Conditions: Malaria
Keywords: safety tolerability pharmacokinetics healthy volunteers phase 1 malaria intravenous iv KAE609 Placebo
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 57
Healthy volunteers: yes

Brief summary:
This was a randomized, subject and investigator-blinded, placebo-controlled, single and multiple ascending intravenous (iv) dose study in healthy subjects to assess the safety and tolerability of KAE609 given in the vein.

Detailed description:
The study consisted of 2 parts: single-ascending dose (SAD) part and multiple ascending dose (MAD) part.

In Part A (Single-ascending dose (SAD) part), it was planned to recruit 6 active, 2 placebo subjects in each cohort:

* Cohort A1: 10.5 mg/placebo
* Cohort A2: 30 mg/placebo
* Cohort A3: 75 mg/placebo
* Cohort A4: 120 mg/placebo
* Cohort A5: 210 mg/placebo

In Part B (Multiple-ascending dose (MAD) part), Subjects were assigned to one of the following treatment arms in a ratio of 2:1 (6 active, 3 placebo):

* Cohort B1: 60 mg/placebo, every 24 hours (q24h) × 5 days
* Cohort B2: 120 mg/placebo, every 24 hours (q24h) × 5 days

Eligible subjects were randomized to receive a single or q24h x 5 doses of either KAE609 or placebo. Safety, tolerability and pharmacokinetics were assessed over the period of 8 days for single dose and 12 days for multiple dose up to end of study visit for each subject.

Arms:
arm 1: Single iv bolus dose of KAE609 or placebo administered at the clinical site by the study personnel. arm 2: Single iv bolus dose of KAE609 or placebo administered at the clinical site by the study personnel. arm 3: Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel. arm 4: Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel. arm 5: Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel. arm 6: Multiple iv bolus doses of KAE609 or placebo administered at the clinical site by the study personnel. arm 7: Multiple iv infusion doses of KAE609 or placebo administered at the clinical site by the study personnel.

Interventions: intervention 1: KAE609 intervention 2: Placebo
Intervention descriptions: intervention 1: * iv bolus administration over approximately 2 min for doses \< 75 mg (Cohorts A1, A2 and B1)
* iv infusion over approximately 10 min for doses ≥ 75 mg (Cohorts A3, A4, A5 and B2) intervention 2: matching placeo for iv administration

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
KAE609
Clinical Trial Protocol CKAE609X2111 / NCT04321252
A randomized, subject and investigator-blinded, placebo 
controlled, single and multiple ascending dose study to 
assess the safety, tolerability, and pharmacokinetics of 
KAE609 administered intravenously in healthy subjects
Document type:
Clinical Trial Protocol
EUDRACT number:
2019-000405-71
Version number:
v02 (Clean)
Clinical Trial Phase:
I
Release date:
29-Oct-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................13
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................16
2
Objectives and endpoints...................................................................................................16
3
Study design ......................................................................................................................17
4
Rationale............................................................................................................................20
4.1
Rationale for study design .....................................................................................20
4.2
Rationale for dose/regimen and duration of treatment ..........................................21
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................23
4.4
Purpose and timing of interim analyses/design adaptations..................................23
4.5
Risks and benefits..................................................................................................24
4.5.1
Blood sample volume............................................................................26
5
Population..........................................................................................................................26
5.1
Inclusion criteria ....................................................................................................27
5.2
Exclusion criteria...................................................................................................27
6
Treatment...........................................................................................................................30
6.1
Study treatment......................................................................................................30
6.1.1
Investigational and control drugs..........................................................30
6.1.2
Additional study treatments ..................................................................30
6.1.3
Treatment arms/group ...........................................................................30
6.2
Other treatment(s)..................................................................................................31
6.2.1
Concomitant therapy.............................................................................31
6.2.2
Prohibited medication ...........................................................................31
6.2.3
Restriction for study subjects................................................................31
6.3
Subject numbering, treatment assignment, randomization....................................32
6.3.1
Subject numbering ................................................................................32
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6.3.2
Treatment assignment, randomization ..................................................32
6.4
Treatment blinding.................................................................................................33
6.5
Dose escalation and dose modification..................................................................35
6.6
Additional treatment guidance...............................................................................37
6.6.1
Treatment compliance...........................................................................37
6.6.2
Recommended treatment of adverse events..........................................37
6.6.3
Emergency breaking of assigned treatment code..................................37
6.7
Preparation and dispensation.................................................................................38
7
Informed consent procedures ............................................................................................38
8
Visit schedule and assessments .........................................................................................39
8.1
Screening ...............................................................................................................47
8.1.1
Eligibility screening ..............................................................................47
8.1.2
Information to be collected on screening failures.................................47
8.2
Subject demographics/other baseline characteristics.............................................47
8.3
Efficacy..................................................................................................................48
8.3.1
Appropriateness of efficacy assessments..............................................48
8.4
Safety/Tolerability.................................................................................................48
8.4.1
Laboratory evaluations..........................................................................49
8.4.2
Electrocardiogram (ECG) .....................................................................49
8.4.3
Holter ECG Monitoring ........................................................................50
8.4.4
Pregnancy and assessments of fertility .................................................50
8.4.5
Appropriateness of safety measurements..............................................51
8.5
Additional assessments..........................................................................................51
8.5.1
Pharmacokinetics ..................................................................................51
9
Study discontinuation and completion ..............................................................................53
9.1
Discontinuation......................................................................................................53
9.1.1
Discontinuation of study treatment .......................................................53
9.1.2
Withdrawal of informed consent...........................................................54
9.1.3
Lost to follow-up...................................................................................55
9.1.4
Study stopping rules..............................................................................55
9.1.5
Early study termination by the sponsor.................................................56
9.2
Study completion and post-study treatment ..........................................................56
10 Safety monitoring and reporting........................................................................................56
10.1
Definition of adverse events and reporting requirements......................................56
10.1.1
Adverse events ......................................................................................56
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10.1.2
Serious adverse events ..........................................................................58
10.1.3
SAE reporting........................................................................................59
10.1.4
Pregnancy reporting ..............................................................................60
10.1.5
Reporting of study treatment errors including misuse/abuse................60
10.2
Additional Safety Monitoring................................................................................60
10.2.1
Liver safety monitoring.........................................................................60
10.2.2
Renal safety monitoring........................................................................61
11 Data Collection and Database management......................................................................62
11.1
Data collection.......................................................................................................62
11.2
Database management and quality control............................................................63
11.3
Site monitoring ......................................................................................................64
12 Data analysis and statistical methods ................................................................................65
12.1
Analysis sets ..........................................................................................................65
12.2
Subject demographics and other baseline characteristics......................................65
12.3
Treatments .............................................................................................................65
12.4
Analysis of the primary endpoint(s) ......................................................................65
12.4.1
Definition of primary endpoint(s).........................................................65
12.4.2
Statistical model, hypothesis, and method of analysis..........................66
12.4.3
Handling of missing values/censoring/discontinuations.......................67
12.4.4
Sensitivity and Supportive analyses......................................................67
12.5
Analysis of secondary endpoints ...........................................................................67
12.5.1
Pharmacokinetics ..................................................................................67
12.6
Analysis of exploratory endpoints.........................................................................68
12.7
Interim analyses.....................................................................................................69
12.8
Sample size calculation..........................................................................................69
12.8.1
Primary endpoint(s)...............................................................................69
13 Ethical considerations and administrative procedures ......................................................70
13.1
Regulatory and ethical compliance........................................................................70
13.2
Responsibilities of the investigator and IRB/IEC..................................................70
13.3
Publication of study protocol and results...............................................................70
13.4
Quality Control and Quality Assurance.................................................................71
14 Protocol adherence ............................................................................................................71
14.1
Protocol Amendments ...........................................................................................71
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15 References .........................................................................................................................72
16 Appendices ........................................................................................................................73
16.1
Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................73
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up......76
List of tables
Table 2-1
Objectives and related endpoints ..........................................................16
Table 6-1
Investigational and control drug............................................................30
Table 6-2
Blinding levels ......................................................................................34
Table 8-1
Assessment Schedule, Part A - SAD.....................................................40
Table 8-2
Assessment Schedule, Part B - MAD ...................................................43
Table 8-3
Assessments and Specifications............................................................48
Table 8-4
Laboratory Assessments........................................................................49
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................60
Table 12-1
Non-compartmental pharmacokinetic parameters ................................68
Table 12-2
Probability of observing events given a range of underlying event 
rates in Part A and Part B......................................................................70
Table 16-1
Liver Event and Laboratory Trigger Definitions ..................................73
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers...73
Table 16-3
Specific Renal Alert Criteria and Actions.............................................76
List of figures
Figure 3-2
Study design - SAD...............................................................................19
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Figure 3-3
Study design - MAD.............................................................................20


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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulation
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
CNS
Central nervous system
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CTA
Clinical trial application
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
ECG
Electrocardiogram
EDC
Electronic Data Capture
EEA
European economic area
EMA
European Medicines Agency
EOS
End of study
EU
European Union
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice
h
hour
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
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Commercial 
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CCI
CCI
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CCI
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CCI
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IRB
Institutional Review Board
iv
intravenous
LDH
lactate dehydrogenase
LFT
Liver function test
MAD
Multiple ascending dose
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
PBPK
Physiologically Based Pharmacokinetic
PK
pharmacokinetic(s)
PT
prothrombin time
q24h
Dosing every 24 hours
QMS
Quality Management System
RBC
red blood cell(s)
SAD
Single ascending dose
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization
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Glossary of terms
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 subject.
Cohort
A specific group of subjects fulfilling certain criteria.
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial.
Dosage
Dose of the study treatment given to the subject 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.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol).
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up) which applies 
across all arms of a study.
Healthy subject
A person with no known significant health problems who volunteers to be a 
study participant.
Investigational drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational Medicinal 
Product," or “test substance”.
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment.
Screen Failure
A subject who is screened but is not treated or randomized.
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.
Study treatment
Any drug or combination of drugs 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 subject permanently stops taking study treatment prior to the 
defined study treatment completion date.
Subject
A trial participant (can be a healthy volunteer or a patient).
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
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Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study.
Withdrawal of 
consent
Withdrawal of consent from the study occurs only when a subject does not want 
to participate in the study any longer and does not allow any further collection 
of personal data.


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Protocol summary
Protocol number
CKAE609X2111
Full Title
A randomized, subject and investigator-blinded, placebo controlled, single 
and multiple ascending dose study to assess the safety, tolerability, and 
pharmacokinetics of KAE609 administered intravenously in healthy subjects
Brief title
Study to assess safety, tolerability and pharmacokinetics of KAE609 
administered intravenously in healthy subjects
Sponsor and 
Clinical Phase
Novartis
Phase I
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to assess the safety and tolerability and 
pharmacokinetics of single and multiple ascending doses of KAE609 
administered by iv infusion in healthy subjects, to support further clinical 
development of KAE609 in patients with severe malaria and to guide dose 
selection for future trials.
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of 
single and multiple iv doses of KAE609 in healthy subjects
Secondary 
Objectives
To assess the pharmacokinetics of single and multiple iv doses of KAE609 in 
healthy subjects
To assess local tolerance at infusion site of KAE609 iv administration
Study design
This is an exploratory, randomized, subject and investigator-blinded, placebo-
controlled, single and multiple ascending iv dose study in healthy subjects. 
The study consists of a single ascending dose part and a multiple ascending 
dose part.
Eligible subjects will be randomized to receive a single or q24h x 5 doses of 
either KAE609 or placebo. Safety, tolerability and pharmacokinetics will be 
assessed over the period of 8 days for single dose and 12 days for multiple 
doses up to end of study visit for each subject.
Population
The study population will be comprised of healthy female and male subjects 
between the ages of 18 and 55 years inclusive. A total of approximately 58 
subjects will be enrolled in the study and randomized to receive KAE609 or 
placebo treatment. 
Key Inclusion 
criteria

Healthy male and female subjects 18 to 55 years of age inclusive, and in
good health as determined by past medical history, physical examination,
vital signs, electrocardiogram, and laboratory tests.

Subjects must weigh at least 50 kg to participate in the study, and must
have a body mass index (BMI) within the range of 18.0 – 30.0 kg/m2.
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Key Exclusion 
criteria

Use of other investigational drugs within 5 half-lives of Screening, or
within 30 days of dosing, whichever is longer; or longer if required by
local regulations.

Significant illness which has not resolved within two (2) weeks prior to
initial dosing.

Pregnant or nursing (lactating) women.

Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant.

Sexually active males unwilling to use a condom during intercourse while
taking investigational drug and for at least 2 weeks after last dose of
investigational drug.
Study treatment
Single or multiple iv doses of:

KAE609

Placebo
Pharmacokinetic 
assessments 

KAE609 plasma concentrations
Key safety 
assessments

Adverse event monitoring

Physical examinations

Vital signs

Monitoring of laboratory markers in blood and urine

Holter monitoring and ECGs
Other 
assessments 
Data analysis
For each part safety and tolerability data will be descriptively summarized. 
The number and percentage of adverse events will be tabulated by body 
system and preferred term with a breakdown by treatment group. Separate 
tables and listings will be prepared presenting adverse event intensity (CTCAE 
grade) and relationship to study treatment. All data for vital signs, ECG 
evaluations, hematology, blood chemistry, and urinalysis will be summarized 
by part, treatment group and visit/time and any abnormalities will be listed by 
part, treatment group, subject and visit/time.
KAE609 concentration data will be listed by part, treatment group, subject and 
visit/sampling time point. Descriptive summary statistics will be provided by 
part, treatment group and visit/sampling time point, which will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, 
minimum and maximum. An exception to this is Tmax for which median, 
minimum and maximum will be presented.
Key words
Safety, tolerability, pharmacokinetics, healthy volunteers, phase 1, Malaria, iv 
KAE609.
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1
Introduction
1.1
Background
Malaria is a preventable and curable disease caused mainly by two protozoan parasites, 
Plasmodium falciparum and Plasmodium vivax. Globally, 3.3 billion people are at risk of 
malaria with an estimated 210 million cases and 584,000 deaths each year, mostly children 
under 5 years of age (World Health Organization 2015). 90% of malaria cases and 91% of 
malaria deaths occur in Africa, the vast majority in young children.
The majority of deaths occur after infection with Plasmodium falciparum. Malaria is an 
acute febrile illness. In an individual, who is not immune to malaria, symptoms usually appear 
10–15 days after the infective mosquito bite. The first symptoms may be mild and difficult to 
recognize as malaria. They arise because of the blood stage parasitemia with consequent 
erythrocyte rupture that produces the acute symptoms (spiking fever, rigors, malaise, headache 
and muscle aches), vascular compromise and organ involvement that can result in complications 
if not rapidly treated. P. falciparum malaria can progress to severe illness and death.
Children with severe malaria frequently develop one or more of the following symptoms: severe 
anaemia, respiratory distress in relation to metabolic acidosis, or cerebral malaria. Also, in 
adults, multi-organ involvement is frequent. Thus, it is vital to initiate effective treatment 
shortly after diagnosis.
The World Health Organization (WHO) recommended treatment of severe malaria is artesunate 
administered either intravenously (iv) or intramuscularly (im) or quinine administered either iv 
or im. There are problems with both of these treatments. There are increasing reports of parasite 
resistance to artemisinins such as artesunate. Resistance has been detected in 5 countries of the 
Greater Mekong subregion: Cambodia, Lao People’s Democratic Republic, Myanmar, Thailand 
and Vietnam (World Health Organization 2011). Studies have confirmed that artemisinin 
resistance has emerged independently in many areas of this subregion. Additionally preparation 
and administration of artesunate injection is complicated. Quinine has to be given by slow 
infusion because of the risk of cardiovascular side effects. In addition, quinine has lower 
efficacy than artesunate.
KAE609, a spiroindolone, represents a new class of potent, fast-acting, schizonticidal 
antimalarial drugs (White et al 2014). It appears to exert its antiplasmodial activity through 
deregulation of Na+ homeostasis in the parasite cytosol through the inhibition of a P-type non-
SERCA ATPase, PfATP4.
KAE609 presents two possible advantages over existing antimalarial drugs for the treatment of 
severe malaria. Firstly, it is a novel antimalarial agent developed with a different mechanism of 
action to other marketed antimalarials and it shows activity against existing drug resistant 
parasites, including artemisinin resistance. Secondly, in early clinical studies, in which KAE609 
was given by the oral route to patients with uncomplicated malaria, parasitemia was 
rapidly reduced 
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reduced more rapidly with KAE609 than has been observed with any other marketed agents 
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Because of its rapid clearance of parasites and a lack of known resistance, KAE609 is being 
progressed for the treatment of severe malaria. In severe malaria, reduction of parasite count is 
one of the top treatment goals and therefore achieving the effective concentration in the 
systemic circulation is important. In addition, many of the severe malaria patients will not be 
able tolerate or take oral treatment. Therefore, iv administration is considered most suitable 
route of administration for KAE609 in severe malaria.
For more information, please refer to the latest edition of the Investigator's Brochure.
1.2
Purpose
The purpose of this study is to assess the safety and tolerability and pharmacokinetics (PK) of 
single ascending doses (SAD) and multiple ascending doses (MAD) of KAE609 administered 
by iv infusion in healthy subjects, to support further clinical development of KAE609 in patients 
with severe malaria and to guide dose selection for future trials.
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 safety and tolerability of single
and multiple iv doses of KAE609 in healthy
subjects

Adverse events, physical examination
findings, vital signs, ECG
findings (including QTcF), safety
laboratory assessments including
chemistry, hematology, and urinalysis
results
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the pharmacokinetics (PK) of single
and multiple iv doses of KAE609 in healthy
subjects

AUC, Tmax, Cmax, CL, Vz, and T1/2

To assess local tolerance at infusion site of
KAE609 iv administration

Findings of physical examination of
infusion site
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3
Study design
This is a randomized, subject and investigator-blinded, placebo-controlled, single and multiple 
ascending iv dose study in healthy subjects. The study consists of two parts and the study 
scheme is shown in Figure 3-1:

Part A is a single ascending dose (SAD) study with 5 cohorts of 8 subjects each

Part B is a multiple ascending dose (MAD) study with 2 cohorts of 9 subjects each
For both parts of the study, each subject will participate in an up to 28- day screening period 
during which a full physical examination, medical history, drug screening, vital signs, ECG 
evaluation and safety laboratory tests evaluation will be performed.
A review of safety and PK data will be conducted at the completion of each cohort prior to 
dosing of the next subsequent cohort. Please also refer to Section 6.5.1 for more details on dose 
escalations. Safety assessments will include physical examinations, ECGs, vital signs, standard 
clinical laboratory evaluations (hematology, blood chemistry, urinalysis) adverse event and 
serious adverse event monitoring.
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Part A: Single-ascending dose study
In Part A sequential cohorts of 8 healthy subjects per cohort will be randomized to receive 
successively higher single iv doses of KAE609 or matching placebo. In each cohort, subjects 
will be randomized in a 3:1 ratio to KAE609 (6 subjects/cohort) or matching placebo 
(2 subjects/cohort). Five planned dose cohorts will be included in Part A (A1, A2, A3, A4 and 
A5). Provisional dose levels are described in Section 6.5.1.2.
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For a detailed outline of safety and other assessments, please refer to Part A Assessment 
Schedule (Table 8-1). If added, any additional dose cohort will follow the same Part A 
Assessment Schedule.
Figure 3-2
Study design - SAD
Part B: Multiple-ascending dose study
In Part B sequential cohorts of 9 healthy subjects per cohort will be randomized to receive 
successively higher iv doses of KAE609 or matching placebo. Two planned dose cohorts will 
be included in Part B (B1 and B2). For Cohort B1, healthy subjects will receive a 60 mg dose 
of KAE609 or matching placebo iv q24h for 5 days. For Cohort B2, healthy subjects will receive 
a 120 mg dose of KAE609 or matching placebo iv q24h for 5 days. In each cohort, subjects will 
be randomized in a 2:1 ratio to KAE609 (6 subjects/cohort) or matching placebo 
(3 subjects/cohort). Provisional dose levels are described in Section 6.5.1.2
For a detailed outline of safety and other assessments, please refer to Part B Assessment 
Schedule (Table 8-2). Any additional cohort will follow the same Part B Assessment Schedule.
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Figure 3-3
Study design - MAD
4
Rationale
4.1
Rationale for study design
This is the first clinical study for KAE609 administered iv with the purpose of establishing 
safety, tolerability and pharmacokinetics in healthy subjects. The rationale for key design 
elements in this study include:

Healthy subjects: Enrolling healthy subjects was chosen to reduce the risk of introducing
confounding variables and to minimize the risk and severity of adverse events.
This minimizes any underlying disease-related findings that may confound data
interpretation that may exist, especially regarding transaminase elevations, which have
been seen in patients with uncomplicated malaria treated with KAE609 and can be present
in patients with severe malaria.

Randomization: Helps to avoid possible bias in the selection and allocation of subjects.

Placebo comparator: Use of a placebo helps assess if any safety or tolerability findings
should be attributed to KAE609 and helps to maintain study blinding.

Blinding: Blinding of subjects with limited un-blinding of investigators and sponsor
minimizes bias in the conduct of the study. The Sponsor's clinical trial team will be
blinded. Representatives of the Sponsor, such as the Translational Medicine Expert, may
be only unblinded to facilitate safety-related decisions. Limited un-blinding of the
investigators and sponsor (e.g., at the time of dose-escalation review) will be allowed if
needed to help with safety-related decisions. The pharmacist at the CRO who prepares the
injections will be unblinded.

Sequential cohorts: This allows for an adequate safety and tolerability assessment prior
to the initiation of each ascending dose.

Sentinel dosing: No sentinel dosing is planned for this study. The predicted toxicities are
monitorable and reversible. There is no expected effect on QT and no CNS toxicities
expected in this study. A QT potential risk was seen in the hERG assay but no effect of
oral KAE609 on QTcF has been observed in healthy subject or patient studies so
far. Sentinel dosing is not likely to reduce the risk in this study.

Domiciliation: Subjects will be domiciled before and during dosing and after last
dosing to allow for close observation of safety and tolerability, and to ensure compliance
with instructions for all subjects.
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4.2
Rationale for dose/regimen and duration of treatment
Following completion of each cohort, apart from safety, available PK data will be reviewed to 
confirm the predictions and to keep the exposure within the AUC and Cmax considered safe 
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Starting dose
Dose escalation
Highest dose
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4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Placebo is selected as the comparator to strengthen the internal validity of the study, to account 
for non-specific study effects on read-outs, to allow for blinding of treatment arms, and to better 
ascertain relation of adverse events to drug treatment. 
4.4
Purpose and timing of interim analyses/design adaptations
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4.5
Risks and benefits
This study will be conducted in healthy adult volunteers to demonstrate the safety and 
tolerability of iv KAE609 at levels beyond projected therapeutic doses. KAE609 has already 
been investigated by the oral route and as of 5-March-2019, 152 patients have been treated in 
phase 2 studies in patients with uncomplicated malaria. KAE609 is now being developed for iv 
administration for the treatment of severe malaria. This is the first study where it is being 
administered to humans by iv route. By the oral route, KAE609 has been shown to be safe and 
well tolerated up to single doses of 300 mg and 150 mg daily for 3 days in healthy subjects. 
In patients dosed up to 75 mg single dose and 50 mg daily up to 3 days oral, KAE609 rapidly 
cleared malaria parasites and was generally well tolerated. However, there is no clinical 
experience to date with the iv form.
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There is no benefit expected for subjects participating in this study. The risk to subjects in this 
trial (listed in Table 7-2 of the IB) will be minimized by adherence to the inclusion/exclusion 
criteria, stopping rules, close clinical monitoring (including multiple laboratory evaluations as 
per the Assessment Schedule), the sequential dose escalation and with PK and safety reviews 
between cohorts.
The COVID-19 pandemic does not impact the benefit/risk assessment for this study. No 
additional risks related to COVID-19 have been identified.
As is the case with any new compound in clinical development, there are unknown risks to 
KAE609 that may be serious and unforeseen.
4.5.1
Blood sample volume
A maximum of 200 mL of blood is planned to be collected over a period of 5 (Part A) or 6 weeks 
(Part B), from each subject as part of the study. Additional samples may be required for safety 
monitoring.
Timings of blood sample collection are outlined in the Assessment Schedules (Table 8-1 and 
Table 8-2).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and/or Instruction Manual.
See the Section 8.5.2.3 on the potential use of residual samples.
5
Population
The study population will be comprised of healthy females of non-child bearing potential and 
males between the ages of 18 and 55 years inclusive. A total of approximately 58 subjects will 
be enrolled in the study and randomized to receive KAE609 or placebo treatment. Up to 
17 additional subjects in up to 2 additional cohorts may be randomized if additional SAD or 
MAD cohorts are deemed necessary.
The investigator must ensure that all subjects being considered for the study meet the following 
eligibility criteria. No additional criteria should be applied by the investigator, in order to ensure 
that the study population will be representative of all eligible subjects.
Each inclusion and exclusion criterion specifies if the criterion should be assessed at screening 
and/or baseline. Pre-dose assessments on Day 1 are not considered for study eligibility. 
A relevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
Refer to Section 9.1.1.1 for information on replacement subjects.
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5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
2. Healthy male and female subjects 18 to 55 years of age inclusive and in good health as
determined by past medical history, physical examination, vital signs, electrocardiogram,
and laboratory tests at screening.
4. Subjects must weigh at least 50 kg to participate in the study, and must have a body mass
index (BMI) within the range of 18.0 – 30.0 kg/m2at screening [BMI = Body weight (kg) /
[Height (m)]2]
5.2
Exclusion criteria
2. Significant illness which has not resolved within two (2) weeks prior to initial dosing.
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21. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, at screening.
22. Use of other investigational drugs within 5 half-lives of Screening, or within 30 days of
dosing, whichever is longer; or longer if required by local regulations
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19. Pregnant or nursing (lactating)  women at screening.
20. Sexually active males, at screening, baseline and during the study, unwilling to use a 
condom during intercourse while taking investigational drug 
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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 subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM and/or Pharmacy Manual.
Refer to the ‘dietary restrictions and smoking’ Section 6.2.3.1 for subjects’ restrictions.
6.1.1
Investigational and control drugs
The investigational drug, KAE609 and the matching placebo will be prepared by Novartis and 
supplied as open labeled bulk medication to the unblinded site pharmacist (Table 6-1). 
An unblinded pharmacist or authorized designee is required to dispense the study drug. 
Drug will be administered at the clinical site by the study personnel in accordance with the 
specified study procedures.
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Sponsor (global 
or local)
KAE609 
15mg/mL (2 
mL vial)
Solution for 
Injection
Intravenous use
Open label bulk 
supply; vials
Sponsor global
Matching Placebo
Solution for 
Injection
Intravenous use
Open label bulk
supply; vials
Sponsor global
6.1.2
Additional study treatments
No additional treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
All dose levels are provisional with the exception of cohort A1 in Part A (SAD).
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6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the concomitant medications / significant non-drug therapies or procedures Case Report 
Forms from screening through the post study safety follow-up call. For further details on 
potential drug-drug interactions, see Investigator's Brochure.
6.2.2
Prohibited medication
Except for any medication which may be required to treat adverse events, no medication 
(including vitamins or herbal remedy) other than study treatment will be allowed from the date 
subject signs the informed consent until the post study safety follow-up call. In case of prior 
use of concomitant medication with long half-life additional time might be needed (e.g. less 
than 5 half-life between drug intake and screening or pharmacodynamic effect has not returned 
to normal). For further details on potential drug-drug interactions, see Investigator's Brochure.
Should a subject have an incidental and limited need for a medication to be taken within the 
restricted pre-dose timeframe (e.g. paracetamol/acetaminophen for a headache, etc.), the 
sponsor should be advised, as administration of any concomitant medication may require the 
subject to be withdrawn.
6.2.3
Restriction for study subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
6.2.3.1
Dietary restrictions and smoking
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6.2.3.2
Other restrictions
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see ‘Subject 
numbering’ section in the SOM.
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 subjects and investigator staff. 
A randomization list will be produced by or under the responsibility of Novartis Global Clinical 
Supply (GCS) using a validated system that automates the random assignment of treatment 
arms to randomization numbers in the specified ratio.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
If only single investigational site, then randomization will be in a sequential fashion using the 
randomization schedule. Randomization should only occur when all baseline data has been 
reviewed and eligibility is confirmed.
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of subjects.
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6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects will remain blinded to study treatment 
throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
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 during treatment allocation and 
subject dosing.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site.
Drug product will be supplied in bulk, so an unblinded pharmacist 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 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.
Trained site staff will be required to administer study treatment. Appropriate measures must be 
taken by the unblinded site staff to ensure that the treatment assignments are concealed from 
the rest of the site staff.
Sponsor staff or delegate
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)
The unblinded field monitors are required to review drug accountability and allocation at 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 subjects. The unblinded monitors will also be able to review 
the treatment allocation cards/randomization list provided to the unblinded pharmacist. 
The names of the unblinded monitor(s) are detailed in the monitoring plan.
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.
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Table 6-2
Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
dose escalation
Subjects/Patients
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site 
staff (see text for 
details)
B
UI
UI
UI
Drug Supply and 
Randomization 
Office
UI
UI
UI
UI
Unblinded 
sponsor staff (see 
text for details)
B
UI
UI
UI
Statistician/statisti
cal 
programmer/data 
analysts
UI
UI
UI
UI
All other sponsor 
staff not identified 
above
B
B
UI
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
The study statistician will be able to access the full randomization list from the start of the study 
and is allowed to share unblinded information with the rest of the clinical trial team as 
appropriate for internal decision purposes, as outlined in Table 6-2. For example, unblinded 
summaries and unblinded individual data can be shared with the team whenever necessary.
The study statistician is also allowed to share treatment assignments with the investigator during 
dose escalation meetings 
CCI 
when knowledge of the 
treatment assignments could aid decision-making.
Study programmers and other personnel involved in study data analysis 
CCI 
are allowed to access treatment assignment information from the start of the study for the 
purpose of data analysis.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project while 
the study is ongoing.
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.
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6.5
Dose escalation and dose modification
For Part A (SAD) and Part B (MAD), safety data reviews will be performed after 
each dose level in order to decide about the progression to the next dose.
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6.5.1.1
Starting dose
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Please see 
Section 4.2 for rational of dose selection and the pharmacy manual for additional details on 
the syringes to be used.
6.5.1.2 
Provisional dose levels
Table 6-3 describes the starting dose and the dose levels that may be evaluated during this trial.
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6.6
Additional treatment guidance
6.6.1
Treatment compliance
In this study subjects will be dosed at the investigator's center by qualified members of the site 
staff. Details of each dose of study drug will be recorded in the CRF.
PK parameters (measures of treatment exposure) will be determined in all subjects treated with 
KAE609, as detailed in the Section 8.5.1.
6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events. Should a subject have an incidental and limited need for a 
medication to be taken within the restricted pre-dose timeframe (e.g., ibuprofen for a headache, 
antibiotic prophylaxis prior to dental surgery, etc.), the sponsor should be advised, as 
administration of any concomitant medication may require the subject to be withdrawn. 
Medication used to treat AEs must be recorded on the Concomitant Medications/Significant
non-drug therapies CRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency breaking of the assigned treatment code must only be undertaken when it is essential 
to treat the subject safely and efficaciously. Most often, study treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study subject who 
presents with an emergency condition. A complete sets of emergency code break cards is 
provided to Novartis - to be distributed to the investigators. All code break cards must be 
retained until the end of the study and returned to Novartis. They must be stored in a secure 
place but be accessible in case of emergency. The investigator will receive a code break card 
for each subject, with the details of study treatment covered by a removable, scratch-off cover. 
In an emergency, the scratch-off cover can be removed to determine the treatment. The scratch-
off covers are not to be removed for any reason other than an emergency. When the investigator 
removes the scratch-off cover he/she must note the date, time, and reason for removing it and 
retain this information with the case report form documentation. The assigned treatment must 
not be recorded on the CRF. The investigator must also immediately inform the Novartis local 
monitor that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the code break cards at any time in case of emergency. The investigator will 
provide:

protocol number

name

subject number
In addition, oral and written information to the subject 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 
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Where possible, subjects should continue with the follow-up visit as per Assessment Schedule 
(Table 8-1 and Table 8-2) after code break.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section (Section 6.1.1).
KAE609 will be administered to the subject at the study center via the following route of 
administration:

iv bolus administration over approximately 2 min (cohorts A1, A2 and B1)

iv infusion over approximately 10 min (cohorts A3, A4, A5 and B2)
Depending on emerging data of this study infusion duration might be adapted (for example 
infusion over 10 min instead of bolus injection).
See the SOM and Pharmacy Manual for further details.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/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 subject source documents.
Novartis will review the investigators/CRO proposed informed consent form to ensure it 
complies with the ICH E6 GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any further changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between 
Investigator's Brochure updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the subject.
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
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A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Refer to the SOM for a complete list of ICFs included in this study.
8
Visit schedule and assessments
Assessment schedule lists all of the assessments and indicates with an “X”, the visits when they 
are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation.
Subjects 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. Subjects 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 EOS visit will be performed. At this EOS visit, the adverse event and concomitant 
medications should be recorded on the CRF.
Specification and timing of each assessment are detailed in the protocol. The methods and 
recording of each assessment may be outlined in the SOM.
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Table 8-1
Assessment Schedule, Part A - SAD
Epoch
Screening
Treatment Period
Post-Treatment Follow-Up
Post Study
Visit Name Screening Baseline
Treatment
Follow-up
EOS
Safety 
Contact
Days
-29 to -2
-1
1
2
3
4
6
8
30
Time (post-
dose)
-
-
-1h1
0h
2min2
10min
30min
1h
3h
4h
6h
12h
24h
48h 72h 120h
-
-
Informed 
consent
X
Inclusion / 
Exclusion 
criteria
S
S
Demography
X
Medical 
history/current 
medical 
conditions
X
Physical 
examination
S
S
S
S
Pregnancy test3
X
X
X
Body height
X
Body weight
X
X
X
Body 
temperature
X
X
X
CCI
CCI
CCI
CCI
CCI
CCI
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Epoch
Screening
Treatment Period
Post-Treatment Follow-Up
Post Study
Visit Name Screening Baseline
Treatment
Follow-up
EOS
Safety 
Contact
Days
-29 to -2
-1
1
2
3
4
6
8
30
Time (post-
dose)
-
-
-1h1
0h
2min2
10min
30min
1h
3h
4h
6h
12h
24h
48h 72h 120h
-
-
12 lead Holter 
continuous 
ECG8
X
ECG evaluation4
X
X
X
X
X
X
X
X
X
X
X
Blood Pressure 
and Pulse Rate
X
X
X
X
X
X
X
X
X
X
Drug 
administration 
record7
X
Injection/infusion 
site observation
X
X 
X 
Blood chemistry
X
X
X
X
X
Hematology
X
X
X
X
X
Urinalysis
X
X
X
X
PK blood 
collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inpatient
X
Concomitant 
medications
X10
Adverse 
events/serious 
adverse events
X10
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Epoch
Screening
Treatment Period
Post-Treatment Follow-Up
Post Study
Visit Name Screening Baseline
Treatment
Follow-up
EOS
Safety 
Contact
Days
-29 to -2
-1
1
2
3
4
6
8
30
Time (post-
dose)
-
-
-1h1
0h
2min2
10min
30min
1h
3h
4h
6h
12h
24h
48h 72h 120h
-
-
Study 
completion 
information
X
Safety Follow up 
Call
S
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Pre-dose
2 Only collected/done in cohorts with bolus injection. 
3 Serum pregnancy test at screening and EOS visit. Urine pregnancy test at baseline. FSH testing at screening.
4 12 lead ECG. Triplicate measurements are required at Screening, Baseline and EOS and single ECG measurements at other timepoints.
10AEs and concomitant medications will be captured in the eCRF through post study safety-follow up call
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Table 8-2
Assessment Schedule, Part B - MAD
Epoch
Screening
Treatment Period
Post-Treatment 
Follow-Up
Post 
Study
Visit Name Screeni
ng
Baselin
e
Treatment
Follow-up
EO
S
Safety 
Contact
Days -29 to -2
-1
1
2
3
4
5
6
7
8
10
12
35
Time (post-
dose)
-
-
-
1h1
0
h
2min
2
10mi
n
30mi
n
1
h
3
h
6
h
12
h
0h
1
0h
1
0h
1
-
1
h
0h
1
2min
2
10mi
n
30mi
n
1
h
3
h
6
h
12
h
24h 48h 72
h
120
h
-
-
Informed 
consent
X
Inclusion / 
Exclusion 
criteria
S
S
Demography
X
Medical 
history/current 
medical 
conditions
X
S
Physical 
examination
S
S
S
S
S
S
Pregnancy 
test3
X
X
X
Body height
X
Body weight
X
X
X
CCI              CCI
CCI 
        CCI
CCI
CCI


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Epoch
Screening
Treatment Period
Post-Treatment 
Follow-Up
Post 
Study
Visit Name Screeni
ng
Baselin
e
Treatment
Follow-up
EO
S
Safety 
Contact
Days -29 to -2
-1
1
2
3
4
5
6
7
8
10
12
35
Time (post-
dose)
-
-
-
1h1
0
h
2min
2
10mi
n
30mi
n
1
h
3
h
6
h
12
h
0h
1
0h
1
0h
1
-
1
h
0h
1
2min
2
10mi
n
30mi
n
1
h
3
h
6
h
12
h
24h 48h 72
h
120
h
-
-
Body 
temperature
X
X
X
X
X
X
12 lead Holter 
continuous 
ECG8
X
X
ECG 
evaluation4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood 
Pressure and 
Pulse Rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug 
administration 
record7
X
X
X
X
X
Injection/infusi
on site 
observation
X
X
X
X
Blood 
chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
PK blood 
collection
X
X5
X5
X
X
X
X
X
X
X
X
X
X5
X5
X
X
X
X
X
X
X
X
X
X
CCI


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Epoch
Screening
Treatment Period
Post-Treatment 
Follow-Up
Post 
Study
Visit Name Screeni
ng
Baselin
e
Treatment
Follow-up
EO
S
Safety 
Contact
Days -29 to -2
-1
1
2
3
4
5
6
7
8
10
12
35
Time (post-
dose)
-
-
-
1h1
0
h
2min
2
10mi
n
30mi
n
1
h
3
h
6
h
12
h
0h
1
0h
1
0h
1
-
1
h
0h
1
2min
2
10mi
n
30mi
n
1
h
3
h
6
h
12
h
24h 48h 72
h
120
h
-
-
X
X
Inpatient
X 
Concomitant 
medications
X9
Adverse 
events/serious 
adverse 
events
X9
Study 
completion 
information
X
Safety Follow 
up Call
S
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X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Pre-dose
2 Only collected/done in cohorts with bolus injection. 
3 Serum pregnancy test at screening and EOS visit. Urine pregnancy test at baseline. FSH testing at screening.
4 12 lead ECG. Triplicate measurements are required at Screening, Baseline, day 3, day 4 and EOS and single ECG measurements at other timepoints.
9 AEs and concomitant medications will be captured in the eCRF through post study safety-follow up call
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8.1
Screening
It is permissible to re-screen a subject once if s/he fails the initial screening or was not 
randomized in the required timeframe. Subjects need to re-consented for re-screening and a new 
subject number must be assigned.
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 at screening and 
once at randomization. If the repeat value remains outside of the specified ranges, the subject 
must be excluded from the study.
8.1.1
Eligibility screening
Results of below screening measurements will be available as source data at the study site and 
will not be recorded within the eCRF.
8.1.2
Information to be collected on screening failures
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the SOM.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. 
Subject demographics include date (if permitted) or year of birth, sex, race and predominant 
ethnicity (if permitted). Relevant medical history/current medical conditions data will also be 
collected until signature of informed consent. Where possible, the diagnoses 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 Section 6.2.1 for further details on what 
information must be recorded on the appropriate page of the eCRF.
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8.3
Efficacy
Efficacy / Pharmacodynamics are not measured in this study.
8.3.1
Appropriateness of efficacy assessments
Efficacy / Pharmacodynamics are not measured in this study.
8.4
Safety/Tolerability
Safety assessments are specified in the Assessment Schedule (Table 8-1 and Table 8-2) which 
details when each assessment is to be performed.
For details on AE collection and reporting, refer to Section 10.1.
Table 8-3
Assessments and Specifications
Assessment
Specification
Physical examination
A complete physical examination at screening 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.
At other visits, a shorter physical exam may be performed to include the 
examination of general appearance.
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 included in the 
Medical History part of the CRF. Significant findings made after signing 
informed consent which meet the definition of an Adverse Event must 
be recorded on the Adverse Event section of the CRF.
Injection/infusion site 
observation
Injection/infusion site must be examined before and after drug 
administration for any changes in appearance or pain.
Local tolerability at the injection/infusion site will be assessed by the 
investigator prior and immediately after each infusion on day 1 (Part A 
and B) and 5 (Part B only).
The following parameters will be evaluated by scoring (none, mild, 
moderate or severe) in each subject:
• Pain
• Itching
• Erythema
• Swelling
• Inflammation
• Phlebitis
• Ulceration
• Necrosis
Infusion reactions also need to be captured as AE according to CTCAE 
criteria.


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Assessment
Specification
Blood pressure and pulse 
rate
Systolic and diastolic blood pressure will be measured after the subject 
has been supine for five minutes, using an automated validated device 
with an appropriately sized cuff. In case the cuff sizes available are not 
large enough for the patient's arm circumference, a sphygmomanometer 
with an appropriately sized cuff may be used.
Body temperature
Oral body temperature will be recorded in °C.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg)
in indoor clothing, but without shoes) will be measured.
8.4.1
Laboratory evaluations
A local laboratory will be used for analysis of all specimens collected.
All abnormal lab results must be evaluated for criteria defining the inclusion/exclusion criteria, 
an adverse event and reported as such if the criteria are met. For those lab adverse events, 
repeated evaluations are mandatory until normalization of the result(s) or until the result is no 
longer considered to be clinically significant.
Table 8-4
Laboratory Assessments
Test Category
Test Name
Hematology
Chemistry
Sodium, potassium, creatinine, BUN or urea, uric acid, chloride, 
albumin, calcium, magnesium, alkaline phosphatase, total bilirubin 
(direct and indirect), bicarbonate/HCO3, LDH, GGT, AST, ALT, 
amylase, lipase, CK, glucose, total cholesterol, triglycerides, total 
protein, C-reactive protein (CRP). Globulin and albumin/globulin ratio 
Urinalysis
Dipstick measurements for bilirubin, blood, glucose, ketones, 
leukocytes, nitrite, pH, protein, specific gravity, urobilinogen. If dipstick 
measurement results are positive (abnormal), results will be captured 
in the CRF. Microscopy must be assessed following an abnormal 
dipstick test with results captured in the CRF.
Pregnancy / FSH Test
Serum / Urine pregnancy test and FSH levels (see Section 8.4.4)
8.4.2
Electrocardiogram (ECG) 
For Part A, triplicate ECGs will be collected at screening, baseline, and at Day 8 (EOS). At other 
times, single ECGs will be collected at all times when PK samples are collected (ECG is not 
needed at 2 min). 
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell 
(WBC) count with differentials and platelet count. Coagulation testing 
including prothrombin time (PT) (also reported as INR), activated 
partial thromboplastin time (aPTT) and fibrinogen 
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For Part B, triplicate ECGs will be collected at screening, baseline, Days 3, 4, and Day 12 (EOS). 
At other times, single ECGs will be collected at all times when PK samples are collected (ECG 
is not needed at 2 min). 
All ECGs will be measured after a 10 min rest in the supine position. The following parameters 
will be reported : PR interval, QRS duration, heart rate, RR interval, QT interval, QTcF.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF and QTcB may be calculated at the site. Unless auto-calculated by the 
ECG machine, the investigator must calculate QTcF at the Screening and/or Baseline visit(s) 
(as applicable) to assess eligibility and continuation in the study.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate.
8.4.3
Holter ECG Monitoring
25-hour Holter monitoring will be conducted on specified days to collect ECG data for QTcF
assessment. These data will not immediately be visible to the site investigator and staff.
The Holter recordings will be transmitted to the selected ECG core laboratory for analysis. ECG
extractions for QTcF analysis will be taken at the same nominal timepoints as the PK draws.
All ECGs will be measured after a 10 min rest in the supine position prior to the PK draws.
In Part A, continuous 12 lead ECG Holter monitoring will be performed for 25 hours on Day 1 
from 1 hour pre-dose through 24 hours post-dose. 
In Part B, continuous 12 lead ECG Holter monitoring will be performed for 24 hours on Days 1 
and 5 from 1 hour pre-dose through 24 hours post-dose.
Full details of all procedures relating to the ECG collection are contained in the SOM and/or 
Holter monitoring manual.
8.4.4
Pregnancy and assessments of fertility
All women will have pregnancy testing. Additional pregnancy testing might be performed if 
requested by local requirements.
At screening and at the end of the study, serum pregnancy test should be performed, while 
during the study duration urinary pregnancy tests are sufficient. In case the pregnancy urine test 
is positive, the result needs to be confirmed with serum test.
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, FSH testing is required of any female 
subject regardless of reported reproductive/menopausal status at screening/baseline.


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8.4.5
Appropriateness of safety measurements
The safety assessments selected are standard for this subject population.
8.5
Additional assessments
Additional assessments are specified below with the Assessment Schedule (Table 8-1 and
Table 8-2) detailing when each assessment is to be performed.
The methods for each assessment and data recording details are specified in the SOM.
8.5.1
Pharmacokinetics
PK samples will be collected at the visits defined in the Assessment Schedule (Table 8-1 and 
Table 8-2). Follow instructions outlined in the SOM regarding sample collection, numbering, 
processing, and shipment. See the potential use of residual samples for more information.
PK samples will be obtained from all subjects, but only samples from KAE609 treated subjects 
will be analyzed.
For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol.
The following PK parameters will be determined using the actual recorded sampling times and 
non-compartmental method(s) with Phoenix WinNonlin (Version 8 or higher): For SAD: C(0), 
Cmax, Tmax, AUC0-24h, AUClast, AUCinf, T1/2, Vss and CL and for MAD: Cmax, Tmax, 
AUC0-24h, Ctrough, AUCtau etc. as applicable from the plasma concentration-time data.
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the terminal 
plasma elimination phase for the determination of T1/2 will include at least 3 data points after 
Cmax. If the adjusted R2 value of the regression analysis of the terminal phase will be less than 
0.75, no values will be reported for T1/2, AUCinf, Vss and CL.
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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment
Section 6.2.2

Any situation in which study participation might result in a safety risk to the subject

Following emergency unblinding

Any laboratory abnormalities (e.g., LFT increase) that in the judgment of the investigator,
taking into consideration the subject's overall status, prevent the subject from continuing
receiving the study medication

If a liver or renal event occurs, follow guidelines outlined in Section 16.1 (Appendix 1)
and Section 16.2 (Appendix 2) regarding discontinuation of study treatment.

Deviation from the planned dose regimen for the study drug
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects 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 withdrawal of informed consent Section 9.1.2). In case only study treatment 
is discontinued, where possible, they should return for the follow-up visits as per 
Assessment Schedule. Subjects who prematurely discontinue the study (treatment and visits) 
for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the EOS visit will be performed.
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 subject/pre-designated contact as specified in the
lost to follow-up section. This contact should preferably be done according to the study visit
schedule.
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If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular
telephone contact with the subject, or with a person pre-designated by the subject. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
9.1.1.1
Replacement policy
If a subject is considered as non-evaluable for a dose escalation decision, enrollment of a new 
subject to the current cohort will be considered if there is less than the required number of 
evaluable subjects. Enrollment of new subjects may be considered until at least the minimum 
number (6 for SAD and 7 for MAD) or at most the maximum number (for SAD 8 and MAD 9) 
of evaluable subjects is achieved within the cohort.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
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 subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation (EOS visit) at the time of the subject's study withdrawal should be made as detailed 
in the Assessment schedule (Table 8-1 and Table 8-2).
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.


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9.1.3
Lost to follow-up
For subjects 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 subject, e.g. dates of telephone 
calls, registered letters, etc. A subject 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
Cohort stopping rules and dose escalation decision points:
Dose escalation, as well as continued dosing within any given cohort, will be paused and may 
be stopped based on full review of all available clinical safety data and discussion with the 
Investigator if any of the following occur:

Any treatment-emergent SAEs, except those that are clearly and incontrovertibly due to
extraneous causes

Two or more subjects in the same cohort experience a similar AE which was assessed as
CTCAE grade 3 or greater 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

Two or more subjects experience Grade 2 or higher hypersensitivity reactions

Two or more subjects experience Grade 3 or higher injection site reactions.

Two or more subjects with QTcF greater than 500 msec and/or an increase greater than
60 msec, expected to be related to the study treatment
The severity of adverse events will be graded by the study site investigator (or sub-investigator) 
based on CTCAE and captured in the CRF (see Section 10.1). This information will be used to 
quantify events that may lead to subject’s discontinuation or stopping dose escalation.
Drug administration of subsequent cohorts will only be triggered if an adequate safety and 
tolerability profile has been confirmed from the preceding cohort.
Safety reviews will be conducted jointly between medically qualified representatives of the 
Sponsor and Investigator and a joint decision will be made. If a dose level is identified to be 
intolerable, the preceding dose level will be defined as the maximum tolerated dose.
Overall study stopping rules:
Enrollment in the study will be placed on hold and dosing held if any of the rules for a cohort 
or dose escalation are met as above.
The study may resume following the safety review, if the investigator and Sponsor agree it is 
safe to proceed.


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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 subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and
efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible for EOS visit 
as per Assessment Schedule and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator or sponsor 
depending on local regulation will be responsible for informing IRBs/IECs of the early 
termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their EOS  visit , and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by 
the Investigator, or in the event of an early study termination decision, the date of that decision.
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
All randomized and/or treated subjects should have a safety follow-up call conducted 30 days 
after last administration of study treatment. The information collected is kept as source 
documentation. All SAEs reported during this time period must be reported as described in 
Section 10.1.3 and SOM. Documentation of attempts to contact the subject should be recorded 
in the source documentation.
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 subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.


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The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The Common Toxicity Criteria (CTC) AE grade (version 5 or higher)

Adverse events will be assessed and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE)

If CTCAE grading does not exist for an adverse event, use 1=mild; 2=moderate, 3=severe; 
and 4=life threatening. CTCAE grade 5 (death) is not used, but is collected in other CRFs 
(e.g., End of Study Visit, Death/Survival).
2. its relationship to the study treatment
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

No treatment given

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome 
a. not recovered/not resolved;
b. recovered/resolved;
c. recovering/resolving,
d. recovered/resolved with sequelae;
e. fatal; 
f.
or unknown.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
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Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure.
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
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in healthy 
subjects.
Follow the instructions found in the SOM for data capture methodology regarding AE collection 
for subjects that fail screening.
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 conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

elective or pre-planned treatment for a pre-existing condition and has not worsened
since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may
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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 subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment  must be reported to Novartis/ safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
SAEs occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis.
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 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.


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10.1.4
Pregnancy reporting
Only women of non child bearing potential are eligible for this study and no pregnancy in 
women is expected.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
The newborn will be followed up for a minimum of 1 year after delivery.
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, subject 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 collected in 
the dose administration record 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 Dose 
Administration 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, 
respective sections above.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
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The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion
of the standard base liver CRF pages
Please refer to Table 16-1 in Appendix 1 for complete definitions of liver laboratory triggers 
and liver events.
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 16-2. Repeat liver chemistry tests (ALT, AST, TBL, 
PT/INR, ALP and G-GT) to confirm elevation.

These liver chemistry repeats will be performed using the local laboratory. Repeated
laboratory test results must be reported as appropriate.

If the initial elevation is confirmed, close observation of the subject will be initiated,
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Discontinuation of study treatment
section), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

These investigations can include based on investigator’s discretion: serology tests,
imaging and pathology assessments, hepatologist’s consultancy; obtaining more
detailed history of symptoms and prior or concurrent diseases, history of concomitant
drug use, exclusion of underlying liver disease
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
Refer to the SOM for additional details.
10.2.2
Renal safety monitoring
Every renal laboratory trigger or renal event as defined in Table 16-3 (in Appendix 2) should 
be followed up by the investigator or designated personnel at the trial site as summarized in 
Section 16.2 (in Appendix 2).
Refer to the SOM for additional details.
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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 (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
eSource is a data collection system allowing electronic capture of source data and study data, 
as required per protocol. eSource is intended to be used for this study. If it is not possible to use 
eSource for source data capture due to exceptional circumstances, data capture and data 
management will revert to paper and other electronic methods as appropriate.
This study will incorporate electronic technology (eSource DDE) to capture source documents 
and source data electronically, consistent with final (CDER 2013) FDA guidance regarding 
electronic source and regulations related to the maintenance of adequate subject case histories 
(21 CFR 312.62 [b]). All electronic source documentation and data collected in this study will 
“meet the same fundamental elements of data quality (e.g. attributable, legible, 
contemporaneous, original, and accurate) that are expected of paper records” into a system that 
is fully validated and conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the system(s) until they have been appropriately trained.
Study sites using eSource DDE will be supplied with a tablet PC to directly record subject data 
and clinical observations on electronic forms with a similar look, feel, and behavior to paper 
forms. The system will permit the collection of both structured and unstructured information 
including ad-hoc comments, drawings, and relevant clinical notes the investigative site deems 
important. Information to be originally captured and reviewed electronically shall include 
details of the subject visit and the protocol required assessments performed as a part of these 
visits, medical history, and concomitant medications.
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Certain data may be captured via other source documentation (such as safety laboratory data 
report, imaging) and then transcribed, uploaded or transferred into the eSource DDE system. 
This, and any additional data treated in this manner, will be source data verified by the study 
field monitor per the monitoring plan and the location of source data (i.e. source, paper or a 
local electronic system) will be documented prior to study start. The eSource system has the 
ability to illustrate when a document has been entered from another source. When using an 
electronic source record as the original point of data capture, there is no additional data entry 
step for the site for data collected directly into the application. Rather, the electronic source 
record directly populates the study database.
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis.
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely.
The investigator must certify that the data entered into eSource are complete and accurate. 
After database lock, the investigator will receive copies of the subject 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 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused supplies to 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.


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11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eSource or eCRFs) with the investigators and their staff. During the study, Novartis employs 
several methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of subject 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/delegated CRO/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 subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
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 CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
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12
Data analysis and statistical methods
The analysis will be conducted on all subject data at the time the trial ends, under the direction 
of Novartis personnel in compliance with internal documents and standards.
12.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment received, where 
treatment received is defined as the randomized/assigned treatment if the patient took at least 
one dose of that treatment or the first treatment received if the randomized/assigned treatment 
was never received.
The safety analysis set includes all subjects who received at least one dose of any study 
treatment.
The PK analysis set will include all subjects with at least one valid (i.e. not flagged for 
exclusion) KAE609 concentration data, who received study drug and had no protocol deviations 
with relevant impact on the interpretability of the PK data.
Within a study part, all placebo subjects from all cohorts will be pooled.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data will be listed by part, treatment group and subject. 
Summary statistics will be provided by part and 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 listed by part, 
treatment group and subject.
12.3
Treatments
The safety set will be used for the analyses below.
Data for study treatment administration, concomitant medications and significant non-drug 
therapies prior to and after the start of the study treatment will be listed by part, treatment group 
and subject.
12.4
Analysis of the primary endpoint(s)
The primary aim of the study is to determine the safety and tolerability of KAE609 after single 
and multiple iv doses in healthy subjects. All safety analyses will be performed on the safety 
analysis set.
12.4.1
Definition of primary endpoint(s)
The primary endpoints are safety and tolerability assessments including adverse events, vital 
signs, ECG findings (including QTcF), safety laboratory assessments including chemistry, 
hematology, and urinalysis results assessed at baseline up to Day 8 in Part A and up to Day 12 
in Part B (EOS).


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12.4.2
Statistical model, hypothesis, and method of analysis
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. Graphical representations of the safety data may be produced.
Adverse events
All information obtained on adverse events will be displayed by part, treatment group and 
subject. The number and percent of patients with adverse events will be tabulated by system 
organ class and preferred term with a breakdown by treatment group. A subject with multiple 
adverse events within a system organ class is only counted once towards the total of the system 
organ class. Separate tables and listings will present adverse event severity (CTCAE grade) and 
relationship to study treatment.
The number (and percent) of subjects with adverse events of infusion site reaction may be 
summarized by treatment group.
Vital signs
If normal ranges are available, vital signs abnormalities (and relevant orthostatic changes) will 
be flagged and will be listed by part, subject and visit/time. Summary statistics may be provided 
by part, treatment group and visit/time.
ECG evaluations
Abnormal ECG data will be flagged and will be listed by part, treatment group, subject and 
visit/time. Summary statistics may be provided by part, treatment group and visit/time.
Holter ECG data analysis
The relationship between change from baseline in time-matched QTcF and KAE609 plasma 
concentration will be explored using linear mixed effects modeling. Other ECG parameters (QT, 
QTcB, HR, PR interval and QRS) will be summarized. Data from the SAD and MAD parts of 
the study will be pooled for this assessment. The change from baseline in QTcF will be the 
dependent variable in the model, KAE609 plasma concentration will be a covariate, and time a 
categorical variable. A random intercept for each subject will be specified. Placebo subjects 
will be included in the analysis with a plasma concentration of 0. The placebo-corrected change 
from baseline in QTcF and the two-sided 90% confidence interval will be extracted from the 
model at the geometric mean maximum plasma concentration for each treatment.
A plot of raw QTcF  change vs KAE609 plasma concentration will be presented together with 
the estimated slope and 90% Confidence Interval (CI) from the statistical model.


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The analysis results for categorical outliers and T-wave morphology will be summarized in 
frequency tables with counts and percentages for both number of subjects and number of 
timepoints. For categorical outliers, the number of subjects (%) and timepoints will be 
determined by treatment group for the following:

increase in QTcF from baseline of > 30 msec and > 60 msec

absolute QTcF values > 500 msec

PR change from baseline > 25% increase resulting in PR > 220 msec

QRS change from baseline > 25% increase resulting in QRS > 120 msec

heart rate change from baseline > 25% decrease resulting in heart rate < 50 beats per
minute

heart rate change from baseline > 25% increase resulting in a heart rate > 100 beats per
minute
For T-wave morphology, the analysis will be focused on the treatment emergent changes.
Clinical laboratory evaluations
If normal ranges are available, laboratory data abnormalities will be flagged and will be listed 
by part, treatment group, subject and visit/time. Summary statistics may be provided by part, 
treatment group and visit/time.
Individual profile plots of laboratory data (e.g. sodium, potassium, calcium, AST and ALT) will 
be provided. Graphical summary of these laboratory parameters will also be provided by part 
and treatment group.
12.4.3
Handling of missing values/censoring/discontinuations
No imputation of missing data will be considered for safety and tolerability analysis.
12.4.4
Sensitivity and Supportive analyses
Not applicable.
12.5
Analysis of secondary endpoints
The secondary objective is to evaluate the pharmacokinetics of single and multiple ascending 
iv doses of KAE609 in healthy subjects.
12.5.1
Pharmacokinetics
For each part, KAE609 plasma concentration data will be listed by subject, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/
sampling time point, Commercially Confidential Information
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Commercially Confidential Information


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PK parameters will be listed by subject. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum. An exception to this is Tmax where median, minimum and maximum will be 
presented.
PK concentration data from this study may be used for population PK modeling. If performed, 
the results will be reported separately.
Table 12-1
Non-compartmental pharmacokinetic parameters 
AUC0-t
The AUC from time zero to time t (e.g. 24h) (mass x time x volume-1)
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (lz) of a semi 
logarithmic concentration-time curve (time). Use qualifier for other half-lives
CL
The total body clearance of drug from the plasma (volume x time-1)
Vss
The apparent volume of distribution at steady state from an intravenously 
administered dose (volume)
12.6
Analysis of exploratory endpoints
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12.7
Interim analyses
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
In Part A, 8 subjects will be enrolled into each dose level cohort. Six of the subjects in each 
cohort will receive KAE609 and 2 subjects will receive placebo. In Part B, 9 subjects will be 
enrolled in each dose level cohort with 6 subjects receiving KAE609 and 3 subjects receiving 
placebo.
With 6 subjects receiving KAE609 in each iv cohort in Part A and Part B, it is highly probable 
that adverse events will be observed if the underlying adverse event rate is medium to high. 
For instance, if the underlying adverse event rate is 1 in every 5 subjects then there is a 74% 
chance that this adverse event will be detected in at least 1 subject on active treatment. 
Conversely, adverse events with low event rates are unlikely to be detected in this part of the 
study. For instance, if the underlying adverse event rate is 1 in every 100 subjects then the 
probability of observing this adverse event in at least 1 subject on active treatment is only 6%.
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Table 12-2
Probability of observing events given a range of underlying event 
rates in Part A and Part B
Underlying event rate
Probability of 
observing no subjects* 
with adverse event
Probability of 
observing at least 1 
subject* with adverse 
event
Probability of 
observing at least 2 
subjects* with adverse 
event
1 in 100
94%
6%
< 1%
1 in 20
74%
26%
3%
1 in 10
53%
47%
11%
1 in 5
26%
74%
34%
1 in 2
2%
98%
89%
* Out of 6 subjects on active treatment
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 informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. 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
This study only involves healthy subjects and as such Novartis will register the protocol as 
required to databases specified by local regulations (e.g. EudraCT during CTA filing for studies 
in EU/EEA). After study completion (defined as last patient last EOS visit) and finalization of 
the study report, results of this trial may be submitted for publication (e.g. peer-reviewed 
journal) or registered to databases where required by local regulations.
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 site initiation 
visit.


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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
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 subjects 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 subject 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 subject 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.
CDER (2013) US Department of Health and Human Services, Food and Drug Administration, 
Guidance for Industry: Electronic Source Data in Clinical Investigations. Rockville, MD.
White NJ (2017) Malaria parasite clearance. Malar. J. 16(1) p. 88.
White NJ, Pukrittayakamee S, Phyo AP, et al (2014) Spiroindolone KAE609 for falciparum 
and vivax malaria. N. Engl. J. Med. p. 403-10.
World Health Organization (2011). Global plan for artemisinin resistance containment. 
Geneva: 2011.
World Health Organization (2015). World Malaria Report 2014. Geneva: 2015.


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16
Appendices
16.1
Appendix 1: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST ≤ 5 x ULN
· 1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone 
pathology)

TBL > 2 × ULN (in the absence of known Gilbert 
syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST > 3 × 
ULN and TBL > 2 × ULN [mainly conjugated fraction] 
without notable increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, or 
rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study 
treatment immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)


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Protocol No. CKAE609X2111
Criteria
Actions required
Follow-up monitoring
> 3 × ULN and INR > 1.5

Discontinue the study 
treatment immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 
hours

If elevation persists, 
continue follow-up 
monitoring

If elevation persists for 
more than 2 weeks, 
discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied by 
symptomsb

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
> 2 × ULN (in the absence of 
known bone pathology)

Repeat LFT within 48 
hours

If elevation persists, 
establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence of 
known Gilbert syndrome)

Repeat LFT within 48 
hours

If elevation persists, 
discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)


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Criteria
Actions required
Follow-up monitoring
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice

Discontinue the study 
treatment immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.


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Protocol No. CKAE609X2111
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase 25 – 49% compared 
to baseline
Confirm 25% increase after 24-48h
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase ³ 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption
Consider patient hospitalization /specialized 
treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-
fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or ≥3 
mg/mmol;
Protein-creatinine ratio (PCR )≥150 mg/g or >15 
mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or 
discontinuation
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed
Monitor patient regularly (frequency at investigator’s discretion) until either:
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, 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.

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Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
KAE609
CKAE609X2111 / NCT04321252
A randomized, subject and investigator-blinded, placebo 
controlled, single and multiple ascending dose study to 
assess the safety, tolerability, and pharmacokinetics of 
KAE609 administered intravenously in healthy subjects
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR
Document status:
Final
Release date:
29-Apr-2021
Number of pages:
12
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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................3
1
Introduction .........................................................................................................................4
1.1
Scope of document ..................................................................................................4
1.2
Study reference documentation ...............................................................................4
1.3
Study objectives.......................................................................................................4
1.4
Study design and treatment......................................................................................5
2
First interpretable results (FIR) ...........................................................................................7
3
Interim analyses...................................................................................................................7
4
Statistical methods: Analysis sets........................................................................................7
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................8
5.1
Variables..................................................................................................................8
5.2
Descriptive analyses ................................................................................................8
5.3
Statistical model, assumptions and hypotheses .......................................................9
5.3.1
Model checking procedures ....................................................................9
5.3.2
Graphical presentation of results.............................................................9
6
Statistical methods for Pharmacodynamic (PD) parameters...............................................9
7
Statistical methods for safety and tolerability data..............................................................9
7.1
Variables..................................................................................................................9
7.2
Descriptive analyses ..............................................................................................10
7.3
Graphical presentation...........................................................................................12
8
Statistical methods for biomarker data..............................................................................12
9
Exploratory objectives.......................................................................................................12
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................8
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1
Introduction
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CKAE609X2111”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Final study protocol (v02) and site operation manual (SOM v01) are available at the time of 
finalization of the original Statistical Analysis Plan.
1.3
Study objectives
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the safety and tolerability of single
and multiple iv doses of KAE609 in healthy
subjects

Adverse events, physical examination
findings, vital signs, ECG
findings (including QTcF), safety
laboratory assessments including
chemistry, hematology, and urinalysis
results
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the pharmacokinetics (PK) of single
and multiple iv doses of KAE609 in healthy
subjects

AUC, Tmax, Cmax, CL, Vz, and T1/2

To assess local tolerance at infusion site of
KAE609 iv administration

Findings of physical examination of
infusion site
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1.4
Study design and treatment
This is a randomized, subject and investigator-blinded, placebo-controlled, single and multiple 
ascending iv dose study in healthy subjects. The study consists of two parts and the study 
scheme is shown in Figure 1-1:

Part A is a single ascending dose (SAD) study with 5 cohorts of 8 subjects each

Part B is a multiple ascending dose (MAD) study with 2 cohorts of 9 subjects each
For both parts of the study, each subject will participate in an up to 28- day screening period 
during which a full physical examination, medical history, drug screening, vital signs, ECG 
evaluation and safety laboratory tests evaluation will be performed.
A review of safety and PK data will be conducted at the completion of each cohort prior to 
dosing of the next subsequent cohort.  Safety assessments will include physical examinations, 
ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, 
urinalysis) adverse event and serious adverse event monitoring.
Part A: Single-ascending dose study
In Part A sequential cohorts of 8 healthy subjects per cohort will be randomized to receive 
successively higher single iv doses of KAE609 or matching placebo. In each cohort, subjects 
will be randomized in a 3:1 ratio to KAE609 (6 subjects/cohort) or matching placebo (2 
subjects/cohort). Four planned dose cohorts will be included in Part A (A1, A2, A3 and A4).
 
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Figure 1-2
Study design - SAD
Part B: Multiple-ascending dose study
In Part B sequential cohorts of 9 healthy subjects per cohort will be randomized to receive 
successively higher iv doses of KAE609 or matching placebo. Two planned dose cohorts will 
be included in Part B (B1 and B2). For Cohort B1, healthy subjects will receive a 60 mg dose 
of KAE609 or matching placebo iv q24h for 5 days. . For Cohort B2, healthy subjects will 
receive a 120 mg dose of KAE609 or matching placebo iv q24h for 5 days. In each cohort, 
subjects will be randomized in a 2:1 ratio to KAE609 (6 subjects/cohort) or matching placebo 
(3 subjects/cohort).
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Figure 1-3
Study design - MAD
2
First interpretable results (FIR)
3
Interim analyses
4
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment,
the treatment actually received will be used for the analysis.
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The safety analysis set will include all subjects who received at least one dose of any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
TRT01
Incorrect dose administered
Exclude subject from PK 
analysis set at 
pharmacokineticist 
discretion
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
The secondary objective is to evaluate the pharmacokinetics of single and multiple ascending 
iv doses of KAE609 in healthy subjects.
5.1
Variables
The pharmacokinetic parameters are described as follows and will be calculated separately from 
the KAE609 concentration data:

Part A (SAD): Cmax, Tmax, AUClast, AUCinf, AUC0-t (AUC0-24), T1/2, Vss and CL

Part B (MAD): Cmax, Tmax, AUC0-24h, T1/2 Day 1 and Cmax, Tmax, AUCtau
(AUC0-24), AUClast, , T1/2, Vss and CL
5.2
Descriptive analyses
For each part, KAE609 plasma concentration data will be listed by subject, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point, 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. 
PK parameters will be listed by subject. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
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maximum. An exception to this is Tmax where median, minimum and maximum will be 
presented.
5.3
Statistical model, assumptions and hypotheses
5.3.1
Model checking procedures
Graphical check will be performed.
5.3.2
Graphical presentation of results
Arithmetic mean (SD) plasma concentration data will be plotted across time, with separate line
types for each treatment.
Overlaying individual plasma concentration-time profiles will be generated.
Scatterplots of Cmax and AUC parameters versus dose will be created with the estimated power 
model curve overlaid.
6
Statistical methods for Pharmacodynamic (PD) parameters
Not applicable.
7
Statistical methods for safety and tolerability data
The primary objective of this study is to assess the safety and tolerability of single and multiple 
ascending iv doses of KAE609 in healthy subjects.
7.1
Variables
The primary safety and tolerability variables are adverse events, vital signs (blood pressure, 
pulse rate, body temperature), ECG intervals, laboratory measurements, as well as subject 
demographics, baseline characteristics, and treatment information.
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7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by part, treatment group and 
subject. Summary statistics will be provided by part and treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by part, treatment group and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by part, treatment group and subject.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by part, treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by part, treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. Summary statistics will be provided by part, treatment 
and visit/time.
Local tolerance at infusion site
Local tolerance at infusion site will be summarized by part and treatment group. 
Adverse events
All information obtained on adverse events will be displayed by part, treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by system organ 
class and preferred term with a breakdown by treatment, and separately by preferred term and 
treatment. A subject with multiple adverse events within a system organ class is only counted 
once towards the total of this system organ class and treatment.
The number and percentage of subjects with adverse events by maximum severity of adverse 
events will be tabulated by system organ class and preferred term with a breakdown by 
treatment.
The number and percentage of subjects with adverse events classified as related to study drug 
will be tabulated by system organ class and preferred term with a breakdown by treatment.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on all <on-
treatment/treatment emergent> adverse events which are not serious adverse events and on all 
<on-treatment/treatment emergent> serious adverse events and SAE suspected to be related to 


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study treatment will be provided by system organ class and preferred term on the safety set 
population.
If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Holter ECG data analysis
The relationship between change from baseline in time-matched QTcF and KAE609 plasma 
concentration will be explored using linear mixed effects modeling. Other ECG parameters (QT, 
QTcB, HR, PR interval and QRS) will be summarized. Data from the SAD and MAD parts of 
the study will be pooled for this assessment. The change from baseline in QTcF will be the 
dependent variable in the model, KAE609 plasma concentration will be a covariate, and time a 
categorical variable. A random intercept for each subject will be specified. Placebo subjects 
will be included in the analysis with a plasma concentration of 0. The placebo-corrected change 
from baseline in QTcF and the two-sided 90% confidence interval will be extracted from the 
model at the geometric mean maximum plasma concentration for each treatment.
A plot of raw QTcF  change vs KAE609 plasma concentration will be presented together with 
the estimated slope and 90% Confidence Interval (CI) from the statistical model.
The analysis results for categorical outliers and T-wave morphology will be summarized in 
frequency tables with counts and percentages for both number of subjects and number of 
timepoints. For categorical outliers, the number of subjects (%) and timepoints will be 
determined by treatment group for the following:

increase in QTcF from baseline of > 30 ms and > 60 ms

absolute QTcF values  > 500 ms

PR change from baseline > 25% increase resulting in PR > 220 ms

QRS change from baseline > 25% increase resulting in QRS > 120 ms

heart rate change from baseline > 25% decrease resulting in heart rate < 50 beats per
minute

heart rate change from baseline > 25% increase resulting in a heart rate > 100 beats per
minute
For T-wave morphology, the analysis will be focused on the treatment emergent changes.
A cardiac safety report will be prepared separately.


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7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Statistical methods for biomarker data
Not applicable.
9
Exploratory objectives
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