A Randomized, Subject and Investigator Blinded, Placebo-controlled Multicenter Study to Assess the Efficacy and Safety of CMK389 in Patients With Moderate to Severe Atopic Dermatitis
Phase: PHASE2
Conditions: Atopic Dermatitis
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
CMK389
Clinical Trial Protocol CCMK389B12201 / NCT04836858
A randomized, subject and investigator blinded, placebo-
controlled multicenter study to assess the efficacy and 
safety of CMK389 in patients with moderate to severe 
atopic dermatitis
Document type:
Amended Protocol Version
EUDRACT number:
2020-003406-31
Version number:
v02 (Clean)
Clinical Trial Phase:
II
Release date:
04-Mar-2022
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...............................................................................................................10
Protocol summary..............................................................................................................19
1
Introduction........................................................................................................................23
1.1
Background............................................................................................................23
1.2
Purpose...................................................................................................................24
2
Objectives and endpoints...................................................................................................25
2.1
Primary estimands..................................................................................................26
2.2
Secondary estimands..............................................................................................27
3
Study design.......................................................................................................................27
4
Rationale ............................................................................................................................29
4.1
Rationale for study design......................................................................................30
4.2
Rationale for dose/regimen and duration of treatment...........................................31
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................31
4.4
Purpose and timing of interim analyses/design adaptations ..................................32
4.5
Risks and benefits ..................................................................................................32
4.5.1
Blood sample volume............................................................................33
5
Study Population................................................................................................................34
5.1
Inclusion criteria ....................................................................................................34
5.2
Exclusion criteria ...................................................................................................34
6
Treatment...........................................................................................................................37
6.1
Study treatment ......................................................................................................37
6.1.1
Investigational and control drugs ..........................................................37
6.1.2
Additional study treatments...................................................................37
6.1.3
Treatment arms/group ...........................................................................37
6.2
Other treatment(s) ..................................................................................................37
6.2.1
Concomitant therapy .............................................................................38
6.2.2
Prohibited medication............................................................................38
6.2.3
Rescue medication.................................................................................40
6.2.4
Restriction for study participants...........................................................40
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6.3
Participant numbering, treatment assignment, randomization...............................41
6.3.1
Participant numbering ...........................................................................41
6.3.2
Treatment assignment, randomization...................................................41
6.4
Treatment blinding.................................................................................................42
6.5
Dose escalation and dose modification..................................................................43
6.6
Additional treatment guidance...............................................................................44
6.6.1
Treatment compliance ...........................................................................44
6.6.2
Recommended treatment of adverse events ..........................................44
6.6.3
Emergency breaking of assigned treatment code ..................................44
6.7
Preparation and dispensation .................................................................................45
6.7.1
Handling of study treatment and additional treatment ..........................45
7
Informed consent procedures.............................................................................................46
8
Visit schedule and assessments..........................................................................................48
8.1
Screening................................................................................................................54
8.1.1
Eligibility screening...............................................................................54
8.1.2
Information to be collected on screening failures .................................54
8.2
Participant demographics/other baseline characteristics........................................55
8.3
Efficacy..................................................................................................................55
8.3.1
IGA........................................................................................................55
8.3.4
Appropriateness of efficacy assessments ..............................................60
8.4
Safety .....................................................................................................................60
8.4.1
Laboratory evaluations..........................................................................61
8.4.2
Electrocardiogram (ECG)......................................................................63
8.4.3
Pregnancy and assessments of fertility..................................................63
8.4.4
Appropriateness of safety measurements ..............................................64
8.5
Additional assessments ..........................................................................................64
9
Study discontinuation and completion...............................................................................69
9.1
Discontinuation and completion ............................................................................69
9.1.1
Study treatment discontinuation and study discontinuation..................69
9.1.2
Withdrawal of informed consent...........................................................70
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9.1.3
Lost to follow-up...................................................................................71
9.1.4
Study stopping rules ..............................................................................71
9.1.5
Early study termination by the sponsor.................................................71
9.2
Study completion and post-study treatment...........................................................72
10 Safety monitoring and reporting........................................................................................72
10.1
Definition of adverse events and reporting requirements......................................72
10.1.1
Adverse events.......................................................................................72
10.1.2
Serious adverse events...........................................................................74
10.1.3
SAE reporting........................................................................................75
10.1.4
Pregnancy reporting...............................................................................76
10.1.5
Reporting of study treatment errors including misuse/abuse ................76
10.2
Additional Safety Monitoring................................................................................77
10.2.1
Liver safety monitoring.........................................................................77
10.2.2
Renal safety monitoring ........................................................................78
10.2.3
Data Monitoring Committee..................................................................78
11 Data Collection and Database management ......................................................................78
11.1
Data collection .......................................................................................................78
11.2
Database management and quality control ............................................................78
11.3
Site monitoring.......................................................................................................79
12 Data analysis and statistical methods.................................................................................80
12.1
Analysis sets...........................................................................................................80
12.2
Participant demographics and other baseline characteristics.................................80
12.3
Treatments..............................................................................................................80
12.4
Analysis of the primary endpoint(s)/estimand(s)...................................................81
12.4.1
Definition of primary endpoint(s)/estimand(s)......................................81
12.4.2
Statistical model, hypothesis, and method of analysis ..........................81
12.4.3
Handling of remaining intercurrent events of primary estimand ..........82
12.4.4
Handling of missing values not related to intercurrent event................82
12.5
Analysis of secondary endpoints/estimands ..........................................................83
12.5.1
Safety endpoints ....................................................................................83
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12.8
Sample size calculation..........................................................................................86
12.8.1
Primary endpoint(s)...............................................................................86
12.8.2
Secondary endpoint(s)...........................................................................87
13 Ethical considerations and administrative procedures.......................................................88
13.1
Regulatory and ethical compliance........................................................................88
13.2
Responsibilities of the investigator and IRB/IEC..................................................88
13.3
Publication of study protocol and results...............................................................88
13.4
Quality Control and Quality Assurance.................................................................88
14 Protocol adherence.............................................................................................................89
14.1
Protocol amendments.............................................................................................89
15 References..........................................................................................................................90
16 Appendices.........................................................................................................................93
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................93
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements...........................................................................................................94
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up......96
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List of tables
Table 2-1
Objectives and related endpoints...........................................................25
Table 4-1
Rationale for study design.....................................................................30
Table 6-1
Overview of study medication...............................................................37
Table 6-2
Prohibited medication............................................................................38
Table 6-3
Blinding and unblinding plan................................................................43
Table 8-4
Investigator Global Assessment (IGA) .................................................56
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................76
Table 16-1
Liver Event Definitions.........................................................................94
Table 16-2
Actions required for Liver Events.........................................................95
Table 16-3
Exclusion of underlying liver disease....................................................95
Table 16-4
Specific Renal Alert Criteria and Actions.............................................96
Table 16-5
Renal Event Follow Up .........................................................................97
List of figures
Figure 3-1
Study Design Schematic........................................................................28
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List of abbreviations
AD
Atopic Dermatitis 
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BSA
Body-surface area
BUN
Blood Urea Nitrogen
CMO&PS 
Chief Medical Office and Patient Safety
CO
Country Organization
COA
Clinical Outcome Assessment
COPD
Chronic obstructive pulmonary disease
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CTT
Clinical Trial Team
CV
coefficient of variation
DBP
Diastolic Blood Pressure
DIN
Drug Inducted Nephrotoxicity
DMC
Data Monitoring Committee
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
EOS
End of Study 
EOT
End of Treatment 
FIH
First in Human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GWAS
Genome-wide association studies
h
Hour
HBsAg
Hepatitis B surface antigen
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HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human immunodeficiency virus
i.v.
intravenous
IA
Interim Analysis 
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFNγ
Interferon gamma
IGA
Investigator Global Assessment 
IL-18
Interleukin-18
IL-18BP
Interleukin-18 Binding Protein
IL-18R1
Interleukin-18 receptor 1
IL4Ra
Interleukin 4 Receptor alpha
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
JAK
Janus Kinase
K14
Keratin 14
LDH
lactate dehydrogenase
LTBI
Latent tuberculosis (TB) infection 
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
MoA
Mechanism of Action
NIRT
Novartis Interactive Response Technology 
NK
Natural killer cells
NLR
NOD-like receptor
NLRC4
NLR family CARD domain containing 4
NLRP3
NLR family pyrin domain containing 3
NRS
Numerical Rating Scale
PCR
Protein-creatinine ratio
PD
Pharmacodynamic(s)
PDE4
Phophodiesterase 4
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pQTL
protein quantitative trait loci
PRO
Patient Reported Outcomes
QD
Once a day
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RBC
red blood cell(s)
RNA
Ribonucleic acid
rRNA
Ribosomal ribonucleic acid
s.c.
subcutaneous
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SCORAD
SCORing Atopic Dermatitis
SD
standard deviation
SEB
Staphylococcal enterotoxin B
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
Tuberculosis
TCI
Topical calcineurin inhibitors
TCS
Topical Corticosteroids
TDAR
T-cell dependent antibody response 
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization 
WoC
Withdrawal of Consent
WoCBP
Women of child-bearing potential 
XIAP
X-linked inhibitor of apoptosis protein
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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
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days)
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 case report forms (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 
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Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
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
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
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 
the related clinical question of interest, which might or might not be the same 
as the study treatment.

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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.
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 
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Protocol summary
Protocol number
CMK389B12201
Full Title
A randomized, subject and investigator blinded, placebo-controlled multicenter 
study to assess the efficacy and safety of CMK389 in patients with moderate 
to severe atopic dermatitis (AD)
Brief title
Study of efficacy and safety of CMK389 in moderate to severe AD participants
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Biologic
Study type
Interventional
Purpose and 
rationale
The main aim of this study is to assess preliminary efficacy, safety and 
tolerability of CMK389 in participants with moderate to severe AD
Primary 
Objective(s) 
To assess the efficacy of CMK389 versus placebo in participants with 
moderate to severe AD
Secondary 
Objectives
To assess the safety and tolerability of CMK389 in participants with moderate 
to severe AD
Study design
This is a randomized, placebo-controlled, parallel-group, non-confirmatory, 
investigator and participant blinded study in adult participants with moderate 
to severe AD. 
During 
 of treatment period CMK389 or placebo will be 
administered intravenously (i.v.) or subcutaneously (s.c.)
Approximately 64 eligible participants with AD will be randomized into one of 
four treatment arms (randomization 4:1:2:1):

Arm 1: 32 participants treated i.v. with 10 mg/kg CMK389

Arm 2: 8 participants treated i.v. with placebo

Arm 3: 16 participants treated s.c. with 300 mg CMK389

Arm 4: 8 participants treated s.c. with placebo
Study population
The study population will consist of adult female and male participants with 
moderate to severe AD.
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Key Inclusion 
criteria

Adult male or female participants with chronic AD, according to the
American 
Academy 
of 
Dermatology 
Consensus 
Criteria
(Eichenfield et al 2014), aged 18 to 65 years, present for at least 1 year
before screening.

Moderate to severe AD defined as:

Investigator Global Assessment (IGA) score of ≥ 3 (on a scale of 0 to
4, in which 3 is moderate and 4 is severe) at Baseline (or Screening
if Baseline is omitted)

Eczema Area and Severity Index (EASI) score of ≥ 12 at Baseline (or
Screening if Baseline is omitted)

Pruritus Numerical Rating Scale (NRS) of at least ≥ 3 at Baseline (or
Screening if Baseline is omitted)

Participants who are candidates for a systemic therapy, defined as e.g.
inadequate response to treatment with topical medications, or from whom
topical treatments are otherwise medically inadvisable (e.g., because of
important side effects or safety risks, patients with large affected body
surface areas), as assessed by the investigator

Participants must have a body mass index (BMI) at screening within the
range of 18 to ≤35 kg/m2. BMI = Body weight (kg) / [Height (m)]2
Key Exclusion 
criteria

Any skin disease that, in the opinion of the investigator, would confound
the diagnosis or evaluation of AD disease activity (e.g., Netherton
Syndrome, or other ichthyoses, cutaneous T-Cell Lymphoma, extensive
contact dermatitis, chronic actinic dermatitis and other forms of eczema,
such as seborrheic and microbial eczema).

Participants taking prohibited medication not completing the wash out
period as specified in Table 6-2.

Use of other investigational drugs at the time of enrollment, or within 5 half-
lives of enrollment, or until the expected PD effect has returned to
baseline, whichever is longer; or longer if required by local regulations.

Any active, recent or recurrent systemic or localized infection at screening
or prior to first treatment which in the opinion of the investigator
immunocompromises the participant and/or places the participant at
unacceptable risk for immunomodulatory therapy, such as:

Any acute bacterial, fungal, or viral (e.g. herpes simplex, herpes
zoster, chicken pox) skin/mucosal infection that has not resolved
within 2 weeks prior to first treatment or within 12 months in case of
ezcema herpeticum

Clinically infected AD within 4 weeks prior to first treatment.

Tuberculosis (TB)
Human Immunodeficiency Virus (HIV)
Hepatitis B
Hepatitis C

Evidence of active or latent tuberculosis (TB) infection, as determined
by Quantiferon test at screening (Note: if Quantiferon test is
indeterminate, it may be repeated once. Two indeterminate
Quantiferon tests will be considered as evidence of TB infection.
Furthermore, after anti-TB treatment, participants with history of or
latent TB may become eligible according to national guidelines)

History of primary or secondary immunodeficiency, or a positive HIV
(Chemiluminescence and Polymerase Chain Reaction)) test result

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
Positive hepatitis B surface antigen (HBsAg) and/or positive hepatitis
B core antibody (anti-HBc)

Positive hepatitis C antibody (anti-HCV), unless it can be documented
that the participant has received highly-effective HCV-specific
antiviral therapy, HCV RNA levels are measured, and HCV RNA is
undetectable at least 12 weeks after conclusion of HCV-specific
antiviral therapy

Any other current or past clinical significant medical condition, including
psychiatric condition, which in the Investigator’s opinion may interfere with
safety of participants, study objectives or adherence to the protocol.

Participants with confirmed abnormal absolute neutrophil count (ANC) of
<1.5 x 109/L or with thrombocytopenia of < 75.0 x 109/L at screening and
baseline (unless baseline visit is omitted)

History of malignancy of any organ system (other than localized basal cell
carcinoma of the skin), treated or untreated, within the past 5 years,
regardless of whether there is evidence of local recurrence or metastases

History of hypersensitivity to any component of the study drug product, or
to drugs of similar chemical classes (i.e., IgG-1 related biologic agents)

History of severe or serious allergy or hypersensitivity reactions, such as
anaphylactic shock, asthma, or uncontrolled urticaria.

Women of child-bearing potential (WoCBP), defined as all women
physiologically capable of becoming pregnant, unless they are using highly
effective methods of contraception while taking study treatment and for 6
months after last dose.
Study treatment

CMK389 10 mg/kg i.v.:

Matching placebo i.v.:

CMK389 300 mg s.c:

Matching placebo s.c.:
Treatment of 
interest
The randomized treatment (the investigational treatment CMK389 or the 
placebo treatment) taken for the entire study duration without any use of 
prohibited medications or use of rescue medication taken after the first 
6 weeks
Efficacy 
assessments
IGA response (defined as clear or almost clear and at least 2 point reduction 
from baseline) at Week 16 
Key safety 
assessments

AE monitoring using CTCAE grading

Physical examinations

Monitoring of laboratory markers in blood and urine

ECG

Vital signs
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Other 
assessments
Data analysis
The IGA data will be listed and summarized by treatment group. Placebo 
groups will be pooled.
All information obtained on adverse events will be displayed by treatment 
group (CMK389 10 mg/kg i.v., Placebo i.v., CMK389 300 mg s.c., Placebo s.c., 
and Pooled placebo) 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 double-blind 
treatment but increased in severity based on preferred term) will be 
summarized.
Key words
Atopic Dermatitis, Safety, Efficacy
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1
Introduction
1.1
Background
Atopic dermatitis (AD) is a chronic inflammatory skin disease that commonly presents first 
during early infancy and childhood. It is characterized by poorly defined erythema with edema, 
vesiculation, and weeping in the acute stage and skin thickening (lichenification) in the chronic 
stage (Eichenfield 2004, Williams et al 1994). These symptoms result in a severely reduced 
quality of life (QOL). In particular, pruritus (or itch), that continues throughout the day and 
worsens at night causes sleep loss and impacts everyday activities and psychosocial wellbeing 
(Bieber 2010, Weidinger and Novak 2016). AD is commonly associated with other atopic and 
inflammatory disorders, such as asthma, allergic rhinitis and food allergy. Usually the disease 
regresses during adolescence but symptoms may also persist into adulthood. Two to ten percent 
of adults and up to 20% of children have AD, of which approximately 70% and 16%, 
respectively, are moderate to severe (Hanifin and Reed 2007, Emerson et al 1998). Depending 
on the severity of the disease different therapeutic options may be proposed. The basis of AD 
treatment are emollients in patients of all severity stages. Additionally in patients suffering from 
milder forms of the disease, treatment with either topical corticosteroids (TCS), topical 
calcineurin inhibitors (TCI) or topical phophodiesterase 4 (PDE4) inhibitors are used. Patients 
suffering from more severe disease and failing to sustain response to topical agents are generally 
treated with phototherapy and systemic immunosuppressive drugs like cyclosporine 
(Eichenfield et al 2014, Sidbury et al 2014). Only in rare cases and transiently are oral 
corticosteroids used, as they are associated with side effects and a rebound effect. Cyclosporine 
is approved as systemic therapy for severe AD in Europe, but renal toxicity and other adverse 
events (AEs) limit its long term use. Phototherapy carries the risk of future skin cancer and is 
not practical for many patients. Currently the only globally approved systemic therapy for 
treatment of moderate to severe AD is dupilumab (anti-Interleukin 4 Receptor alpha (IL4Ra) 
antibody). According to Simpson et al (2016), in moderate to severe AD patients, a response 
rate of 38% was observed (compared to 10% for placebo) following 16 weeks treatment with 
dupilumab. This proportion of patients describes those who reach 0 (clear) or 1 (almost clear) 
on a 5-point Investigator Global Assessment (IGA) scale. Oral Janus kinase inhibitors are as 
well in late stage development, and seem to demonstrate similar efficacy as compared to 
dupilumab; however, they may have significant safety concerns, such as infection risks, risk of 
malignancies and thromboembolic events. Thus, there is still a high unmet medical need for 
additional systemic treatment options in moderate to severe AD patients.
 IL-18 (a downstream component of 
the inflammasome) is a pro-inflammatory cytokine associated with the induction of Th1 
responses, enhanced type I macrophage activation and NK/CD8+ T cell cytotoxicity. IL-18 
levels are strongly correlated with AD disease severity, and its receptor (Interleukin-18 receptor 
1: IL-18R1) expression is genetically associated with AD. IL-18 has been shown to also induce 
type 2 immune responses in Th2, T resident memory 
 cells which are regarded as key 
drivers of the type 2 immune response in AD.
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Indeed, serum IL-18 levels are increased in AD patients, and correlate with disease severity 
(Thijs et al 2015, Zedan et al 2015, Gohar et al 2017). IL-18 was observed to be the single most 
overexpressed protein in the epidermis of pediatric AD patients and associated with AD disease 
activity (McAleer et al 2019, Hulshof et al 2019). In peripheral blood lymphocyte cultures from 
AD patients stimulated with staphylococcal enterotoxin B (SEB), IL-18 levels were significantly 
correlated with IL-4 levels and AD disease activity (SCORAD) (Suwarsa et al 2017).
In preclinical models such as Keratin 14 (K14)/IL-18 transgenic mice which overexpress IL-18 
in keratinocytes in the skin, IL-18 contributes to the development of AD-like inflammatory 
lesions independently of IgE/STAT6 (Konishi et al 2002). Similarly, keratinocyte-specific 
Casp1 transgenic mice (K14Casp1Tg), which display high levels of mature IL-18, develop AD 
like itchy skin lesions with age (Tsutsui et al 2011; Yamanaka et al 2000) and blockade of 
IL-18 prevented Staphylococcus aureus induced AD-like disease model in mice 
(Terada et al 2006). In vivo administration of IL-18 causes Th2 differentiation and increases 
IgE production in a CD4+ T cell–, IL-4– and STAT6–dependent fashion in mice 
(Yoshimoto et al 2000; Hoshino et al 2000).
In addition, emerging genetic evidence further supports the causal relationship of IL-18 
pathway and AD; the IL-18 receptor is one of the 5 top genes dysregulated in AD patients in a 
large Genome-wide association studies (GWAS) study on 21,000 cases and 95,000 controls 
(Paternoster et al 2015). Mendelian randomization applied to AD GWAS and serum pQTL data 
seems to causally implicate genetically-driven higher levels of IL18R1 as an increased AD risk 
(Sun et al 2018, McGowan et al 2019).
1.2
Purpose
The purpose of this proof of concept study is to determine whether CMK389 displays the safety 
and efficacy profile to support further development in participants with moderate to severe AD.
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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the efficacy of CMK389 in
participants with moderate to severe AD

IGA response (defined as clear or almost
clear and at least 2 point reduction from
baseline) at Week 16
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the safety and tolerability of
CMK389 in participants with AD

Number, seriousness and frequency of
adverse events over time
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2.1
Primary estimands
The primary clinical question of interest is: What is the effect of the CMK389 treatment versus 
placebo on IGA response rate after 16 weeks of treatment in participants with moderate to 
severe AD without any relevant use of prohibited medication or use of rescue medication taken 
after the first 6 weeks.
Prohibited or rescue medication are relevant when their use may have a potential confounding 
effect on the efficacy assessment.
The justification for targeting this treatment effect is that we wish to estimate the effect of the 
study drug for the full duration when administered without any relevant use of prohibited 
medication or use of rescue medication taken after the 6 first weeks. 
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The primary estimand is described by the following attributes:
1. Population: Adult participants with moderate to severe AD is the target population for
biologics (Beck et al 2014, Simpson et al 2016) and is defined by an IGA score of
moderate to severe (3 or 4) and an EASI score of at least 12. Further details about the
population are provided in Section 5.
2. Primary variable: IGA response (defined as clear or almost clear and at least 2 point
reduction from baseline) at Week 16.
3. Treatment of interest: the randomized treatment (the investigational treatment CMK389 or
the placebo treatment) taken for the entire study duration without any use of prohibited
medications or use of rescue medication taken after the first 6 weeks.
4. The summary measure: Treatment difference of the CMK389 and placebo in absolute
responder rates.
Handling of remaining intercurrent events:
1. Use of rescue therapy (after first 6 weeks of treatment)
2. Use of prohibited medication to treat AD symptoms or with impact on efficacy
3. Study treatment discontinuation due to lack of efficacy
4. Study treatment discontinuation due to AE related to AD, e.g. worsening of AD
5. Study treatment discontinuation due to AE not related to AD or due to lack of tolerability
6. Study treatment discontinuation due to other reasons (e.g. administrative if participant
relocates to a region where the trial is not offered, or withdrawal of informed consent)
For the intercurrent events 1 to 4, a composite strategy will be used: use of any therapy 
(prohibited or rescue medication taken after the first 6 weeks) as well as any study treatment 
discontinuation due to lack of efficacy or due to AE related to AD are considered as unfavorable 
outcome, i.e. the participant will be treated as a non-responder.
For the intercurrent events 5 to 6, a treatment policy strategy will be used and the intercurrent 
event will be ignored.
2.2
Secondary estimands
Not Applicable.
3
Study design
This is a randomized, placebo-controlled, parallel-group, non-confirmatory, investigator and 
participant blinded study in adult participants with moderate to severe AD. 
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Approximately 64 eligible participants with moderate to severe AD will be randomized into 
one of four treatment arms (randomization 4:1:2:1):

Arm 1: 32 participants treated i.v. with 10 mg/kg CMK389

Arm 2: 8 participants treated i.v. with placebo

Arm 3: 16 participants treated s.c. with 300 mg CMK389

Arm 4: 8 participants treated s.c. with placebo
The study will include adult participants with moderate to severe AD. For details please refer 
to inclusion/exclusion criteria in Section 5.
After confirmation of eligibility, participants will be included in one of the above mentioned 
arms. Efficacy over time will be measured by the clinical scores, such as IGA 
Safety will be monitored throughout the study by physical exams, vital signs, ECG recordings, 
adverse events and safety laboratory monitoring. Refer to Assessment schedule (Section 8) for 
details.
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4
Rationale
As this is the first time that an anti-IL18 compound is tested in AD participants, the goal is to 
demonstrate preliminary efficacy of CMK389. To avoid any bias associated with an open label 
study, a placebo controlled study offers not only the option to compare to participants without 
relevant interfering treatment but also the possibility of a double blind study, as study supplies 
can be packaged and labeled accordingly. As CMK389 is administered by two routes of 
administration, i.v. and s.c., the placebo group is also split into i.v. and s.c. administrations to 
ensure a double blind design.
In order to reduce the number of participants exposed to placebo, a randomization of 4:1:2:1 
(CMK389 i.v., placebo i.v., CMK389 s.c., placebo s.c.) has been chosen.  CCC
The comparison to placebo in this 
double blind, prospective and randomized trial allows comparison with many other studies 
conducted in AD, in particular using biologics, such as the SOLO studies with dupilumab 
(Beck et al 2014, Simpson et al 2016). Placebo controlled studies have been and still are 
conducted in adult AD at later development stages and in larger numbers; e.g. studies with 
lebrikizumab (see ClinicalTrials.gov Identifier: NCT04146363 and NCT04178967) or 
nemolizumab (Ruzicka et al 2017) (and see also ClinicalTrials.gov Identifier: NCT03985943 
and NCT03989349) or with upadacitinib (see ClinicalTrials.gov Identifier: NCT03568318 and 
NCT03569293). In particular in AD, two recent open label proof of concept trials have shown 
initial signs of efficacy (Yi-Ling et al 2019, Diamant et al 2018), but no efficacy was observed 
when studied in well conducted, double blind, placebo controlled studies. 
The study population of adult participants with moderate to severe AD is the target population 
for biologics (Beck et al 2014, Simpson et al 2016). To be eligible for inclusion in this trial, 
patients need to have an AD severity defined by an IGA score of moderate to severe and an 
EASI score of at least 12 as well as a minimum of 3 in the pruritus numerical rating scale (NRS). 
This mimimum score is a bit lower than previous large trials in moderate to severe AD 
(inclusion criteria of EASI 16, see Simpson et al 2016, Guttman-Yassky et al 2020a, 
Guttman-Yassky et al 2020b) in order to facilitate recruitment without compromising the 
scientific outcome. Furthermore, a similar threshold has also been used previously in other 
Phase 2 trials with biologics (Wollenberg et al 2019 and Simpson et al 2019). Prior to 
enrollment in this trial treatments of AD and systemic immunosuppressives, including steroids, 
are washed out, using typical and relevant wash out periods. Only topical non medicated 
emollients are allowed to be used.
This study is only open for adult participants, as safety data for a younger populations have not 
yet been collected and preliminary efficacy in adults is not yet established. At the time of 
protocol preparation, only adult healthy volunteers have been exposed to CMK389, and a proof 
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of concept trial in adult participants in pulmonary sarcoidosis is planned to be conducted in 
parallel.
4.1
Rationale for study design
Table 4-1
Rationale for study design
Placebo controls
The placebo group is used to define the natural history of disease under the 
study's conditions. Comparison of placebo to the active group provides the 
most rigorous test of efficacy. The comparison to placebo is being used for 
many studies including late stage development trials (Simpson et al 2016, 
Guttman-Yassky et al 2020a,Guttman-Yassky et al 2020b,Wollenberg 
et al 2019, Simpson et al 2019) to enable a rigourous and double blind 
comparison. In this study, placebo exposed participants are reduced to 
a quarter of overall study population. 
 Participants may use emollients as 
basis therapy during the study, and may use oral antihistamines for 
symptomatic itch relief. If medically justified and disease severity is 
worsening, participants may use other rescue treatments (standard of 
care) as well.
Randomization
Randomization is used to avoid "selection bias" in the assignment of 
participants to treatment groups. Randomization also serves to balance 
the treatment groups with respect to many known and unknown 
confounding 
variables; 
and 
randomization 
forms the 
basis 
of 
assumptions for our statistical tests. In this study randomization was set 
up so as to favor recruitment of participants in treatment arm 1 (CMK389 
i.v. administration).
Blinding
Conscious and unconscious biases are avoided within treatment arms 
("detection 
bias" 
and 
"reporting bias", 
pertaining 
to 
outcome 
assessment) 
by 
ensuring 
that 
participants 
and 
investigators 
are unaware of the treatment assignment.
As CMK389 is administered as an i.v. and a s.c. drug, the corresponding 
placebo will be administered as i.v. and s.c. to ensure double blind 
design. Thus the above described biases will be limited to the minimum, 
as investigators and participants will be blinded if the participant will 
receive active or placebo. However, investigators and participants will 
not be blinded to the route of administration either i.v. or s.c, but will not 
know whether the participant is in the active or placebo group. As the 
study drugs are supplied to the site as bulk supplies, an unblinded 
pharmacist or a nurse or delegate is needed to prepare the drug supplies 
and may not discuss any details with the personnel directly in contact 
with the participant.  
Duration of treatment
This treatment duration is expected to 
provide information about efficacy of CMK389 in the AD participant population 
and is in line with currently conducted placebo controlled large trials with 
systemic treatments in AD which are between 12 and 16 weeks of treatment 
with 
biologics 
(Simpson et al 2016, 
Ruzicka et al 2017, 
Guttman-Yassky et al 2020a, Guttman-Yassky et al 2020b).
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4.2
Rationale for dose/regimen and duration of treatment
The chosen timepoint of 16 weeks for the primary endpoint is in alignment with many randomized 
controlled studies in AD using biologics, in particular with the phase 3 trial of dupilumab 
(Simpson et al 2016, Guttman-Yassky et al 2020a, Guttman-Yassky et al 2020b).
 
 
 
 
 
 CMK389 300mg s.c. dosing is added to the study to support a 
second dose level and generate data to develop the s.c. route of administration in late stage 
studies. 
 
 
 
 
 
Statistically, the study is adequately powered to test the efficacy of CMK389 i.v. versus placebo. 
CMK389 s.c. will be descriptively compared to placebo, but there will be no formal statistical 
test.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
In this study, the corresponding placebo to CMK389 will be used as comparator to provide 
objective evidence of clinical efficacy and enable a double blind comparison to avoid 
unconscious biases associated with uncontrolled studies. To establish clinical efficacy in a proof 
of concept study, where the use of a placebo control is established even in phase 3 studies for 
up to 16 weeks, is one of the highest scientific standards for early studies. The placebo 
controlled design will as well provide objective evidence to compare safety and 
pharmacodynamic (PD) data and provide the opportunity to historically compare to other 
placebo controlled trials.
Participants will need to be washed out from the concomitant treatment, but can continue basic 
therapy with emollients and may also use oral antihistamines for symptomatic relief of itch. 
If study participants experience any worsening of AD, the investigator can initiate rescue 
treatment or treatment discontinuation, if medically justified.
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As CMK389 is administered using the i.v. and s.c. route, to keep the blind placebo is also 
administered using the i.v. and s.c. route.
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
CMK389 is a 
 targeting IL-18, a mechanism of action (MoA) that has not 
yet been tested in AD. There is thus no proven direct medical benefit for participants who will 
participate in this study as this is the first time CMK389 is administered to AD participants. 
CMK389 has not yet been tested in any studies in patients, 
No clear dose relationship was established for adverse events or organ 
classes such as infections, or gastro-intestinal disorders, nor in safety laboratory monitoring.
Clinical studies with compounds with a similar MoA, such as Interleukin-18 Binding Protein 
(IL-18BP) or IL-18 antagonists (such as tadekinig, GSK-1070806 or AEVI-007/MEDI2338) have 
been conducted in adult Still's disease (AOSD, Gabay et al 2018, Kiltz et al 2020). Tadekinig is 
currently in later stage development in macrophage activation syndrome associated with NLR 
family CARD domain containing 4 (NLRC4) mutation and X-linked inhibitor of apoptosis 
protein (XIAP) deficiency (ClinicalTrials.gov Identifier: NCT03113760). Other completed 
studies incude chronic obstructive pulmonary disease (COPD, NCT01322594), diabetes 
(McKie et al 2016) or transplant participants (NCT02723786). Studies in Crohn's disease and 
Behcet disease are currently running or of unknown status (NCT03681067, NCT03522662). 
To our knowledge, none of the studies had significant safety issues; the transplant study was 
terminated due to lack of efficacy.
CMK389 is being developed for its expected immunomodulating activity. Participants treated 
with CMK389 may be at an increased risk of infection. 
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In addition, administration of CMK389 carries the risk of anaphylaxis and/or hypersensitivity-
type reactions. 
 Participants with a history of hypersensitivity to any components of the drug product 
or with a history of anaphylaxis or serious hypersensitivity syndrome will be excluded.
The risk of an overdose is limited as the drug will be administered by the study personnel and 
not by the participant.
WoCBP must be informed that 
taking the study treatment may involve unknown risks to the fetus if pregnancy were to occur 
during the study, and agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. Only WoCBP who take highly 
effective contraception can participate in the trial. If there is any question that the participant 
will not reliably comply, they should not be entered or continue in the study.
Blocking IL-18 with CMK389 may impair the innate and cytotoxic immune responses that play 
a role in viral clearance. IL-18 contributes to antiviral immune responses by promoting 
interferon-gamma production by T cells, natural killer cells, and natural killer T cells and 
supports the induction of cytotoxic T cells. Impaired cytotoxic T cell responses may impair the 
killing of virus-infected cells. CMK389 should not impair the production of SARS-CoV-2 
specific antibodies. However, the inflammasome and the pivotal mediators IL-1β, IL-18, and 
NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) contribute to the hyper-
inflammatory response that results in severe pulmonary tissue damage after initial SARS-CoV 
and SARS-CoV-2 infections. Patients with severe COVID-19 and respiratory failure have 
elevated levels of IL-1β and its downstream cytokine IL-6, as well as interferon-gamma (IFNγ) 
and IP-10 (CXCL10), both downstream markers of IL-18 pathway activation. 
 
To minimize these potential risks, appropriate eligibility criteria and specific dose-limiting 
toxicity definitions, as well as specific stopping rules, are included in this protocol.
4.5.1
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over the period of 28 
weeks from each participant as part of the study. Additional samples may be required for safety 
monitoring.
Timings of blood sample collection are outlined in the Assessment schedule Section 8.
A summary blood log is provided in the laboratory manual. Instructions for sample collection, 
processing, storage and shipment information are also available in the laboratory manual.
See the Section 8.5.3.1 on the potential use of residual samples.
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5
Study Population
The study population will consist of adult female and male participants with moderate to severe 
AD. It is planned to randomize approximately 64 participants globally.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
3. Adult male or female participants with chronic atopic dermatitis, according to the American
Academy of Dermatology Consensus Criteria (Eichenfield et al 2014), aged 18 to 65 years,
present for at least 1 year before screening.
4. Moderate to severe AD defined as:

IGA score of ≥ 3 (on a scale of 0 to 4, in which 3 is moderate and 4 is severe) at Baseline
(or Screening if Baseline is omitted).

EASI score of ≥ 12 at Baseline (or Screening if Baseline is omitted).

Pruritus (NRS) of at least ≥ 3 at Baseline (or Screening if Baseline is omitted).
5. Participants who are candidates for a systemic therapy, defined as e.g. inadequate response
to treatment with topical medications, or for whom topical treatments are otherwise
medically inadvisable (e.g. because of important side effects or safety risks, patients with
large affected body surface areas) as assessed by the investigator.
6. Participants must have a body mass index (BMI) at screening within the range of 18 to
≤35 kg/m2. BMI = Body weight (kg) / [Height (m)]2. No rounding of calculated BMI value
to nearest integer should be done when assessing for eligibility.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Any skin disease that, in the opinion of the investigator, would confound the diagnosis or
evaluation of AD disease activity (e.g., Netherton Syndrome, or other ichthyoses, cutaneous
T-Cell Lymphoma, extensive contact dermatitis, chronic actinic dermatitis and other forms
of eczema, such as seborrheic and microbial eczema).
2. Participants taking prohibited medication not completing the wash out period as specified
in Table 6-2.
3. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or
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4. Any active, recent or recurrent systemic or localized infection at screening or prior to first
treatment which in the opinion of the investigator immunocompromises the participant
and/or places the participant at unacceptable risk for immunomodulatory therapy, such as:

Any acute bacterial, fungal, or viral (e.g. herpes simplex, herpes zoster, chicken pox)
skin/mucosal infection that has not resolved within 2 weeks prior to first treatment or
within 12 months in case of ezcema herpeticum.

Clinically infected AD within 4 weeks prior to first treatment.

Any other infection requiring treatment with systemic antibiotics, antivirals,
antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to first treatment.

Tuberculosis (TB):

Evidence of active or latent tuberculosis (TB) infection, as determined by
Quantiferon test at screening (Note: if Quantiferon test is indeterminate, it may be
repeated once. Two indeterminate Quantiferon tests will be considered as evidence
of TB infection. Furthermore, after anti-TB treatment, participants with history of
or latent TB may become eligible according to national guidelines).

Human Immunodeficiency Virus (HIV):

History of primary or secondary immunodeficiency, or a positive HIV
(Chemiluminescence and Polymerase Chain Reaction test result.

Hepatitis B:

Positive hepatitis B surface antigen (HBsAg) and/or positive hepatitis B core
antibody (anti-HBc).

Hepatitis C:

positive hepatitis C antibody (anti-HCV), unless it can be documented that the
participant has received highly-effective HCV-specific antiviral therapy, HCV
RNA levels are measured, and HCV RNA is undetectable at least 12 weeks after
conclusion of HCV-specific antiviral therapy.
5. Any other current or past clinically significant medical condition, including psychiatric
condition, which in the Investigator’s opinion may interfere with safety of the participant,
study objectives or adherence to the protocol.
6. Participants with confirmed abnormal absolute neutrophil count (ANC) of <1.5 x 109/L or
with thrombocytopenia of < 75.0 x 109/L at screening and baseline (unless baseline visit is
omitted).
7. History of malignancy of any organ system (other than localized basal cell carcinoma of the
skin), treated or untreated, within the past 5 years, regardless of whether there is evidence
of local recurrence or metastases.
8. History of hypersensitivity to any component of the study drug product, or to drugs of
similar chemical classes (i.e., IgG-1 related biologic agents).
9. History of severe or serious allergy or hypersensitivity reactions, such as anaphylactic shock,
asthma, or uncontrolled urticaria.
10. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing,
or longer if required by local regulation.
11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
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12. Women of child-bearing potential (WoCBP), defined as all women physiologically capable
of becoming pregnant, unless they are using highly effective methods of contraception
while taking study treatment and for 6 months after last dose. Highly effective contraception
methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
participant. 
Periodic 
abstinence 
(e.g. 
calendar, 
ovulation, 
symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female participants on the
study, the vasectomized male partner should be the sole partner for that participant.

Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS),
or other forms of hormonal contraception that have comparable efficacy (failure rate
< 1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered not 
of child bearing potential.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the Informed Consent Form 
(ICF).

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6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for participant numbering, prescribing/dispensing and taking study treatment are 
outlined in the Pharmacy Manual.
6.1.1
Investigational and control drugs
Table 6-1
Overview of study medication
Investigational 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor 
CMK389 150mg
Powder for 
solution for 
injection/infusion
Intravenous use
Subcutaneous 
use
Open label bulk 
supply; vials
Novartis
CMK389 Placebo
5% Dextrose 
Solution or 5% 
Glucose Solution
Intravenous use
Infusion bags 
only
Locally procured 
by sites
CMK389 Placebo
Solution for 
Injection
Subcutaneous 
use
Open label bulk 
supply; vials
Novartis
6.1.2
Additional study treatments
No other treatment beyond investigational drug and placebo control drug are included in this 
trial.
6.1.3
Treatment arms/group
Participants will be randomized to one of the following 4 treatment arms in a ratio of 4:1:2:1 

Arm 1: CMK389 10 mg/kg i.v.

Arm 2: Placebo i.v.

Arm 3: CMK389 300 mg s.c

Arm 4: Placebo s.c.
6.2
Other treatment(s)
Not applicable.

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6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including use of medicated 
and non medicated emollients used for AD, physical therapy, blood transfusions, vaccination) 
administered after the participant was enrolled into the study must be recorded on the 
appropriate electronic Case Report Forms (eCRFs). 
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 Norvartis to determine if the participant should continue participation 
in the study.
6.2.2
Prohibited medication
Table 6-2
Prohibited medication 
Medication
Prohibition period (Wash-
out) 
Action taken if taken in the 
prohibition period
Non-biologic systemic 
immunosuppressive and/or 
anti-inflammatory treatments 
for treatment of AD including 
but not limited to systemic 
corticosteroids (e.g. i.v., i.m. or 
oral)*, cyclosporine, tacrolimus, 
cyclophosphamide, azathioprin
e, methotrexate, 
mycophenolate mofetil, as well 
as leukotriene inhibitors (such 
as montelukast), oral 
phosphodiesterase 4 (PDE4) 
inhibitors (such as apremilast), 
and oral Janus kinase (JAK) 
inhibitors (e.g. baricitinib)  
Adrenocorticotropic hormone 
analogs
Within 4 weeks (or 3 months 
for i.m. administered 
corticosteroids) prior to first 
dose of CMK389 until End of 
Treatment (EoT)
Wash-out : do not randomize
Treatment: discontinue study 
drug
Follow-up: to be discussed on 
case by case basis 
Any biologic therapy to treat 
AD
3 months prior to first dose of 
CMK389 until EoT
Wash-out : do not randomize
Treatment: discontinue study 
drug
Follow-up: to be discussed on 
case by case basis 
Other biologic therapy (such as 
but not limited to etanercept, 
adalimumab, infliximab, 
omalizumab, secukinumab) 
with the exception of insulin 
and botulinum toxin.
3 months or 5 x half-lives 
(whatever is longer) prior to 
first dose of CMK389 until EoT
Wash-out : do not randomize
Treatment: discontinue study 
drug
Follow-up: to be discussed on 
case by case basis 

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Medication
Prohibition period (Wash-
out) 
Action taken if taken in the 
prohibition period
Live Vaccination
3 months prior to first dose of 
CMK389 until EoS
Wash-out: do not randomize
Treatment: discontinue study 
drug
Follow-up: to be discussed on 
case by case basis 
Topical corticosteroids (TCS) of 
higher potency than lowest 
potency TCS (e.g. 
hydrocortisone)** 
Topical calcineurin inhibitors 
(TCI)** 
Topical phosphodiesterase 4 
(PDE4) inhibitor 
(e.g. Crisaborole)** 
Topical JAK inhibitors
2 weeks prior to first dose of 
CMK389 until EoT
Wash-out: do not randomize
Treatment/Follow up: to be 
discussed on case by case 
basis 
Topical corticosteroids (TCS) of 
lowest potency (e.g. 
hydrocortisone)**
Other topical medicated 
treatment for AD such as tar, 
antimicrobials, bleach baths, 
etc.
Note: Non-medicated 
emmolients including medical 
device creams (such as 
Atopiclair®) are permitted.
1 week prior to first dose of 
CMK389 until EoT
Wash-out : do not randomize
Treatment: discontinue study 
drug
Follow-up: to be discussed on 
case by case basis
Phototherapy, tanning booths 
or excessive sun exposure
4 weeks prior to first dose of 
CMK389 until EoT
Wash-out: do not randomize
Treatment: discontinue study 
drug
Follow-up: to be discussed on 
case by case basis 
Any Investigational Treatment
Within 5 half-lives of Baseline 
or until the expected 
pharmacodynamic effect has 
disappeared, whichever is 
longer; or longer if required by 
local regulations
Wash-out: do not 
randomize, and rescreen 
participant after wash-out if the 
recruitment period is still 
ongoing
Treatment: discontinue study 
drug
Follow-up: to be discussed on 
case by case basis 
* Inhaled corticosteroids (CS) or nasal sprays and eye drops are not considered systemic
immunosuppressive treatment.
**Rescue therapy used as per Section 6.2.3 (only if medically necessary i.e., to control intolerable AD
symptoms, as assessed by investigator) is not considered a prohibited medication.

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6.2.3
Rescue medication
Rescue treatment may be needed if participants experience an AD flare. As a basis therapy, 
participants should be advised to use emollients as needed, if these are non-medicated topical 
formulations. If pruritus occurs, and is causing moderate to severe itch, oral H1-antihistamines 
may be considered. The Investigator is advised to avoid prescribing any medicated rescue 
treatment between week 12 and 16.
However, if a flare occurs, and if it is medically indicated, transient use of topical treatments, 
such as topical calcineurin inhibitors (TCI), topical phosphodiesterase 4 (PDE4) inhibitor, or 
low to mid potent topical corticosteroids (TCS) (i.e. not higher potency than mometasone 
furoate cream 0.1% or similar) may be used before week 12. If possible use the topical treatment 
on the most affected areas and restrict use to these areas. The use of these rescue treatments 
must be reported as concomitant therapies and on what anatomical areas these were used. 
 
 
If the need for rescue therapy arises between scheduled study visits, the participant may come 
for an unplanned visit for the investigator to assess the participant. Investigators must remind 
participants that they should use rescue medication only if really needed (i.e. to control 
intolerable AD symptoms) and only when instructed by the investigator because the use of 
rescue medication may affect the validity of study results negatively. Rescue medication use 
must be stopped as soon as not needed anymore as assessed by the investigator.
After a participant is given rescue medication, in particular topical treatments, the participant 
will have to bring the rescue medication tube/container to the site. Rescue medication 
tubes/container will be weighed at the time of dispensing and every subsequent visit and the 
weight used recorded in the appropriate eCRF.
Medically indicated treatments should be initiated in the interest of the participant, whenever 
an adverse event occurs, but no specific treatments are recommended.
6.2.4
Restriction for study participants
Participants should be informed and reminded of the restriction of topical and systemic 
treatments for AD. Please refer to Section 6.2.3 (Rescue medication), if participants need to 
report these medications and the quantity used to the site personnel, which will be recorded in 
the eCRFs.
In addition, participants should be reminded that excessive sun exposure should be avoided as 
much as possible. Thus, visits to sun tanning or UV parlors and/or sun bathing are not allowed 
until after week 16.
If participants are allergic, they should be reminded that they should signal all known allergies 
in order to be able to track possible trigger factors for AD flares. Participants should be 
instructed to avoid any known allergens, when possible. 
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6.2.4.1
Dietary restrictions and smoking
Participants should be reminded to fast (having had their last meal the evening, 
approx 6-12 hours before visit) at all visits before coming to the site for clinical chemistry blood 
sample.
6.2.4.2
Other restrictions
The use of emollients as outlined in Section 6.2.3 should not be carried out for at least 2 hours 
before clinical assessments and 
 are done.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is uniquely identified in the study by a Participant Number (Participant No.), 
which 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. Once assigned, the Participant 
No. will not be reused. The Participant No. consists of the Center Number/Site Number 
(as assigned to the investigative site) with a sequential participant number suffixed to it, so that 
each participant is numbered uniquely across the entire database. Upon signing the informed 
consent form (ICF), the participant is assigned to the next available sequential Participant No.
Example: 1001001, 1001002, etc. where "1001" is the center number/site number and "001", 
and "002" are the sequential incrementing participant numbers.
6.3.2
Treatment assignment, randomization
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 Novartis IRT (NIRT), 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.
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
The overall randomization ratio will be 4:1:2:1 (CMK389 i.v., placebo i.v., CMK389 s.c., 
placebo s.c.). 
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6.4
Treatment blinding
This is a participant and investigator-blinded study. Participants and investigators will remain 
blinded to study treatment throughout the study, except where indicated below.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site.
Drug product will be supplied in bulk, so an unblinded pharmacist (or other qualified and trained 
staff preparing study drug for administration) who is independent of the study team will be 
required in order to maintain the blind. This unblinded pharmacist will receive a randomization list or 
treatment allocation cards from Novartis Global Clinical Supply (GCS) with the appropriate treatment 
allocation numbers. Appropriate measures must be taken by the unblinded pharmacist to ensure that 
the treatment assignments are concealed from the rest of the site staff.
Sponsor staff
The following unblinded sponsor roles are required for this study

Unblinded field monitor(s)

Unblinded clinical staff managing drug re-supply to site

Unblinded sample analyst(s) (PK, IG)
The unblinded field monitors are required to review drug accountability and allocation at the 
site. The unblinded monitors are not provided with a randomization list directly but will be unblinded 
through review of source documentation compiled by the unblinded pharmacist, which details 
treatment allocation to individual participants. The unblinded monitors will also be able to review the 
treatment allocation cards/randomization list provided to the unblinded pharmacist.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
Study programmers and other personnel involved in study data analysis 
 are 
allowed to access treatment assignment information for the purpose of conducting interim analyses.
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All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Table 6-3
Blinding and unblinding plan
Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single 
participant 
unblinded)
Participants
B
B
UI
Site staff
B
B
UI
Unblinded site 
staff (see text for 
details)
B
UI
UI
Global Clinical 
Supply and 
Randomization 
Office
UI
UI
UI
Unblinded 
sponsor staff (see 
text for details)
B
UI
UI
Unblinded 
Pharmacovigilanc
e sponsor staff
B
UI
UI
Statistician/statisti
cal programmer/ 
data analysts
B
B
UI
Independent 
committees used 
for assessing 
interim results, if 
required (e.g. 
DMC)
UI
UI
UI
All other sponsor 
staff not identified 
above
B
B
UI
Key:
UI: Allowed to be unblinded on individual participant level
B: Remains blinded
NA: Not applicable to this study
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Study medication will be administered at site. Any deviations from protocol mandated dose are 
to be recorded in eCRF.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants treated with CMK389 as detailed in Section 8.5.2.
6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs), as no specific AE have been detected with CMK389. 
Participants are required to undergo observation for maximum of one hour post-infusion prior 
to leaving site (or longer if deemed necessary by the investigator).
Acute infusion or hypersensitivity reactions: In the event of an acute infusion or 
hypersensitivity reaction, the investigator should consider the criteria for treatment 
discontinuation (Section 9.1.1), and the participant should be treated with antihistamines and 
glucocorticoids. Depending on severity, participants may also require supplemental oxygen, 
volume expansion, catecholamines and transfer to an intensive care setting. Plasmapheresis to 
decrease the systemic concentration of CMK389 may be considered dependent on the 
participant’s condition. Participants should be observed for at least four hours after resolution 
of signs and symptoms; and those who have experienced severe infusion reactions should be 
closely observed for 24 hours after resolution because of the risk for a biphasic episode.
Infections: In the event of an infection, the investigator should consider the criteria for 
treatment discontinuation (Section 9.1.1), as well as consider early treatment with specific 
antimicrobial therapy on the basis of clinical diagnosis or suspicion thereof (e.g., antiviral 
treatment for herpes simplex or zoster) in consultation with infectious disease experts, as 
appropriate.
Medication used to treat AEs must be recorded on the appropriate eCRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to do so in order to treat 
the participant safely. Blinding codes may also be broken after a participant discontinues 
treatment due to disease progression if deemed essential to allow the investigator to select the 
participant’s next treatment regimen, and after discussion and agreement with the sponsor. 
Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency condition. 
Emergency treatment code breaks are performed using the NIRT. When the investigator 
contacts the system to break a treatment code for a participant, he/she must provide the 
requested participant identifying information and confirm the necessity to break the treatment 
code for the participant. The investigator will then receive details of the investigational drug 
treatment for the specified participant and a fax or email confirming this information. The 
system will automatically inform the Novartis monitor for the site and the study team that the 
code has been broken.

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It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the NIRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

participant number
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given 
participant and, if applicable, whether the participant can continue with follow up assessments.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under Section 6.1.1 
(Investigational and control drugs). Please refer to Pharmacy manual for detailed instructions 
about study medication preparation and administration.
As per the treatment assigned to the participant, investigator staff will select the study treatment 
to dispense to the participant. The study medication has a label. A unique medication number 
is printed on the study medication label.
6.7.1
Handling of study treatment and additional treatment
Study treatment must be received and acknowledged by a designated staff at the study site, 
handled and stored safely and properly and kept in a secured location to which only the 
investigator and designated site staff have access. Upon receipt, all study treatment must be 
stored according to the instructions specified on the labels and in the Pharmacy Manual.
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.
An unblinded pharmacist or other qualified and trained site staff are required to prepare the 
study drug and placebo for administration. Please refer to the pharmacy manual for details.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study 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 study 
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.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study 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.
In this study there is no additional treatment apart from study treatment.

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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.
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 ICH 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 (IN) 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:

Main study consent, which also include: 

As applicable, Pregnancy Outcomes Reporting Consent for female participants
WoCBP must be informed that taking the study treatment may involve unknown risks to the 
fetus if pregnancy were to occur during the study and agree that in order to participate in the 
study they must adhere to the contraception requirements.
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A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
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8
Visit schedule and assessments
The Assessment Schedule lists all of the assessments and 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 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 (EoS/Early 
discontinuation visit). At this final visit, all dispensed investigational product should be reconciled, and the adverse event and concomitant 
medications should be recorded on the eCRF.
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of providing continuing care may be implemented. 
Phone calls, virtual contacts (e.g. teleconsultation) or visits by site staff/home nursing service to the participant´s home depending on local 
regulations and capabilities, can replace on-site study visits, for the duration of the pandemic until it is safe for the participant to visit the site 
again.
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8.1
Screening
If participant failed initial screening, re-screening of the participant is allowed after consultation 
with Sponsor.
In the case where a safety laboratory assessment at screening and/or 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.
Local guidelines and regulations need to be strictly followed regarding the screening and 
monitoring of the SARS-CoV-2 (COVID-19).
8.1.1
Eligibility screening
8.1.1.1
Hepatitis screen, HIV screen
All participants will be screened for Hepatitis B surface antigen (HBsAg) and hepatitis B core 
antibody (anti-HBc).
Screening for Hepatitis C will be based in HCV antibodies and if positive, HCV RNA levels 
should be determined.
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second 
technique available at the laboratory site e.g. Polymerase Chain Reaction.
Appropriate counseling will be made available by the Investigator in the event of a positive 
confirmatory test. Notification of state and federal authorities, as required by law, will be the 
responsibility of the Investigator. Results will be available as source data and will not be 
recorded within the eCRF. All samples will be shipped to the central laboratory.
8.1.1.2
Quantiferon Test
Blood tuberculosis testing with the Quantiferon assay (QuantiFERON®-TB Gold In-Tube) will 
be performed as specified in the Assessment schedule in Section 8. For the details regarding 
sample preparation and shipment please refer to the laboratory manual.
Note: if Quantiferon test is indeterminate, it may be repeated once. Two indeterminate 
Quantiferon tests will be considered as evidence of TB infection. Furthermore, after anti-TB 
treatment, participants with history of or latent TB may become eligible according to national 
guidelines.
Any significant findings will be recorded in the "Relevant medical history/Current medical 
conditions" section of the eCRF.
8.1.2
Information to be collected on screening failures
Participants who sign an ICF and are subsequently found to be ineligible prior to randomization 
will be considered a screen failure. The visit date, demographic information, informed consent 
(and withdrawal of informed consent, if applicable), SAE, Death (if applicable) pages must also 
be completed for screen failure participants who experience SAE. No other data will be entered 
into the clinical database for participants who are screen failures and experience no SAE. (see 

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Section 10.1.3. SAE reporting for details). If the participant fails to be randomized, the NIRT 
must be notified within 2 days of the screen failure that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered early terminators. The reason for early termination should be recorded on 
the appropriate eCRF.
8.2
Participant demographics/other baseline characteristics
Participant demographics: age, sex, race, predominant ethnicity (if permitted) and relevant 
medical history/current medical conditions (until date of signature of informed consent) will be 
recorded in the eCRF. Where possible, the diagnosis and not symptoms should be recorded.
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the protocol Section 6.2.1 for further details on 
what information must be recorded on the appropriate page of the eCRF.
8.3
Efficacy
Severity of AD will be measured by Clinical Outcomes Assessments (COAs) such as IGA 
(Investigator Global Assessment);
The primary endpoint is IGA response at week 16.
8.3.1
IGA
The IGA scale used in the study is vIGA-ADTM (Validated Investigator Global Assessment 
scale for Atopic Dermatitis). The IGA rating scale is used to determine the severity of AD 
symptoms and clinical response to treatment. It reflects a participant’s overall disease severity 
for the whole body based on a 5-point scale. The 5-point scale includes: clear, almost clear, 
mild, moderate, and severe disease.
IGA response is defined as clear or almost clear after week 16 with at least a 2 point-reduction 
from baseline.
The scale is a static scale and does not refer to previous status of the participant. The Investigator 
or trained qualified designee will complete the IGA assessment on each of the visits as outlined 
in the Assessment Schedule. Whenever possible, the IGA assessments should be performed by 
the same evaluator throughout the study.
The IGA should always be conducted as the first clinical assessment, 
. It must be based on a whole body skin inspection. 
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Table 8-4
Investigator Global Assessment (IGA)
Score
Morphological Description
0 - Clear
No inflammatory signs of atopic dermatitis (no erythema, no lichenification, no 
oozing/crusting). 
Postinflammatory 
hyperpigmentation 
and/or 
hypopigmentation may be present.
1 - Almost Clear
Barely perceptible erythema, barely perceptible induration/papulation, and/or 
minimal lichenification. No oozing or crusting.
2- Mild
Slight but definite erythema (pink), slight but definite induration/papulation, 
and/or slight but definite lichenification. No oozing or crusting.
3 - Moderate
Clearly 
perceptible 
erythema 
(dull 
red), 
clearly 
perceptible 
induration/papulation, and/or clearly perceptible lichenification. Oozing and 
crusting may be present.
4 - Severe
Marked erythema (deep and bright red), marked induration/papulation, and/or 
marked lichenification. Disease is widespread in extent. Oozing or crusting 
may be present.
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8.3.4
Appropriateness of efficacy assessments
The efficacy measurements included in this study have been and are used in clinical trials 
evaluating efficacy in AD and are standard for this indication (Eichenfield et al 2014, 
Simpson et al 2016, Beck et al 2014, Chopra and Silverberg 2018).
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
During the COVID-19 pandemic that limits or prevents on-site study visits regular phone or 
virtual calls may occur (every 4 weeks or more frequently if needed) for safety monitoring and 
discussion of the participant´s health status until the participant can again visit the site.
For details on AE collection and reporting, refer to Section 10.1.1 Adverse Events.
Assessment
Specification
Physical examination
A complete physical examination 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.
A short physical exam will include the examination of general 
appearance and vital signs (Systolic and Diastolic Blood pressure [SBP 
and DBP] and pulse). A short physical exam will be done at Day 29 visit 
except at visit at Baseline/Day 1 and at Day 113 when complete physical 
examination will be completed.
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 eCRF that captures medical history. Significant findings 
made after signing informed consent which meet the definition of an 
Adverse Event must be recorded as an adverse event.
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Assessment
Specification
Vital signs
Vital signs will include the collection of tympanic body temperature 
(recorded in °C), blood pressure (BP) and pulse measurements.
After the participant has been sitting for 3 minutes, with back supported 
and both feet placed on the floor, systolic and diastolic BP will be 
measured using an automated validated device, with an appropriately 
sized cuff. In case the cuff sizes available are not large enough for the 
participant's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used.
If vital signs are out-of-range at screening and/or baseline two additional 
readings can be obtained, so that up to three consecutive assessments 
are made, with the participant seated quietly for approximately five 
minutes preceding each repeat assessment. 
In case of repeated vital assessments, the eCRF should contain all 
repeat measurements.
Height and weight
Height is obtained in centimeters (cm) and body weight is obtained in 
kilograms (kg) and rounded to the nearest 0.1 kg. Weight is obtained in 
indoor clothing, without shoes.
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2
Screening visit weight will be used for dose calculations by the
pharmacist.
8.4.1
Laboratory evaluations
In the case where a laboratory range is not specified by the protocol, but a value is outside the 
reference range for the laboratory at screening and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the Investigator 
(in consultation with the sponsor, if considered relevant by PI) and shall be based, in part, upon 
the nature and degree of the observed abnormality. The assessment may be repeated once prior 
to randomization.
In all cases, the Investigator must document in the source documents the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study.
A central laboratory will be used for analysis of all safety specimens collected. In case of need 
for clarification or follow-up on adverse event or liver/renal event,  local laboratory might be 
used in addition to central laboratory assessment. Results from all local laboratory re-testing 
should be entered in appropriate eCRF pages. Details on the collection, shipment of samples 
and reporting of results by the central laboratory are provided to investigators in the central 
laboratory manual.
Participants should be reminded to fast (having had their last meal the evening, approx. 6-12 
hours before visit) at all visits before coming to the site for clinical chemistry blood sample.

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Clinical Chemistry
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments.
Test Category
Test Name
Hematology
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell 
(WBC) count with differentials (neutrophils, basophils, eosinophils, 
monocytes, lymphocytes) and platelet count 
Chemistry
The chemistry panel (fasting at all visits) will include: albumin, 
alkaline phosphatase, total and differentiated bilirubin, calcium, 
chloride, serum bicarbonate, creatinine, creatine kinase (CK), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
α-amylase, 
γ- 
glutamyltransferase (GGT), 
glucose, 
sodium, 
potassium, 
inorganic 
phosphorus, 
total 
protein, 
lactate 
dehydrogenase (LDH), magnesium, blood urea nitrogen (BUN), uric 
acid, lipase, triglycerides, cholesterol (direct LDL, HDL cholesterol 
and LDL cholesterol) and serum ketones. 
The chemistry panel will also include total immunoglobulin E (IgE) 
and high sensitivity C-reactive Protein (CRP) as specific markers for 
AD.
Urinalysis
Semi-quantitative ‘dipstick’ evaluation of the urine for the following 
parameters will be performed centrally: specific gravity, pH, glucose, 
protein, bilirubin, ketones, nitrite, leukocytes and blood. If the dipstick 
result is positive for nitrite, leucocytes and/or blood, microscopic 
analysis will be done (including white blood cells, red blood cells and 
casts). Urine culture and sensitivity test may be performed locally as 
per investigator’s discretion. 
Hepatitis and HIV markers
anti-HIV antibody, HBsAg, anti-HBc, anti-HCV, HCV RNA(if 
applicable)
Pregnancy test
Serum / Urine pregnancy test (refer to Section 8.4.3 Pregnancy and 
assessments of fertility)

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8.4.2
Electrocardiogram (ECG)
ECGs will be analyzed locally and performed with ECG machines at the investigator sites. 
Investigator sites will follow their own procedures relating to the ECG collection and reporting.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Single 12-lead ECGs are collected and results are entered into the appropriate eCRF page. 
The original ECGs appropriately signed, must be collected and archived at the study site.
Each ECG tracing must be labeled with study number, participant initials, participant number, 
date and time, and filed in the study site source documents. Investigator should document 
clinical evaluation in source. For any ECGs with participant safety concerns, two additional 
ECGs must be performed to confirm the safety finding. Clinically significant ECG findings at 
baseline must be discussed with the sponsor before administration of study treatment.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate.
8.4.3
Pregnancy and assessments of fertility
All WoCBP will have pregnancy testing during the study until EoS at the defined assessment 
visits. As additional follow up period is required for screening of pregnancy, a monthly urinary 
pregnancy test must be conducted for 6 months after the last dose of study drug. More urinary 
tests can be done at the discretion of the investigator. A home urine pregnancy test kit will be 
provided to participants by the site.
WoCBP should be instructed to use highly effective contraception during the study and after 
EoS (for 6 months after the last dose of study drug).
At EoS, the site will ask the participant to conduct the pregnancy test(s) as defined in assessment 
schedule Table 8-3 and will call the patient to remind her. The participant should communicate 
the results of the pregnancy test(s) to the site. A positive pregnancy test must trigger a pregnancy 
report to the sponsor (see Section 10.1.4). If pregnancy is discovered after EoS, the participant 
should be asked to come for a visit to the site and to read and sign the pregnancy consent form 
to allow the Study Doctor to ask about her pregnancy.

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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.
In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH) 
testing is required of any female participant regardless of reported reproductive/menopausal 
status at screening.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
8.5
Additional assessments
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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 medication
Section 6.2.2 and rescue medication Section 6.2.3

Any situation in which study participation might result in a safety risk to the participant

Following emergency unblinding

Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis,
fever, chills, urticaria, dyspnea, headache, myalgia, hypotension. Immediate interruption
of the infusion or injection to administer study treatment is required in such cases.

For liver events, please see Section 10.2.1. For renal events, please see Section 10.2.2

If a liver or renal event occurs, follow guidelines outlined in Section 16.2 and
Section 16.3 regarding discontinuation of study treatment.
The reasons for treatment discontinuation must be collected in line with the intercurrent events 
introduced in Section 2.1 and the “treatment” attribute described in Section 2 and Section 6.
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 'Withdrawal of Informed Consent' section). Where possible, 
they should return for the assessments indicated in the Assessment Schedule in Section 8. If they 
fail to return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, 
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.

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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 NIRT to register the participant’s discontinuation from 
study treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code Section 6.6.3.
9.1.1.1
Replacement policy
Participants may be replaced until the study has 64 total evaluable participants. The evaluability 
of the participant will be defined by availability of baseline data and suitable EoT visit data as 
well as the administration of at least 3 out of 4 doses of the study drug. If any patient 
discontinues treatment because of prohibited medication (refer to Section 6.2.2), the patient will 
not be replaced and will be considered as a non-responder for the primary analysis.
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, the participant 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.
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 in Section 8.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.

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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
Enrollment in the study will be placed on hold if any of the following occurs cumulatively 
across all of the cohorts:

Two or more drug related Serious Adverse Events (SAEs);

Two or more participants experience hypersensitivity reactions or injection reactions of 
moderate to severe intensity;

Two or more participants experience a similar AE which was assessed as severe in 
intensity and are considered as potentially related to the study treatment;

The Sponsor considers that the number and/or severity of AEs, abnormal safety 
monitoring tests, or abnormal laboratory findings justify putting the study on hold.
The study may resume following a safety review, if the Investigators and Sponsor agree it is 
safe to proceed. Any restart of the study following a full safety review will require notification 
to health authorities or submission and approval of a substantial amendment, whichever is 
appropriate based on local requirements.
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

Regulatory or Medical reasons

Slow recruitment
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.

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9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their End of study (EOS) visit 
for males and females of not child bearing potential (EOS V199 or V299) and for WoCBP [EOS 
(V199 or V299) and V399], 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 of that decision. 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 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 investigator and/or referring physician based on patient 
availability for follow-up. The investigator must provide follow-up medical care for all patients 
who are prematurely withdrawn from the study, or must refer them for appropriate ongoing 
care.
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 
until the end of the study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
AEs of Special Interest comprise hypersensitivity reactions such as serum sickness and 
anaphylaxis (as defined by Sampson criterion #1; Sampson et al 2006). 
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 10.1.5 for an overview 
of the reporting requirements.
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.
Abnormal laboratory values or test results constitute adverse events 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.

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Clinically significant abnormal laboratory values or test results should 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 underlying disease. Investigators have the responsibility for managing the safety of 
individual participant and identifying adverse events. Alert ranges for liver and kidney related 
events are included in Section 16.2 and Section 16.3 respectively.
Adverse events must be recorded in the appropriate eCRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. The severity grade
a. Adverse events will be primarily assessed and graded according to the 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials”. A copy of the Toxicity Grading Scale can be 
found in the Investigator Portal.
b. For any adverse event not listed in the “Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”, the adverse 
event will be assessed and graded according to the “Common Terminology Criteria 
for Adverse Events”, version 5.0 (CTCAE v5.0). A copy of the CTCAE Grading 
Scale can be found in the Investigator Portal.
c. For infusion-related reactions, event will also be assessed and graded according to the 
CTCAE v5.0
2. Its relationship to the study treatment

Yes or

No
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 investigational treatment.
All adverse events must be treated appropriately. Action taken with investigational treatment 
may include one or more of the following:

no action taken (e.g. further observation only)

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

non-drug therapy given

participant hospitalized/participant’s hospitalization prolonged (see Section 10.1.2 for 
definition of SAE)

its outcome (not recovered/not resolved; recovered/resolved, recovered/resolved with 
sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.

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Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure. 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 medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an IN or an 
Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the participant.
The investigator must also instruct each participant to report any new event (beyond the 
protocol observation period) that the participant, or the participant’s personal physician, 
believes might reasonably be related to study treatment. This information must be recorded in 
the investigator’s source documents; however, if the AE meets the criteria of an SAE, it must 
be reported to Novartis.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
10.1.2
Serious adverse events
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical condition(s)) which meets any one of the following 
criteria:

is fatal or life-threatening

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 the start of study drug

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

social reasons and respite care in the absence of any deterioration in the participant’s
general condition

is medically significant, e.g. defined as an event that jeopardizes the participant or may
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 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 ICH E2D 
Guideline 2004).

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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. 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 ICH E2D Guideline 2004).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the eCRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per 
Section 10.1.3.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety immediately, without undue delay (and under no circumstance later than within 
24 hours) of learning of its occurrence (Note: If more stringent, local regulations regarding reporting 
timelines prevail). Detailed instructions regarding the submission process and requirements are to be 
found in the investigator folder provided to each site.
Screen Failures and Run-In 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.
For participants considered Run-In Failures, SAEs occurring after the participant has provided 
informed consent until the time the participant is deemed a Run-In Failure must be reported to 
Novartis.
Randomized OR Treated Participants: SAEs collected between time participant signs ICF 
until 30 days after the participant has discontinued or stopped study treatment.
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 (and under no circumstance later than within 24 hours) of 
the investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). 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 IN to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported.

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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 30 day period 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 within 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 study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
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 (EMA definition).
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.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF 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 study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
eCRF (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 
Section 10.1.

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10.2
Additional Safety Monitoring
Not applicable.
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 16-1 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, every liver event defined in Table 16-1 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 16-1. Repeat 
liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm elevation within 
48-72 hours.

These liver chemistry repeats will be performed using the central laboratory. If results will
not be available from the central laboratory in timely manner, then the repeats can also be
performed additionally at a local laboratory to monitor the safety of the participant. If a liver
event is subsequently reported, any local liver chemistry tests previously conducted that are
associated with this event should have results recorded on the appropriate eCRF.

If the initial elevation is confirmed, close observation of the participant will be initiated,
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 9.1.1 Discontinuation of study
treatment section), if appropriate.

Hospitalization of the participant if appropriate.

Causality assessment of the liver event.

Thorough follow-up of the liver event should include:

Repeating liver chemistry tests two or three times weekly. Testing should include ALT,
AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x Upper Limit of Normal
(ULN), fractionation into direct and indirect bilirubin is required. To rule out muscular
origin of transaminase elevations, CPK should be measured along with liver chemistry tests.
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or the
study drug has been discontinued and the participant is asymptomatic. Retesting should be
continued up to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special
diets.

Exclusion of underlying liver disease, as specified in Table 16-3.

Imaging such as abdominal US, CT or MRI, as appropriate.

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.

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All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF.
10.2.2
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Section 16.3.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the eCRF.
10.2.3
Data Monitoring Committee
This study will include a data monitoring committee (DMC), which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify, or terminate a trial.
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (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 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 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 CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 

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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 
World Health Organization (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.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Screenings, randomizations, as well as randomization codes and data about all treatment arms 
assigned to the participant will be tracked using an Interactive Response Technology (IRT).. 
The system will be supplied by Novartis, who will also manage the database. The data will be 
sent electronically to Novartis team (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded 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. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and Good Clinical Practice (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 Good Clinical Practice, 
the progress of enrollment, and to ensure that study 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/CRA 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 eCRFs 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).

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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. 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 eCRFs 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.
12.1
Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment received.
The safety analysis set will include all participants who received any study drug.
The PK analysis set will include all participants with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug.
The PD analysis set will include all participants who received any study drug and had 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 for the Safety set.
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 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, minimum, 
and maximum will be presented.
The duration of exposure to study treatment will be summarized by treatment group. 
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. Additionally, rescue therapy as well 
as concomitant anti-histamines will be summarized 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 assess efficacy of CMK389 in participants with moderate to 
severe AD. This will be evaluated by assessing the IGA response at Week 16. This analysis will 
be performed on the PD analysis set. For the efficacy analyses, the two placebo groups (placebo 
s.c. and i.v.) will be pooled together.
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary estimand, including the primary endpoint, is defined in Section 2.1. It is based on 
the IGA response at week 16.
12.4.2
Statistical model, hypothesis, and method of analysis
The IGA data will be listed and summarized by treatment group. Placebo groups will be pooled. 
Summary tables will be presented by treatment group and visit which include absolute and 
relative frequencies.
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12.4.3
Handling of remaining intercurrent events of primary estimand
Use of any therapy (prohibited or rescue medication taken after the first 6 weeks) as well as any 
study treatment discontinuation due to lack of efficacy or due to an AE related to AD are 
considered as unfavorable outcomes, and therefore the participants will be treated as non-
responders (composite strategy). Study treatment discontinuation due to other reasons and AEs 
not related to AD or due to lack of tolerability will be handled with a treatment policy strategy 
(i.e. they will be ignored).
12.4.4
Handling of missing values not related to intercurrent event
Missing data imputations will be discussed in the Statistical Analysis Plan (SAP) in detail.
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12.5
Analysis of secondary endpoints/estimands
Assessing safety and tolerability of CMK389 in participants with AD is the secondary 
 
 objective of the study.
12.5.1
Safety endpoints
For all safety analyses, the safety set will be used. All tables, figures and listings tables will be 
presented by treatment group and pooled placebo group (placebo s.c. and placebo i.v.).
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, if there were death during the study. 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 first administration of study treatment to 112 
days after the date of the last actual administration of any study treatment.
Adverse events
All information obtained on adverse events will be displayed by treatment group (CMK389 10 
mg/kg i.v, Placebo i.v, CMK389 300 mg s.c, Placebo s.c, and Pooled placebo) 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 double-blind 
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.
The number (and proportion) of participants with adverse events of special interest (i.e. 
hypersensitivity reactions such as serum sickness and anaphylaxis) will be summarized.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
The study is powered for the comparison between CMK389 10mg/kg i.v. vs placebo where both 
groups of placebo i.v. and placebo s.c. will be pooled together. The additional treatment group 
of CMK389 300mg s.c. will not be statistically tested against placebo.
 illustrates the operating characteristics for the design with 32 participants 
randomized to CMK389 10mg/kg i.v. and 16 participants on placebo. 
The MAP prior for the placebo group is included in the analysis. Assuming the true treatment 
difference in IGA rate is 36% between CMK389 10mg/kg i.v. and placebo and assuming that 
the true placebo IGA rate is 7%, the probability of meeting the dual efficacy criteria as stated 
in Section 12.4.2 is 80%.
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12.8.2
Secondary endpoint(s)
Not applicable.
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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 Good Clinical Practice, 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 Institutional Review Board/Independent Ethics Committee (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.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as EudraCT. In addition, 
after study completion (defined as last patient last visit) and finalization of the study report 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. 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 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.

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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 Health Authorities, 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.
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
References
References are available upon request
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WC01-5.

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Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate eCRF. Any clinically significant abnormal 
laboratory value should be evaluated and followed-up by the investigator until normal or a cause 
for the abnormality is determined. See Section 16.2 for specific liver event and laboratory test 
trigger definitions and follow-up requirements. See Appendix 3 for specific renal alert criteria 
and actions. Post-baseline vital signs will be flagged as notable abnormalities as follows:
1. Systolic/Diastolic blood pressure: ≥25% decrease or ≥25 % increase from baseline
2. Pulse: ≥110 bpm with ≥15% change from baseline, or <50 bpm with ≥15% change from 
baseline

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16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases
ALT or AST > 3 × ULN and TBL > 2 × ULN without 
initial increase in ALP to > 2 × ULN
ALT or AST elevation with coagulopathy
ALT or AST > 3 × ULN and INR > 1.5 (in the absence 
of anticoagulation)
ALT or AST elevation accompanied by 
symptoms
ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or 
vomiting, or rash, or eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation
ALP > 2 × ULN (in the absence of known bone 
pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver 
toxicity

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Table 16-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 5 to ≤ 8 × ULN

If confirmed, consider interruption or 
discontinuation of study drug

If elevation persists for more than 2 weeks, 
discontinue the study drug

Establish causality

Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 3 to ≤ 5 × ULN 
(patient is asymptomatic)
Monitor liver chemistry tests two or three times 
weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 
hours

If elevation is confirmed, measure 
fractionated ALP; if >50% is of liver origin, 
establish hepatic causality

Complete CRFs per liver event guidance*
Any AE potentially indicative of liver toxicity

Consider study treatment interruption or 
discontinuation 

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the CRF Completion Guidelines.
Table 16-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E
IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, 
HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis
Ultrasound or MRI
Hypoxic/ischemic hepatopathy
Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease
Caeruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin

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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-4
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase 50 % +
OR if <18 years old, eGFR 35 mL/min/1.73 m2

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected

Consider patient hospitalization and 
specialized treatment
New onset dipstick proteinuria ≥ 3+
OR
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset hematuria ≥ 3+ on urine dipstick

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury

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Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.)

Whenever a renal event is identified, a detailed patient history and examination are indicated
to identify and potentially eliminate risk factors that may have initiated or contributed to the
event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain,
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic
failure, contrast media or other known nephrotoxin administration, or other diseases or
causes, e.g., dehydration due to delirium, tumor lysis
Table 16-5
Renal Event Follow Up
FOLLOW-UP OF RENAL EVENTS

Urine dipstick and sediment microscopy evidence of DIN:  crystals, red blood cells
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial
cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or

Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio
stabilization at a new level with ±50% variability over last 6 months.

Analysis of urine markers in samples collected over the course of the DIN event