the RAS peptide(s) in question and estimate a posterior 
distribution of PASP and RV size ratio for those given values, and

use the posterior distribution to determine the probability of RV dysfunction (for a 
future individual participant), defined (following the definition of 
moderate/severe pulmonary circulatory disease given in Boissier, 2013) as:
o
PASP > 40 mmHg
o
RV size ratio > 0.6
The advantage of this method is that all the information on the continuous scales of PASP 
and RV size ratio is maintained throughout the modelling process, and that dichotomising 
 
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participants into binary categories takes place at the end after the modelling has been 
done.
In order to evaluate the estimated effect of administering rhACE2 on RV outcomes (via 
its effect on the RAS peptides), predictions for the probability of RV dysfunction will be 
calculated for specific, pre-determined values of RAS peptide measurements that 
represent reasonable estimates for each RAS peptide both before and after dosing with 
rhACE2 in this patient population. These values will be hereafter referred to as reference 
values (the first reference value, hereafter referred to as the pre-dose reference and the 
second reference value, hereafter referred to as the post-dose reference reflect). Note: the 
terminology "pre-dose" and "post-dose" should not be taken to imply that investigational 
product is used in this study; these values should be taken as being borrowed from that 
interventional study. Furthermore, the term "reference values" in this context should not 
be interpreted as upper or lower limits to the normal range. They represent the best guess 
available for a patient's typical experience before and after rhACE2 administration.
Initially, the basic model described below would be attempted. If model convergence 
issues are encountered with that model it is unlikely that more complicated models 
involving covariates would fit, and covariate exploration may not be attempted. However, 
if covariate exploration is attempted the addition of covariates would be dependent on a 
combination of changes in DIC and expert judgement (including the biological rationale 
for the covariate and/or global structures of other statistical models fitted to comparable 
data types). To simplify reporting only model outputs from the final selected model 
would be formally reported (included in the CPSR), but a description / short justification 
for the selected model would be included in the CPSR.
At the time of writing, the reference values for Ang II (and for completeness Ang(1-7) 
and Ang(1-5)) were as follows:
ANG II (pg/mL)
ANG 1-7 (pg/mL)
ANG 1-5 (pg/mL)
Optional endpoint
“Pre-dose” 
reference value
30.0
2.0
n/a
“Post-dose” 
reference value
8.0
30.0
n/a
An additional sensitivity analysis (to be computed alongside the above) in case the 
reference study values are discordant with the observed values will use the observed data 
to determine the references as follows
 
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Sensitivity
ANG II (pg/mL)
ANG 1-7 (pg/mL)
ANG 1-5 (pg/mL)
Optional endpoint
Sensitivity “Pre-
dose” reference 
value
Upper Quartile of 
Observed ANG II
Lower Quartile of 
Observed ANG 1-7
Lower Quartile of 
Observed ANG 1-5
Sensitivity “Post-
dose” reference 
value
Lower Limit of 
Quantification
Upper Quartile of 
Observed ANG 1-7
Upper Quartile of 
Observed ANG 1-5
The relationship between Ang II (as the explanatory variable) and the joint bivariate 
distribution of PASP and RV size ratio (the outcome variables) will be analysed using a 
Bayesian multivariate linear regression model. 
The multivariate normal model is specified as follows:
where yitj represents the observed value for the ith participant, the tth time-point and the 
jth outcome (i.e. 
representing PASP and 
=2 representing RV size ratio), 
represents the expected value for the th participant, th time-point (
) and the jth 
outcome (j=1 and j=2 as above), and Σ represents a  variance-covariance (vcov) matrix 
for the two outcome variables. 
The expected values, 
, are modelled as follows:
where:

αj is the intercept term for the jth outcome (i.e. PASP or RV size),

βj represents the vector of slope coefficients for all participant-level variables in 
the model for the jth outcome,

xi represents the vector of observed participant-level variables values for the ith 
participant (if applicable – initial model structures would not involve such 
covariates but Age at Screening and Sex would be added first to be consistent 
with the study protocol),

γtj represents the matrix of slope coefficients for all timepoint-level variables in 
the model for the jth outcome at time-point t,

zit represents the matrix of observed time-point-level variables for the ith 
participant at time-point t (e.g. log10- transformed RAS).
 
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The vcov matrix
is specified within each study participant, as a Kronecker product of 
the inter- and intra-marker vcov matrices 
and 
, respectively:
(the notation 
represent the Kronecker product)
The 
inter-marker vcov matrix
assumes a constant inter-marker bivariate correlation, 
, across 
measured at the same 
The 
vcov matrix structure, when
,
implies independence between both markers.
The 
inter-marker vcov matrix assumed as
implies an intra-marker AR(1) process structure with common correlation parameter 
The dimension of the 
is determined by the number of timepoints (
) the 
marker measurements are measured at. Note: Initial simulation work showed an UN 
(Unstructured) form of vcov for 
results in convergence issues due to parameter 
estimation issues; hence why AR(1) is preferred. A potential drawback to using 
Kronecker product is that it forces the inter-marker relationship though time to be the 
same for both response variables; but the Kronecker product requires estimation of fewer 
parameters (improved chance of model convergence) and recognises the repeated 
measures (time) structure whilst allowing it to be handled as a nuisance parameter in the 
final inferences (albeit with the previous caveat).
Given the above assumptions the 
vcov structure is derived as follows:
 
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Uninformative prior distributions are assigned for α, β, γ, 
and 
as follows:

For each αj outcome variable a normal distribution with mean zero, large variance 
(e.g. 1E6) would be used as a non-informative prior,

each element in the vector β is assigned a distribution with the same specifications 
as for α,

each element in the matrix γ is assigned a distribution with the same specifications 
as for α and the elements of β,

, defined as the inverse of 
, is assigned an uninformative Wishart prior 
distribution: 
where: 
and 
.

The 
parameter 
is assigned uninformative uniform prior distribution over 
interval.

Note: Simulations suggest that the model convergence is improved if the response 
variables (or more specifically their covariance parameter estimates) are roughly 
on the same scale (range). Therefore, if required, the response variables may be 
re-scaled for model fitting, but model inferences/results should be displayed using 
the original scale of the response variable. 

Note: Simulation work suggests that model convergence may also be sensitive to 
the software used (due to the complexities of estimating the vcov parameters and 
the limitations of Gibbs samplers being most efficient when the priors are 
conjugate to the likelihood of the parameters; once a Kronecker Product vcov is 
involved the conjugacy is not spotted automatically by most software). The first 
intent is to use SAS PROC MCMC, but if that does not work then R may be used 
(e.g. an appropriate package that implements JAGS) and if R fails then Stan may 
be used. Although a Bayesian implementation of the above model is desired if 
convergence issues are encountered then SAS PROC MIXED may be used to 
estimate the required model parameters (it may also as part of the QC checking of 
the model)

Note: For IA1 (and IA2 and final analysis, if required) model simplification may 
occur to improve model convergence (e.g. γ parameter would only contain terms 
for the RAS peptides and not other time dependent terms such as separate slopes
for each visit and endpoint combination).

The initial model structure would consist of nine parameters, a slope and intercept 
for the two linear regressions of RAS biomarker level against outcome (PASP or 
RV Size raio) (four parameters), four parameters of 
, and one parameter 
( ) for 
Estimates for the posterior distributions of coefficients in the model will be obtained 
using an MCMC simulation running a suitable number of chains for an appropriate 
number of iterations each to ensure satisfactory convergence of the MCMC sampling 
algorithm. Nominally, a minimum of 3 chains would be used to produce the Gelman-
Rubin diagnostics, though these numbers may be adjusted as necessary and chain 
 
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convergence may require separate model runs (e.g. SAS PROC MCMC requires separate 
model runs to assess the Gelman-Rubin chain convergence (with a zero burn in); but the 
final MCMC model used for inference requires a non-zero burn in; necessitating separate 
modelling runs. However, the final model run should utilise one of the sets of starting 
parameters used in the Gelman-Rubin investigations).
The corresponding secondary pharmacodynamic analyses (using Ang(1-7), and 
optionally Ang(1-5), in place of Ang II) and a model including Ang II and Ang(1-7) as 
joint independent variables of interest may be used to support the primary analysis. 
Details are provided in Section 7.2.
Posterior estimates for the predictive probability of RV dysfunction will be made for the 
two sets of reference values of Ang II described above (exception is if joint modelling 
using Ang II and Ang(1-7) is being attempted). If other covariates are included in the 
final inference model these predictions should be made using the observed mean value 
for continuous variables and the observed mode value for categorical variables (exception 
being terms like CENTRE or SEX which would be predict for the average of the 
corresponding levels). Note: Observed margins may be used if there is a good clinical 
rationale to do so (assessed on a covariate by covariate basis). 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

See above
Model Specification

See above
Model Checking & Diagnostics

“Bayesian Statistics Best Practice at GSK – Clinical Trials using Bayesian Inference” (effective 
20-Apr-2017) gives guidance on model checking and diagnostics that would be applicable to 
the MCMC modelling in this study.
Model Results Presentation

See above
Subgroup Analyses

Not planned.
Sensitivity and Supportive Analyses

See above. Only the final (chosen) model form would be used to produce the 
Tables/Listings/Figure outputs supporting the CPSR.

If the joint modelling strategy fails then an alternative strategy would be to derive the RV 
 
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dysfunction status for each participant (using the same criteria) and analyse the collection of 
derived binary outcomes, accounting for the repeated measures made on each participant 
(e.g. logistic regression modelling techniques). The final logit model (including any covariates) 
would be used to determine the probabilities (and differences) for the sets of “pre and post” 
dose Ang II reference values to be fed into the decision-making criteria. Any such approach 
wold be documented in the CSR.
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables
The variables to be included in the secondary pharmacodynamic analysis are the same as 
for the primary pharmacodynamic analysis, with the addition of the following 
independent variables:

Ang(1-7) on Study Days 1, 2 and 3

(Optionally) Ang(1-5) on Study Days 1, 2 and 3 (if the correlation between 
Ang(1-7) and Ang(1-5) values is not too high – otherwise the analysis would not 
be expected to add additional insights/value)

Note: The planned modelling using similar techniques to the primary analysis for 
the Ang II/Ang(1-7) response on Study Days 1, 2 and 3 will not be attempted. 
Incidence rates would be assessed across 
i)
the entire study (the outcome taking the value of the worst case observed) and 
ii) on an individual visit basis (Note: Screening and Day 1 data would be combined 
and labelled as Day 1; the worst case outcome used in any combination)
The following rates would be assessed

Incidence rates of ARDS diagnosis

Incidence rates of PCD or ACP (any right ventricular dysfunction; regardless of 
PCD or ACP severity level)

Incidence rates of PCD (Moderate PCD (not severe enough to qualify as ACP))

Incidence rates of Non-severe ACP

Incidence rates Severe ACP
Additionally, the worst case PCD/ACP diagnosis across the study would be combined 
with the ARDS diagnosis to form the following categories
o
ARDS and No PCD or ACP
o
ARDS and PCD
o
ARDS and Non-Severe ACP
o
ARDS and Severe ACP
7.2.2.
Summary Measure
For the Ang(1-7) and Ang(1-5) endpoints described above:

The posterior predictive probability of RV dysfunction for pre-determined “pre-
dose” Ang II and Ang(1-7) values (or Ang(1-5)),
 
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
The posterior predictive probability of RV dysfunction for pre-determined “post-
dose” Ang II and Ang(1-7) values (or Ang(1-5)), and

The difference between the two (Note: Although the difference will still be 
computed as Pre-Post for Ang(1-7) and Ang(1-5) negative values would be a 
favourable outcome).
For the incidence rate variables 

The At Risk population would be used to filter the individuals going into the 
subsequent analysis dataset

For rates relating to an individual visit 
o
The big N value would not represent distinct participants but instead 
represents the maximum number of visits in the analysis dataset (derived 
by counting the number of subject visits where any ARDS or PCD/ACP 
assessment was made (expecting three visits per subject – but may reduce 
if subjects withdraw/die before day 3))
o
the little n value would represent the number of completed visits for that 
item
o
Freq. represents the number of positive occurrences (Subjects with a Yes 
response)
o
Rate (%) = 100 * Freq. / n [little n]
o
The 95% CI for the rate (%) should be derived using Wilson Score 
interval with continuity correction methodology

For rates relating to the entire study 
o
The big N value represents the number of participants for whom an ARDS 
or PCD/ACP assessment was made at any time in the study
o
Freq. represents the number of positive occurrences (Subjects with a Yes 
response)
o
Rate (%) = 100 * Freq. / N [big N]
o
The 95% CI for the rate (%) should be derived using Wilson Score 
interval with continuity correction methodology
Any modifications to the above would be described in the CSR.
7.2.3.
Population of Interest 
The secondary pharmacodynamic analyses will be based on the Evaluable population, 
unless otherwise specified.
All analyses involving incidence rate endpoints will be based on the At Risk population 
unless otherwise specified.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
Since there is no investigational product in the study simplistic approaches will be taken 
to deal with intercurrent events. Any data driven alternative strategies implemented 
would be described in the CSR.
 
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7.2.5.
Statistical Analyses / Methods
The secondary statistical analyses are divided into three subcategories, with the first 
being variations on the primary analysis: analyses following the same form as the 
primary analysis but using a different RAS peptide measurement in place of Ang II. 
The second subcategory models the joint association of Ang II and Ang(1-7) on RV 
function (Note: if the observed data ranges do not permit parameter estimation/model 
convergence of the proposed model then simpler alternative models may not be 
attempted; but if they are any methodology would be described in the CSR).
The third subcategory of the secondary analyses is an estimate of disease incidence 
within the mechanically ventilated population.
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.5.1.
Supportive Models to the Primary analysis, using other RAS peptides 
in place of Ang II
Supportive models to the primary analysis will be conducted following the same 
methodology as the primary analysis models (see Section 7.1) but with changes as 
described below.
The first supportive model will include Ang(1-7) as a time-point-level covariate instead 
of Ang II, and the corresponding reference value from Section 7.1.5.
Note: An optional supportive model would include Ang(1-5) as a time-point-level 
covariate instead of Ang II, and the corresponding reference value from Section 7.1.5. 
This model may be attempted if the Ang II and Ang(1-7) modelling does not produce a 
clear/consistent outcome and/or the observed level of correlation between Ang(1-5) and 
Ang(1-7) data is deemed likely to result in a different conclusion (a priori expectation 
Ang(1-7) and Ang(1-5) data will be highly correlated, and so any modelling would be 
expected to produce similar conclusions and duplication would not add value).
7.2.5.2.
Combined model of the joint association of Ang II and Ang (1-7) with 
RV function
Endpoint / Variables

PASP and RV Size Ratio on Day 1, Day 2 and Day 3 where available

Time matched concentration of Ang II (Denoted as A in model specification)

Time matched concentration of Ang (1-7) (Denoted as B in model specification)
Model Specification
The relationship between Ang II and Ang(1-7) (as joint explanatory variables) and the 
 
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joint bivariate distribution of PASP and RV size ratio (the outcome variables) will be 
analysed using a Bayesian multivariate non-linear regression model. 
For simplicity, the repeated measures aspect of the data structure is not being modelled 
by first intent and Hill coefficients are assumed to be 1. If data permit, a similar strategy 
to the primary analysis that accounts for repeated measures may be attempted (e.g. 
Kronecker product with an AR(1) structure for Tigma), but only the model used for final 
inference would be reported. If data do not permit the planned model to be fitted no 
further modelling is proposed. However, if alternative model(s) are attempted and 
successful, they would be described in the CSR).
The multivariate normal model is specified as follows (for maximum flexibility time has 
been left in the parameter definitions) :
where yitj represents the observed value for the ith participant, the tth time-point and the 
jth outcome (i.e. 
representing PASP and 
=2 representing RV size ratio), 
represents the expected value for the th participant, th time-point (
) and the jth 
outcome (j=1 and j=2 as above), and Σ represents a  variance-covariance (vcov) matrix 
for the two outcome variables. 
The expected values, 
, are modelled as follows:
Where,
Basalj is the response in the absence of A and B for the jth outcome
MaxAj is the response to saturating concentrations of A in the absence of B for the jth 
outcome
MaxBj is the response to saturating concentrations of B in the absence of A for the jth 
outcome
MaxABj is the response in the presence of saturating concentrations of both ligands for the 
jth outcome
EC50jA|B=0 is the EC50 of A in the absence of B for the jth outcome
EC50jB|A=0 is the EC50 of B in the absence of A for the jth outcome
EC50jB|A∞is the EC50 of B in the presence of saturating concentrations of A for the jth 
outcome
[A] is time matched concentration of AngII (to aid review 
[B] is time matched concentration of Ang(1-7) (to aid review 
 
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Also note that EC50jA|B=0 x EC50jB|A∞= EC50jB|A=0 x EC50jA|B∞, so the equation is 
symmetrical in A & B.
The vcov structure for Σ(6x6) is constructed using the same approach as the primary 
analysis model but with an Identity matrix used for Tigma by first intent
Uninformative prior distributions are assigned for the parameters as follows:

Model parameters Basalj, MaxAj, MaxBj, MaxABj, EC50jA|B=0, EC50jB|A=0 and 
EC50jB|A∞(for j=1 (PASP) and 2 (RV Size ratio)) will each be assigned a prior of 
Normal(Mean=0, Var=1^E6). Note: By first intent these are all independent prior 
statements and correlation structures between related parameters would be 
expected to be observed in the observed posterior covariances of the model 
parameters (see Sensitivity analyses sections for alternative prior structures if 
model convergence issues are encountered). 

, defined as the inverse of 
, is assigned an uninformative Wishart prior 
distribution: 
where: 
and 
.

Model Checking & Diagnostics

As per Primary analysis
Model Results Presentation

Once the model parameters have been estimated analogous predictions of the Posterior 
Probability of RV dysfunction (and differences between pre and post dose AngII levels) would 
be obtained as per Primary analysis. However, twice the number of items would be produced 
because there would be a need to condition on the two “pre and post dose” values for Ang(1-7)
for each set of Ang II values.
Subgroup Analyses

Not planned
Sensitivity and Supportive Analyses
 
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
If model convergence issues are encountered the prior structure may be modified to group 
related sets of parameters together using a MVN (multivariate normal distribution). Two MVN 
priors distributions may be set up (one for each j) using parameters Basalj, MaxAj, MaxBj, 
MaxABj, EC50jA|B=0, EC50jB|A=0 and EC50jB|A∞ . The MVN mean would be a vector of zeros 
and the prior for the vcov matrix of the model parameters would be an inverse-wishart with 
R=Identity (7x7) and df=7.

An AR(1) structure may be attempted for the Tigma vcov matrix and would use an 
uninformative uniform prior distribution over -1,1 interval for parameter ρ
7.2.5.3.
Analysis of disease incidence within the mechanically ventilated 
population
The incidence of ACP and PCD in the population will be presented as summary tables, 
by study day, and overall (i.e. diagnosis at any time during the three-day study period).
Descriptive statistics (N (population), #Occurrences (Freq.), number at risk (n), Incidence 
Rate and 95% CI for Rate (methodology for 95% CI: Wilson Score interval with 
continuity correction))
 
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7.3.
Exploratory Efficacy Analyses
No exploratory analyses are planned due to the early termination of the study.
 
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8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
The details of the planned displays are provided in Appendix 10: List of Data Displays.
8.1.
Adverse Events Analyses
Only Serious Adverse Events (SAEs) relating to study procedures or any GSK 
medications are being recorded and reported in this study. SAEs will be presented as a 
summary table and a listing, and will be based on GSK Core Data Standards.
8.2.
Clinical Laboratory and Other Safety Analyses
Chemistry and Haematology Laboratory evaluations and Vital Signs test results will be 
presented as summary tables and listings. Additionally, all values of potential clinical 
importance will be presented as listings, together with all other measurements of the same 
test in the same participant. These displays will be based on GSK Core Data Standards.
 
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9.
REFERENCES
Boissier F, Katsahian S, Razazi K, Thille AW, Roche-Campo F, Leon R, et al. 
Prevalence and prognosis of cor pulmonale during protective ventilation for acute 
respiratory distress syndrome. Intensive Care Med. 2013 Oct;39(10):1725-1733.
El-Khatib MF, Jamaleddine GW, A New Oxygenation Index for Reflecting 
Intrapulmonary Shunting in Patients Undergoing Open-Heart Surgery CHEST 2004; 
125:592–596
de Man, Tu, Handoko, et al Dysregulated Renin–Angiotensin–Aldosterone System 
Contributes to Pulmonary Arterial Hypertension Am J Respir Crit Care Med Vol 186, Iss. 
8, pp 780–789, Oct 15, 2012.
Vincent J-L., Moreno R., Takala J., Willatts S., De Mendonca A., Bruning H., Reinhart 
C.K., Suter P.M., Thijs L.G., The SOFA (Sepsis-related Organ Failure Assessment) score 
to describe organ dysfunction/failure. Intensive Care Med (1996) 22:707-710
 
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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Evaluable Population
10.1.1.
Exclusions from Evaluable Population
Subjects with major/important protocol deviations will be considered for exclusion from 
Evaluable Population.  The Protocol Deviation Management Plan (PDMP) will be used to 
determine major/important protocol deviations that will lead to exclusion from the 
Evaluable Population (Note: In the event the PDMP retains the template text / default 
terminology which refers to “per protocol population” it would be interpreted as the 
“Evaluable population” for study 205821).
In addition, a subject meeting any of the following criteria will be excluded from the 
Evaluable population (or if more applicable, only the relevant timepoint(s) excluded):
Number
Exclusion Description
01
Participants whose day 1, day 2 and day 3 samples were all lost or for whom the post 
sample processing was unable to produce evaluable results would be excluded from the 
evaluable population
If a single day (or two days) are impacted by the above reason(s) then the participant shall 
remain in the evaluable population, but the impacted time points would be removed from the 
analysis.
02
If a single day (or two days) are impacted by the ECHO results that are later deemed of 
insufficient quality (e.g. this may be discovered by independent review/adjudication of 
source notes) then those data points would be removed from the analysis (but the 
participant would remain in the evaluable population). If all of the day 1, day 2 and day 3 
ECHO results are impacted in this way then the participant would be removed from the 
evaluable population.
03
If the participant takes a prohibited concomitant medication that, in the opinion of the GSK 
medical monitor, may confound / interfere with the estimation of the true relationship 
between RAS peptides and an endpoint then any post con-med observations would be 
removed from the corresponding analysis.
 
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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
Procedure
Study Period
Notes
Screening1
Day 
1
Day 
2
Day 
3
Up to day 
28
Start of mechanical 
ventilation  
X
Inclusion/exclusion 
criteria
X
Reason for intubation (underlying 
diagnosis e.g. sepsis, pneumonia) to be 
collected where possible.
Informed consent 
(ICF)
X
Consent process will be followed as 
outlined in Informed Consent Process 
(Section 12.3.3)
Demography
X
If it is not possible to collect at screening 
can be collected at any point during the 
study.
Height and weight 
X
Collected for the purposes of evaluating 
BMI. Clinical estimates are acceptable if 
direct measurement is not possible.
Medical history 
X
If possible to collect, includes medication 
and cardiovascular risk factors. If it is not 
possible to collect at screening can be 
collected at any point during the study.
Diagnosis of 
pulmonary 
circulatory 
dysfunction (PCD) 
and acute cor 
pulmonale (ACP)  
X
X
X
As per echocardiographic output.
Participant status 
X
X
X
X
Intubation status, proned status; 
diagnosis of acute respiratory distress 
syndrome (ARDS) including severity at 
time of diagnosis (if available). Post 
screening status to be assessed at the 
same time point as echocardiogram (1 
hour).
Participant 
management
X
X
X
X
Management with extracorporeal 
membrane oxygenation (ECMO) and 
extracorporeal CO2 (ECCO2R) removal. 
Post screening status to be assessed at 
the same time point as echocardiogram 
(1 hour).
 
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Procedure
Study Period
Notes
Screening1
Day 
1
Day 
2
Day 
3
Up to day 
28
Simplified acute 
physiology score 
(SAPS II)
X
To be taken at time of intubation.
Sequential Organ 
Failure (SOFA) score
X
X
X
X
Echocardiogram
X
X
X
Transthoracic echocardiogram (TTE) 
and/or transoesophageal 
echocardiogram (TOE). First 
echocardiogram must be completed 
within 48 hours of starting mechanical 
ventilation (but 24 hours, whenever 
possible); the following echocardiograms 
will be undertaken as per standard of 
care 24 hours apart (± 2 hours) on 
subsequent consecutive days (Day 2 
and 3).
Vital signs
X3
X
X
X
Blood pressure (mean arterial, systolic 
and diastolic), heart rate, body 
temperature to match echocardiogram 
time points (± 30 minutes)2.
Laboratory 
assessments
X
X
X
X
Clinical chemistry and haematology.
Ventilator settings 
X3
X
X
X
Includes tidal volume, respiratory rates, 
static respiratory compliance, level of 
positive end expiratory pressure (PEEP), 
peak and plateau ventilator pressures, 
mean airway pressure and driving 
pressure. Measurements to be taken at 
intubation and at the time of each 
echocardiogram (± 30 mins)2.
Lung function and 
blood gas measures 
X3
X
X
X
Oxygen saturation(SaO2) via pulse 
oximetry. 
Arterial Blood Gases (ABGs) measuring 
partial pressure of oxygen and carbon 
dioxide (PaO2 and PaCO2).4 Oxygen 
requirement (FiO2) should be 
documented at the same time point. 
pH, lactate and bicarbonate levels and 
base excess or deficit when available 
should also be documented when ABGs 
are assessed. Measurements to be 
taken at intubation and at the time of 
each echocardiogram (± 30 mins)2.
 
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Procedure
Study Period
Notes
Screening1
Day 
1
Day 
2
Day 
3
Up to day 
28
Electrical Impedance 
Tomography
X
X
X
X
Measurements to be taken at intubation 
and at the time of each echocardiogram 
when available (±2 hours)2.
Serious Adverse 
Event (SAE) Review
<=======================>
SAEs will only be collected during the 3 
day observation period or until 
participant withdrawal, whichever is 
sooner.  
Concomitant 
medication review
<=======================>
Only specified prescription medication 
(name, start and end dates required) as 
described in Section 7.1 of the protocol. 
Vasopressor use to be documented for 
each time point of echocardiography.
Intensive Care Unit 
(ICU) length of stay
<=======================>
Will be recorded daily up to 28 days.
Ventilator free days
<=======================>
Will be recorded daily up to 28 days; 
however, follow up is not necessary 
beyond hospital discharge.
In hospital mortality
<=======================>
Will be recorded daily up to 28 days; 
however, follow up is not necessary 
beyond hospital discharge.
Biomarkers 
Blood sample for 
renin-angiotensin 
system (RAS) 
biomarkers
X
X
X
Blood samples to be taken at the same 
time as echocardiography (± 30 mins)2.
Blood sample for 
biomarkers
X
X
X
Blood samples to be taken at the same 
time as echocardiography (± 30 mins)2.
1.
Screening may be considered part of Day 1.
2.
When multiple measurements are to be taken at the same time in relation to echocardiography, blood 
sampling for RAS peptides should be given priority. Other measurements (e.g. ventilator settings) to be 
prioritized as per investigator for patient care. 
3.
Will be recorded at the time of intubation if available.
4.
Where available, a blood sample is required for arterial blood gases (ABGs) for PaO2/FiO2 and oxygenation 
index. A FiO2 measurement should be assessed at the same time point as ABGs are taken for PaO2.
 
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10.3.
Appendix 3: Assessment Windows
10.3.1.
Definitions of Assessment Windows for Analyses
Data management will maintain the allowable visit/sampling windows for study 
procedures. Calendar days will be used rather than 24 hour intervals from the start of the 
1st echo measurement on Day 1, since it is unlikely study procedures will cross midnight. 
Both date and times are typically collected on the eCRF so if required elapsed times can 
be used.
 
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10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study Phases
10.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 4 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
 
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used. If required, the currently supported 
versions of R and STAN software may be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Compound
: GSK2586881
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards.
Generation of RTF Files

RTF files will be generated for the final reporting effort.
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
Unscheduled Visits

Unscheduled will not be included in summary tables and/or figures.

If unscheduled visits are included (decision on a case by case basis), the most appropriate method 
would be used (e.g. summaries displayed by slotting the unscheduled visits to analysis time points 
 
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as per Section 10.3.1)).   

All unscheduled visits will be included in listings and figures (when they relate to individual participants 
– e.g. participant level response vs time profiles).
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.

Where possible, use the same plotting symbol/linestyle/colour combination for a participant in all 
relevant Figures to facilitate easy cross comparison across different data types
 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window (as per Section 10.3.1) the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the mean will be 
taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Echo Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Echo Date → Study Day = Ref Date – First Echo Date

Ref Data ≥ First Echo Date → Study Day = Ref Date – (First Echo Date) + 1    
Study Date/Time (Time 0h)

Calculated as the elapsed time since the date and time of the first echocardiogram

Used to align observations of different domains within an individual participant

Preference to derive using the same algorithm as the HARP standard helper macros and to display 
using an appropriate format to the range of values being displayed (e.g. xx days yy hours zz minutes or 
xx minutes and zz seconds)

10.6.2.
Study Population
Age

Age is approximated as only year of birth is captured:

Age = Calendar Year at Time of Informed Consent – Year of Birth

Age is sometimes referred to in this RAP as Age at Screening (but should be interpreted as Age at 
time of informed consent)
10.6.3.
Pharmacodynamic / Biomarker
RAS Biomarkers

Ang II/Ang(1-7) is calculated as the ratio of the value of Ang II to the corresponding (same-day) value of 
Ang(1-7). If either Ang II or Ang(1-7) is missing for a given Study Day then the ratio will also be derived 
as missing.

If required Ang II / Ang(1-5) (or any other ratio combination of the RAS peptides) would be derived and 
processed in an analogous way to the Ang II / Ang(1-7) ratio.
For the derivation of AngII / Ang(1-7) ratios, the following will apply:
 
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Flags
Numerator (ANGII)
BLQ
Data
ALQ
Missing
Denominator (ANG1-7)
BLQ
(1/2 LLQ of ANGII) / 
(1/2 LLQ of Ang(1-7))
ANGII / 
(1/2 LLQ of Ang(1-
7))
(ULQ of ANGII) / 
(1/2 LLQ of Ang(1-7))
Missing
Data
(1/2 LLQ of ANGII) / 
Ang(1-7)
ANGII / Ang(1-7)
(ULQ of ANGII) / 
Ang(1-7)
Missing
ALQ
(1/2 LLQ of ANGII) / 
(ULQ of Ang(1-7))
ANGII / 
(ULQ of Ang(1-7))
(ULQ of ANGII) / 
(ULQ of Ang(1-7))
Missing
Missing
Missing
Missing
Missing
Missing
LLQ / ULQ = Lower / Upper Limit of Quantification, BLQ / ALQ = Below / Above Limit of Quantification
Note:  The status of the numerator and denominator / outcome should be sufficiently tracked to 
allow subsequent Summary Tables to display the amount of imputation necessary.
Note: all other pharmacodynamic/biomarker endpoints derived from other items should
be auto-calculated on the eCRF and therefore supplied in SI datasets.
In general, it is assumed that biomarker endpoints will require variance stabilising 
transformations, such as taking a loge transformation prior to analysis (and that summary 
statistics appropriate to loge normally distributed data will apply for all summaries; log 
base 10 may also be used in place of natural logarithms).  However, this assumption will 
be considered for each endpoint individually prior to the generation of summary tables or 
statistical analysis, and if deemed more appropriate, a loge transformation will not be 
applied, or non-parametric methods may be employed.
If transformations are used then the results will be reported on the back-transformed scale 
unless otherwise stated.
Unless otherwise specified the following applies to the biomarkers

Values below LLQ will be set as LLQ/2

Values above the upper limit of quantification (ULQ) will be set as ULQ

Imputed values will be used for the purposes of the computation of change from baseline and for 
summaries, plots and analysis, if deemed applicable. 

Number of data imputed will be highlighted in the summary tables & listings will report the values as 
below LLQ or above ULQ, alongside the imputed result used in statistical analyses. 

If multiple LLQ’s and ULQ’s are available per assay (i.e. multiple runs with different standard curves are 
utilised) then the LLQ and/or ULQ value used for the above purposes shall be the minimum of the 
available LLQs and/or the maximum of the BLQ’s.
10.6.4.
Reason for Intubation
The reason for intubation is captured in the eCRF using a free text field. To allow these 
items to be summarised succinctly each free text entry will be mapped to a common set 
of nomenclature. Upon receiving the data transfer associated with the planned data 
review (e.g. planned interim and/or end of study reporting) a list of the unique free text 
 
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entries from the reason for intubation field will be supplied to the medical monitor, who 
will assign each entry into one of the following categories (Note: each participant may 
only be assigned to a single category). Additional categories may be added based upon 
the observed data if deemed necessary by the medical monitor. Only categories that have 
terms mapped to them need to be displayed. A listing of unique free text terms and the 
mappings should also be produced (using similar design concepts to the Adverse Event 
shell AE2)
ID Number
Allowable mapping of free text
(display in the order listed here)
0
Not Applicable (not intubated)
1
Sepsis
2
Pneumonia
3
Acute Respiratory Failure
4
Cardiac Cause
5
Neurologic event
6
Other reason for intubation
7
No reason for intubation supplied
10.6.5.
Oxygenation Index (OI)
The derivation of Oxygenation Index was omitted from the protocol in error and has been 
documented in the RAP for completeness.
Oxygenation index (OI) (sometimes termed oxygenation factor) is another measure of 
gas exchange and pulmonary efficiency which factors in the mean airway pressure (Paw) 
term in the calculation step [El-Khatib, 2004].
It is calculated using Equation 1,
Equation 1
Oxygenation index
proportion
a
not 
and
%
a
as
entered
is
FiO2
and
mmHg
in 
measured
are
  
PaO2
and
Pressure
Airway 
Mean 
where
PaO2
Pressure
Airway 
Mean 
*
FiO2
(%)
Index 
n 
Oxygenatio

10.6.6.
Echocardiogram (Choosing between TTE and TOE results for 
subsequent statistical analyses)
This section describes how to choose which result to select for subsequent statistical 
analyses when multiple options exist. They are based on the echocardiogram parameters 
after InForm Post Go Live 3.1 (implemented approx. Jan 2019). Table 2, Table 3, Table 
4, Table 5, Table 6 and Table 7 enumerate the possible data combinations and which 
values to select for the planned echocardiogram endpoints.
 
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Table 2
Selection algorithm (conditional on eCRF input) for the endpoints 
listed in Table 3
ID#
eCRF state for TTE 
(Transthoratic 
echocardiography)
eCRF state for 
TOE
(Transesophageal 
echocardiography)
Selected value 
for statistical 
analyses
Text value to 
display in 
listings
1
<Blank>
<Blank>
Missing (“.”)
No result
2
<Blank>
Not Done
Missing (“.”)
No result
3
<Blank>
Numerical entry
<TOE value>
<TOE value>
4
Not Done
<Blank>
Missing (“.”)
No result
5
Not Done
Not Done
Missing (“.”)
No result
6
Not Done
Numerical entry
<TOE value>
<TOE value>
7
Numerical entry
<Blank>
<TTE value>
<TTE value>
8
Numerical entry
Not Done
<TTE value>
<TTE value>
9
Numerical entry
Numerical entry
<TTE value>
<TTE value>
Table 3
Endpoints to apply the Table 2 selection criteria to
CVTSTCD
Description
AK001
Ratio of RV to LV End-Diastolic Area
AK003
Systolic Eccentricity Index
AK006
Max Velocity S Wave at Tricuspid Annulus
AK007
Fractional Area Contraction
AK008
Acc Time of RV Ejection Flow (Tacc)
AK009
Mean Acc of RV Ejection Flow at End Exp
AK010
Mean Acc of RV Ejec Flow at End Exp-Insp
AK005
IVC Diameter at End Expiration
AK011
Respiratory Variations of RV VTI
TAPSE
Tricuspid Annular Plane Systol Excursion
AK012
Respiratory Variations of SVC Diameter
CARDOUT
Cardiac Output (CO)
LVEJ
Left Ventricular Ejection Fraction
AK013
LV Velocity (E') Tissue of Annulus
AK014
LV Early to Late Filling Velocities
 
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Table 4
Selection algorithm for Paradoxical Septal Motion (CVTSTCD = 
AK002)
ID#
eCRF state for TTE 
(Transthoratic 
echocardiography)
eCRF state for 
TOE
(Transesophageal 
echocardiography)
Selected value 
for statistical 
analyses
Text value to 
display in 
listings
1
ZZND (Not Done)
ZZND (Not Done)
Missing 
(“<blank>”)
Not Done
2
ZZND (Not Done)
N (No)
N
No
3
ZZND (Not Done)
Y (Yes)
Y
Yes
4
N (No)
ZZND (Not Done)
N
No
5
N (No)
N (No)
N
No
6
N (No)
Y (Yes)
Y
Yes
7
Y (Yes)
ZZND (Not Done)
Y
Yes
8
Y (Yes)
N (No)
Y
Yes
9
Y (Yes)
Y (Yes)
Y
Yes
Note: If only one result is present (e.g. a TTE value only but no TOE value databased) then the selected text should 
be the value present (i.e. Yes, No or Not Done as appropriate to the available result).
Table 5
Selection algorithm for TPG (Trans-tricuspid pressure gradient, 
CVTSTCD = AK004)
ID#
eCRF state for TTE 
(Transthoratic 
echocardiography)
eCRF state for 
TOE
(Transesophageal 
echocardiography)
Selected value 
for statistical 
analyses
Text value to 
display in 
listings
1
<Blank>
<Blank>
Missing (“.”)
No result
2
<Blank>
Numerical entry
<TOE value>
<TOE value>
3
Numerical entry
<Blank>
<TTE value>
<TTE value>
4
Numerical entry
Numerical entry
<TTE value>
<TTE value>
Table 6
Selection algorithm for RAP (Right atrial pressure; Potential results 
could come from either ERATRIAP or AI001 CVTSTCD record but 
only possible to receive one of those codes for each 
participant/timepoint combination)
RAP 
“Estimated” 
or 
“Measured”
ID#
eCRF state 
for 
Measured 
(CVP)
eCRF state for TTE 
(Transthoratic 
echocardiography)
eCRF state for TOE
(Transesophageal 
echocardiography)
Selected 
value for 
statistical 
analyses
Text value 
to display in 
listings
“Estimated” 
(i.e. only 
ERATRIAP 
record 
exists for 
that 
1
N/A (No 
AI001 
record)
<Blank>
<Blank>
Missing 
(“.”)
No result
2
<Blank>
Numerical entry
<TOE 
value>
<TOE 
value>
3
Numerical entry
<Blank>
<TTE 
value>
<TTE 
value>
 
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RAP 
“Estimated” 
or 
“Measured”
ID#
eCRF state 
for 
Measured 
(CVP)
eCRF state for TTE 
(Transthoratic 
echocardiography)
eCRF state for TOE
(Transesophageal 
echocardiography)
Selected 
value for 
statistical 
analyses
Text value 
to display in 
listings
participant / 
timepoint)
4
Numerical entry
Numerical entry
<TTE 
value>
<TTE 
value>
“Measured” 
(i.e. only 
AI001 
record 
exists for 
that 
participant / 
timepoint)
5
<Blank>
N/A (No 
ERATRIAP 
record)
N/A (No 
ERATRIAP 
record)
Missing 
(“.”)
No result
6
Numerical 
entry
<Measured 
value>
<Measured 
value>
Note: In the listing of Echocardiogram endpoints when the RAP is “measured” then the 
TTE and TOE columns should be populated with Not applicable and only the “Selected” 
column would be populated. 
Table 7
Selection algorithm for PASP (Pulmonary artery systolic pressure, 
CVTSTCD = AH001CAL)
ID#
Selected TPG value 
(see Table 5)
Selected RAP value 
(See Table 6)
Selected value 
for statistical 
analyses
Text value to 
display in 
listings
1
Missing (“.”)
Missing (“.”)
Missing (“.”)
No result
2
Missing (“.”)
Numerical entry
Missing (“.”)
No result
3
Numerical entry
Missing (“.”)
Missing (“.”)
No result
4
Numerical entry
Numerical entry
<TPG + RAP>
<TGP + RAP>
Note: All PASP values in analysis and reporting datasets and consequent tables, 
listings and figures will be re-derived by stats and programming using the 
algorithms in Table 7. 
PASP values are also automatically derived within the eCRF form and are supplied in the 
data management transfer of the CV dataset under the CVTSTCD of “AH001”. However, 
it has been noted in test data transfers that the auto calculation does not always derive 
correct results due to the complexities of the data source combinations (e.g. Participant 
 Day 1 had a TPG from the TOE method but an estimated RAP from the TTE 
method but the eCRF autocalculation incorrectly supplied a missing PASP 
value).Therefore there is a need to programmatically re-drive PASP and as a consequence 
there will be additional records in ARDATA versions of the CV dataset compared to the 
SI version (CVTSTCD = AH001CAL).
 
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To facilitate sensitivity analyses regarding the frequency/reason of “missing” PASP 
values an additional variable may be created in ARDATA datasets (as required) that 
tracks the inputs to the PASP calculation (see Table 8). This tracking variable would not 
need to be displayed in the listing of echocardiogram endpoints.
Table 8
Additional variable/result to track the derived PASP inputs (assigned 
a CVTSTCD = AH001src)
AH001src 
value
TPG source used 
in derivation of 
PASP (see Table 
5)
RAP source used 
in derivation of 
PASP (See Table 
6)
1
Missing (“.”)
Missing (“.”)
2
Missing (“.”)
TTE
3
Missing (“.”)
TOE
4
Missing (“.”)
Measured
5
TTE
Missing (“.”)
6
TTE
TTE
7
TTE
TOE
8
TTE
Measured
9
TOE
Missing (“.”)
10
TOE
TTE
11
TOE
TOE
12
TOE
Measured
10.6.7.
Sequential Organ Failure Assessment (SOFA) score
The score will be calculated on a daily basis. Adrenergic agents that do not appear in 
Vincent, 1996 and for which a highest dose has been recorded, will be assigned a SOFA 
score of 2. Zero points are assigned if none of the points scoring criteria are met. If any of 
the information required to derive an individual SOFA component score is missing or 
cannot be obtained, then that component score will be set to a missing value.
The SOFA score will be calculated by summing the individual component scores 
(individual components derived as below). Note: Central Nervous System component 
will not be used in deriving the SOFA score in Study 205821: 

 
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SOFA Score / 
Variable (x)
0
1
2
3
4
Respiration:
PaO2/FiO2
(mmHG)
x 400
300 x 
< 400
200 x < 300
100 x < 200
x < 100
With Respiratory support
(Note: if PaO2/FiO2 in these categories 
but subject not on respiratory support 
then a score of 2 should be assigned)
Coagulation:
Platelets (10^3 
/ mm^3)
x 150
100 x 
< 150
50 x < 100
20 x < 50
x < 20
Liver:
Bilirubin 
(mol/L)
x < 20
20 x < 
33
33 x < 102
102 x < 204
x 204
Cardiovascular
:
Hypotension
(Adrenergic 
agents 
administered 
for at least one 
hour; doses 
are in 
g/kg/min)
Mean 
Arterial 
Pressur
e 70 
mmHg
Mean 
Arterial 
Pressur
e < 70 
mmHg
Dopamine≤5.
0
(µg/kg/min)
or any dose 
of:
Dobutamine
Or any dose 
of an 
adrenergic 
agent not 
listed here or 
in Vincent
(1996)
Dopamine 5.1-15.0
(µg/kg/min)
or Epinephrine≤0.1
or 
Norepinephrine≤0.
1
Dopamine > 15.0
(µg/kg/min)
or Epinephrine>0.1
or
Norepinephrine>0.
1
Central 
Nervous 
System:
Glasgow 
Coma Score
x 15
13 x 
14
10 x 12
6 x 9
x < 6
Renal:
Creatinine 
(mol/L)
                          
x 110
110 < x 
170
170 < x 300
300 < x 440
[Or 
Urine output < 500 
mL/day]
x > 440 
[Or
Urine output < 200 
mL/day]
Note: Central Nervous System scoring algorithm has been included above for completeness but in Study 205821 it is 
not expected to form part of the overall SOFA total
In the SI.CONMEDS record (for vasopressors) the units may have to be converted from 
g/min to g/kg/min dose by merging on the weight from the vital signs dataset (and 
other unit conversions may be required for the other SOFA components). 
PaO2/FiO2 values from the eCRF form should be double checked for accuracy (e.g. 
visual inspection of raw datasets to determine if they in the expected ranges for the stated 
unit).
 
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10.6.8.
Oxygen Saturation
The oxygen saturation may be calculated from the provided ratio SaO2/FiO2 readout if 
the eCRF field for Oxygen Saturation (Vitals eCRF) is blank or missing.
10.6.9.
Calculation of PaO2 / FiO2 and SpO2 / FiO2
If required (e.g. because the automatically calculated eCRF field is blank or the units 
used in the auto-derived field appear to be incorrect) and sufficient source data are 
available then:

The PaO2/FiO2 endpoint can be calculated when patients are intubated and have 
an arterial line present. Prior to computing the ratio the PaO2 may need to be 
converted from kPa units to mmHg using the conversion rate 1/0.133. FiO2 
should be expressed as a proportion and not a percentage when deriving the ratio.

SpO2/ FiO2 will be calculated as a ratio of percentages.
10.6.10.
Construction of ARDATA.ALLCVTS
Guidance on the structure of the master A&R dataset that will hold potential covariate 
variables (for use in model building) is contained in Table 9.
 
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Table 9
Suggested Metadata for ARADTA.ALLCVTS (Modifications may be made if required, e.g. to add/remove variables 
based on questions arising from observed data – the HARP metadata form would capture the final specification 
used). SAS label text and units to be added as appropriate to the data item.
Type
Variable Name
Details
Suggestions for derivation / data source
Info
STUDYID
STUDYID
ARDATA.CV (Unique list of subjid, centreid and visitnum 
combinations where at least one PASP and/or RV Size Ratio 
result was evaluable in CMANALFL=1 records)
VISITNUM 20.00 = DAY 1
VISITNUM 30.00 = DAY 2
VISITNUM 40.00 = DAY 3
Info
SUBJID
SUBJID
Info
USUBJID
USUBJID
Info
CENTREID
CENTREID
Info
INVID
INVID
Info
VISITNUM
VISITNUM
Info
VISIT
VISIT
Info
SUBJLEV
Extraction of set of subject level records
Only a single flag of 1 allowed per subject. Usually Day 1 
record if present, day 2 (or 3) otherwise
Subject
AGE
Age at Screening
ARDATA.DEMO (AGE)
Subject
SEX
Sex
ARDATA.DEMO (SEX)
Subject
VSBMI
BMI at Screening
ARDATA.VITALS (VSBMI)
Subject
SAPSII
SAPS II at Screening
DMDATA.CC (Select CCORRSN where CCTESTCD=CC001)
Subject
RSINTU
Reason for Intubation at Screening 
(Categorical)
ARDATA.PR (Select the derived variable PRMIND which 
contains the mapping of the free text variable (PRINDC) for 
reason for intubation at screening visit (VISITNUM=10); see 
Section 10.6.4)
Time
INTUI
Intubated by Study Day (Binary Y/N)
ARDATA.PR (Where PRTREAT=INTUBATION & VISITNUM in 
(20,30,40))
For each subject and visitnum match:
Set corresponding INTUI to Y if PROCCUR = Y for Day <i>; Set 
to N otherwise
Subject
ARDSX
ARDS Diagnosis at any time (Binary Y/N)
DMDATA.FACE (Where FCETSTCD=FCEBU001)
Set to Y if Any of FCEORSCD = ZZY for a subject; Set to N 
otherwise
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Time
ARDSI
ARDS Diagnosis by Study Day (Binary 
Y/N)
DMDATA.FACE (Where FCETSTCD=FCEBU001)
Treat any Screening results as being from Day 1 (use the worst 
case outcome as Day 1 result). For each subject and visitnum 
match:
Set corresponding ARDSI to Y if FCEORSCD = ZZY for Day 
<i>; Set to N otherwise
Note: Class any SCREENING result as DAY 1 record for the 
purposes of ARDS diagnosis
Subject
INOX
Inhaled Nitric Oxide at any time (Binary 
Y/N)
DMDATA.FACM (Where FCMTSTCD=FCMAX001)
Set to Y if Any of FCMORSCD = ZZY for a subject; Set to N 
otherwise
Time
INOI
Inhaled Nitric Oxide by Study Day (Binary 
Y/N)
DMDATA.FACM (Where FCMTSTCD=FCMAX001)
Treat any Screening results as being from Day 1 (use the worst 
case outcome as Day 1 result). For each subject and visitnum 
match:
Set corresponding INOI to Y if FCMORSCD = ZZY for Day <i>; 
Set to N otherwise
Subject
VASOX
Vasopressor, Inotrope or other Vasoactive 
agent at any time (Binary Y/N)
DMDATA.FACM (Where FCMTSTCD=FCMAX002)
Set to Y if Any of FCMORSCD = ZZY for a subject; Set to N 
otherwise
Time
VASOI
Vasopressor, Inotrope or other Vasoactive 
agent by Study Day (Binary Y/N)
DMDATA.FACM (Where FCMTSTCD=FCMAX002)
Treat any Screening results as being from Day 1 (use the worst 
case outcome as Day 1 result). For each subject and visitnum 
match:
Set corresponding VASOI to Y if FCMORSCD = ZZY for Day 
<i>; Set to N otherwise
Subject
PRONEX
Proned at any time (Binary Y/N)
ARDATA.PR (Where PRTREAT=MECHANICAL 
VENTILATION; exclude records with PRREFID=SOFA)
Set to Y if Any of Subjects records have PRONE=Y
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Time
PRONEI
Proned by Study Day (Binary Y/N)
ARDATA.PR (Where PRTREAT=MECHANICAL VENTILATION 
& VISITNUM in (20,30,40); exclude records with 
PRREFID=SOFA)
For each subject and visitnum match:
Set corresponding PRONEI to Y if PRONE = Y for Day <i>; Set 
to N otherwise
Subject
ECMOX
ECMO at any time (Binary Y/N)
ARDATA.PR (Where PRTREAT= EXTRACORPOREAL 
MEMBRANE OXYGENATION)
Set to Y if Any of Subjects records have PROCCUR=Y
Time
ECMOI
ECMO by Study Day (Binary Y/N)
ARDATA.PR (Where PRTREAT= EXTRACORPOREAL 
MEMBRANE OXYGENATION & VISITNUM in (20,30,40))
For each subject and visitnum match:
Set corresponding ECMOI to Y if PROCCUR = Y for Day <i>; 
Set to N otherwise
Subject
ECCO2RX
ECCO2R at any time (Binary Y/N)
ARDATA.PR (Where PRTREAT= EXTRACORPOREAL CO2 
REMOVAL)
Set to Y if Any of Subjects records have PROCCUR=Y
Time
ECCO2RI
ECCO2R by Study Day (Binary Y/N)
ARDATA.PR (Where PRTREAT= EXTRACORPOREAL CO2 
REMOVAL & VISITNUM in (20,30,40))
For each subject and visitnum match:
Set corresponding ECCO2RI to Y if PROCCUR = Y for Day 
<i>; Set to N otherwise
Subject
LCONDT
Last Contact Date (Date)
ARDATA.DS (Where DSSCATCD=4 & VISITNUM=0)
Select DSSTDT
Subject
LCONDY
Last Contact Study Day (Continuous)
ARDATA.DS (Where DSSCATCD=4 & VISITNUM=0)
Select DSSTDY
Subject
FUDT
Date of Follow Up Visit (Date)
DMDATA.VISIT (Where VISITNUM=50)
Select VISITDT
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Subject
DTHHOSP
In hospital mortality (Categorical Y/N/U)
DMDATA.SS (Where VISITNUM=50 & SSTESTCD=AD009)
Set to Y if SSORRSCD=ZZY; to N if  SSORRSCD=ZZN and to 
U if SSORRSCD=ZZUNK
Subject
DERDTHDT
Derived Death Date (Date)
Set to the earliest of the dates obtained from…
DMDATA.DTH (match on SUBJID and select DDDT)
Or
LCONDT variable if DTHHOSP = Y
Or
If no dates located above but subject has DMDATA.STATUS 
DTHBWIND=Y then set to a derived date corresponding to day 
3 (relative to that subjects date of 1st echo)
Otherwise set to missing
Subject
DERDTHDY
Derived Death Study Day (Continuous)
The study day of the DERDTHDT (relative to time zero – the 
date of 1st echo)
Set to missing if DERDTHDT = missing
Subject
DTH28
Death by Day 28 (Categorical Y/N/U)
Set to Y if DERDTHDY not missing & 28
Set to N if [DERDTHDY = missing & LCONDY 28] or 
[DERDTHDY 28]
Set to U otherwise
Subject
SURVIND
Survival Censoring Indicator (Categorical)
Set to 0 if DERDTHDT not missing
Set to 1 (censored time) otherwise
<Note: Indicator variable should be used in conjunction with 
LCONDY in any time to event analyses>
Subject
ICUDY
Length of stay (days) in ICU (Continuous)
DMDATA.HRU (Where HUCLVCD=4)
Select HUNDYCAR
Subject
HOSPDY
Length of stay (days) in Hospital 
(Continuous)
DMDATA.HRU (Where HUCLVCD=8)
Select HUNDYCAR
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Subject
DYWOVNT
Ventilation Free Days (1 to 28) 
(Continuous)
DMDATA.HRU (Where HUSCATCD=3)
Select DYWOVNT
Subject
SGX1TO3
Any Surgery between Day 1 and Day 3 
(Binary Y/N)
DMDATA.SURGERY (Where VISITNUM=50)
Select SPYN
Time
RVDYSI
Single variable capturing RV Dysfunction 
Status by Study Day (Categorical:
1=No PCD
2=Moderate PCD (not severe enough to 
qualify as ACP)
3 = Non-severe ACP
4 = Severe ACP)
ARDATA.CV (Where CVANALFL=1 & CVTSTCD in (AK015, 
AK016))
For each subject and visitnum match Set to:

1 if CVTSTCD=AK015 & CVORRSCD=N

2 if [CVTSTCD=AK015 & CVORRSCD=Y] & 
[CVTSTCD=AK016 & CVORRSCD=51]

3 if [CVTSTCD=AK015 & CVORRSCD=Y] & 
[CVTSTCD=AK016 & CVORRSCD=52]

4 if [CVTSTCD=AK015 & CVORRSCD=Y] & 
[CVTSTCD=AK016 & CVORRSCD=53]
Subject
RVDYSX
Single variable capturing Worst observed 
RV Dysfunction Status at any time 
(Categorical)
MAX of RVDYSI variable (group by SUBJID)
Subject
PCDACPX
Any PCD or ACP at any time in study 
(Binary Y/N)
Set to Y if RVDYSX in (2,3,4)
Set to N otherwise
Time
PCDACPI
Any PCD or ACP by Study Day (Binary 
Y/N)
Set to Y if RVDYSI in (2,3,4)
Set to N otherwise
Subject
NORVDYSX
Did not have PCD or ACP at any time in 
study (Binary Y/N)
Set to Y if RVDYSX = 1
Set to N otherwise
Time
NORVDYSI
Did not have PCD or ACP on Study Day 
(Binary Y/N)
Set to Y if RVDYSI = 1
Set to N otherwise
Subject
PCDX
Worst case was PCD at any time in study 
(Binary Y/N)
Set to Y if RVDYSX = 2
Set to N otherwise
Time
PCDI
PCD on Study Day (Binary Y/N)
Set to Y if RVDYSI = 2
Set to N otherwise
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Subject
ACPX
Worst case was ACP at any time in study 
(Binary Y/N)
Set to Y if RVDYSX = 3
Set to N otherwise
Time
ACPI
ACP on Study Day (Binary Y/N)
Set to Y if RVDYSI = 3
Set to N otherwise
Subject
SEVACPX
Worst case was Severe ACP at any time in 
study (Binary Y/N)
Set to Y if RVDYSX = 4
Set to N otherwise
Time
SEVACPI
Severe ACP on Study Day (Binary Y/N)
Set to Y if RVDYSI = 4
Set to N otherwise
Subject
ARDNOX
ARDS but no PCD or ACP at any time in 
study (Binary Y/N)
Set to Y if [ARDSX=Y & NORVDYSX=Y]
Set to N otherwise
Subject
ARDPCDX
ARDS and worst case PCD at any time in 
study (Binary Y/N)
Set to Y if [ARDSX=Y & PCDX =Y]
Set to N otherwise
Subject
ARDACPX
ARDS and worst case ACP at any time in 
study (Binary Y/N)
Set to Y if [ARDSX=Y & ACPX =Y]
Set to N otherwise
Subject
ARDSACPX
ARDS and worst case Severe ACP at any 
time in study (Binary Y/N)
Set to Y if [ARDSX=Y & SEVACPX =Y]
Set to N otherwise
Time
GII
Global Inhomogeneity Index (Continuous)
DMDATA.CC (Select CCORRSN where CCTESTCD=BY001 & 
VISITNUM in (20,30,40))
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Time
<Various Vital Signs>
SYSBP
DIABP
HEART
TEMP
RESP
VSPO2BLD
VSMAP
VSPPV
Take names/properties directly from 
dataset (Continuous)
DMDATA.VITALS (Where VISITNUM in (20,30,40) & VSREFID 
^= SOFA)
Select (use same name)
SYSBP
DIABP
HEART
TEMP
RESP
VSPO2BLD
VSMAP
VSPPV
Match on subjid and visitnum
Time
OI
Oxygenation Index (Continuous)
DMDATA.RE (Where VISITNUM in (20,30,40) & 
RETESTCD=AC002)
Select REORRSN
Match on subjid and visitnum
Time
PAO2
Partial pressure of arterial O2 (mmHg) 
(Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=PAO2_BLP)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
PAO2DM
DateTime of PAO2 Sample (DateTime)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=PAO2_BLP)
For each subject select the most recent non-missing 
LBORRESN value from visitnum 10,20 (and set result to have 
visitnum=20) prior to merging by subject and visitnum
Combine LBDT and LBACTTM into a single datetime formatted 
variable
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Time
PACO2
Carbon dioxide partial pressure (mmHg) 
(Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=PCO2_BLP)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
LACT
Serum Lactate (mmol/L) (Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=LACT_PLC)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
HC03
Serum Bicarbonate (mEq/L) (Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=HC03_PLC)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
PH
Blood pH (Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=PH_BLG)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
BASEXA
Base excess (arterial whole blood) 
(mEq/L) (Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=BASEXA_BLC)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Time
BDEFA
Base deficit (arterial whole blood) (mEq/L) 
(Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=BDEFA_BLC)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
TROPI
Troponin I (UG/L) (Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=TROPI_PLC)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
TROPT
Troponin T (UG/L) (Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
^=SOFA & LBTESTCD=TROPT_PLC)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
PFSOFA
PaO2/FiO2 entered onto SOFA form 
(Continuous)
DMDATA.LAB (Where VISITNUM in (10,20,30,40) & LBREFID 
=SOFA & LBTESTCD=PAO2FI_BLQ)
For each subject select the most recent non-missing value from 
visitnum 10,20 (and set result to have visitnum=20) prior to 
merging by subject and visitnum
Select LBORRESN
Time
FIO2
Fraction of Inspired Oxygen (%) 
(Continuous)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD=FPRAW005)
Select FPRORSN. Match on subjid and visitnum
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Time
FIO2DM
DateTime of FIO2 Sample (DateTime)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD=FPRAW005)
Combine FPRDT and FPRTM into a single datetime formatted 
variable Match on subjid and visitnum 
Time
PFDIFF
Difference between PaO2 and FiO2 
Sampling occasions (mins)
(PAO2DM - FIO2DM) converted into minutes
Time
PFECRF
PaO2/FiO2 derived (Continuous)
PAO2 / (FIO2 / 100)
Time
PFECRF30
PaO2/FiO2 (sampling within 30 mins) 
(Continuous)
Select PFECRF if ABS(PFDIFF) 30; set to missing otherwise
Time
FPRBH001
Static Respiratory System Compliance 
(mL/cm H2O) (Continuous)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD= FPRBH001)
Select FPRORSN. Match on subjid and visitnum
Time
FPRBH003
Pressure Support Ventilation (Binary Y/N)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD= FPRBH003)
Match on subjid and visitnum
Set Y if FPRORSCD=ZZY
Set N otherwise
Time
FPRAB001
Tidal Volume (mL) (Continuous)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD= FPRAB001)
Select FPRORSN. Match on subjid and visitnum
Time
FPRAB002
Positive End Expiratory Pressure PEEP 
(cm H2O) (Continuous)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD= FPRAB002)
Select FPRORSN. Match on subjid and visitnum
Time
FPRAB003
Peak Ventilatory Pressure (cm H2O)
(Continuous)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD= FPRAB003)
Select FPRORSN. Match on subjid and visitnum
Time
FPRAB008
Plateau Ventilatory Pressure (cm H2O)
(Continuous)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD= FPRAB008)
Select FPRORSN. Match on subjid and visitnum
 
 
 
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Type
Variable Name
Details
Suggestions for derivation / data source
Time
FPRBH004
Mean Airway Pressure (cm H2O)
(Continuous)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD= FPRBH004)
Select FPRORSN. Match on subjid and visitnum
Time
FPRBH005
Driving Pressure (cm H2O) (Continuous)
DMDATA.FAPR (Where VISITNUM in (20,30,40) & 
FPRTSTCD= FPRBH005)
Select FPRORSN. Match on subjid and visitnum
Time
<Various Echo endpoints and 
the key RAS peptides>
Take from source dataset
ARDATA.STATSCAT (drop STUDYID, CENTREID, INVID, 
INVNAME, AGE, SEX, RACE, RACECD, ATRTCD, ATRTGRP, 
TRTCD, TRTGRP, USUBJID, VISIT, AH001AC, AK015, AK016 
variables)
Select remaining variables and match on subjid and visitnum
 
 
 
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10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as having 
completed the Day 3 assessments as shown in the SoA. 

Withdrawn subjects may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified (e.g. because they withdrew consent as detailed in the study 
protocol).

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
Missing 
Categorical 
Covariates

In the statistical models of RAS peptides as predictors of measures of RV function (and 
other associated models), a number of categorical covariates (e.g. sex, prior history of 
RAS modulators, type of echocardiogram, use of vasopressors, proning status, use of 
nitric oxide) may be required. The following rules should be applied to variables that are 
to be included in the final statistical model:

In the unlikely event that sex is not recorded for a participant, then data from that 
participant will not be included.

For prior history of RAS modulators, a participant is assumed not to have had such a 
history unless explicitly reported otherwise.

For the other variables listed above, which are recorded on each study day, the 
following imputation algorithm should be applied for missing values:
o
If the same variable is not missing on a previous study day (including screening, if 
applicable), impute the most recent known value.
o
Otherwise, if the same variable is not missing on a subsequent study day, impute 
the value from the nearest time point after the missing one.

Otherwise, keep the value as missing and exclude the participant from the analysis
10.7.2.1.
Handling of Missing and Partial Dates/Times
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Adverse 

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
 
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Element
Reporting Detail
Events
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Note: Due to usage of local labs, care should be taken to ensure each supplied unit has 
been converted into the units given below before applying the PCI criteria (if applicable –
any multipliers of LLN / ULN do not require units).
PCI values have been taken from Study ACE114622 (mild to moderate ARDS). Since no 
investigational product is being administered in this study any PCI flags will act more as 
an awareness for the study team when interpreting the RAS peptides / other clinical 
outcomes for those individuals. Any lab tests which the medical monitor has not specified 
PCI ranges for are denoted as “NA” but will still be reviewed as part of the Min/Max 
variables in the Summary tables.
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag 
(Relative –
Multipliers of LLN)
High Flag 
(Relative –
Multipliers of ULN)
Platelet Count 
0.4
NA
Red Blood Cell (RBC) Count
NA
NA
While Blood Cell (WBC) Count 
(absolute)
0.67
1.82
Haemoglobin 
Male
0.67
1.03
Female
0.67
1.13
Hematocrit 
Ratio of 
1
Male
0.3
0.54
Female
0.3
0.54
(Total) Neutrophils
NA
NA
Lymphocytes 
NA
NA
Monocytes
NA
NA
Eosinophils
NA
NA
Basophils
NA
NA
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag 
(Relative –
Multipliers of LLN)
High Flag 
(Relative –
Multipliers of ULN)
Urea / BUN
NA
NA
Chloride
NA
NA
Creatinine
NA
2
Potassium
0.86
1.10
Sodium
NA
NA
Total CO2
NA
NA
Total Bilirubin
NA
NA
 
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Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag 
High Flag 
Troponin I
(Note: Has been spelt as 
Troponon in Protocol)
ng/mL
NA
> 0.04
Troponin T
(Note: Has been spelt as 
Troponon in Protocol)
ng/mL
NA
> 0.10
10.8.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
<85
>160
Diastolic Blood Pressure
mmHg
<45
>100
Heart Rate
bpm
<40
>110
 
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10.9.
Appendix 9: Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
BLQ
Below Limit of Quantification
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CPSR
Clinical Pharmacology Study Report (interchangeable with the CSR 
abbreviation)
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DIC
Deviance Information Criteria
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
LAR
Legally Acceptable Representative
LLN
Lower Limit of Normal
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
 
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Abbreviation
Description
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SoA
Schedule of Assessments (also known as Time and Events table)
SOP
Standard Operation Procedure
TA
Therapeutic Area
TBC
To Be Confirmed
TFL
Tables, Figures & Listings 
ULN
Upper Limit of Normal
ULQ
Upper Limit of Quantification
10.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
 
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10.10.
Appendix 10: List of Data Displays
10.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Safety
2.1 to 2.n
2.1 to 2.n
Pharmacodynamic and / or Biomarker
3.1 to 3.n
3.1 to 3.n
Participant Status and / or Other Clinical 
Assessments
4.1 to 4.n
4.1 to 4.n
Statistical Modelling
5.1 to 5.n
5.1 to 5.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
10.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Participant Status and / or Other Clinical 
Assessments
OCA_Fn
OCA_Tn
OCA_Ln
Statistical Modelling
SM_Fn
SM _Tn
SM _Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.10.3.
Deliverables
Delivery Priority 1
Description
SAC X
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
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10.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Enrolled
ES1
Summary of Subject Disposition for the 
Subject Conclusion Record
ICH E3, FDAAA, EudraCT, CONSORT
SAC 1
1.2.
Screened
ES6
Summary of Screening Status and Reasons 
for Screen Failure
Journal Requirements
SAC 1
1.3.
Safety
NS1
Summary of Number of Subjects by Country 
and Site ID
EudraCT/Clinical Operations
SAC 1
Protocol Deviations
1.4.
Safety
DV1
Summary of Important Protocol Deviations
ICH E3
SAC 1
Population Analysed
1.5.
Enrolled
SP1A
Summary of Study Populations 
IDSL
SAC 1
1.6.
Enrolled
SP2A
Summary of Exclusions from the 
Safety/Evaluable/Completed/At Risk
Populations
IDSL
If possible separate page for each population (this may 
require non-standard wrapper macro to call the standard 
macro separately for each population)
If the Evaluable with prohibited conmed population is 
different to evaluable add it in (otherwise footnote the 
evaluable table to indicate they are the same)
SAC 1
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.7.
Safety
DM1
Summary of Demographic Characteristics by 
PCD/ACP status
ICH E3, FDAAA, EudraCT
Instead of the set of treatment variables (columns) please 
use “No PCD/ACP” and “Any PCD/ACP” and “All 
Participants” as columns to group the subjects 
As well as the standard set of demography items (Sex, Age, 
Age Group, Height, Weight, BMI) please also include the 
following Disease specific baseline variables (with units if 
applicable) to facilitate manuscript publication (mixture of 
continuous and categorical variables)
Baseline should be the earliest non-missing value from 
SCREENING or DAY 1 visits. Do not display values from 
Days 2 or 3 (if multiple timepoints are available for an item)
SAPSII, SOFA, PaO2/FiO2 (from SOFA form), PaO2, FiO2, 
PaCO2, Oxygenation Index, Reason for Intubation (use the 
mapped variable not free text results), Proned, Receiving 
Inhaled Nitric Oxide, “Managed with Vasopressors, inotropes 
or other vasoactive agents”, ECMO, ECCO2R, Global 
Inhomogeneity Index, SpO2, Serum Lactate, Serum 
Bicarbonate, pH, Base excess (arterial whole blood), Base 
deficit (arterial whole blood), Central Venous Pressure, Static 
respiratory system compliance, Respiratory rate (not from 
vitals but from FAPR), Pressure support (Y/N), Tidal Volume, 
PEEP, Peak Pressure, Plateau Pressure, Mean Airway 
Pressure, Driving Pressure, In-hospital Mortality 
(Y/N/Unkown)
Note: Summarise with n, Median, Lower and Upper quartiles, 
Min and Max:
Length of stay in ICU, Length of stay in hospital, Ventilation 
free days 
SAC 2
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.8.
Safety
DM11
Summary of Age Ranges
EudraCT
SAC 2
Prior and Concomitant Medications
1.9.
Safety
MH4
Summary of Current Medical Conditions
ICH E3 
SAC 2
1.10.
Safety
MH4
Summary of Past Medical Conditions
ICH E3
SAC 2
1.11.
Safety
CM1
Summary of Concomitant Medications
ICH E3
Exclude the SOFA related records
SAC 2
 
 
 
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10.10.5.
Safety Tables
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious Adverse Events
2.1.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
Conditional output: a listing on its own 
may be sufficient if there are few 
events.
Display lines showing “Drug-related 
SAE” and “Drug-related Fatal SAE” 
should be omitted as there is no study 
drug involved.
SAC 2
Laboratory
2.2.
Safety
LB1
Summary of Clinical Chemistry Values by Timepoint
ICH E3
Exclude the SOFA related records
There is no baseline in this study as 
there is no treatment being 
administered. Therefore the only data 
that can be presented is raw values 
rather than changes from baseline.
SAC 2
 
 
 
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
Safety
LB1
Summary of Haematology Values by Timepoint
ICH E3
Exclude the SOFA related records
There is no baseline in this study as 
there is no treatment being 
administered. Therefore the only data 
that can be presented is raw values 
rather than changes from baseline.
SAC 2
Vital Signs
2.4.
Safety
VS1
Summary of Vital Signs by Timepoint
ICH E3
Exclude the SOFA related records
There is no baseline in this study as 
there is no treatment being 
administered. Therefore the only data 
that can be presented is raw values 
rather than changes from baseline.
SAC 2
 
 
 
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10.10.6.
Pharmacodynamic and Biomarker Tables
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Echocardiography
3.1.
Evaluable
PD_T1 
(ECHO)
Summary of Echocardiogram Measurements by Timepoint
Two separate statistics tables: 1) for 
continuous, 2) for qualitative echo 
measurements.
SAC 1
3.2.
Evaluable
SM_T1
(ECHO)
Within- and Between-Subject Variability of Continuous 
Echocardiogram Measurements
SAC 1
RAS Biomarkers
3.3.
Evaluable
PD_T2
(RAS)
Summary of RAS Biomarker Measurements by Timepoint
Present results for levels and log
transformed in two separate tables.
SAC 1
3.4.
Evaluable
SM_T1
(RAS)
Within- and Between-Subject Variability of RAS Biomarker 
Measurements
SAC 1
 
 
 
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Participant Status and Other Clinical Assessments: Tables
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Disease Diagnosis Status
4.1.
At risk
OCA_T1
(DISEASE_INCIDENCE)
Summary of ARDS, PCD and ACP Incidence Rates by 
Timepoint and Study
Create two tables: 1) summarizing of 
number of the cases, where patient 
may contribute multiple times and 2) 
with overall incidence rates including 
the joint categories. 
Note: Shell does not contain all items 
to be displayed
SAC 1
 
 
 
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10.10.7.
Pharmacodynamic and Biomarker Figures
Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Echocardiography
3.1.
Evaluable
PD_F2
(SCAT3D_YN)
Scatterplot of PASP vs RV Size Ratio marked by Paradoxical 
Septal Motion Status
Scatterplot of (x-axis) PASP vs (y-
axis) RV size ratio. Paradoxical Septal 
Motion Status is marked by black(Y)-
grey(N) colour. For Not Done PSM 
status leave blank (i.e. do not plot a
coloured circle within the data point)
SAC 1
RAS Biomarkers
3.2.
Evaluable
PD_F1
(SCAT2D)
Scatterplots of Ang II, Ang(1-7) and Ang(1-5) combinations
Display with a Log10-transformed x 
and y axis scales.
Separate page/plot for each 
combination.
Present Ang II Vs Ang(1-7), Ang II Vs 
Ang(1-5) and Ang(1-7) Vs Ang(1-5) in 
listed order
SAC 1
3.3.
Evaluable
PD_F4
(SERIES1D)
Individual Line Plots of RAS Biomarkers by Timepoint
On separate pages, time series plots 
for RAS biomarker readouts: Ang II, 
Ang(1-7), Ang(1-5), Ang II/Ang(1-7) 
ratio per visit (use log10 scale for y-
axis). If the number of subject is too 
large omit the legend.
SAC 1
 
 
 
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Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.4.
Evaluable
PD_F2
(SCAT3D_YN)
Scatterplots of Selected Echocardiography Endpoints Vs 
selected RAS biomarkers by Paradoxical Septal Motion Status
On separate pages, scatterplots of (x-
axis) RAS biomarker readouts: Ang II, 
Ang(1-7), Ang(1-5), Ang II/ Ang(1-7) 
ratio (using log10 axis scale), vs (y-
axis) PASP and RV size ratio 
readouts.  Paradoxical Septal Motion 
Status is marked by black(Y)-grey(N) 
colour. For Not Done PSM status 
leave blank (i.e. do not plot a coloured 
circle within the data point)
SAC 1
3.5.
Evaluable
PD_F3
(SCAT3D_CONT)
Scatterplots of PASP vs. RV Size Ratio marked by RAS 
biomarker levels
On separate pages, scatterplots for
(x-axis) PASP vs (Y-axis ) RV size 
ratio coloured by RAS biomarker 
readouts: Ang II, Ang(1-7), ANG II/ 
Ang(1-7) ratio and Ang(1-5) on 
rainbow colour scale (no log-
transformation). For each RAS 
biomarker scatterplot without and with 
visit marks provided.
SAC 1
 
 
 
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10.10.8.
Statistical Modelling Tables
Statistical Modelling: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Preparatory Analysis
5.1.
Evaluable
SM_T2 
(BICORR_PHARM)
Bivariate Correlations of RAS Biomarkers with
Pharmacodynamic Endpoints
Consider three different measures of 
correlation:1) derived from the 
bivariate mixed effect model and its 
between-marker Sigma vcov matrix 2) 
Pearson correlation 3) Spearman 
correlation 
A version of this output should be 
produced as soon as possible after the 
interim or final analysis has been 
triggered in order to enable the team to 
decide a) which covariates to include 
in the models and b) which of the 
conditional outputs (if any) to produce. 
List of continuous covariates to be
provided at run time by statistician
SAC 1
 
 
 
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Statistical Modelling: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
5.2.
Evaluable
SM_T2 
(BICORR_CONT)
Bivariate Correlations of Ang II, Ang(1-7), PASP and RV Size 
Ratio with Continuous Covariates
Consider three different measures of 
correlation:1) derived from the 
bivariate mixed effect model and its 
between-marker Sigma vcov matrix 2) 
Pearson correlation 3) Spearman 
correlation
A version of this output should be 
produced as soon as possible after the 
interim or final analysis has been 
triggered in order to enable the team to 
decide which covariates to include in 
the primary and secondary models. 
List of continuous covariates to be 
provided at run time by statistician
SAC 1
5.3.
Evaluable
SM_T3
(ECHO_RAS_ 
CAT)
Summary Statistics of RAS biomarkers and Echocardiogram 
Endpoints by Categorical Covariates
A version of this output should be 
produced as soon as possible after the 
interim or final analysis has been 
triggered in order to enable the team to 
decide which covariates to include in 
the primary and secondary models.
List of categorical covariates will be 
provided by statistician at time of 
analysis
SAC 1
 
 
 
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Statistical Modelling: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Statistical Modelling
5.4.
Evaluable
SM_T4 (MODEL1)
Summary of Primary Model Results: Ang II as a Predictor of 
PASP and RV Size Ratio
On separate pages: 
Table 1) subtitle: Model Parameters 
Values with Statistics
Table 2) subtitle: PASP and RV Model 
Predictions for Reference Ang II 
Values: Pre-dose <Ang_II_level> 
(pg/mL) and Post-dose <Ang_II 
_level> (pg/mL)
Table 3) subtitle: Probability of RV 
Disfunction Given Reference Ang II 
Values: Pre-dose <Ang_II_level> 
(pg/mL) and Post-dose <Ang_II 
_level> (pg/mL)
Add any sensitivity reference value 
results onto separate pages. For clear 
separation the subtitles start with 
‘SENSITIVITY:’
SAC 1
 
 
 
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Statistical Modelling: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
5.5.
Evaluable
SM_T4 (MODEL2)
Summary of Secondary Model Results: Ang(1-7) as a Predictor 
of PASP and RV Size Ratio
On separate pages:
Table 1) subtitle: Model Parameters 
Values with Statistics
Table 2) subtitle: PASP and RV Model 
Predictions for Reference Ang(1-7) 
Values: Pre-dose < Ang(1-7)_level> 
(pg/mL) and Post-dose < Ang(1-
7)_level> (pg/mL)
Table 3) subtitle: Probability of RV 
Disfunction Given Reference Ang(1-7)
Values: Pre-dose < Ang(1-7)_level> 
(pg/mL) and Post-dose < Ang(1-
7)_level> (pg/mL)
Add any sensitivity reference value 
results onto separate pages. For clear 
separation the subtitles start with 
‘SENSITIVITY:’
SAC 1
 
 
 
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Statistical Modelling: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
5.6.
Evaluable
SM_T4 (MODEL3)
Summary of Secondary Model Results: Ang(1-5) as a Predictor 
of PASP and RV Size Ratio
[conditional output]
On separate pages:
Table 1) subtitle: Model Parameters 
Values with Statistics
Table 2) subtitle: PASP and RV Model 
Predictions for Reference Ang(1-5) 
Values: Pre-dose < Ang(1-5)_level> 
(pg/mL) and Post-dose < Ang(1-
5)_level> (pg/mL)
Table 3) subtitle: Probability of RV 
Disfunction Given Reference Ang(1-5)
Values: Pre-dose < Ang(1-5)_level> 
(pg/mL) and Post-dose < Ang(1-
5)_level> (pg/mL)
Only analysis would be the sensitivity 
reference value, but still start the 
subtitles with ‘SENSITIVITY:’
SAC 1
5.7.
Evaluable
SM_T4 (MODEL4)
Summary of Secondary Model Results: Ang II and Ang(1-7) as 
Joint Predictors of PASP and RV Size Ratio
[conditional output]
Model only run if data permit
SAC 1
 
 
 
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10.10.9.
Statistical Modelling Figures
Statistical Modelling: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Statistical Modelling Figures
5.1.
Evaluable
SM_F1
Scatterplot of PASP vs RV Size Ratio, Coloured by Ang II Value, 
with Posterior Prediction Regions for RV Function Measurements 
for Protocol-Defined Reference Values of Ang II 
On separate pages: 
Figure 1) the scatterplot version with 
no visit marks and subtitle: Pre-dose 
<Ang_II_level> (pg/mL) and Post-
dose <Ang_II _level> (pg/mL) Ang II
Figure 2) the scatterplot version with 
visit marks and subtitle: Pre-dose 
<Ang_II_level> (pg/mL) and Post-
dose <Ang_II _level> (pg/mL) Ang II
Figure 3) subtitle: PASP Median and 
95% Equal-Tailed Credibility Intervals 
for Pre-dose <Ang_II_level> (pg/mL) 
and Post-dose <Ang_II _level> 
(pg/mL) Ang II
Figure 4) subtitle: RV size Median 
and 95% Equal-Tailed Credibility 
Intervals for Pre-dose <Ang_II_level> 
(pg/mL) and Post-dose <Ang_II 
_level> (pg/mL) Ang II
Figure 5) subtitle: Prediction Regions 
for RV Function Measurements for 
Pre-dose <Ang_II_level> (pg/mL) and 
Post-dose <Ang_II _level> (pg/mL) 
Ang IIAdd any sensitivity reference 
value results onto separate pages. 
For clear separation the subtitles start 
SAC 1
 
 
 
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Statistical Modelling: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
with ‘SENSITIVITY:’
5.2.
Evaluable
SM_F1
Scatterplot of PASP vs RV Size Ratio, Coloured by Ang(1-7) 
Value, with Posterior Prediction Regions for RV Function 
Measurements for Protocol-Defined Reference Values of Ang(1-
7)
On separate pages: 
Figure 1) the scatterplot version with 
no visit marks and subtitle: Pre-dose 
<Ang(1-7)_level> (pg/mL) and Post-
dose <Ang(1-7) _level> (pg/mL) 
Ang(1-7)
Figure 2) the scatterplot version with 
visit marks and subtitle: Pre-dose 
<Ang(1-7)_level> (pg/mL) and Post-
dose <Ang(1-7) _level> (pg/mL) 
Ang(1-7)
Figure 3) subtitle: PASP Median and 
95% Equal-Tailed Credibility Intervals 
for Pre-dose <Ang(1-7)_level> 
(pg/mL) and Post-dose <Ang(1-7) 
_level> (pg/mL) Ang(1-7)
Figure 4) subtitle: RV size Median 
and 95% Equal-Tailed Credibility 
Intervals for Pre-dose <Ang(1-
7)_level> (pg/mL) and Post-dose 
<Ang(1-7) _level> (pg/mL) Ang(1-7)
Figure 5) subtitle: Prediction Regions 
SAC 1
 
 
 
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Statistical Modelling: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
for RV Function Measurements for 
Pre-dose <Ang(1-7)_level> (pg/mL) 
and Post-dose <Ang(1-7) _level> 
(pg/mL) Ang(1-7)
Add any sensitivity reference value 
results onto separate pages. For 
clear separation the subtitles start 
with ‘SENSITIVITY:’
5.3.
Evaluable
SM_F1
Scatterplot of PASP vs RV Size Ratio, Coloured by Ang(1-5) 
Value, with Posterior Prediction Regions for RV Function 
Measurements for Protocol-Defined Reference Values of Ang(1-
5)
[conditional output]
On separate pages: 
Figure 1) the scatterplot version with 
no visit marks and subtitle: Pre-dose 
<Ang(1-5)_level> (pg/mL) and Post-
dose <Ang(1-5) _level> (pg/mL) 
Ang(1-5)
Figure 2) the scatterplot version with 
visit marks and subtitle: Pre-dose 
<Ang(1-5)_level> (pg/mL) and Post-
dose <Ang(1-5) _level> (pg/mL) 
Ang(1-5)
Figure 3) subtitle: PASP Median and 
95% Equal-Tailed Credibility Intervals 
for Pre-dose <Ang(1-5)_level> 
(pg/mL) and Post-dose <Ang(1-5) 
_level> (pg/mL) Ang(1-5)
Figure 4) subtitle: RV size Median 
and 95% Equal-Tailed Credibility 
Intervals for Pre-dose <Ang(1-
5)_level> (pg/mL) and Post-dose 
<Ang(1-5) _level> (pg/mL) Ang(1-5)
Figure 5) subtitle: Prediction Regions 
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Statistical Modelling: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
for RV Function Measurements for 
Pre-dose <Ang(1-5)_level> (pg/mL) 
and Post-dose <Ang(1-5) _level> 
(pg/mL) Ang(1-5)
Only analysis would be the sensitivity 
reference value, but still start the 
subtitles with ‘SENSITIVITY:’
5.4.
Evaluable
SM_F2
Boxplots of Ang II, Ang(1-7), Ang(1-5), PASP and RV Size Ratio 
by Categorical Covariates. Auxiliary output for Table 5.3
[conditional output]
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10.10.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC 1
2.
Enrolled
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC 1
Protocol Deviations
3.
Safety
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC 1
4.
Enrolled
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC 1
Populations Analysed
5.
Enrolled
SP3a
Listing of Subjects Excluded from Any Population
ICH E3
SAC 1
Demographic and Baseline Characteristics
6.
Safety
DM2
Listing of Demographic Characteristics
ICH E3
Use same set of variables as the 
corresponding summary table
SAC 2
Prior and Concomitant Medications
7.
Safety
CP_CM3
Listing of Concomitant Medications
IDSL
Exclude the SOFA related records
SAC 2
Adverse Events Section is not applicable as non-serious AEs are not being databased
Serious and Other Significant Adverse Events
8.
Safety
AE8CPa
Listing of Serious Adverse Events
ICH E3
SAC 2
9.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC 2
10.
Safety
AECP8
Listing of Serious Adverse Events Leading to Withdrawal from 
Study
ICH E3
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
11.
Safety
LB5
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
Exclude the SOFA related records
SAC 2
Vital Signs
12.
Safety
VS4
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
Exclude the SOFA related records
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10.10.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacodynamic and Biomarker Listings
13.
Evaluable
PD_L1
Listing of Echocardiograph Measurements
Include all echo measures except the 
original eCRF PASP (AH001), 
AH001src, the programmatically 
derived variable containing the 
combined RAP (RAP), AK015 and 
AK016 which concern the ACP/PCD 
and its severity (those are displayed in 
Listing 19). Keep the order as in 
Section 5.5. 
Except for Estimated and Measured 
RAP have blank records if no result 
obtained for a test to maintain 
consistency of output for each subject 
and visit combination
SAC 1
14.
Evaluable
PD_L2
Listing of RAS Biomarker Values
Listing on non-transformed levels. 
Include Ang II / Ang(1-7) ratio and 
ANG(1-5)
SAC 1
Participant Status and Other Clinical Assessments Listings
15.
At Risk
OCA_L5
Listing of Disease Diagnosis Status
Match to items in Table 4.1
SAC 1
16.
Safety
AE2 (Modified)
Listing of Relationship between Reasons for Intubations and 
Verbatim Text
Display the Mapped categories (in 
place of System Organ Class – in the 
order implied in Section 10.6.4) and all 
of the free text reasons within each 
mapping (in place of Verbatim text) and 
omit the Preferred Term column (from 
the AE2 shell)
SAC 1
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Statistical Modelling Listings
17.
Evaluable
SM_L1
Listing of Primary Statistical Model Output: Ang II as a Predictor
of PASP and RV Size Ratio
Start with Gelman-Rubin diagnostics for 
model parameters convergence given 
different starting points. Mark 
considered burn-in period. Further, 
include model printouts from PROC 
MCMC for parameter estimates and 
PASP and RV Size Ratio predictions 
given Ang II reference values.
SAC 1
18.
Evaluable
SM_L1
Listing of Secondary Model Results: Ang(1-7) as a Predictor of 
PASP and RV Size Ratio
Start with Gelman-Rubin diagnostics for 
model parameters convergence given 
different starting points. Mark 
considered burn-in period. Further 
include model printouts from PROC 
MCMC for parameter estimates and 
PASP and RV Size Ratio predictions 
given Ang(1-7) reference values.
SAC 1
19.
Evaluable
SM_L1
Listing of Secondary Model Results: Ang(1-5) as a Predictor of 
PASP and RV Size Ratio
[conditional output]
Start with Gelman-Rubin diagnostics for 
model parameters convergence given 
different starting points. Mark 
considered burn-in period. Further 
include model printouts from PROC 
MCMC for parameter estimates and 
PASP and RV Size Ratio predictions 
given Ang(1-5) reference values.
SAC 1
20.
Evaluable
SM_L1
(Modified for 
model structure 
/ parameters)
Listing of Secondary Model Results: Ang II and Ang(1-7) as 
Joint Predictors of PASP and RV Size Ratio
[conditional output]
SAC 1
 
 
 
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10.11.
Appendix 11: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request
 
 
 
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