Phase 2, Randomized, Controlled, Open Label Multi-center Study to Assess Efficacy and Safety of DFV890 for the Treatment of SARS-CoV-2 Infected Patients With COVID-19 Pneumonia and Impaired Respiratory Function
Phase: PHASE2
Conditions: COVID-19 Pneumonia, Impaired Respiratory Function
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
DFV890
Clinical Trial Protocol CDFV890D12201 / NCT04382053
Phase 2, randomized, controlled, open label multi-center 
study to assess efficacy and safety of DFV890 for the 
treatment of SARS-CoV-2 infected patients with COVID-19 
pneumonia and impaired respiratory function
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2020-001870-32
Version number:
01 (Clean)
Clinical Trial Phase:
II
Release date:
22-JUN-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................21
1
Introduction .......................................................................................................................25
1.1
Background............................................................................................................25
1.1.1
Innate immunity during viral infection .................................................25
1.1.2
Reduced activation of NLRP3 inflammasome in asymptomatic host 
species ...................................................................................................26
1.1.3
Excessive inflammasome activation in the elderly...............................26
1.1.4
Coronavirus activation of the inflammasome may promote lung 
pathology...............................................................................................27
1.1.5
Inflammasome activation by mechanical ventilation and ARDS .........27
1.1.6
Translational evidence that the NLRP3 inflammasome is activated 
in patients with coronavirus lung pathology.........................................27
1.1.7
Inflammasome in acute organ injury and sepsis ...................................28
1.1.8
Summary...............................................................................................28
1.2
DFV890 .................................................................................................................29
1.3
Purpose ..................................................................................................................32
2
Objectives and endpoints...................................................................................................32
2.1
Primary estimands .................................................................................................33
2.2
Secondary estimands .............................................................................................34
3
Study design ......................................................................................................................34
4
Rationale............................................................................................................................35
4.1
Rationale for study design .....................................................................................35
4.2
Rationale for participant numbers and endpoint....................................................36
4.3
Rationale for choice of background therapy..........................................................37
4.4
Rationale for dose/regimen and duration of treatment ..........................................37
4.5
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................39
4.6
Purpose and timing of interim analyses/design adaptations..................................39
4.7
Risks and benefits..................................................................................................39
4.7.1
Potential benefits and risks to study participants..................................39
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4.7.2
Potential risks to participants ................................................................39
4.7.3
Overall risk benefit................................................................................41
4.8
Blood sample volume ............................................................................................42
5
Study Population ...............................................................................................................42
5.1
Inclusion criteria....................................................................................................42
5.2
Exclusion criteria...................................................................................................43
6
Treatment...........................................................................................................................44
6.1
Study treatment......................................................................................................44
6.1.1
Investigational and control drugs..........................................................44
6.1.2
Additional study treatments ..................................................................45
6.1.3
Treatment arms/group...........................................................................45
6.2
Other treatment(s)..................................................................................................45
6.2.1
Concomitant therapy.............................................................................45
6.3
Participant numbering, treatment assignment, randomization ..............................48
6.3.1
Participant numbering...........................................................................48
6.3.2
Treatment assignment, randomization..................................................48
6.4
Treatment blinding.................................................................................................49
6.5
Dose escalation and dose modification..................................................................49
6.6
Additional treatment guidance...............................................................................49
6.6.1
Treatment compliance...........................................................................49
6.6.2
Recommended treatment of adverse events..........................................50
6.6.3
Emergency breaking of assigned treatment code..................................50
6.7
Preparation and dispensation.................................................................................50
6.7.1
Handling of study treatment and additional treatment..........................50
6.7.2
Instruction for prescribing and taking study treatment .........................51
7
Informed consent procedures ............................................................................................51
8
Visit schedule and assessments .........................................................................................52
8.1
Screening ...............................................................................................................56
8.1.1
Information to be collected on screening failures.................................56
8.2
Participant demographics/other baseline characteristics .......................................56
8.2.1
Demographic information.....................................................................56
8.2.2
Prior and concomitant medications.......................................................57
8.3
Efficacy..................................................................................................................57
8.3.1
APACHE II severity of disease score...................................................57
8.3.2
Clinical status (9-point ordinal scale) ...................................................57
8.3.3
CRP .......................................................................................................57

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8.3.4
Appropriateness of efficacy assessments..............................................57
8.4
Safety.....................................................................................................................57
8.4.1
Laboratory evaluations..........................................................................58
8.4.2
Special clinical laboratory evaluations..................................................58
8.4.3
Physical examination ............................................................................58
8.4.4
Vital signs .............................................................................................59
8.4.5
Height and weight .................................................................................59
8.4.6
Electrocardiogram (ECG) .....................................................................59
8.4.7
Pregnancy and assessments of fertility .................................................60
8.4.8
Chest X-ray ...........................................................................................60
8.4.9
Appropriateness of safety measurements..............................................60
8.5
Additional assessments..........................................................................................60
8.5.1
SARS-CoV-2 virus testing....................................................................60
9
Study discontinuation and completion ..............................................................................63
9.1
Discontinuation and completion............................................................................63
9.1.1
Study treatment discontinuation and study discontinuation .................63
9.1.2
Withdrawal of informed consent...........................................................64
9.1.3
Lost to follow-up...................................................................................65
9.1.4
Study stopping rules..............................................................................65
9.1.5
Early study termination by the sponsor.................................................65
9.2
Study completion and post-study treatment ..........................................................65
10 Safety monitoring and reporting........................................................................................66
10.1
Definition of adverse events and reporting requirements......................................66
10.1.1
Adverse events ......................................................................................66
10.1.2
Serious adverse events ..........................................................................67
10.1.3
SAE reporting .......................................................................................68
10.1.4
Pregnancy reporting ..............................................................................69
10.1.5
Reporting of study treatment errors including misuse/abuse................69
10.2
Additional Safety Monitoring................................................................................70
10.2.1
Liver safety monitoring.........................................................................70
10.2.2
Data Monitoring Committee .................................................................71
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11 Data Collection and Database management......................................................................71
11.1
Data collection.......................................................................................................71
11.2
Database management and quality control............................................................71
11.3
Site monitoring ......................................................................................................72
12 Data analysis and statistical methods ................................................................................73
12.1
Analysis sets ..........................................................................................................73
12.2
Participant demographics and other baseline characteristics.................................73
12.3
Treatments .............................................................................................................73
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................74
12.4.1
Definition of primary endpoint(s)/estimand(s) .....................................74
12.4.2
Statistical model, hypothesis, and method of analysis..........................74
12.4.3
Handling of remaining intercurrent events of primary estimand..........74
12.4.4
Handling of missing values not related to intercurrent event ...............74
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................74
12.4.6
Supplementary analysis.........................................................................74
12.4.7
Supportive analyses...............................................................................74
12.5
Analysis of secondary endpoints/estimands..........................................................74
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................74
12.5.2
Safety endpoints....................................................................................75
12.6
Analysis of exploratory endpoints.........................................................................76
12.8
Interim analyses.....................................................................................................77
12.9
Sample size calculation..........................................................................................77
12.9.1
Primary endpoint(s)...............................................................................77
12.9.2
Secondary endpoint(s)...........................................................................77
13 Ethical considerations and administrative procedures ......................................................77
13.1
Regulatory and ethical compliance........................................................................77
13.2
Responsibilities of the investigator and IRB/IEC..................................................77
13.3
Publication of study protocol and results ..............................................................78
13.4
Quality Control and Quality Assurance.................................................................78
14 Protocol adherence ............................................................................................................78
14.1
Protocol amendments.............................................................................................78
15 References .........................................................................................................................80
16 Appendices ........................................................................................................................85
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16.1
Appendix 1: 9-point ordinal scale determination ..................................................85
16.2
Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ..........................................................................................................86
16.3
Appendix 3: Severity of disease classification systems ........................................88
16.4
Appendix 4: Severity of hepatic impairment (Child-Pugh)...................................90
List of tables
Table 2-1
Objectives and related endpoints ..........................................................32
Table 6-1
Investigational and control drug............................................................45
Table 6-2
Concomitant medications to be used with caution................................48
Table 6-3
Dose and treatment schedule.................................................................51
Table 8-1
Assessment schedule.............................................................................53
Table 8-2
Clinical laboratory tests (locally)..........................................................58
Table 10-1
Guidance for capturing the investigational treatment errors 
including misuse/abuse .........................................................................70
Table 16-1
9-point ordinal scale..............................................................................85
Table 16-2
Liver event and laboratory trigger definitions ......................................86
Table 16-3
Follow up requirements for liver laboratory triggers............................87
Table 16-4
APACHE II...........................................................................................88
Table 16-7
Child-Pugh scores and classification ....................................................90
List of figures
Figure 1-1
Working model for ORF3a-induced activation of the NLRP3 
inflammasome.......................................................................................29
Figure 3-1
Study design..........................................................................................34
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List of abbreviations
%
Percentage
°C
Degrees Celsius
°F
Degrees Fahrenheit
AE(s)
Adverse event(s)
AIDS
Acquired immune deficiency syndrome
AKI
Acute kidney injury 
ALB
Albumin
ALP
Alkaline phosphatase
ALT
Alanine transaminase 
APACHE II
Acute Physiology and Chronic Health Evaluation II
APTT
Activated partial thromboplastin time
ARDS
Acute respiratory distress syndrome 
AST
Aspartate transaminase 
ATC
Anatomical Therapeutic Chemical 
AUC
Area Under the Curve
BiPAP
Bilevel positive airway pressure 
BMI
Body mass index 
NT-proBNP
N-Terminal ProB-type Natriuretic Peptide
BP
Blood Pressure
bpm
Beats per minute
BUN
Blood Urea Nitrogen
CAPS
Cryopyrin-associated periodic syndromes
Center No.
Center Number
CIs
Confidence Interval(s)
CKD
Chronic kidney disease 
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
cm
Centimeters 
Cmax
Maximum serum concentration
CMO&PS
Novartis Chief Medical Office and Patient Safety
CO
Country Organisation
COVID-19
Coronavirus disease 2019 
CPAP 
Continuous positive airway pressure
CRF
Case Report Form
CRP
C-reactive protein
CSR
Clinical Study Report
CT scan
Computed tomography scan
CTC
Common Toxicity Criteria
CV
Coefficient of variation
CVD
Cardiovascular diseases 
CXR
Chest X-ray 
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CYP
Cytochrome P450
CYP2C9
Cytochrome P450 2C9
CYP3A
Cytochrome P450, family 3, subfamily A
CYP3A4
Cytochrome P450 3A4
DBP
Diastolic blood pressure
DDE
Direct Data Entry 
dL
Deciliter
DMC
Data monitoring committee 
DNA
Deoxyribonucleic acid
eATP
Extracellular adenosine triphosphate 
ECG
Electrocardiogram
ECMO
Extracorporeal membrane oxygenation 
eCRFs
Electronic Case Report Forms 
EDC
Electronic data capture 
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency 
EOS
End of Study
EOT
End of Treatment
EU
European Union
FAS
Full Analysis Set 
FIH
First-in-human 
FiO2
Fraction of inspired oxygen
g
Gram
GCP
Good Clinical Practice
GCS
Global Clinical Supply 
GFR
Glomerular filtration rate 
GGT
Gamma-glutamyl-transferase
GLP
Good Laboratory Practice 
h
Hours
HA
Health Authority
HDL
High-density lipoprotein
HV(s)
Healthy volunteer(s)
IB
Investigator's Brochure
IBD
Inflammatory bowel disease 
IC50
half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
ICU
Intensive care unit 
IEC
Independent Ethics Committee
IFN-γ
Interferon-gamma
IL
Interleukin

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IMMs
Inflammatory monocyte-macrophages
IN
Investigator Notification
INR
International normalized ratio 
IP-10/CXCL10
Interferon gamma-induced protein 10 / C-X-C motif chemokine 10
IRB
Institutional Review Board
IRT
Interactive Response Technology 
IUD
Intrauterine device 
IUS
Intrauterine system 
kg
Kilogram
L
Liter
LDH
Lactate dehydrogenase 
LDL
Low-density lipoprotein
LPS
Lipopolysaccharide 
m
Meter
m2
Square meter
MABEL
Minimum anticipated biological effect level 
MAP
Mean arterial pressure
MedDRA
Medical Dictionary for Regulatory Activities 
mEq
Milliequivalents 
mg
Milligram
min
Minute
mL
Milliliter
mm3
Cubic millimeter
mmHg
Millimeter of mercury
MR scan
Magnetic resonance scan
NASH
Non-alcoholic steatohepatitis 
NF-kB
Nuclear factor kappa-light-chain-enhancer of activated B cells
ng
Nanogram
NK cells
Natural killer cells 
nM 
Nanomolar
NOAEL
No-observed-adverse-effect level 
PA
Posteroanterior
PaO2
Partial pressure of oxygen
Participant No.
Participant Number
PBMCs
Peripheral blood mononuclear cells
PCR 
Polymerase chain reaction
PD
Pharmacodynamic 
PEEP
Positive end-expiratory pressures 
pH
Power of hydrogen
PoC
Proof of Concept
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PoM
Proof of Mechanism 
PR
Pulse rate
PRR
Pattern recognition receptors 
PT
Prothrombin time 
PT/INR
Prothrombin time/international normalized ratio
PTT
Partial thromboplastin time 
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RRT
Renal replacement therapy
SAE(s)
Serious Adverse Event(s)
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic blood pressure
SD
Standard deviation
SMQ
Standardized MedDRA Query 
SoC
Standard of care 
SOP(s)
Standard Operating Procedure(s)
SpO2
Peripheral oxygen saturation
SUSARs
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
TLR
Toll-like receptor 
TNF-α
Tumor necrosis factor alpha
Ub
Ubiquitin
ULN
Upper limit of normal
US
United States of America
WHO
World Health Organization
μg
Microgram
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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Cohort
A specific group of participants fulfilling certain criteria and generally treated at 
the same time
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol 
Enrollment
Point/time of participant entry into the study at which informed consent must 
be obtained 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and eCRFs into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate
Estimand
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication 
number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)

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Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in participants with established disease and 
in those with newly-diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Perpetrator drug
A drug which affects the pharmacokinetics of the other drug
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Randomization 
number
A unique identifier assigned to each randomized participant
Run-in Failure
A participant who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to participant’s intervention or 
other treatment)
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant 
Study treatment
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination and 
may consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 

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the related clinical question of interest, which might or might not be the same 
as the study treatment.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.
Victim drug 
The drug that is affected by the drug-drug interaction
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 

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Protocol summary
Protocol number
CDFV890D12201
Full Title
Phase 2, randomized, controlled, open label multi-center study to assess 
efficacy and safety of DFV890 for the treatment of severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infected patients with coronavirus 
disease 2019 (COVID-19) pneumonia and impaired respiratory function
Brief title
Study of efficacy and safety of DFV890 in patients with COVID-19 
pneumonia
Sponsor and 
Clinical Phase
Novartis 
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the efficacy and safety of DFV890 
in addition to current standard of care (SoC) compared with SoC alone in 
controlling the inflammatory syndrome and resultant acute respiratory 
distress syndrome (ARDS) in hospitalized patients presenting with COVID-
19 pneumonia and impaired respiratory function
Primary Objective(s) 
The primary objective of the study is to evaluate the effect of DFV890 in 
addition to SoC, compared with SoC alone, on the Acute Physiology and 
Chronic Health Evaluation II (APACHE II) score
Secondary 
Objectives
The secondary objectives of this study are:

To evaluate the effect of DFV890 in addition to SoC, compared with
SoC alone, on inflammatory status

To evaluate the effect of DFV890 in addition to SoC, compared with
SoC alone, on clinical status

To evaluate the safety of DFV890 in addition to SoC, compared with
SoC alone
Study design
This is a Phase 2, randomized, controlled, open label multi-center study to 
assess the efficacy and safety of DFV890 for the treatment of SARS-CoV-2 
infected patients with COVID-19 pneumonia and impaired respiratory 
function.
The study consists of four parts:
Screening / Baseline visit (Day -1 to 1): lasts up to a maximum of 24 
hours and comprises a screening / baseline assessment. This visit will be 
used to confirm that the study inclusion and exclusion criteria are met and 
serves as baseline assessment prior to randomization.
Treatment period (Day 1-15): Participants in the investigational treatment 
arm will receive DFV890 
. orally or via a nasogastric feeding 
tube administered for a total of 14 days 
 in addition to SoC. 
Study drug will be supplied in tablet form which can be crushed, allowing 
for both oral and nasogastric administration. Participants in the control arm 
will receive SoC alone. 
Participants will be randomized as soon as possible, but within a maximum 
of 24 hours after screening in a 1:1 ratio to receive either DFV890 in 
addition to SoC or SoC alone. 
CCI
CCI

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Study assessments will be conducted every 2 days for hospitalized 
participants. 
The End of Treatment (EOT) visit will take place on Day 15. If participants 
are discharged from the hospital prior to Day 15, assessments on the day 
of discharge should be performed according to the schedule listed under 
Day 15; participants will continue to take the investigational treatment at 
home to complete the 14-day treatment period and the participants should 
return to the site for the Day 15/EOT assessment (all other visits between 
discharge and Day 15 can be omitted). If a hospital visit is not possible at 
Day 15, then home nursing services may be used to support this last visit 
where these are available in accordance with local guidelines and should 
include all possible assessments (e.g., oxygen saturation with portable 
monitors).
Follow-up (Day 16-29): After completion of the 14 day- treatment period, 
participants will be observed until Day 29 or discharged from hospital, 
whichever is sooner. Study assessments to be conducted every 2 days for 
hospitalized participants.
If participants are discharged from hospital prior to Day 29, a study visit 
conducted by telephone will occur on Day 29 (all other visits between 
discharge and Day 29 can be omitted).
30-day safety follow-up assessment (Day 45): A follow-up visit for safety
will be conducted by telephone.
Study population
Approximately 120 male and female patients between 18 and 80 years of 
age, inclusive.
The study population includes adult male and female SARS-CoV-2 infected 
patients who are hospitalized and diagnosed with COVID-19 pneumonia and 
impaired respiratory function.
Key Inclusion 
criteria

Male and female patients aged 18-80 years inclusive at screening

Clinically diagnosed with the SARS-CoV-2 virus by polymerase chain
reaction (PCR) or by other approved diagnostic methodology within 7
days prior to randomization

Hospitalized with COVID-19-induced pneumonia evidenced by chest
X-ray, computed tomography scan (CT scan) or magnetic resonance
scan (MR scan), taken within 5 days prior to randomization (within 24
hours in patients in the Netherlands)

Impaired respiratory function, defined as peripheral oxygen saturation
(SpO2) ≤93% on room air or partial pressure of oxygen (PaO2) /
fraction of inspired oxygen (FiO2) <300 millimeter of mercury (mmHg)
at screening. For cities located at altitudes greater than 2500 m above
sea level, these will be substituted with SpO2 <90% and PaO2/FiO2
<250 mmHg.

APACHE II score of ≥10 at  screening

C-reactive protein (CRP) ≥20 mg/L and/or ferritin level ≥600 μg/L at
screening

Body mass index of ≥18 to <40kg/m2 at screening
Key Exclusion 
criteria

Suspected active or chronic bacterial (including Mycobacterium
tuberculosis), fungal, viral, or other infection (besides SARS-CoV-2)

In the opinion of the investigator, progression to death is imminent and
inevitable within the next 24 hours, irrespective of the provision of
treatment

Intubated prior to randomization

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
Previous treatment with anti-rejection and immunomodulatory drugs
within the past 2 weeks, or within the past 30 days or 5 half-lives
(whichever is the longer) for immunomodulatory therapeutic antibodies
or prohibited drugs (see Section 6.2.1.2), with the exception of
hydroxychloroquine, chloroquine or corticosteroids:

For  COVID-19 infection, ongoing corticosteroid treatment is
permitted at doses as per local SoC

For non-COVID-19 disorders, ongoing corticosteroid treatment is
permitted at doses up to and including prednisolone 10 mg daily
or equivalent (see Section 6.2.1)

In patients in the Netherlands only, the use of hydroxychloroquine
and/or chloroquine in the past 2 weeks are exclusionary

Serum alanine transaminase (ALT) or aspartate transaminase
(AST) >5 times upper limit of normal detected within 24 hours at
screening or at baseline (according to local laboratory reference
ranges) or other evidence if severe hepatic impairment (Child-Pugh
Class C, see Appendix 4)

Absolute peripheral blood neutrophil count of ≤1000/mm3

Estimated GFR (eGFR) ≤30 mL/min/1.73m2 (based on CKD-EPI
formula)

Patients currently being treated with drugs known to be strong or
moderate inducers of isoenzyme CYP2C9 and/or strong inhibitors of
CYP2C9 and/or strong inducers of cytochrome P450, family 3,
subfamily A (CYP3A) (see list of prohibited drugs: Section 6.2.1.2) and
the treatment cannot be discontinued or switched to a different
medication prior to starting study treatment

Patients with innate or acquired immunodeficiencies

Patients who have undergone solid organ or stem cell transplantation
Study treatment

DFV890
 in addition to Standard of Care (SoC)

Standard of Care
Treatment of 
interest
The randomized treatment (the investigational treatment DFV890 in addition 
to SoC or control treatment of SoC alone)
Efficacy 
assessments

APACHE II severity of disease score on Day 15 or on day of discharge
(whichever is earlier) with worst case imputation for death

9-point ordinal scale (Appendix 1):

Survival without the need for invasive mechanical ventilation at
Days 15 and 29

At least one level improvement in clinical status at Days 15 and 29

Clinical status over time

Serum CRP levels

Number of participants with Adverse Event (AE), serious adverse
events (SAE), clinically significant changes in laboratory measures,
and vital signs
Pharmacodynamic 
assessments
The pharmacodynamic objective for this study is to characterize the 
pharmacodynamic effects of DFV890 in patients with COVID-19 
pneumonia via longitudinal measures of a number of analytes relative to 
baseline including the following:

CRP,
CCI
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Key safety 
assessments

Incidence and severity of adverse events

Clinically significant changes in laboratory measures

Vital signs, electrocardiogram (ECG), Height and weight

Physical examination

Chest X-ray (CXR), CT or MR scan
Other assessments 
SARS-CoV-2 virus to be measured within 7 days prior to randomization 
Data analysis
The primary endpoint will be evaluated by an analysis of covariance model 
including treatment group and the three stratification factors (age, anti-viral 
therapy, and presence of ≥1 comorbidities) as factors and baseline 
APACHE-II score as a covariate.
For efficacy and pharmacodynamics endpoints, descriptive statistics 
(mean, standard deviation, median, minimum and maximum) will be 
provided for variables that are of the numeric or continuous type, while 
frequency distributions (with number and percent) will be provided for 
categorical variables.
All listings and tables will be presented by treatment group. 
Key words
COVID-19 pneumonia, SARS-CoV-2, APACHE II, DFV890, inflammasome
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1
Introduction
1.1
Background
As of 22-Apr-2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 
has been confirmed in over 2.5 million people worldwide, with over 179,000 deaths to date due 
to coronavirus disease 2019 (COVID-19). The mortality rate of approximately 4-5% is
significantly higher than that seen with seasonal influenza (less than 1%) and between 5-10% 
of COVID-19 patients develop lung injury, respiratory distress progressing to acute respiratory 
distress syndrome (ARDS) requiring prolonged ventilator support over weeks that results in 
intensive care units, hospitals and health care systems becoming overwhelmed.
ARDS is characterized by pro-inflammatory cytokine release, inflammatory cellular infiltrate 
and cell death resulting in severe pulmonary damage and the development of respiratory failure 
that requires mechanical ventilation with high positive end-expiratory pressures (PEEP) to 
maintain life. In patients with a prior history of hypertension, diabetes and cardiovascular 
disease, poor outcomes have been reported that may be as result of poor underlying cardiac 
reserve meaning that patients develop cardiac failure in response to ventilation, with pulmonary 
edema further exacerbating respiratory failure (Zhou et al 2020a).
Targeted treatment of the underlying hyper-inflammatory syndrome that occurs after initial 
SARS-CoV-2 infection in COVID-19 patients with respiratory failure has the potential to 
reduce the requirements for mechanical ventilation, the duration of mechanical ventilation and 
to improve the outcome for patients while also significantly reducing the demand on health care 
systems.
1.1.1
Innate immunity during viral infection
The innate immune system is the first line of defense against pathogens, including viruses. 
Pattern recognition receptors (PRR) are part of this system and are sensors for microbial 
structures. To safeguard the immune response, viruses can be sensed by many partially 
redundant, but also distinct classes of innate immune receptors, such as the nucleic-acid sensors, 
MDA-5 and RIG-I or members of inflammasome and Toll-like receptor (TLR) families. These 
sensors initiate a protective response that begins with the production of pro-inflammatory 
cytokines, such as type I interferons that restrict viral replication. In a subsequent wave of the 
host reaction to viruses, danger signals are released as tissues are damaged and cells are killed 
by the virus. The recognition of these danger signals by innate immune signaling receptors 
trigger further inflammatory responses (Horvath et al 2011, Franchi et al 2014). A key sensor 
for danger signals released from dying cells is the NLRP3 inflammasome, which, upon 
activation, leads to the production and release of active IL-1and IL-18. 
At low levels during initial stages of the disease, these cytokines amplify the innate immune 
response against viruses (Tate et al 2016) and promote the development of adaptive immune 
responses against the virus, providing long-term protection and reducing the risk of re-infection 
(Ichinohe et al 2009). However, when tissue damage from the virus or immune response is 
extensive, NLRP3 activation and the subsequent IL-1and IL-18 production can be excessive 
and beyond what is required to support an adaptive response, contributing to morbidity and 
mortality.

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The concerted actions of the inflammasome will lead to exacerbated edema by direct activation 
of endothelial cells, increased tissue damage through neutrophil reactive species, and excessive 
type II interferon through IL-18 on T cells and natural killer cells (NK cells), and elicit or 
exacerbate other broad pro-inflammatory pathways, including IL-6, IL-17 and tumor necrosis 
factor alpha (TNF-α) (McAuley et al 2013, Ren et al 2017). Consistent with NLRP3 playing an 
underlying role in pulmonary pathology during viral infection, it has been shown in mice 
infected with influenza that inhibition of the NLRP3 inflammasome in the symptomatic phase 
of the infection reduces systemic inflammation as well as lung pathology without impairing 
viral clearance (Tate et al 2016, Coates et al 2017, Jia et al 2018).
Particularly, IL-18 is already constitutively expressed in the airway epithelium and parenchyma 
of human bronchial biopsies and its expression is largely further increased under inflammatory 
conditions such as in pulmonary sarcoidosis (Cameron et al 1999). IL-18 may not only activate 
Type 1 and Type 2 helper T cells and cytotoxic T cells, but has been reported to promote NK 
cell -mediated tissue damage. This was shown in the context of fulminant hepatitis A viral 
infection, in which inherited IL-18BP deficiency (the natural scavenger of bioactive IL-18) 
resulted in excessive NK cell activation by IL-18 and lead to the uncontrolled killing of human 
hepatocytes (Belkaya et al 2019). Together, IL-1β and IL-18 can trigger innate and adaptive 
immune 
responses 
at 
the 
same 
time 
leading 
to 
exacerbated
inflammation
(Vanden Berghe et al 2014).
1.1.2
Reduced activation of NLRP3 inflammasome in asymptomatic host 
species
Bats are a reservoir of rapidly reproducing and highly transmissible viruses such as coronavirus. 
Indeed, the bat is the most likely source of origin of SARS-CoV-2, the causative virus of 
COVID-19 (Zhou et al 2020b). One notable feature of the bat immune system is that they are 
asymptomatic while carrying coronaviruses. The presumed reason why bats are asymptomatic 
is that, compared to other animals, viruses in bats do not induce a robust host inflammatory 
response, which in turn prevents the symptoms and pathology caused by tissue damage that 
occur when high levels of inflammation are generated. Recent findings indicate that NLRP3, 
but not other pro-inflammatory pathways such as NF-kB, is 10-30 -fold less active in bats than 
in human cells. Importantly, coronavirus replication in bat and human peripheral blood 
mononuclear cells (PBMCs), and in PBMCs in which NLRP3 activity is inhibited, is 
comparable, confirming that NLRP3 does not play a role in controlling viral replication 
(Ahn et al 2019). This data suggests that NLRP3 inhibition may reduce the excessive 
inflammatory response responsible for the lung tissue damage that occurs in patients with 
COVID-19 without compromising antiviral immunity
1.1.3
Excessive inflammasome activation in the elderly
It is well documented that aging is clinically associated with an increase in levels of pro-
inflammatory cytokines (e.g., IL-18, IL-6, IL-1Ra) (Ferrucci et al 2005). In mice, the pathway 
that mediates this chronic pro-inflammatory state is NLRP3-dependent (Youm et al 2013). 
Remarkably, NLRP3 activity in alveolar macrophages is greater in old mice compared to young 
mice, and this leads to an increased level of inflammation and fibrosis in older mice compared 
to younger mice (Stout-Delgado et al 2016). The increased NLRP3 activity in the elderly may 

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partly explain why the risk of severe pneumonia and death following infection with 
SARS-CoV-2 is positively associated with the age of patients. 
1.1.4
Coronavirus activation of the inflammasome may promote lung 
pathology
Coronaviruses have been extensively studied in previous epidemic outbreaks. Even if the 
genomic information or structure of the current SARS-CoV-2 virus is not identical, the 
pathogenic mechanisms especially in severe cases seem to resemble very well previous viruses 
like SARS-CoV-1. Coronaviruses express transmembrane pore-forming proteins (Envelope (E) 
and Open reading frame (ORF) 3a, ORF8b) that alter ion conductance (Figure 1-1), eventually 
promoting K+ efflux, which in turn activates NLRP3 (ORF3a (Yue et al 2018, Chen et al 2019, 
Siu et al 2019); E (Nieto-Torres et al 2015); ORF8b (Shi et al 2019). Consistent with the 
pathogenic role of NLRP3 in coronavirus-induced lung pathology, mice infected with viruses 
that express a form of protein E that can sustain viral replication, but that is not able to induce 
NLRP3 
activation, 
fail 
to 
produce 
IL-1
and 
do 
not 
develop 
pneumonia 
(Nieto-Torres et al 2014). In addition, factors generated during lung damage, such as 
extracellular adenosine triphosphate (eATP) (Rosli et al 2019) and uric acid (Gasse et al 2009, 
Braga et al 2017), can also activate NLRP3 and promote an excessive innate immune response. 
The activation of this disproportionate innate immune response in turn leads to the accumulation 
of pathogenic inflammatory monocyte-macrophages (IMMs), resulting in elevated lung 
cytokine/chemokine levels, vascular leakage, and tissue damage (Channappanavar et al 2016). 
Collectively, these observations provide a mechanistic basis for NLRP3 in excessive 
inflammation to coronavirus infection.
1.1.5
Inflammasome activation by mechanical ventilation and ARDS
In severe COVID-19, non-invasive and invasive mechanical ventilation is applied as a life 
supporting therapy. Mechanical stretch especially in the inflamed and stressed tissue is leading 
to eATP release. eATP is sensed by the purinergic receptor P2X7 leading to potent NLRP3 
inflammasome activation (Eckle et al 2007, Matsuyama et al 2008). This cascade of events 
further amplifies tissue inflammation and ARDS. In mice, IL-18 expression is increased in the 
lungs after intraperitoneal administration of lipopolysaccharide (LPS) or the occurrence of 
hemorrhage (Kawayama et al 2012). Furthermore, a neutralizing anti-IL-18 antibody has been 
shown to reduce the lung inflammatory damage in a murine acute lung injury model
(Abdel Fattah et al 2015).
1.1.6
Translational evidence that the NLRP3 inflammasome is activated in 
patients with coronavirus lung pathology
Infections with highly pathogenic respiratory viruses, such as SARS-CoV-1 and SARS-CoV-2, 
initiate a cytokine burst that causes acute lung injury and ARDS. Patients manifest lung injury 
at the time during which viral load is actually falling, indicating that, in humans, significant 
damage to the lungs is likely mediated by an excessive immune response rather than direct viral 
cytopathic effects.

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One of the key cytokines driving inflammation in the bronchoalveolar space in patients with 
ARDS is IL-1(Pugin et al 1996). It enhances the production of other cytokines with a longer 
half-life, such as IL-6, which accumulates in a sustained manner during the disease and 
(Olman et al 2004, Zhang et al 2004) The pathogenic role of IL-1in the lungs is supported by 
findings in rat that transient lung expression of IL-1via adenoviral gene transfer causes a local 
increase of the pro-inflammatory cytokines IL-6 and TNF-α and a vigorous acute inflammatory
tissue response, which then leads to progressive interstitial fibrogenesis (Kolb et al 2001). 
Another cytokine that may have a pathogenic effect is IL-18. Levels of IL-18 are elevated in 
the serum of patients with SARS-CoV-1 (Huang et al 2005). IL-18 promotes lung fibrosis 
(Zhang et al 2019) and the production of Type 1 helper T cell cytokines that mediate alveolar 
epithelial cell death. Consistent with this hypothesis, the expression of IL-18 in the lung induces 
type 1, type 2, and type 17 cytokines and stimulates alveolar destruction causing vascular 
remodeling and airway fibrosis (Kang et al 2012). Interestingly, an interferon-gamma type 
cytokine storm was described post SARS coronavirus infection (Kawayama et al 2012). Thus, 
the existing data provide evidence for an important role of IL-18 in lung injuries of different 
origins.
1.1.7
Inflammasome in acute organ injury and sepsis
Beyond the acute and life-threatening respiratory complications severe COVID-19 patients 
develop acute kidney injury (AKI) and sepsis (Zhou et al 2020a) contributing significantly to 
overall mortality. NLRP3 inhibition in animal models of sepsis reduces inflammation and tissue 
damage, enhances phagocytosis, and leads to increased survival. (Jin et al 2017). Sepsis, tissue 
damage and suboptimal supply of oxygen to the kidney together with common comorbidities 
in severe COVID-19 patients such as hypertension and diabetes are increasing the risk of AKI. 
NLRP3 has been described to contribute to septic (Yang et al 2019), ischemia/reperfusion 
(Han et al 2020), virus (Liu et al 2019) and rhabdomyolysis (Komada et al 2015) induced AKI
(Cao et al 2015). Furthermore, urinary IL-18 is one the earliest and most predictive markers for 
patients at risk of developing AKI (Parikh et al 2005). Amelioration of sepsis and AKI by 
NLRP3 inhibition may improve patients’ “manageability” and thereby could increase overall 
survival.
1.1.8
Summary
The inflammasome and the pivotal mediators IL-1β, IL-18 and NLRP3 are known contributors 
to the hyper-inflammatory response that results in severe pulmonary tissue damage after initial 
SARS-CoV-1 and SARS-CoV-2 infections. Treatment with a NLRP3 inhibitor in patients with 
severe COVID-19 pulmonary disease is expected to reduce inflammation, reverse lung 
pathology and may improve ventilation and clinical outcomes. Importantly, available evidence 
strongly supports the concept that these treatments would not increase viral persistence or other 
morbidity related to a SARS-CoV-2 infection especially when administered at the later stage of 
the disease as respiratory failure develops.

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Figure 1-1
Working model for ORF3a-induced activation of the NLRP3 
inflammasome
Note: On one hand, ORF3a interacts with TRAF3 to activate NF-kB, resulting in transcription of the 
pro-IL-1β gene. On the other hand, ORF3a interacts with TRAF3 to promote ASC ubiquitination, 
leading to activation of caspase 1 and IL-1β maturation. ORF3a sufficiently activates both signals 
required for NLRP3 inflammasome activation. Ub, ubiquitin. Source: Siu et al (2019).
1.2
DFV890
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1.3
Purpose
The purpose of this study is to evaluate the efficacy and safety of DFV890 in addition to current 
standard of care (SoC) compared with SoC alone in controlling the inflammatory syndrome and 
resultant ARDS in hospitalized patients presenting with COVID-19 pneumonia and impaired 
respiratory function. DFV890 
 will be dosed 
 for 14 days. 
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To evaluate the effect of DFV890 in addition
to SoC, compared with SoC alone, on the
Acute Physiology and Chronic Health
Evaluation II (APACHE II) score
Endpoint(s) for primary objective(s)

APACHE II severity of disease score on Day
15 or on day of discharge (whichever is
earlier) with worst case imputation for death
Secondary Objective(s)

To evaluate the effect of DFV890 in addition
to SoC, compared with SoC alone, on
inflammatory status
Endpoint(s) for secondary objective(s)

Serum C-reactive protein (CRP) levels

To evaluate the effect of DFV890 in addition
to SoC, compared with SoC alone, on
clinical status
Endpoints based on the 9-point ordinal scale 
(Appendix 1):

Survival without the need for invasive
mechanical ventilation at Days 15 and 29

At least one level improvement in clinical
status at Days 15 and 29

Clinical status over time

To evaluate the safety of DFV890 in addition
to SoC, compared with SoC alone

Number of participants with Adverse Events
(AE), Serious Adverse Events (SAE),
clinically significant changes in laboratory
measures, and vital signs
CCI
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2.1
Primary estimands
The primary clinical question of interest is: What is the effect of DFV890 in addition to SoC 
versus SoC alone in SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired 
respiratory function on APACHE-II severity of disease score taking into account early 
discharge from hospital or death but regardless of investigational treatment discontinuation?
The justification for the primary estimand is that it will capture the combined effect of 
investigational treatment in participants who remain in hospital for 14 days, the effect on early 
discharge within 14 days and the effect on death rate within 14 days, in a manner than reflects 
clinical practice.
The primary estimand is described by the following attributes:
1. Population: SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired
respiratory function. Further details about the population are provided in Section 5.
2. Endpoint: APACHE II severity of disease score on Day 15 or on day of discharge
(whichever is earlier) with worst case imputation for death. Participants who die on Day 15
or earlier will be assigned the highest observed APACHE II score of any of the participants
at any time during the trial. Note this imputation for death takes precedence over the
APACHE II score on day of discharge.
3. Treatment of interest: the randomized treatment (the investigational treatment DFV890 in
addition to SoC or control treatment of SoC alone).
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4. Handling of remaining intercurrent events: Treatment discontinuation for any reason will
be ignored and thus follow a treatment policy strategy i.e. participants who discontinue
treatment will be treated in the same manner as those that continue the treatment as planned.
5. Summary measure: The difference in variable means between treatments.
2.2
Secondary estimands
Not applicable.
3
Study design
This is a Phase 2, randomized, controlled, open label multi-center study to assess the efficacy 
and safety of DFV890 for the treatment of SARS-CoV-2 infected patients with COVID-19 
pneumonia and impaired respiratory function (Figure 3-1).
Written informed consent will be obtained from participants before any study related 
assessments or procedures are performed. Thereafter, medications and eligibility criteria will 
be reviewed by study personnel. All participants signing informed consent must be registered 
by study staff in the Interactive Response Technology (IRT).
Assessments during the study will occur per the schedule of study assessments as described in
Table 8-1.
Figure 3-1
Study design
*If participant discharged from hospital prior to Day 15, investigational treatment should be
taken at home to complete the 14-day treatment period.
The study consists of four parts:
1. Screening / Baseline visit (Day -1 to 1): lasts up to a maximum of 24 hours and comprises
a screening / baseline assessment. This visit will be used to confirm that the study inclusion
and exclusion criteria are met and serves as baseline assessment prior to randomization.
Those randomized to the DFV890 investigational treatment arm can commence
administration with either the morning or evening dose, depending upon time of
randomization. Baseline blood tests will be performed in all participants; those who screen
fail because of study inclusion / exclusion criteria (e.g., serum CRP, liver function tests),
will not undergo randomization.
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2. Treatment period (Day 1-15): Participants in the investigational treatment arm will receive
DFV890 
orally or via a nasogastric feeding tube administered for a total of 14
days 
in addition to SoC. Study drug will be supplied in tablet form which can be
crushed, allowing for both oral and nasogastric administration. Participants in the control
arm will receive SoC alone.
Participants will be randomized as soon as possible, but within a maximum of 24 hours after
screening in a 1:1 ratio to receive either DFV890 in addition to SoC or SoC alone.
Study assessments will be conducted every 2 days for hospitalized participants.
The End of Treatment (EOT) visit will take place on Day 15. If participants are discharged 
from the hospital prior to Day 15, assessments on the day of discharge should be performed 
according to the schedule listed under Day 15; participants will continue to take the 
investigational treatment at home to complete the 14-day treatment period and the 
participants should return to the site for the Day 15/EOT assessment (all other visits between 
discharge and Day 15 can be omitted). If a hospital visit is not possible at Day 15, then 
home nursing services may be used to support this last visit where these are available in 
accordance with local guidelines and should include all possible assessments (e.g., oxygen 
saturation with portable monitors).
3. Follow-up (Day 16-29): After completion of the 14 day- treatment period, participants will
be observed until Day 29 or discharged from hospital, whichever is sooner. Study
assessments to be conducted every 2 days for hospitalized participants.
If participants are discharged from hospital prior to Day 29, a study visit conducted by
telephone will occur on Day 29 (all other visits between discharge and Day 29 can be
omitted).
4. 30-day safety follow-up assessment (Day 45): A follow-up visit for safety will be
conducted by telephone.
4
Rationale
4.1
Rationale for study design
This is a randomized, controlled, open-label, multicenter study in hospitalized adult patients 
(≥18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. This 
design supports the assessment of preliminary efficacy 
 and 
safety of DFV890 in addition to SoC in this critically ill patient population.
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The Screening / Baseline visit will be used to confirm that the study inclusion and exclusion 
criteria are met and for performing baseline clinical observations and biological sampling 
(blood, urine). Patients meeting the inclusion and exclusion criteria will be acutely unwell and 
it is anticipated that recruitment and randomization will take place relatively rapidly, with entry 
into the study taking place within a maximum of 24 hours of screening. This is justified based 
upon the clinical severity of illness in patients admitted with COVID-19 associated pneumonia 
and impaired respiratory function and their likelihood of deterioration shortly after hospital 
admission.
During the Treatment period participants will be randomized in a 1:1 ratio to receive either 
DFV890 
 in addition to SoC or SoC alone for a total of 14 days. Randomization is 
justified as there is at present no clinical evidence that DFV890 will be efficacious in reducing 
disease severity in COVID-19 patients. The 1:1 randomization ratio was chosen to maximize 
the statistical power for the primary analysis whilst minimizing the overall sample size.
The Study Endpoints measure clinical status,
 and laboratory 
values, including serum CRP, 
 and safety during 
and after the 14-day treatment period. 
4.2
Rationale for participant numbers and endpoint
The total sample size of 120 participants randomized in a 1:1 ratio to the two treatment groups 
allows for an adequate assessment on the chosen primary endpoint.
The primary endpoint for this study is the APACHE II score (range 0 to 71) on day 15 or on 
day of discharge (whichever is earlier) with worst case imputation for death as this disease 
severity score provides a comprehensive structured assessment of the clinical, physiological 
and laboratory parameters that have been routinely employed by physicians in the current 
situation to access the overall clinical status of COVID-19 patients with pneumonia and 
respiratory failure (Yang et al 2020, Wang et al 2020). In particular, the APACHE II disease 
severity score captures the clinically relevant physiologic variables for an aggregate score, with 
higher scores indicating more severe disease, with a median score of 18 reported for non-
survivors of COVID-19. The APACHE II score will not be used by investigators to direct 
medical management of participants in this study. 
To establish clinical efficacy based on APACHE II score, a sample size of 60 participants per 
treatment group provides 80% power when testing on an 10% 1-sided alpha level under the 
assumption that DFV890 in addition to SoC reduces the APACHE II score by 3.6 points more 
than SoC alone (assumed standard deviation of 9.2 based on Wang et al (2020)). The type I 
error rate of 10% is considered an acceptable false positive risk for an exploratory study.
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Other clinical endpoints such as those derived from the 9-point ordinal scale were considered 
as primary endpoints. 
4.3
Rationale for choice of background therapy
There is at present no health authority (HA) approved treatments for COVID-19 or its sequelae, 
including the cytokine storm which develops in those most severely affected. Current SoC in 
the European Union (EU) and United States of America (US) includes a variety of supportive 
therapies, ranging from the administration of supplementary oxygen to full intensive care 
support, alongside the use of antiviral agents and intravenous corticosteroids, though there is 
considerable inter-center variability regarding the use of these. Local SoC is permitted in all 
participants of the study, though every effort will be made by investigators to standardize this 
within individual centers.
4.4
Rationale for dose/regimen and duration of treatment
The median hospital stay for COVID-19 has been reported to be 12 days with an interquartile 
range of 1 to 14 days (Cao et al 2020). Therefore, a duration of treatment for 14 days seems 
reasonable and was thus selected for this study.
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4.5
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The study has been designed to compare the use of DFV890 in addition to SoC with SoC alone. 
Although there are no approved treatments for COVID-19, SoC therapy for patients with 
COVID-19 pneumonia includes a range of supportive care and anti-viral treatments with 
inter-center variability. There is no comparator or placebo therapy administered. 
SoC is therefore appropriate as the control for this 
study.
4.6
Purpose and timing of interim analyses/design adaptations
4.7
Risks and benefits
4.7.1
Potential benefits and risks to study participants 
The participants enrolled in this study will have COVID-19-associated pneumonia, impaired 
respiratory function and evidence of an inflammation syndrome with a significant risk of the 
development of ARDS requiring prolonged mechanical ventilation and ICU stay to maintain 
life. Currently, apart from supportive medical care that is of limited benefit in this population, 
there are no approved therapeutics targeting the underlying inflammatory process to improve 
oxygenation, reverse respiratory failure and reduce the complications of SARS-CoV-2 infection 
to improve the overall clinical outcome.
4.7.2
Potential risks to participants
The risk to participants in this trial will be minimized by adherence to the eligibility criteria, 
close clinical monitoring, frequent follow-up, minimal duration of the study, stopping rules and 
periodic review of safety data by an independent DMC. 
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4.7.3
Overall risk benefit
 In the context of the 
potential clinical benefit for patient population with limited effective therapeutic options, the 
overall safety profile of DFV890 is acceptable, and the benefit/risk favorable. In addition to the 
risks noted above, there may be risks to DFV890 that are serious and unforeseen. Therefore, 
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the risks to participants in this trial will be minimized by adherence to the eligibility criteria, 
close clinical monitoring, frequent follow up, minimal duration of the study, stopping rule 
 
4.8
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period 
of 28 days, from each participant as part of the study. Approximately 190 mL blood will be 
collected over the first 15 days during which participants are hospitalized. For hospitalization 
of 28 days a total blood volume of approximately 250 mL will be collected. Sample volume 
may vary according to local laboratory standard. Additional samples may be required for safety 
monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1).
5
Study Population
The study population includes adult male and female SARS-CoV-2 infected patients who are 
hospitalized and diagnosed with COVID-19 pneumonia and impaired respiratory function.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male and female patients aged 18-80 years inclusive at screening
2. Signed Informed Consent Form (ICF) by patient capable of giving consent, or, when the
patient is not capable of giving consent, by his or her legal/authorized representative (if
allowed according to local requirements in participating countries excluding Germany)
3. Clinically diagnosed with the SARS-CoV-2 virus by polymerase chain reaction (PCR) or
by other approved diagnostic methodology within 7 days prior to randomization
4. Hospitalized with COVID-19-induced pneumonia evidenced by chest X-ray, computed
tomography scan (CT scan) or magnetic resonance scan (MR scan), taken within 5 days
prior to randomization (within 24 hours in patients in the Netherlands)
5. Impaired respiratory function, defined as peripheral oxygen saturation (SpO2) ≤93% on
room air or partial pressure of oxygen (PaO2) / fraction of inspired oxygen (FiO2)
<300 millimeter of mercury (mmHg) at time of screening. For cities located at altitudes
greater than 2500 m above sea level, these will be substituted with SpO2 <90% and
PaO2/FiO2 <250 mmHg.
6. Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score of ≥10
at time of screening
7. CRP ≥20 mg/L and/or ferritin level ≥600 μg/L at screening
8. Body mass index of ≥18 to <40kg/m2 at screening
9. Ability to comply with the study protocol, in the investigator's judgment
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5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
2. Suspected active or chronic bacterial (including Mycobacterium tuberculosis),
fungal, viral, or other infection (besides SARS-CoV-2)
3. In the opinion of the investigator, progression to death is imminent and inevitable
within the next 24 hours, irrespective of the provision of treatment
4. Intubated prior to randomization
5. Patients who have explicitly expressed the wish not to receive intensive care support
when this would be indicated based on their condition
6. Previous treatment with anti-rejection and immunomodulatory drugs within the past
2 weeks, or within the past 30 days or 5 half-lives (whichever is the longer) for
immunomodulatory therapeutic antibodies or prohibited drugs (see Section 6.2.1.2),
with the exception of hydroxychloroquine, chloroquine or corticosteroids:

For COVID-19 infection, ongoing corticosteroid treatment is permitted at
doses as per local SoC

For non-COVID-19 disorders, ongoing corticosteroid treatment is permitted at
doses up to and including prednisolone 10 mg daily or equivalent
(see Section 6.2.1)

In patients in the Netherlands only, the use of hydroxychloroquine and/or
chloroquine in the past 2 weeks are exclusionary
7. Serum alanine transaminase (ALT) or aspartate transaminase (AST) >5 times upper
limit of normal detected within 24 hours at screening or at baseline (according to
local laboratory reference ranges) or other evidence if severe hepatic impairment
(Child-Pugh Class C, see Appendix 4)
8. Absolute peripheral blood neutrophil count of ≤1000/mm3
9. Estimated GFR (eGFR) ≤30 mL/min/1.73m2 (based on CKD-EPI formula)
11. Patients currently being treated with drugs known to be strong or moderate inducers
of isoenzyme CYP2C9 and/or strong inhibitors of CYP2C9 and/or strong inducers
of cytochrome P450, family 3, subfamily A (CYP3A) (see list of prohibited drugs:
Section 6.2.1.2) and the treatment cannot be discontinued or switched to a different
medication prior to starting study treatment
12. Any serious medical condition or abnormality of clinical laboratory tests that, in the
investigator’s judgment, precludes the patient’s safe participation in and completion
of the study
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15. Patients with innate
or
acquired immune deficiencies
16. Patients who have undergone solid organ or stem cell transplantation
18. Participation in any other clinical trials of investigational medicinal products.
6
Treatment
6.1
Study treatment
A separate Pharmacy Manual is not provided. The investigational treatment preparation for 
DFV890 is described in Section 6.1.1 and Section 6.7.
6.1.1
Investigational and control drugs
The study will enroll participants who require hospitalization and will receive either DFV890 
in addition to the available SoC or the available SoC alone. 
The investigational drug DFV890 will be prepared by the sponsor as 25 mg tablets. 
Investigational drug will be supplied to the investigator as open-label patient-specific kits.

DFV890 
 will be administered orally 
Participants discharged prior to Day 15 will be provided with
individual medication diary cards to record each administration of investigational treatment
at home.

If a participant becomes intubated during the course of the study, study drug can be
administered as follows, according to the local SoC:

For participants unable to ingest tablets, study drug can be administered through a
nasogastric tube (8 French or greater) as follows:

Suspend
in approximately 40 mL of water with stirring for
approximately 3 minutes
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
The suspension can then be administered through a nasogastric tube using an
appropriate syringe.

The tube should be rinsed with approximately 70 mL of water

Duration of treatment is 14 days.
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global or 
local)
DFV890 25 mg
Tablet 
Oral use 
Open label patient 
specific kits; blisters
Sponsor (global)
6.1.2
Additional study treatments
Participants assigned to the DFV890 arm will receive DFV890 
in addition to SoC 
and participants assigned to the control arm will receive SoC alone. SoC administered beside 
the study treatment will be supplied by the investigational site. No other treatment beyond 
DFV890 is included in this study.
6.1.3
Treatment arms/group
Participants will be assigned at randomization to one of the following treatment arms/groups in 
a ratio of 1:1:

DFV890
. + SoC for 14 days

SoC alone for 14 days
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms (CRF).
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study.
If participants are discharged from hospital prior to Day 15, they must be told to notify the 
Treating Physician about any new medications he / she takes after the start of DFV890 
investigational treatment.
During the course of the study, participants may receive anti-viral treatment (e.g., 
hydroxychloroquine, chloroquine, remdesivir, faripivavir, ritonavir, lopinavir), convalescent 
plasma containing high titres of anti SARS-CoV-2 antibodies, intravenous, oral or inhaled 
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corticosteroids (e.g. dexamethasone), antibiotics and other agents where these form part of SoC 
for the treatment of COVID-19 infection in their participating centre. 
Participants are permitted to receive low-dose corticosteroids (up to a maximum of 10 mg/day 
prednisolone equivalent) for the treatment of non-COVID-19 disorders.
The SoC will be administered according to the local practices and the known dosage 
recommendations, contraindications, warnings and interactions with other drugs must be 
observed for the drugs used concomitantly as SoC.
Whilst the protocol defines experimental immunomodulatory treatments including anti-IL-6 
monoclonal antibodies as prohibited (Section 6.2.1.2), participants with significantly 
deteriorating clinical status may still receive such therapies in rescue situations where their 
treating physician is of the opinion that the potential benefit of such therapy outweighs the risks. 
In this situation participants receiving DFV890 therapy should immediately discontinue 
DFV890 (see Section 6.2.1.2 and Section 9.1.1). However, these DFV890-treated participants, 
as well as those receiving experimental immunomodulatory therapies following completion of 
their 14-day treatment period with DFV890 and those in the control arm receiving SoC alone 
should remain in the study and the Investigator should continue collecting data on outcomes 
through the study visit schedule.
6.2.1.1
DFV890 potential for drug-drug interaction
Clinical studies to investigate drug-drug interactions with Cytochrome P450 (CYP) 
substrates/modulators and DFV890 have not been performed yet. Evaluation and 
recommendations are based on in vitro / preclinical data and physiology-based PK simulations, 
and there are no clinical data confirming whether such interactions will occur in participants. 
DFV890 as a victim: DFV890 is expected to be eliminated mainly via hepatic CYP-mediated 
metabolism with CYP2C9 (68%) and CYP3A4 (30%) as the main contributing enzymes. 
DFV890 may therefore be affected by CYP2C9 and/or CYP3A4 interactions. Chronic dosing 
with dual CYP2C9/CYP3A4 inducers (e.g., 600 mg rifampicin) is expected to induce both 
enzymes, thereby increasing the risk of reducing DFV890 drug exposure by approximately 4-
fold to sub-therapeutic levels. Co-administration of DFV890 with strong inhibitors of CYP2C9 
(e.g., 200 mg fluconazole, or 2 g sulfaphenazole) is expected to reduce enzymatic metabolic 
capacity, thereby increasing the risk of increasing DFV890 drug exposure by approximately 3-
fold. When dosed with strong CYP3A inhibitors, the DFV890 AUC is expected to increase on 
average by approximately 1.6-fold.
DFV890 as perpetrator: Due to its in vitro weak-to-moderate CYP3A4 induction potential, 
DFV890 can potentially decrease systemic exposure of sensitive CYP3A4 substrates by 
approximately 2-fold or some oral hormonal contraceptives (e.g., ethinylestradiol) by 20-30%.
In this proposed clinical study protocol, modulators (strong or moderate inducers and strong 
inhibitors) of CYP2C9 and/or strong inducers of CYP3A are prohibited (Section 6.2.1.2). Drugs 
that are metabolized by CYP3A or which are strong/moderate inhibitors of CYP3A should be 
used with caution (Section 6.2.1.3). 
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6.2.1.2
Prohibited drugs and herbal medications

Experimental immunomodulatory therapies for the treatment of COVID-19, including, but
not limited to canakinumab and other anti-IL-1 antibodies, tocilizumab and other anti-IL-6
antibodies, ruxolitinib and other JAK inhibitors, eculizumab and other complement
inhibitors. Where any of these therapies are administered as rescue therapy or for any other
reason, DFV890 must be immediately discontinued.

Strong or moderate inducers of CYP2C9 or strong inducers of CYP3A including
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, mitotane and
St. John’s wort (Hypericum perforatum)

Strong inhibitors of CYP2C9 including miconazole, berberine
(herbal product),
sulfaphenazole, fluconazole, resveratrol (herbal product)

All investigational medications being concurrently used as part of another investigational
clinical trial.
6.2.1.3
Drugs to be used with caution
DFV890 was identified in vitro as a substrate of CYP3A, so an increase in systemic exposure 
of DFV890 by not more than 1.6-fold when co-administered with strong or moderate CYP3A 
inhibitors such as antiviral drugs (e.g., ritonavir), antifungal (e.g., itraconazole, ketoconazole) 
and antibiotics (e.g., erythromycin, clarithromycin) cannot be ruled out. Investigators may, at 
their discretion, co-administer known inhibitors of CYP3A, but their duration should be kept as 
short as possible, and participants must be closely monitored.
In vitro metabolism studies showed that DFV890 might have the potential to induce the 
metabolism of drug substrates metabolized by isoenzyme CYP3A by up to 2-fold. Investigators 
at their discretion may administer concomitant medications known to be metabolized by 
CYP3A4/5. Participants receiving such medications may require dose titration or increase of 
the concomitant drug. Particularly, caution is advised when DFV890 is co-administered with 
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Table 6-2
Concomitant medications to be used with caution
Category
Drug Names
Strong inhibitors of 
CYP3A
ombitasvir/paritaprevir/dasabuvir/ritonavir, indinavir/ritonavir, tipranavir/ritonavir, 
ritonavir, cobicistat, indinavir, ketoconazole, troleandomycin, telaprevir, 
danoprevir/ritonavir, elvitegravir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir, 
itraconazole, voriconazole, mibefradil, clarithromycin, posaconazole, telithromycin, 
grapefruit juice, conivaptan, nefazodone, nelfinavir, idelalisib, boceprevir, 
atazanavir/ritonavir, darunavir/ritonavir
Moderate inhibitors of 
CYP3A
aprepitant, amprenavir, atazanavir, cimetidine, ciprofloxacin, crizotinib, cyclosporine, 
darunavir, diltiazem, dronedarone, erythromycin, faldaprevir, fluconazole, grapefruit 
juice, imatinib, isavuconazole, netupitant, nilotinib, tofisopam, verapamil
Narrow therapeutic 
index substrates of 
CYP3A
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus
Sensitive substrates of 
CYP3A
alfentanil, alpha-dihydroergocryptine, aprepitant, atazanavir, atorvastatin, avanafil, 
bosutinib, brotizolam, budesonide, buspirone, cobimetinib, conivaptan, danoprevir, 
darifenacin, darunavir, dasatinib, dronedarone, ebastine, eletriptan, elvitegravir, 
eplerenone, everolimus, felodipine, fluticasone, grazoprevir, ibrutinib, indinavir, 
isavuconazole, ivabradine, ivacaftor, levomethadyl acetate, lomitapide, lopinavir, 
lovastatin, lumefantrine, lurasidone, maraviroc, midazolam, midostaurin, naloxegol, 
neratinib, nisoldipine, paritaprevir, perospirone, quetiapine, ridaforolimus, saquinavir, 
sildenafil, simeprevir, simvastatin, tacrolimus, ticagrelor, tilidine, tipranavir, tolvaptan, 
triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, voclosporin
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the ICF, the participant is assigned to the next 
sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.
6.3.2
Treatment assignment, randomization
At randomization visit, all eligible participants will be randomized via IRT to one of the 
treatment arms. The investigator or his/her delegate will contact the IRT after confirming that 
the participant fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization 
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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms. A randomization list will be 
produced by or under the responsibility of Novartis Global Clinical Supply (GCS) using a 
validated system that automates the random assignment of treatment arms to randomization 
numbers in the specified ratio. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Treatment will be open to participants, investigator staff/persons performing the assessments 
and the Novartis study team.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted 
without consultation with Novartis.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Treatment will be recorded on the appropriate electronic Case Report Form (eCRF).
For investigational treatment administration at home the investigator must promote compliance 
by instructing the participant to take the investigational treatment exactly as prescribed and by 
stating that compliance is necessary for the participant’s safety and the validity of the study. 
The participant must also be instructed to contact the investigator if he/she is unable for any 
reason to take the investigational treatment as prescribed. Compliance will be assessed by the 
investigator and/or study personnel at each visit using pill counts (if applicable) and information 
provided by the participant. This information should be captured in the source document at each 
visit. All investigational treatment dispensed and returned must be recorded in the Drug 
Accountability Log.
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6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs) in this patient population. 
 AKI is common in patients with severe COVID-19. Treatment is supportive, 
with the institution of renal replacement therapy where this is indicated.
Medication used to treat AEs must be recorded on the appropriate CRF.
6.6.3
Emergency breaking of assigned treatment code
Not applicable. This is an open-label study and the treatment allocation will be known to 
participants, investigators and the Novartis team. 
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1).
A unique medication number is printed on the study medication label.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all investigational treatment must be stored according 
to the instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) Quality Assurance.
Medication labels will be in the local language (or in English in case allowed according to local 
regulation) and comply with the legal requirements of each country. They will include storage 
conditions for the investigational treatment but no information about the participant except for 
the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by monitors during site visits or remotely and at the completion of the trial. 
Participants discharged prior to Day 15 will be asked to return all unused investigational 
treatment and packaging at the end of the study or at the time of discontinuation of 
investigational treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable.
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6.7.2
Instruction for prescribing and taking study treatment
Table 6-3
Dose and treatment schedule
Investigational / Control Drug
(Name and Strength)
Dose
Frequency and/or Regimen
DFV890 25 mg
Daily 
 (14 days)
Participants should take DFV890
at approximately the same time each day 
Participants discharged prior to Day 15 will be provided with individual medication diary cards 
to record each administration of investigational treatment at home. These will be checked 
regularly by site staff.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC)-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements in participating countries excluding Germany), the participant 
must be informed about the study to the extent possible given his/her understanding. If the 
participant is, or becomes capable of doing so, he/she must indicate agreement by personally 
signing and dating the written informed consent document. The consenting process for all study 
participants will be performed according to the applicable local regulations and described in the
ICF.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.
Novartis will provide to investigators in a separate document a proposed ICF that complies with 
the International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Good Clinical Practice (GCP) guidelines and regulatory requirements 
and is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the participant informed consent and 
should be discussed with the participant during the study as needed. Any new information 
regarding the safety profile of the investigational drug that is identified between IB updates will 
be communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the participant.
The following informed consents are included in this study:
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
Main study consent, which also includes:


As applicable, Pregnancy Outcomes Reporting Consent for female participants or the
female partners of any male participants who took study treatment

Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all assessments when they are performed. All data 
obtained from these assessments must be supported in the participant’s source documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. If participant is prematurely 
discontinued from the study at any visit before Day 15, then assessments of EOT visit should 
be performed and if participant is prematurely discontinued at any visit after Day 15, then 
assessments of EOS visit should be performed. At the final EOT visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications recorded on the CRF.
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Table 8-1
Assessment schedule
Period
Screening / 
Baseline / 
Treatment
Treatment2, 3, 12
Post-Treatment 
Follow-up
Safety 
follow-up
Visit Name
Screening / 
Baseline /
Treatment16
Treatment
EOT14 / 
Discharge4
Follow-up5
(if hospitalized 
assessments performed at 
site every 2 days; 
if discharged only 
telephone call on Day 29)
30-days
safety 
follow-up 
(post last 
treatment)15
Days
-1 to 1
2
4
6
8
10
12
14
15
(+2 days)
17, 19, 
21, 23, 
25, 27
29 / EOS
(-1/+3 
days)
45 
(+/-3 
days)
Domiciled (as required)
X
X
X
X
X
X
X
X
X
X
X
Informed consent 
1
X1
Inclusion / Exclusion criteria
X
Demography
X
Medical history/current medical conditions
X
Presence SARS-CoV-2 virus / viral load6
X
Chest X-ray (CXR), CT or MR scan6
X
X13
Randomization (IRT)
X
Physical examination
S
S
S
Vital signs7
X
X
X
X
X
X
X
X
X
X
X
Respiratory status (spont. breathing, FiO2, ventilator parameters, ECMO), fluid 
balance, need for RRT
X
X
X
X
X
X
X
X
X
X
X
APACHE II,
X
X
X
X
X
X
X
X
X
X
X
Clinical Status Evaluation with 9-category ordinal scale
X
X
X
X
X
X
X
X
X
X
X
Weight and Height8
X
X
X
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Period
Screening / 
Baseline / 
Treatment
Treatment2, 3, 12
Post-Treatment 
Follow-up
Safety 
follow-up
Visit Name
Screening / 
Baseline /
Treatment16
Treatment
EOT14 / 
Discharge4
Follow-up5
(if hospitalized 
assessments performed at 
site every 2 days; 
if discharged only 
telephone call on Day 29)
30-days
safety 
follow-up 
(post last 
treatment)15
Days
-1 to 1
2
4
6
8
10
12
14
15
(+2 days)
17, 19, 
21, 23, 
25, 27
29 / EOS
(-1/+3 
days)
45 
(+/-3 
days)
ECG evaluation (local)
X
X
Blood chemistry including CRP,
)9
X
X
X
X
X
X
X
X
X
X
X
Hematology (local lab)9
X
X
X
X
X
X
X
X
X
X
X
Coagulation (local lab)9
X
X
X
X
X
X
X
X
X
X
X
Drug administration record (DFV890)
X 
X
Concomitant medications/Therapies including inotropic support
X
X
X
X
X
X
X
X
X
X
X
Adverse events/serious adverse events
X
X
Safety Follow up Call
X
S
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
1.
Informed consent must be signed prior to any study-related procedure.
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Period
Screening / 
Baseline / 
Treatment
Treatment2, 3, 12
Post-Treatment 
Follow-up
Safety 
follow-up
Visit Name
Screening / 
Baseline /
Treatment16
Treatment
EOT14 / 
Discharge4
Follow-up5
(if hospitalized 
assessments performed at 
site every 2 days; 
if discharged only 
telephone call on Day 29)
30-days
safety 
follow-up 
(post last 
treatment)15
Days
-1 to 1
2
4
6
8
10
12
14
15
(+2 days)
17, 19, 
21, 23, 
25, 27
29 / EOS
(-1/+3 
days)
45 
(+/-3 
days)
2.
Study treatment may start immediately after obtaining the screening/baseline measurements and confirming eligibility and is administered for a total 14 days.
3.
If a participant is discharged prior to Day 15 (this will be considered as Early Discharge visit), study medication should be administered at home to complete the 14 days treatment.
4.
If a participant is discharged prior to Day 15, then assessments on the day of discharge should be performed according to the schedule listed under Day 15 and participant should
return to the site for the Day 15/EOT assessment (if hospital visit is not possible, then home nursing allowed). A visit window of +2 days is allowed for participants discharged prior to
Day 15. Visits between day of discharge and Day 15 can be omitted.
5.
If a participant is discharged prior to Day 29 during the follow-up period (this will be considered as Discharge visit), then assessments on the day of discharge should be performed
according to the schedule listed under Day 29. Participant will be contacted by telephone on Day 29 and only follow-up call, AE/SAE and concomitant medication/therapies information
will be collected in the CRF. Visits between day of discharge and Day 29 can be omitted. If a participant is still hospitalized, all assessments should be performed every 2 days until
Day 29 at the site.
6.
Results confirming positive SARS-CoV-2 virus by PCR or by other approved diagnostic methodology available within 7 days and chest X-ray, CT or MRI scan within 5 days prior to
randomization may be used for eligibility.
7.
Vital signs include heart rate, respiratory rate (if not on mechanical ventilation), systolic and diastolic blood pressure and body temperature. Oxygen saturation (if not on mechanical
ventilation), PaO2/FiO2 (if arterial, capillary or alternative blood gas measured) should be measured at the same time as the vital sign measurements.
8.
Height will be measured only at Screening/Baseline/Treatment visit. If not possible to measure height, it can be reported by the participant.
9.
Hematology, coagulation and blood chemistry including CRP,
 should be measured by the local laboratory. 
10.
11.
12.
During the treatment period, all assessments should be performed in the morning pre-dose.
13.
Chest X-ray, CT or MRI scan at Day 15 (or on day of discharge if prior to Day 15) will be collected only if performed according to local SoC and if visit at the hospital is possible. The
same method should be used at Day 15 (or on day of discharge if prior to Day 15) as was used at study entry.
14.
If participant is discharged prior to Day 15, home nursing services can be considered and should include all possible assessments (e.g., oxygen saturation with portable monitors).
15.
Safety follow-up call will be performed 30-days after last study treatment together with SAE data collection.
16.
All procedures performed as part of local standard of care in this hospitalization, prior to the patient being enrolled into the trial, may be used for screening/baseline assessments
provided that they were performed on the same day that the patient was enrolled in the trial.
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8.1
Screening
It is permissible to re-screen a participant once if s/he fails the initial screening.
In the case where a safety laboratory assessment at screening/initial baseline is outside of the 
range specified in the exclusion criteria, the assessment may be repeated once prior to 
randomization. If the repeat value remains outside of the specified ranges, the participant must 
be excluded from the study.
8.1.1
Information to be collected on screening failures
Participants who sign an ICF and subsequently found to be ineligible prior to randomization 
will be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate CRF. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event during the screening phase (see Section 10.1.3 for reporting details). If 
the participant fails to be randomized, the IRT must be notified within 2 days of the screen fail 
that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form.
8.2
Participant demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Participant race and ethnicity are collected and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as required 
by HA.
8.2.1
Demographic information
Demographic data to be collected at screening on all participants include: year of birth or age, 
gender, race, ethnicity 
Any relevant medical history including date of onset of COVID-19 disease symptoms, date of 
diagnosis of COVID-19 disease protocol solicited medical history, and/or current medical 
conditions before obtaining informed consent will be recorded in the Medical History CRF. 
Significant findings that are observed after the participant has provided informed consent and 
that meet the definition of an AE must also be recorded in the AE CRF. Whenever possible, 
diagnoses and not symptoms will be recorded.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
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8.2.2
Prior and concomitant medications
Relevant prior and concomitant medications will be captured at the screening visit. Any changes 
to the ongoing medications or any new concomitant medications will be recorded in CRF on an 
ongoing basis throughout study participation.
8.3
Efficacy
Samples will be collected at the timepoints defined in the Assessment Schedule (Table 8-1) and 
will be obtained and evaluated in all participants at all dose levels, including the SoC treatment 
arm.
8.3.1
APACHE II severity of disease score
APACHE II (Acute Physiology And Chronic Health Evaluation) records various parameters 
grouped in vital signs, oxygenation, chemistry and hematology; in addition age and Glasgow 
Coma score is part of the APACHE II score (Knaus et al 1985) (Table 16-4). The worst value 
for each parameter in the last 24 hours will be entered in the CRF. Parameters for APACHE II 
will be recorded at screening/baseline, Day 2 and then every other day until Day 29 for 
hospitalized participants irrespective of ICU admission. The score will be recorded only for the 
screening/baseline visit in the CRF.
Blood gas measurement is required for completion of the APACHE II Score (PaO2 alone where 
the FiO2 is <50% or where the participant is not intubated, and PaO2 and PaCO2 for calculation 
of A-a O2 gradient where FiO2 is ≥50% or the participant is intubated). Where participants have 
an arterial line sited, an arterial blood sample should be used. Participants without an arterial 
line sited should have either an arterial, capillary or alternative blood sample collected.
8.3.2
Clinical status (9-point ordinal scale)
Assessment of clinical status using a 9-point ordinal scale (WHO 2020) will be recorded at 
screening/baseline, Day 2 and then every other day until Day 29 for hospitalized participants
(Appendix 1). If a participant is discharged from the hospital, the assessment will be made by 
phone on the visit dates noted in Table 8-1. Each day, the worse score for the previous day will 
be recorded, i.e. on Day 3, Day 2 score is obtained and recorded as Day 2.
8.3.3
CRP
Blood samples will be collected according to the Assessment Schedule (Table 8-1), performed 
locally and recorded in the CRF.
8.3.4
Appropriateness of efficacy assessments
The efficacy endpoints selected for this study are clinically relevant and in keeping with those 
employed in other studies of patients with COVID-19 pneumonia (WHO 2020).
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed (see Table 8-1).

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For details on AE collection and reporting, refer to AE section (Section 10.1).
8.4.1
Laboratory evaluations
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
Laboratory evaluations will be performed by the local laboratory.
8.4.2
Special clinical laboratory evaluations
All abnormal laboratory results must be evaluated for criteria defining an adverse event and 
reported as such if the criteria are met. For those laboratory adverse events, repeated evaluations 
are mandatory until normalization of the result(s) or until the result is no longer considered to 
be clinically significant. 
Safety clinical laboratory tests will be performed locally (see Table 8-2) and recorded in the 
CRF.
Table 8-2
Clinical laboratory tests (locally)
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells,
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils)
Chemistry
Albumin (ALB), Alkaline phosphatase, ALT , AST , Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), Bicarbonate, 
Calcium, Magnesium, Phosphorus, Sodium, Potassium, Creatinine, 
Creatine kinase, Total Bilirubin (TBL), Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, 
Glucose (non-fasting), CRP
Coagulation*
Prothrombin time (PT), International normalized ratio [INR]), Partial 
thromboplastin time (PTT), Activated partial thromboplastin time 
(APTT)
Pregnancy Test
Urine/Serum pregnancy test (refer to Section 8.4.7)
*Coagulation assessment should include only those tests routinely performed according to local
standard of care.
8.4.3
Physical examination
A complete physical examination will be performed according to the Assessment Schedule 
(Table 8-1).
This will include the examination of general appearance, skin, neck (including thyroid), eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed. 
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be recorded on the appropriate CRF that captures medical history. Significant findings made 
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after signing informed consent which meet the definition of an Adverse Event must be recorded 
as an adverse event.
8.4.4
Vital signs
Vital sign measurements include respiratory rate, pulse rate (PR), systolic and diastolic blood 
pressure, and body temperature. Peripheral oxygen saturation on room air should also be 
measured at the same time as the vitals. For participants requiring supplemental oxygen, the 
oxygen flow rate (L/min) and/or FiO2 should be recorded.
Vital signs will include the collection of body temperature (recorded in °C) as per local practice, 
blood pressure (BP) and pulse measurements.
8.4.5
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured as specified in Table 8-1.
If height cannot be measured, the value reported by the participant will be entered in the CRF.
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2
The Screening Visit height measurement will be used for BMI calculations throughout the study.
8.4.6
Electrocardiogram (ECG)
ECG assessments will be taken locally. 
ECGs must be recorded after 10 minutes of rest in the supine position to ensure a stable baseline.
In the case of a series of assessments, ECG should be first assessment obtained while the 
participant is at rest.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Single 12-lead ECGs are to be collected with ECG machines available at the site. Single 12-lead 
ECGs are collected, and results are entered into the appropriate eCRF page. The original ECGs 
on non-heat-sensitive paper, appropriately signed, must be collected and archived at the study 
site. Alternatively 5-lead ECGs are allowed to be collected if 12-lead ECG is not available.
If an ECG performed as local SoC on the day of screening is utilized as part of the screening 
assessment, then the  same diagnostic method (e.g. 5-lead or 12-lead) should be used 
consistently thereafter throughout the trial.
Each ECG tracing must be labeled with study number, participant’s initials, Participant No., 
date and time, and filed in the study site source documents. 
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate. If necessary, a cardiologist may 
be consulted.

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8.4.7
Pregnancy and assessments of fertility
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. 
8.4.7.1
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
8.4.8
Chest X-ray
A standard chest X-ray (posteroanterior (PA) view) (CXR), chest CT or MR scan, will be 
performed as per standard local practice to diagnose pneumonia; except for those who have had 
a valid test done within 5 days of randomization (within 24 hours in patients in the Netherlands). 
The radiological examination performed at Day 15 (or on day of discharge if prior to Day 15) 
will be collected only if performed according to local SoC and if visit at the hospital is possible.
The same method should be used at Day 15 (or on day of discharge if prior to Day 15) as was 
used at study entry.
Additional assessments may be performed, as needed.
Results from chest X-ray, CT scan or MR scan will be recorded in the CRF.
8.4.9
Appropriateness of safety measurements
The safety assessments selected are appropriate for this protocol which utilizes a compound 
which has not previously been used in a patient population and where the safety profile has not 
therefore been established. The assessments are relevant to the critical care setting and will 
enable determination of both safety therapeutic response in this setting. 
8.5
Additional assessments
8.5.1
SARS-CoV-2 virus testing
SARS-CoV-2 virus to be measured using PCR at Screening (except for those who have had a 
valid test done within 7 days of randomization), 
Documentation of the method used should be available in the source notes.
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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances:

Participant/guardian decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment section
(Section 6.2.1.2), including where these treatments are administered as ‘rescue’ therapy

Serum total bilirubin, ALT or AST are consistently elevated >10 times the upper limit of
normal confirmed on two consecutive measurements that are performed at least 24 hours
apart

Any situation in which study participation might result in a safety risk to the participant

Emergence of adverse events that in the judgment of the investigator, taking into account
the participant’s overall status, prevent the participant from continuing participation in the
study

Any laboratory abnormalities that in the judgment of the investigator, taking into
consideration the participant’s overall status, prevents the participant from continuing
participation in the study

Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, fever,
chills, urticaria, dyspnea, headache, myalgia, and hypotension.
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If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2). Where possible, they should return for the assessments 
indicated in the Assessment Schedule (Table 8-1). If they fail to return for these assessments 
for unknown reasons, every effort (e.g. telephone, e-mail, and letter) should be made to contact 
the participant/pre-designated contact as specified in the lost to follow-up section 
(Section 9.1.3). This contact should preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
Participants who withdraw from the study will not be replaced.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore,
and

Does not want any further visits or assessments
and

Does not want any further study-related contacts
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.

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All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g., dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study.
9.1.4
Study stopping rules
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety
and efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up
appropriately by the Investigator or, in the event of an early study termination decision, the date 
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of that decision (e.g., Each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them).
All randomized and/or treated participants should have a safety follow-up call conducted 30 
days after last administration of investigational treatment. The information collected is kept as 
source documentation. All SAEs reported during this time period must be reported as described 
in Section 10.1.3. Documentation of attempts to contact the participant should be recorded in 
the source documentation.
Continuing care should be provided by the investigator and/or referring physician based on 
participant availability for follow-up.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. Severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression
of underlying illness (i.e. progression of the study indication) the assessment of causality
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a
lack of efficacy or progression of underlying illness are not caused by the trial drug, they
happen in spite of its administration and/or both lack of efficacy and progression of

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underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not
resolved must be reported
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which
seriousness criteria have been met
5. Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. Its outcome (i.e. recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued until the end of study. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.
10.1.2
Serious adverse events
A Serious Adverse Event (SAE) is defined as any adverse event [appearance of (or worsening 
of any pre-existing)] undesirable sign(s), symptom(s), or medical conditions(s) which meets 
any one of the following criteria:

fatal

life-threatening

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Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until the last study visit must be reported to Novartis safety 
immediately, without undue delay, under no circumstances later than 24 hours of learning of its 
occurrence. Detailed instructions regarding the submission process and requirements are to be 
found in the investigator folder provided to each site.
Screen Failures (e.g. a participant who is screened but is not treated or randomized): SAEs 
occurring after the participant has provided informed consent until the time the participant is 
deemed a Screen Failure must be reported to Novartis.

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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, under no circumstances later than 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval 
or otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a CMO & PS Department associate may urgently 
require further information from the investigator for health authority reporting. Novartis may 
need to issue an Investigator Notification (IN) to inform all investigators involved in any study 
with the same study treatment that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the last study visit should only be reported to Novartis Safety if 
the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis immediately, without undue delay, 
under no circumstances later than 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the investigational
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
Pregnancy outcomes will be followed-up at the following times:

1 month after the estimated date of delivery,

3 months after the estimated date of delivery (for a live birth only), and

12 months after the estimate date of delivery (for a live birth only).
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition).

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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal
product, which is accompanied by harmful physical or psychological effects.
Investigational treatment errors and uses outside of what is foreseen in the protocol will be 
recorded on the appropriate CRF irrespective of whether or not associated with an AE/SAE and 
reported to Safety only if associated with an SAE. Misuse or abuse will be collected and 
reported in the safety database irrespective of it being associated with an AE/SAE within 24 
hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the investigational treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1, Section 10.1.2, Section 10.1.3).
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 16-2 in Appendix 2 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, every liver event defined in Table 16-3 should 
be followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-3. Repeat 
liver chemistry tests (i.e., ALT, AST, TBL), prothrombin time/international normalized ratio
(PT/INR), alkaline phosphatase (ALP) and GGT) to confirm elevation.

These liver chemistry repeats should be performed using the local laboratory used by the
site. Repeated laboratory test results must be reported as appropriate.

If the initial elevation is confirmed, close observation of the participant will be initiated,
including consideration of treatment interruption if deemed appropriate.


Hospitalization of the participant if appropriate

Causality assessment of the liver event
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
Thorough follow-up of the liver event should include

Based on investigator’s discretion: serology tests, imaging and pathology assessments,
hepatologist’s consultancy; obtaining more detailed history of symptoms and prior or
concurrent diseases, history of concomitant drug use, exclusion of underlying liver
disease
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.2.2
Data Monitoring Committee
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the electronic data 
capture (EDC) system until they have been trained. Automatic validation programs check for 
data discrepancies in the eCRFs, allow modification and/or verification of the entered data by 
the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated Clinical Research Organization) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
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of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Screenings, randomizations, exit statuses, as well as randomization codes and data about all 
treatment arms assigned to the participant will be tracked using an Interactive Response 
Technology (IRT). 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis/moved to restricted 
area to be accessed by independent programmer and statistician. Any changes to the database 
after that time can only be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource Direct Data 
Entry (DDE) or eCRFs) with the investigators and their staff. During the study, 
Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of participant records, the accuracy of data capture / data entry, the adherence to the protocol 
and to GCP, the progress of enrollment, and to ensure that investigational treatment is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis clinical research associate organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters and provide reports to Novartis clinical teams to assist with trial 
oversight.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original ICF signed by the participant (a 
signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The investigator must give the monitor 
access to all relevant source documents to confirm their consistency with the data capture and/or 
data entry. Source data verification may be done on-site, if possible, or remotely, if the field 
monitor does not have access or have limited access to the site due to the current COVID-19 
pandemic. Different approaches can be used depending on site medical records, and some of 
them could include sharing the information through electronic systems or platforms provided 

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by a third party. In all cases investigator and sponsor must adhere to the recommendations 
established by the applicable Health Authorities.
Novartis monitoring standards require full verification for the presence of informed consent, 
adherence to the inclusion/exclusion criteria, documentation of SAEs, and of data that will be 
used for all primary variables. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the participants will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. The analysis will be conducted on all participant data at the 
time the trial ends.
12.1
Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment(s) 
randomized. 
The Safety analysis set will include all randomized participants. 
The PD analysis set will include all randomized participants with no protocol deviations with 
relevant impact on PD data.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group. Categorical data will be presented as frequencies 
and percentages. For continuous data, mean, standard deviation, median, minimum, and 
maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be listed and 
summarized by system organ class and preferred term by treatment group.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in days to DFV890 will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system by treatment group. 
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12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary aim of the study is to evaluate the effect of DFV890 in addition to SoC compared 
with SoC alone on the APACHE II score. A decrease in the score is considered a favorable 
outcome.
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary estimand, including the primary endpoint is defined in Section 2.1 of this protocol. 
It is based on the APACHE-II score.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint will be analyzed by an analysis of covariance model including treatment 
group and the three stratification factors as factors and baseline APACHE-II score as a covariate. 
The analysis will be performed on the safety analysis set. The mean differences of DFV890 in 
addition to SoC vs SoC alone will be reported with 90% confidence intervals (CIs). The 1-sided 
p-value for the overall treatment factor will be reported.
The primary objective will be achieved if the null hypothesis that DFV890 in addition to SoC 
is not different to SoC alone is rejected using a one side alpha of 10%. 
12.4.3
Handling of remaining intercurrent events of primary estimand
As described in Section 2.1, discontinuation of study treatment for any reason will be ignored. 
12.4.4
Handling of missing values not related to intercurrent event
Handling of missing APACHE II scores or components of APACHE II scores at Day 15 or on 
day of discharge will be specified in the Statistical Analysis Plan.
12.4.5
Sensitivity analyses for primary endpoint/estimand
If there are imbalances in demographic or baseline characteristics between the two treatment 
groups, then an ANCOVA model similar to the primary analysis model with the additional 
inclusion of these demographic or baseline characteristics as covariates may be fitted.
12.4.6
Supplementary analysis
Not applicable
12.4.7
Supportive analyses
Not applicable
12.5
Analysis of secondary endpoints/estimands
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Descriptive statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for variables that are of the numeric or continuous type, while frequency distributions 
(with number and percent) will be provided for categorical variables.

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Analyses of the hospital outcomes will be fully specified in the SAP.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The on-treatment period lasts from the date of randomization to Day 29.
12.5.2.1
Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of randomized 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events and other significant adverse events leading to discontinuation.
12.5.2.2
Vital signs
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time.
12.5.2.3
ECGs
PR, QRS, QT, QTcF, and RR intervals will be obtained from ECGs (12- or 5-lead) for each 
participant during the study. ECG data will be read and interpreted locally.
Categorical analysis of QT/QTcF interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTcF intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced by treatment group.
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.

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12.5.2.4
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Serum CRP levels will be analyzed on a log-scale fitting a repeated measures mixed model 
including treatment group, study day, the three stratification factors and log transformed 
baseline CRP as a covariate. Interactions between study day and each of the terms in the model 
will also be included. The back-transformed ratios of DFV890 in addition to SoC vs SoC alone 
will be reported with 90% CIs. The 1-sided p-value for the overall treatment factor will be 
reported.
12.6
Analysis of exploratory endpoints
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12.8
Interim analyses
12.9
Sample size calculation
12.9.1
Primary endpoint(s)
To establish clinical efficacy based on APACHE II score a sample size of 60 participants per 
treatment group provides 80% power when testing on an 10% 1-sided alpha level under the 
assumption that DFV890 in addition to SoC reduces the APACHE II score by 3.6 points more 
than SoC alone (assumed standard deviation of 9.2 based on Wang et al (2020)).
12.9.2
Secondary endpoint(s)
For the analysis of CRP a sample size of 60 participants per treatment group provides 80% 
power when testing on an 1% 1-sided alpha level under the assumption that DFV890 in addition 
to SoC reduces CRP by 44% more than SoC alone (assumed CV of 1.3 based on the range of
variability observed in Chen et al (2020) and previous studies with canakinumab).
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US CFR 21), and with the ethical principles laid 
down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, consent form updates, participant recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
participants. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made.
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13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the CSR the results of this trial will be submitted for publication and posted 
in a publicly accessible database of clinical trial results, such as the Novartis clinical trial results 
website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and HAs, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.

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Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
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16
Appendices
16.1
Appendix 1: 9-point ordinal scale determination
The ordinal scale is an assessment of the clinical status at the first assessment of a given study 
day. Each day, the worse score for the previous day will be recorded. i.e. on Day 3, Day 2 score 
is obtained and recorded as Day 2. The scale is as follows:
Table 16-1
9-point ordinal scale
Patient State
Descriptor
Score
Uninfected
No Clinical or virological evidence of infection
0
Ambulatory
No limitation of activities
1
Limitation of activities
2
Hospitalized
Mild disease
Hospitalized, no oxygen therapy
3
Oxygen by mask or nasal prongs
4
Hospitalized
Severe disease
Non-invasive ventilation or high-flow oxygen
5
Intubation and mechanical ventilation
6
Ventilation + additional organ support - pressors, 
RRT, ECMO
7
Dead
Death
8
Source: WHO (2020)

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16.2
Appendix 2: Liver event and laboratory trigger definitions and 
follow-up requirements
Table 16-2
Liver event and laboratory trigger definitions 
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin normal at 
baseline: 

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone
pathology)

TBL > 3 × ULN (in the absence of known Gilbert
syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST >
3 × ULN and TBL > 2 × ULN [mainly conjugated
fraction] without notable increase in ALP to > 2 ×
ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general)
malaise, fatigue, abdominal pain, nausea, or
vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver
toxicity*
If ALT or AST abnormal at baseline:

ALT or AST > 3x baseline or > 300 U/L (whichever
occurs first)
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms
ULN: upper limit of normal
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Table 16-3
Follow up requirements for liver laboratory triggers
Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated), ALT 
or AST
>1.5 – 3.0 ULN

Repeat LFTs within 48-72
hours
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the absence
of known Gilbert syndrome)

Repeat LFT within 48-72
hours

Establish causality

Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate CRF
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline (ALT, AST, TBL, ALB, 
PT/INR, ALP and GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 10 x ULN

Discontinue DFV890

Establish causality

Record the AE and
contributing factors(e.g.
conmeds, med hx, lab)in
the appropriate CRF
ALT, AST, TBL, ALB, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially indicative of 
a liver toxicity*

Hospitalization if clinically
appropriate

Establish causality

Record the AE and
contributing factors(e.g.,
conmeds, med hx, lab)in
the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.
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16.3
Appendix 3: Severity of disease classification systems 
Table 16-4
APACHE II
Variable
Unit
Age
years
Glasgow Coma Score
Vitals
Body temperature
oC
Mean arterial pressure (MAP)
mmHg
Heart rate 
Beats per minute (bpm)
Respiratory rate
breaths/m
Oxygenation 
FiO2
%
PaO2
mmHg
Arterial pH
PaCO2
mmHg
Altitude of site
Meters above sea level
Chemistry
Sodium
mEq/L
Potassium 
mEq/L
Creatinine 
mg/dL
Acute Renal Failure
Yes/No
Hematology
Hematocrit 
%
White blood cell (WBC) count
x109/L
Severe organ system insufficiency or is 
immunocompromised
Yes/No
Source: Knaus et al (1985)
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16.4
Appendix 4: Severity of hepatic impairment (Child-Pugh)
Table 16-7
Child-Pugh scores and classification
Points scored for observed findings
1 point
2 points
3 points
Encephalopathy 
grade*
Absent
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum 
bilirubin(µmol/L)
<34.2
34.2 – 51.3
>51.3
Serum albumin (g/L)
>35
28 – 35
<28
Prothrombin time 
(INR)
<1.16
1.16 – 1.56
>1.56
Classification
Child-Pugh grade
Child-Pugh A
Child-Pugh B
Child-Pugh C
Points required
5 – 6
7 – 9
10 – 15
*Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity
Source: FDA (2003)