Conditions: Malaria
Keywords: uncomplicated Plasmodium falciparum Malaria.
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 188
Healthy volunteers: no

Brief summary:
KAE609 will be evaluated primarily for hepatic safety of single and multiple doses in sequential cohorts with increasing doses.This study aims to determine the maximum safe dose of the investigational drug KAE609 in malaria patients.

Detailed description:

Arms:
arm 1: KAE609 10 mg once daily (QD) for 1 day arm 2: KAE609 25 mg once daily (QD) for 1 day arm 3: KAE609 10 mg (QD) for 3 days arm 4: KAE609 50 mg once daily (QD) for 1 day arm 5: KAE609 25 mg once daily (QD) for 3 days arm 6: KAE609 75 mg once daily (QD) for 1 day arm 7: KAE609 50 mg once daily (QD) for 3 days arm 8: KAE609 150 mg once daily (QD) for 1 day arm 9: Coartem® control

Interventions: intervention 1: KAE609 intervention 2: Coartem
Intervention descriptions: intervention 1: Exploration of different doses of KAE609 to establish safety profile. intervention 2: Control Arm

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
KAE609
Clinical Trial Protocol CKAE609A2202 / NCT03334747
A Phase 2, multi-center, randomized, open-label, dose-
escalation study to determine safety of single (QD) and 
multiple (3 QD) doses of KAE609, given to adults with 
uncomplicated Plasmodium falciparum malaria
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
N/A
Version number:
04 (clean)
Clinical trial phase:
Phase IIa
Release date:
27-May-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Amendment 3 ....................................................................................................................10
Amendment 2 ....................................................................................................................11
Amendment 1 ....................................................................................................................11
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................19
2.1
Objectives and related endpoints...........................................................................19
3
Investigational plan ...........................................................................................................20
3.1
Study design...........................................................................................................20
3.2
Rationale for study design .....................................................................................23
3.3
Rationale for dose/regimen, route of administration and duration of treatment....23
3.4
Rationale for choice of comparator .......................................................................24
3.5
Purpose and timing of interim safety review.........................................................24
3.6
Risks and benefits..................................................................................................25
4
Population..........................................................................................................................26
4.1
Inclusion criteria ....................................................................................................26
4.2
Exclusion criteria...................................................................................................27
5
Treatment...........................................................................................................................29
5.1
Study treatment......................................................................................................29
5.1.1
Investigational and control drugs..........................................................29
5.1.2
Additional treatment..............................................................................30
5.2
Treatment arms......................................................................................................30
5.3
Treatment assignment and randomization.............................................................31
5.4
Treatment blinding.................................................................................................31
5.5
Treating the patient................................................................................................32
5.5.1
Patient numbering .................................................................................32
5.5.2
Dispensing the study drug.....................................................................32
5.5.3
Handling of study and additional treatment..........................................32


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5.5.4
Instructions for prescribing and taking study treatment........................33
5.5.5
Permitted dose adjustments and interruptions of study treatment ........34
5.5.6
Rescue medication ................................................................................34
5.5.7
Prior and concomitant medication ........................................................35
5.5.8
Prohibited medication ...........................................................................36
5.5.9
Emergency breaking of assigned treatment code..................................37
5.6
Study completion and discontinuation...................................................................37
5.6.1
Study completion and post-study treatment..........................................37
5.6.2
Discontinuation of study treatment .......................................................37
5.6.3
Premature Study Withdrawal ................................................................38
5.6.4
Withdrawal of informed consent...........................................................39
5.6.5
Loss to follow-up ..................................................................................39
5.6.6
Early study termination by the sponsor.................................................39
6
Visit schedule and assessments .........................................................................................40
6.1
Information to be collected on screening failures..................................................43
6.2
Patient demographics/other baseline characteristics .............................................43
6.3
Treatment exposure and compliance .....................................................................43
6.4
Efficacy..................................................................................................................44
6.4.1
Parasitaemia assessment........................................................................44
6.4.2
Appropriateness of efficacy assessments..............................................45
6.5
Safety.....................................................................................................................45
6.5.1
Physical examination and malaria signs and symptoms .......................45
6.5.2
Vital signs..............................................................................................45
6.5.3
Height and weight .................................................................................45
6.5.4
Laboratory evaluations..........................................................................46
6.5.5
Electrocardiogram (ECG) .....................................................................46
6.5.6
Pregnancy and assessments of fertility .................................................47
6.5.7
Appropriateness of safety measurements..............................................47
6.5.8
Definition of Treatment Failure ............................................................47
49
6.6.1
Pharmacokinetics ..................................................................................49
7
Safety monitoring..............................................................................................................49
7.1
Adverse events.......................................................................................................49
7.2
Serious adverse events...........................................................................................51
7.2.1
Definition of SAE .................................................................................51
7.2.2
SAE reporting........................................................................................52


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7.3
Liver safety monitoring .........................................................................................53
7.4
Renal safety monitoring.........................................................................................54
7.5
Reporting of study treatment errors including misuse/abuse ................................54
7.6
Pregnancy reporting...............................................................................................54
8
Data review and database management.............................................................................55
8.1
Site monitoring ......................................................................................................55
8.2
Data collection.......................................................................................................56
8.3
Database management and quality control............................................................56
8.4
Safety review committee .......................................................................................56
8.5
Adjudication Committee........................................................................................57
9
Data analysis......................................................................................................................57
9.1
Analysis sets ..........................................................................................................57
9.2
Patient demographics and other baseline characteristics.......................................58
9.3
Treatments .............................................................................................................58
9.3.1
Study treatment .....................................................................................58
9.3.2
Prior and concomitant medication ........................................................58
9.4
Analysis of the primary variable(s) .......................................................................59
9.4.1
Primary Variable(s)...............................................................................59
9.4.2
Statistical model, hypothesis, and method of analysis..........................59
9.4.3
Handling of missing values/censoring/discontinuations.......................59
9.4.4
Sensitivity analyses ...............................................................................59
9.5
Analysis of secondary variables ............................................................................59
9.5.1
Efficacy variables..................................................................................59
9.5.2
Safety variables .....................................................................................61
9.5.3
Resource utilization...............................................................................63
9.5.4
Pharmacokinetics ..................................................................................63
63
63
9.7
Interim safety review .............................................................................................64
9.8
Sample size calculation..........................................................................................64
9.8.1
Single arm approach..............................................................................64
9.8.2
Power for comparison of KAE609 with Coartem.................................66
10 Ethical considerations........................................................................................................68
10.1
Regulatory and ethical compliance........................................................................68
10.2
Informed consent procedures.................................................................................68
10.3
Responsibilities of the investigator and IRB/IEC..................................................69


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10.4
Publication of study protocol and results...............................................................69
10.5
Quality Control and Quality Assurance.................................................................69
11 Protocol adherence ............................................................................................................69
11.1
Protocol amendments.............................................................................................70
12 References .........................................................................................................................70
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................71
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................72
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................75
16 Appendix 4: Medications, herbs and toxins as cause of ALT/AST elevations.................76
List of tables
Table 2-1
Objectives and related endpoints ..........................................................19
Table 3-1
Decision criteria for dose escalation based on LFT results with 
KAE609.................................................................................................21
Table 3-2
Estimated mean PK parameters in malaria patients for Cohort 5 
and Cohort 6 in comparison with measured exposures in malaria 
patients and healthy subjects and preclinical toxicity studies...............24
Table 5-1
Dosing scheme ......................................................................................29
Table 6-1
Assessment schedule.............................................................................41
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................54
Table 9-1
Power for comparison with Coartem based on 2-sided Fisher exact 
test .........................................................................................................67
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................72
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...72
Table 15-1
Specific Renal Alert Criteria and Actions.............................................75
Table 16-1
Medications, herbs and toxins as cause of ALT/AST elevations..........76
List of figures
Figure 3-1
Study KAE609A2202 diagram .............................................................22
Figure 9-1
Probability of observing at least 2 safety events by sample size and 
true event rate........................................................................................65
Figure 9-2
Probability of observing at least 3 safety events by sample size and 
true event rate........................................................................................66


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List of abbreviations
ACPR
Adequate Clinical and Parasitological Response
ACR
Albumin-Creatinine Ratio
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical therapeutic Chemical
AUC
Area Under the Curve
AUCinf
Area under the plasma concentration-time curve from zero to infinity
AUClast
Area under the plasma concentration-time curve up to the last measurable 
concentration
AUC0-t
Area under the plasma concentration-time curve from zero to time t of the last 
measurable concentration above the limit of quantification
BID
twice a day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CFR
US Code of Federal Regulations
CI
Confidence Interval
Cmax
Maximum Peak Observed Concentration
CMO&PS
Chief Medical Office and Patient Safety
CRF
Case Report/Record Form (paper or electronic)
eCRF
electronic Case Report/Record Form
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CTCAE
Common Toxicity Criteria for Adverse Events
CYP
Cytochrome
DAR
Dose Administration Record
ECG
Electrocardiogram
EDC
Electronic Data Capture
e.g.
For example (exempli gratia)
EMA
European Medicines Agency
ETF
Early Treatment Failure
EU
European Union
FAS
Full Analysis Set
FBC
Full Blood Count
FCT
Fever Clearance Time
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Serum-γ-Glutamyl Transferase
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure


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ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
International Normalized Ratio (blood clotting test)
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
LCF
Late Clinical Failure
LDH
Lactate dehydrogenase
LFT
Liver function test 
LPF
Late Parasitological Failure
MedDRA
Medical Dictionary for Regulatory Activities
MIC
Minimum Inhibitory Concentration 
NovDTD
Novartis Drug and Therapy Dictionary
OC/RDC
Oracle Clinical/Remote Data Capture
OTC
Over-The-Counter
PoC
Proof of Concept
PCT
Parasite Clearance Time
PCR
Polymerase Chain Reaction
PCV
Packed-Cell volume (hematocrit)
PD
Pharmacodynamic
PK
Pharmacokinetic
PoC
Proof of Concept
PPS
Per-Protocol Set
PSOC
Primary System Organ Class
QD
Once daily (quaque die)
QM
Quality Management
QT
QT interval is a measure of the time between the start of the Q wave and the end 
of the T wave in the heart's electrical cycle
QTc
heart rate-corrected QT
QTcF
QT Interval Corrected by the Fridericia Correction Formula
RBC
Red Blood Cell Count
SAE
Serious Adverse Event
eSAE
electronic Serious Adverse Event
SAF
Safety
SAP
Statistical Analysis Plan
SD
Single Dose
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum-Glutamat-Pyruvat-Transaminase
SOP
Standard Operating Procedure
SUSARs
Suspected Unexpected Serious Adverse Reactions


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Tmax
Time after administration of a drug when the maximum plasma concentration is 
reached
T½
Half-life
ULN
Upper Limit of Normal range
UNS 
Unscheduled Visit
WBC
White Blood Cell
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort 
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient 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 patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures 
described in the protocol)
Period
A portion of the study which serves a specific purpose. Typical periods
are: Screening/Recruitment, Wash-out, Treatment, and Follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
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 drug/treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug(s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
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 
(WoC)
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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Amendment 3
Amendment rationale 
As specified in Section 1.2 and Section 3.5 of the original protocol (version 1), KAE609A2202 
could be amended to study additional cohorts with higher doses if the safety of KAE609 is 
acceptable up to 75 mg single dose. Doses up to 50 mg QD x 3 days and 75 mg single dose 
have been found to be safe and effective in the current KAE609A2202 study as confirmed by 
the Safety Review Committee. Hence, this amendment is being done to add two cohorts with 
higher doses of KAE609 (150 mg single dose and 225 mg/110 mg single dose) to achieve the 
predefined aim of the study i.e. to determine the maximum safe dose of the investigational drug 
KAE609 in malaria patients. In addition, this would provide scope for future studies to use 
higher single doses which may be necessary to achieve adequate cure rates as single dose and 
potentially prevent or slow the emergence of drug resistance. The pharmacokinetic exposure 
for proposed doses are expected to be covered by the previous human or animal safe and 
tolerable exposures (See Section 3.3 for details). 
Changes to the protocol

Protocol summary: Cohorts 5 and 6 with higher single dose of KAE609 (150 mg and 225
mg/110 mg respectively) and Coartem in standard dose as comparator are added. The
planned number of patients is updated to 210 patients. 

Section 1.1: Updated the background to clarify that doses up to 300 mg were already
planned in patients in KAE609X2202 study, however the study was terminated after 75
mg dose.

Section 3.1: Table 3-1 and Figure 3-1 are updated to add Cohorts 5 and 6. Updated that
based on the review of safety data (and any other relevant data) by a safety review.
committee during or after Cohort 5, the dose of KAE609 for Cohort 6 will be either 110
mg or 225 mg. The study could be stopped after Cohort 5 if there is no added advantage
for dosing the patients with 225 mg single dose from the perspective of future clinical
development of KAE609 and its subsequent use in clinical practice.

Section 3.3: Dosing rationale for Cohort 5 and Cohort 6 updated.

Section 3.6: Updated the rationale for safety of 110 mg, 150 mg and 225 mg doses based
on exposure data from previous human or animal studies.

Section 4: The planned number of patients is updated to 210 patients.

Section 4.2: Contraception methods for Women of child-bearing potential updated from
basic to highly effective contraception methods. Also updated to clarify use of additional
non-hormonal method of birth control by patients randomized to receive Coartem.

Section 5.1.1: Table 5-1 updated to add the dosing scheme for Cohorts 5 and 6.

Section 5.2: Radomization scheme for Cohorts 5 and 6 is updated.

Section 5.4: Deleted the statement that “the randomization codes associated with patients
from whom PK samples are taken will be disclosed to PK bioanalysts who will keep PK
results confidential until the time of interim safety review or database lock” as this was not
applicable to this study.


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
Section 5.5.8: Clarification on the use of prohibited medications has been added.

Section 7.1: Investigational drug doses of 150 mg and 225 mg/110 mg is updated. 

Section 7.2.2: Typographical error with reference to erroneous double use of “Novartis” 
corrected.

Section 9.1: Updated the definition of PK analysis set.

Section 9.4.2: Reference to African patient population mentioned as strikethrough is 
removed.

Section 9.7: Cohorts 5 and 6 added to interim safety review criteria.

Section 9.8: Table 9-1 updated with additional rows of 50 and 60 patients treated with 
Coartem and the footnote to the table updated.
Amendment 2
Amendment rationale 
This protocol is being amended to correct errors/inconsistencies, and provide clarifications. 
This includes:

To remove hematology and blood chemistry assessment from randomization visit. 
Hematology and blood chemistry samples are analysed during screening visit and as the 
gap between screening visit and randomization visit is only up to 6 hours, there is no need 
to repeat the analysis of these samples.

To correct the inconsistencies regarding requirement of meal records for Coartem

To clarify & simplify the language regarding history of alcohol and drug abuse.
Changes to the protocol

Table 6-1: 

Removal of hematology and blood chemistry from randomization visit.   

Footer no. 9 is amended to reflect the following: “Meals consumed within 30 min 
prior to dosing and 4 hours post dosing to be documented for Coartem cohort”. 
Likewise, there is no need for superscript 10 and 11 for the Meal record row in Table 
6-1 since this row is only for Coartem arm.

Replacing ‘alcohol test and drug screen’ in Table 6-1 with ‘History of alcohol use and 
drug abuse’ for clarification purpose. Changes to specific sections of the protocol are 
shown in the track changes version of the protocol using strike through colored font 
for deletions and colored underlined for insertions.
Amendment 1
Amendment rationale
This protocol is being amended to correct several errors/inconsistencies, and provide 
clarifications. This includes:


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
To correct an inconsistency regarding the requirement for blinding the technician 
performing hematology, blood chemistry and microscopy readings. Since this is an open 
label study, blinding of technicians is not required.

To make information regarding requirement to collect meal records for KAE patients 
consistent throughout the protocol.

To remove serum phosphorus and uric acid assessment from the list of blood chemistry tests 
since these tests are normally not part of a routine laboratory assessment. There is no signal 
in the pre-clinical and clinical data collected so far to warrant measurement of these 
parameters.

To remove albumin from the list of urinalysis assessment. As protein is already being 
assessed in urine samples, it is not required to have albumin in addition.

To correct an inconsistency regarding the use of progesterone as an oral method of 
contraception. Progesterone is a prohibited medication in this protocol as an alteration in 
progesterone level may occur by concomitant administration with KAE609. However, 
exposure of synthetic progestins is not impacted by KAE609. Hence synthetic progestins 
are allowed as part of oral contraceptives. Therefore, clarification has been provided in the 
section for prohibited medication to allow use of synthetic progestins as part of hormonal 
contraceptives. 

Term “Biochemistry” replaced by “blood chemistry” to maintain consistency throughout 
the protocol.

The terms prior medication and concomitant medication have been defined for further 
clarity to make it consistent with existing information in protocol.

To clarify that in case of treatment discontinuation, patients may be given rescue medication 
at the discretion of the investigator.

Allow potential inclusion of other endemic non-African sites and increase the total number 
of participating sites.

Clarification on personal data and withdrawal of informed consent have been added to 
reflect changes implemented in the informed consent form. 
Changes to the protocol

Glossary: Definition of “Personal Data” and clarification of “Withdrawal of informed 
consent” definition has been added.

List of abbreviations: has been updated based on the changes implemented in this 
amendment.

Protocol summary, Section 4 and 9.4.2: Population is updated to include patients from 
approximately 15 sites in malaria endemic countries. Accordingly any reference to African 
patient population in the protocol (Section 9.4.2) is also removed. Reference to the 
laboratory manual for technical details about microscopy have been added to Protocol 
summary and Section 4.1.

Sections 3.2 and 5.4: Blinding the technicians who perform hematology, blood chemistry
parameters and microscopy readings has been removed as it is not required for this open 
label study.


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
Section 4.2: Details on type of oral contraception have been removed since clarification
about use of progestin has been provided in Section 5.5.8.

Section 5.5.4: Correcting the inconsistency related to requirement for collection of meal
records in KAE patients to make it consistent with the information already provided in Table
6-1.

Section 5.5.7: Defining the terms prior medication and concomitant medication for further
clarity to make it consistent with existing information in Section 9.3.2.

Section 5.5.8: For clarification, it has been added that synthetic progestins are not prohibited.

Section 5.6.2: Information on rescue medication in case of treatment discontinuation has
been added for clarification purposes.

Section 5.6.4: Clarification of withdrawal of informed consent has been added.

Table 6-1:

Addition of Polymerase Chain Reaction (PCR) sampling point at unscheduled visit
(UNS) to be consistent with protocol in order not to miss recrudescence/relapse cases
and to ensure that patient receives rescue medication as soon as treatment failure criteria
are met.

Deleted Interactive Response Technology (IRT) time points at 8 hours, 36 hours and 60
hours for Coartem cohort since IRT will be contacted only once per treatment day to
register the visit in the system.

Correcting the typographical error in the footnote regarding explanation of term ‘UNS’
from ‘Unscheduled treatment discontinuation visit’ to ‘Unscheduled visit’.

Description of how triplicate ECGs should be done, and time window for ECG
assessment have been included in the footnote.

Section 6.2: Body height included in the list of baseline demographic characteristics to
make it consistent with the information in Table 6-1, Sections 6.5.1 and 6.5.3.

Section 6.4.1: Reference to the laboratory manual for details has been added. Correction of
typographical error in instructions for parasite counting to make it consistent with laboratory
manual being implemented in the study: “if less than 100 parasites, counting will be
extended to 500 leukocytes” instead of “less than 10 parasites, counting will be extended to
500 leukocytes” as mentioned in previous version.

Section 6.5.4.2: Phosphorus, and uric acid removed from the blood chemistry testing as not
required in this study.

Section 6.5.4.3: Albumin was also removed from the urinalysis testing as not required
because protein is assessed.

Section 6.5.5: For clarification, a statement on local ECG readout has been added.
Typographical error regarding QTcF increases corrected to be consistent with section
9.5.2.4: ‘> 60 ms from baseline’ replaced by ‘≥ 60 ms from baseline’.

Section 6.5.6: Definition for women of child bearing potential with reference to females
aged 8 years and above is removed since this study includes adult patients only.

Section 6.5.8:  Deleted ‘not able to breast feed’ from the signs/symptoms indicative of
severe/complicated malaria under danger signs as it is not applicable (only adult patients
are included in the study).


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
Sections 7.1 and 7.3, and Appendix 2 and 3: Deleted ‘Study treatment dosage 
increased/reduced’ and ‘Study treatment interrupted’ from the standard text under the 
management of adverse events since change in dose or temporary interruption of treatment 
is not allowed as per the protocol. Interruption was replaced by discontinuation.

Sections 7.2.2 and 7.6: DS&E replaced by CMO & PS to reflect the latest terminology for 
Novartis Safety.

Section 8.3: Typographical error with reference to tracking dosage changes in IRT is 
corrected since no dosage changes are allowed as per the study design. 

Section 12: One reference ‘Hamed and Grueninger 2012’ quoted in section 3.4 was missing 
in the reference list, hence reference list was updated.

Term ‘clinical chemistry’ and ‘biochemistry’ replaced by ‘blood chemistry’ to maintain 
consistency throughout the protocol. 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Global Model Informed Consent.  Sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes 
described in this protocol amendment. 


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Protocol summary
Protocol number
CKAE609A2202
Full Title
A Phase 2, multi-center, randomized, open-label, dose-escalation 
study to determine safety of single (QD) and multiple (3 QD) doses 
of KAE609, given to adults with uncomplicated Plasmodium 
falciparum malaria.
Brief title
Safety of KAE609 in adults with uncomplicated Plasmodium 
falciparum malaria.
Sponsor and Clinical 
Phase
Novartis
Phase IIa
Investigation type
Drug
Study type
Interventional
Purpose and rationale
KAE609 will be evaluated primarily for hepatic safety of single and 
multiple doses in sequential cohorts with increasing doses.
This study aims to determine the maximum safe dose of the 
investigational drug KAE609 in malaria patients.
Primary Objective(s) 
The primary objective of this study is to characterize hepatic safety 
aspects of single- and multiple ascending doses of KAE609 in adult 
malaria patients.
Secondary Objectives
To evaluate overall safety and tolerability of KAE609.
To assess key pharmacokinetic (PK) parameters following treatment 
with KAE609.
To assess the efficacy of KAE609 in patients with uncomplicated 
falciparum malaria.
To assess recrudescence after single and multiple doses of KAE609.
Study design
This will be a multicenter, open label, randomized, dose escalation 
study in adult patients with uncomplicated malaria caused by 
Plasmodium (P.) falciparum.
Population
The study population will consist of male and female patients 
(≥18 years old and ≥ 45 kg) with uncomplicated P. falciparum
malaria.
The plan is to randomize approximately 210
patients in 
approximately 15 sites in malaria endemic countries.
Key Inclusion criteria

Male and female patients ≥ 18 years with a body weight ≥ 45 
kg.


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
Microscopic confirmation of acute uncomplicated P.
falciparum using by Giemsa-stained thick film (refer to the 
laboratory manual for details).

P. falciparum parasitaemia of 500 to 50 000 parasites/µL.

Axillary temperature ≥37.5ºC or oral/tympanic/rectal 
temperature ≥38.0ºC; or history of fever during the previous 24 
hours.

Written informed consent must be obtained before any study 
assessment is performed. If the patient is unable to write, then a 
witnessed consent according to local ethical standards is 
permitted.
Key Exclusion criteria

Mixed Plasmodiun infections.

Signs and symptoms of severe malaria according to World 
Health Organization (WHO) 2016 criteria (WHO 2016).

Known liver abnormalities, liver cirrhosis (compensated or 
decompensated), known active or history of hepatitis B or C 
(testing not required), known gallbladder or bile duct disease, 
acute or chronic pancreatitis.

Clinical or laboratory evidence of any of the following: 

AST/ALT > 1.5 x the upper limit of normal range (ULN), 
regardless of the level of total bilirubin

AST/ALT > 1.0 and ≤ 1.5 x ULN and total bilirubin is > 
ULN

Total bilirubin > 2 x ULN, regardless of the level of 
AST/ALT

History of photodermatitis/increased sensitivity to sun.

Pregnant or nursing (lactating) women.

Known disturbances of electrolyte balance, e.g. hypokalemia, 
hypocalcemia or hypomagnesemia.

Moderate to severe anemia (Hemoglobin level <8 g/dL).
Study treatment
COHORT 1

Treatment arm 1: KAE609 10 mg once daily (QD) for 1 day

Treatment arm 2: Coartem® 80/480 mg twice a day (BID) for 3 
days
COHORT 2

Treatment arm 3: KAE609 25 mg QD for 1 day

Treatment arm 4: KAE609 10 mg QD for 3 days

Treatment arm 5: Coartem 80/480 mg twice a day (BID) for 3 
days
COHORT 3


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
Treatment arm 6: KAE609 50 mg QD for 1 day

Treatment arm 7: KAE609 25 mg QD for 3 days

Treatment arm 8: Coartem 80/480 mg twice a day (BID) for 3 
days
COHORT 4

Treatment arm 9: KAE609 75 mg QD for 1 day

Treatment arm 10: KAE609 50 mg QD for 3 days

Treatment arm 11: Coartem 80/480 mg twice a day (BID) for 3 
days
COHORT 5

Treatment arm 12: KAE609 150 mg QD for 1 day

Treatment arm 13: Coartem 80/480 mg twice a day (BID) for 3 
days
COHORT 6

Treatment arm 14: KAE609 225 mg QD or KAE609 110 mg 
QD for 1 day

Treatment arm 15: Coartem 80/480 mg twice a day (BID) for 3 
days
Key safety 
assessments

Monitoring of laboratory parameters in blood and urine

Adverse event (AE including Serious Adverse Event (SAE)) 
monitoring

Body temperature

Physical examination and malaria signs and symptoms

Vital signs

Electrocardiogram
PK assessments

PK parameters of study drugs (measured by AUC0-24h, 
AUClast, AUCinf, Cmax, Tmax, T½)
Efficacy assessments

Parasitaemia
Data analysis
Data will be summarized by cohort and treatment arm. Data from all 
cohorts pooled will be also summarized for Coartem. For the 
primary variable of at least 2 Common Toxicity Criteria for Adverse 
Events (CTCAE) grades increase from baseline in ALT or AST, and 
Adequate Clinical and Parasitological Response (ACPR; PCR 
corrected and uncorrected ACPR at Days 15 and 29), 2-sided 95% 
confidence intervals (CI) will be constructed using the exact 
(Pearson-Clopper) method. For parasite clearance time and fever 


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clearance time, descriptive statistics (mean, standard error, median, 
quartiles) will be presented using the Kaplan-Meier method.
Key words
Plasmodium falciparum malaria, KAE609, adults


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1
Introduction
1.1
Background
KAE609 is a novel spiroindolone class drug with potent and fast-acting schizonticidal activity, 
which acts by disrupting the malaria parasite Na+ homeostasis by inhibition of the ATPase 
PfATP4. KAE609 has been evaluated in healthy volunteers in single doses up to 300 mg and
repeated doses up to 150 mg (3-day Once daily (QD)) without any significant safety and 
tolerability issue. In the initial patient study, a 3-day QD treatment of 30 mg was well tolerated. 
A subsequent patient study (KAE609X2202) was designed to evaluate efficacy and safety of 
doses from 75 mg single dose to 300 mg single dose in patients in Asia infected with 
Plasmodium falciparum. In KAE609X2202, at a single dose of 75 mg, transient Grade 2-3 LFT 
elevations were however observed in 5/11 patients and the study was terminated (See KAE609 
Investigator Brochure (IB) for further details). In a malaria challenge study with healthy 
volunteers in Australia, transient Grade 3-4 LFT elevations were observed in 3/8 subjects 
following a single dose of 10 mg of KAE609. Following evaluation of these events, it was 
concluded that hepatic toxicity of KAE609 cannot be excluded, and that an additional safety 
dose escalation study should be performed before exploring safety and efficacy in a fixed-dose 
combination of KAE609 with a long acting anti-malarial.
1.2
Purpose 
This Phase 2 study aims to determine the maximum safe dose of the investigational drug 
KAE609 in malaria patients.
The study population consists of adult malaria patients (≥18 years, ≥45 kg body weight) with 
uncomplicated symptomatic malaria caused by Plasmodium (P.) falciparum. 
KAE609 will be evaluated primarily for hepatic safety following administration of single and 
multiple doses (once a day for 3 days) in sequential cohorts with escalating doses. 
In case that safety is acceptable for all consecutive cohorts, a protocol amendment could be 
considered to study additional higher dose(s).
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To characterize hepatic safety aspects 
of single- and multiple ascending doses 
of KAE609 in adult malaria patients
Endpoint(s) for primary objective(s) 

At least 2 CTCAE grades increase from 
baseline in ALT or AST during the 4 
week study period
Secondary Objective(s)
Endpoint(s) for secondary objective(s)


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Objective(s)
Endpoint(s)

To evaluate overall safety and 
tolerability of KAE609.

To assess key PK parameters following 
treatment with KAE609.

To assess the efficacy of KAE609 in 
patients with uncomplicated falciparum
malaria.

To assess recrudescence after single and 
multiple doses of KAE609

Standard 
safety/tolerability 
assessments 
(AE 
incidence 
and 
severity, vital signs, ECG, laboratory 
abnormalities)

PK parameters such as AUC, Cmax, 
Tmax, T½ etc.

PCR-Uncorrected adequate clinical and 
parasitological response (ACPR) and 
PCR-Corrected ACPR at Days 15 and 
29 (i.e., 14 and 28 days post-dose)
Parasite and Fever Clearance Times 
(PCT 
and 
FCT)
before 
rescue 
medication is given

Incidence rate of recrudescence at 
Day 29
3
Investigational plan
3.1
Study design
This will be a multicenter, open label, randomized, dose escalation study to evaluate the hepatic 
safety and tolerability of KAE609 in adult patients (≥18 years and ≥45 kg bodyweight) with 
uncomplicated malaria caused by P. falciparum. 
Starting dose of KAE609 will be a single dose of 10 mg and following acceptable safety results 
in the 10 mg treatment arm, the dose of KAE609 will be increased stepwise up to a single dose 
of 225 mg and multiple doses of 50 mg (QD x3 days) according to schedule below (Figure 3-
1).
Based on the safety pattern observed in previous studies with KAE609, LFT parameters, if they 
rise, are expected to peak within 14 days of treatment. Hence, the decision to escalate to next 
cohort with higher doses will be based on the criteria as specified in the table below (Table 3-
1):


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Table 3-1
Decision criteria for dose escalation based on LFT results with 
KAE609
LFT parameter
Baseline
Maximum post baseline value 
Decision to escalate to 
next cohort
ALT/AST
Within ULN
< 2 times ULN (from Day 1 to
Day 15)
Escalate to next cohort 
after notification to safety 
review committee, after 
all the patients in the 
cohort have been 
followed for at least 14 
days post treatment
(study Day 15).
> 1 to ≤1.5 
ULN
< 2 times baseline (from Day 1 to
Day 15)
ALT/AST
Within ULN
≥2 to < 3 times ULN (from Day 1 
to Day 15)
Escalate to next cohort 
based on review of liver 
safety (and any other 
relevant data) by safety 
review committee, after 
all the patients in the 
cohort have been 
followed for at least 28 
days  post treatment 
(Study Day 29) 
> 1 to ≤1.5 
ULN
≥2 to < 3 times baseline (from 
Day 1 to Day 15)
ALT/AST
Any baseline 
value
≥2 Grade (CTCAE grades) 
increase from baseline (at any 
time point during the study) in:
-
2 patients in a 10 patient cohort 
(Cohorts 1 and 2)
           or 
-
3 patients in a 20 patient cohort
(Cohorts 3, 4, 5 and 6)
Suspend recruitment and 
initiate review of liver 
safety (and any other 
relevant data) by safety 
review committee.
Any further progression 
of the study is based on 
the decision by the safety 
review committee.
In consultation with the safety review committee, Novartis can suspend recruitment and trigger 
safety review any time based on safety signals including any potential Hy’s law case.
Based on the pre-specified criteria (Table 3-1) and the review of the liver safety data by a safety 
review committee, the recruitment in Cohort 5 may be stopped and a lower dose of KAE609 
i.e. 110 mg may be selected for Cohort 6. 
The study could be stopped after Cohort 5 if there is no added advantage for dosing the patients 
with 225 mg single dose from the perspective of future clinical development of KAE609 and 
its subsequent use in clinical practice.


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Figure 3-1
Study KAE609A2202 diagram
Given the expected sub-therapeutic efficacy of the doses of KAE609 in the first 2 cohorts, a 
smaller number (N=10) of patients will be included (10 mg Single Dose (SD), 25 mg SD and 
10 mg 3 Days) to detect potential LFT increases. In the subsequent cohorts a higher number 
(N=20) of patients will be included. All patients will be followed up for 4 weeks with close 
monitoring in an inpatient setting for at least the first 3 days (Study Day 4) for efficacy and 
safety followed by outpatient monitoring  up to Study Day 29.
Patients will remain in the hospital under close supervision until they are discharged by the 
investigator or designee on Study Day 4. To be discharged, patients should present 2 
consecutive study assessments with negative blood smear for P. falciparum parasites and 
clearance of fever. At the discretion of the investigator, patients may remain in hospital for 
additional days if needed.
Coartem® (Artemether-Lumefantrine) will be used as rescue medication in KAE609 patients 
meeting the treatment failure criteria (see Section 5.5.6). Any patient on KAE609 who does not 
need rescue medication up to Study Day 28 will be given Coartem at the end of the study (Study 
Day 29) and will be followed as per standard medical care.
Visits to assess safety and efficacy will be scheduled during the follow-up period as described 
in the assessment schedule table (Table 6-1). If malaria symptoms re-emerge outside the 
scheduled study visits, patients will be instructed to contact the investigator as soon as possible. 
For severe malaria, rescue medication according to local guidance will be used.
Frequent blood samples (see Table 6-1) for monitoring blood chemistry parameters including 
ALP, ALT, AST, total bilirubin (direct and indirect), creatinine phosphokinase levels, LDH, 
and haptoglobin. Additional samples will be collected for safety analyses at baseline and at 
predefined time in case of observed LFT elevations (e.g., viral hepatitis). Additional sera will 
be saved for possible further analyses to assess the mechanism of hepatic toxicity, if needed 
(e.g., miR122).
The safety of the entire study will be overseen by a primarily internal Novartis safety review 
committee with inclusion of at least one external hepatologist (Section 8.4).


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3.2
Rationale for study design
This will be a multicenter, open-label, randomized, sequential, dose escalation study in adults 
with uncomplicated P. falciparum malaria.
The objective of this dose escalation study design is to characterize hepatic safety aspects of 
single- and multiple ascending doses of KAE609 and determine the maximum tolerated dose 
of the investigational drug KAE609 in malaria patients.
Dose escalation sequential design of the study is the standard design for evaluating safety and 
tolerability of a new chemical entity in the early phase (Phase I and II) of clinical development.
Single doses up to 75 mg and repeated dosing up to 30 mg (3 day QD) have been evaluated in 
patients without any significant hepatic tolerability issue with the exception of LFT elevations 
observed in human challenge study at 10 mg single dose and 75 mg single dose in proof of 
concept (PoC) extension study. Single as well as repeated doses will be evaluated in this study 
since knowledge about safety profile of both schedules is important to inform further 
development of the dosing strategy with the best benefit risk profile. Single dosing is a 
necessary step prior to repeat dosing and allows the detection and management of adverse 
events (AE) which may be more severe with repeated dosing. Hence, to characterize the safety 
profile of the entire dose range of KAE609, patients will be first dosed with a single dose of 
lowest strength i.e., 10 mg and be escalated in a stepwise manner. 
Coartem will be used as reference group to help distinguish if the hepatic events and other 
adverse events observed in the study are exclusive to KAE609 or resulting from the disease (P.
falciparum malaria) itself.
Coartem will be dosed in the fed state. Furthermore, KAE609 will be dosed (irrespective of fed 
state) as single dose or QD for 3 days whereas Coartem will be dosed as twice a day (BID) for 
3 days. Considering the differences in food requirement and differential frequency of 
administration for both the drugs, achieving blinding for patients and investigators is not 
feasible. The risk of bias arising out of the open-label design is minimized due to the fact that 
objective endpoints have been chosen for the study.
The patient population will be described in more detail in the Section 4 below
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
As mentioned in Section 1.1 and Section 3.2, KAE609 has been evaluated in single dose up to 
75 mg and repeated dose up to 30 mg (3 day-QD) in malaria patients. It has also been evaluated 
in healthy volunteers in single dose up to 300 mg and repeated doses up to 150 mg (3 day-QD).
Considering the LFT elevations observed at 10 mg single dose (3 out of 8 patients in the Human 
Challenge Study) and at 75 mg single dose (5 out of 11 patients in the PoC extension study), 
and because causal relationship could not be established there is a need to further characterize 
the safety profile of the entire range of doses expected to be used as single doses or repeated 
dose in uncomplicated P. falciparum malaria.
As expected in a dose escalation sequential study, patients will be dosed initially at the lowest 
dose and be escalated in a stepwise manner. Single dosing is a necessary step to repeat dosing 


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and allows the detection and management of adverse events which may emerge or be more 
severe with repeated dosing.
The doses proposed in the newly added Cohort 5 and Cohort 6 are expected to be comparable 
or lower than the exposures which are considered to have acceptable safety and tolerability 
based on human and animal data (Table 3-2). In addition, the unbound exposure in patients 
(unbound fraction 0.08%) are expected to be much lower compared to healthy subjects 
(unbound fraction 0.15%) and dogs (unbound fraction 0.21%) (See KAE609 IB for further 
details).
Table 3-2
Estimated mean PK parameters in malaria patients for Cohort 5 and 
Cohort 6 in comparison with measured exposures in malaria patients
and healthy subjects and preclinical toxicity studies
PK 
Paramete
r
50 mg 
single 
dose 
exposure 
in current 
study
(Observed 
preliminar
y values)
110 mg**
dose in 
patients
(Estimate
d values)
150 mg 
dose in 
patients
(Estimate
d values)
225 mg 
dose in 
patients
(Estimate
d values)
Observed 
300 mg 
dose in 
healthy 
subjects
(Observe
d values) 
IV 5 
mg/kg/da
y for
14 days 
in dogs
(Observe
d values)*
Oral 15 
mg/kg/da
y for
3 days in 
dogs
(Observe
d values)*
Cmax (ng 
/mL)
810
1925
2625
3937
2090
33600
6200
AUC0-
24h 
(µg·h/mL)
12.4
37.4
50.9
76.5
36.0
55.9
119
The estimated exposures are calculated with reasonable assumption of linear pharmacokinetics of 
KAE609
*LOAEL (Lowest observed adverse effect level): Minimal to slight reversible adrenal findings
** A lower dose of KAE609 i.e. 110 mg may be selected for Cohort 6 based on the review of the liver 
safety data of Cohort 5 by a safety review committee.
Dose regimen for Coartem is in accordance with the product label. 
3.4
Rationale for choice of comparator
The control treatment used in this study is Coartem, the artemisinin-based combination therapy 
artemether-lumefantrine. Coartem is widely used for P. falciparum malaria and has a well-
characterized hepatic safety and efficacy profile (Hamed and Grueninger 2012). For these 
reasons, Coartem is considered the appropriate comparator treatment for this study.
3.5
Purpose and timing of interim safety review
Safety data will be reviewed by a safety review committee at predefined time points to decide 
about progression to the next cohort with the escalated doses (see Section 3.1).
In case safety data review is inconclusive for a particular cohort, number of patients in that 
cohort could be increased by up to 100% patients per treatment arm.


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3.6
Risks and benefits
Based on the preclinical and clinical evaluation to date as presented in the IB for KAE609, it 
has been generally safe and well tolerated in patients up to single doses of 75 mg and repeated 
dose of 30 mg (3 day-QD) with the exception of reversible and asymptomatic LFT elevations 
observed with 10 mg single dose in human challenge study and 75 mg single dose in PoC 
extension study. Increase in LFT levels in earlier studies could have been influenced by the 
disease condition itself and/or the specific human challenge model. Hence, this study is being 
performed to characterize the hepatic safety profile of the expected dose range of KAE609 to 
be used in further development. 
For newly added Cohort 5 and Cohort 6, single doses of 150 mg and 225 mg are proposed, 
respectively. PK exposure (AUC) of single dose 150 mg should be comparable to three doses 
of 50 mg once daily, already administered in this study and found to be safe and well tolerated
during interim reviews (data not provided). Estimated AUC0-24h for 225 mg dose would be >2 
fold lower than the exposure which are considered safe based on oral dog toxicology study (15 
mg/kg for 3 days) or comparable with 2 weeks IV toxicity study. The Cmax is also expected to 
be around 1.7 fold lower than Cmax observed in oral dog toxicology study (Table 3-2). 
Following ongoing review of the data of 150 mg dose if the safety events are found to be related 
to PK exposure, then dose of 110 mg may be studied to establish the exposure thresholds.
The risk to patients in this trial will be minimized by compliance with the eligibility criteria and 
study procedures, sequential dose escalation starting from the lowest strength of dose (10 mg), 
close clinical monitoring and minimal treatment duration (single dose evaluated before repeated 
dosing), and by the fact that dose-escalation will be carried out after the known peak time of 
LFT increases (i.e., 14 days) for KAE609. Patients will be hospitalized under close supervision 
until they are discharged by the investigator or designee on Study Day 4. To be discharged, 
patients should present 2 consecutive study assessments with negative blood smear and 
clearance of fever. At the discretion of the investigator, patients may remain in hospital for 
additional days if needed. Patients are advised to use commonly recommended precautions 
when in the sun (e.g. sunscreen, hat, protective clothing). 
In the current study, KAE609 will be given to patients with uncomplicated symptomatic
P. falciparum malaria. KAE609 is expected to reduce the number of circulating malaria 
parasites in the blood of patients and consequently improve their clinical symptoms within the 
first 24 hours. There is also the possibility of complete cure of their illness. 
The risk of developing resistant strains of parasite is possible but low in this small study. 
KAE609 has been earlier evaluated in adult patients with acute, uncomplicated malaria due to 
P. falciparum mono-infection at doses of 75 mg in a PoC extension study and 30, 20 mg, 15 
mg and 10 mg in a Minimum Inhibitory Concentration (MIC) study (Hien et al 2017). In the 
MIC study, treatment failure due to recrudescence was reported in 4 (36%) patients and one 
patient had late treatment failure due to new malaria infection in the PoC extension study at 75 
mg dose. There were no patients with early treatment failure (ETF) in the 30 mg and 15 mg 
dose groups while three patients from the 10 mg dose group (42%) and one patient from the 20 
mg dose group (25%) were ETFs. 


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The risk of any treatment failure (see Section 6.5.8), recrudescence or new infection in this 
study will be managed with rescue medication in the form of standard-of-care pharmacotherapy
(Coartem). This may minimize the likelihood of resistance emergence or spread of infection. 
The current study will include only adult patients (≥18 years) suffering from uncomplicated
symptomatic P. falciparum malaria. Given the expected sub-therapeutic efficacy of the doses 
of KAE609 in the first 2 cohorts, only a small number (N=10) of patients to assess safety events 
will be included (10 mg SD, 25 mg SD and 10 mg 3 Days). Following acceptable safety results 
in these cohorts, higher doses (25 mg 3 days and 50 mg SD or higher) with an increased number 
of patients (20 patients) will be enrolled in the study. Thereafter, the dose of KAE609 may be 
increased sequentially up to 225 mg based on continuous monitoring of safety.
This is the first time that KAE609 will be tested in African patients. All previous studies 
involved Asian and Caucasian participants only.
4
Population
The study population will consist of male and female patients (≥ 18 years old and ≥ 45 kg) with 
confirmed and uncomplicated symptomatic P. falciparum malaria.
Only patients with malaria symptoms and documented P. falciparum counts of 500 to 50 000
parasites/µl (assessed within 6 hours of screen visit) will be further screened for eligibility in 
the study. Routine microscopy data may be used as baseline parasite count for the protocol if 
the assessment was done within 6 hours and is compliant with protocol requirements.
The plan is to randomize approximately 210 patients in approximately 15 sites in malaria 
endemic countries.
A patient who enters screening but is determined not to be eligible to enter the treatment period 
will be considered a screen failure. 
Rescreening of a patient who had failed screening assessments earlier in the study is allowed as 
per investigator discretion and/or after consultation with the sponsor. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
Demography
1. Male and female patients ≥ 18 years with a body weight ≥ 45 kg
Disease specific
2. Microscopic confirmation of acute uncomplicated Plasmodium falciparum using by 
Giemsa-stained thick film (refer to the laboratory manual for details)
3. Plasmodium falciparum parasitaemia of 500 to 50 000 parasites/µL
Health status
4. Axillary temperature ≥37.5ºC or oral/tympanic/rectal temperature ≥38.0ºC; or history of 
fever during the previous 24 hours
5. Negative pregnancy test for patients of childbearing potential


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Regulations
6. Written informed consent must be obtained before any study assessment is performed. If 
the patient is unable to write, then a witnessed consent according to local ethical standards 
is permitted
7. The subject is able to understand and comply with protocol requirements, instructions and 
protocol-stated restrictions and is likely to complete the study as planned
8. Living within reachable distance to the trial site to enable attendance for follow-up visits
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
Medical history and clinical status
1.
Mixed Plasmodiun infections
2.
Signs and symptoms of severe malaria according to World Health Organization (WHO)
2016 criteria (WHO 2016)
3.
Active tuberculosis, or history of taking anti-tuberculosis medications within 12 months 
prior to screening
4.
History of, or current alcohol misuse/abuse defined as five or more drinks on the same 
occasion on each of 5 or more days in the past 30 days
5.
Known liver abnormalities, liver cirrhosis (compensated or decompensated), known active 
or history of hepatitis B or C (testing not required), known gallbladder or bile duct disease, 
acute or chronic pancreatitis
6.
Clinical or laboratory evidence of any of the following: 

AST/ALT > 1.5 x the upper limit of normal range (ULN), regardless of the level of 
total bilirubin

AST/ALT > 1.0 and ≤ 1.5 x ULN and total bilirubin is > ULN

Total bilirubin > 2 x ULN, regardless of the level of AST/ALT
7.
History of photodermatitis/increased sensitivity to sun
8.
Known disturbances of electrolyte balance, e.g. hypokalemia, hypocalcemia or 
hypomagnesemia
9.
Moderate to severe anemia (Hemoglobin level < 8 g/dL)
10. Any confirmed or suspected immunosuppressive or immunodeficient condition, including 
human immunodeficiency virus (HIV) infection
11. Severe malnutrition (Body Mass Index (BMI) < 16.0)
12. Severe vomiting, defined as more than 3 times in the 24 hours prior to inclusion in the 
study or severe diarrhea defined as more than 3 times watery stools per day
13. Pregnant or nursing (lactating) women
14. Sexually active patients not willing to practice effective contraception
15. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 


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dosing and for 30 days after administration of KAE609. Highly effective contraception 
methods include:
-
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject).
-
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment.
-
Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.
-
Use of oral,  injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate < 1%), for example hormone 
vaginal ring or transdermal hormone contraception. Coartem/Riamet may reduce the 
effectiveness of hormonal contraceptives. Therefore, patients randomized to Coartem 
using oral, transdermal patch, or other systemic hormonal contraceptives should be advised 
to use an additional non-hormonal method of birth control.
-
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug.
-
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.
16. Sexually active males must use a condom during intercourse while taking drug and for at 
least 30 days after stopping the study medication and should not father a child in this period. 
A condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid
17. Patients with a family history of congenital prolongation of the QTc interval or sudden 
death or with any other clinical condition known to prolong the QTc interval such as 
patients with a history of symptomatic cardiac arrhythmias, with clinically relevant 
bradycardia or with severe cardiac disease
18. Patients taking drugs that are known to prolong the QTc interval
19. Resting QTcF > 450 ms (males), QTcF > 460 ms (females) at screening
20. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in 
case of participation in the study. The investigator should make this determination in 
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21. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases
22. Known chronic underlying disease such as sickle cell disease, and severe cardiac 
impairment.
23. Patients with serum creatinine ≥2 X ULN in the absence of dehydration. In case of 
dehydration, patients with serum creatinine ≥2 X ULN after oral or parenteral rehydration.
24. Inability to tolerate oral medication, to drink.
25. Patients taking any drug which is metabolized by the cytochrome (CYP) 2D6 enzyme (e.g.,
flecainide, metoprolol, imipramine, amitriptyline, clomipramine).
26. Patients taking drugs that are strong inducers of CYP3A4 such as rifampicin, 
carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum)
27. Known hypersensitivity to any of the agents used in the study
Interfering substances
28. Patients with prior antimalarial therapy or antibiotics with antimalarial activity within less 
than five (5) plasma half-lives (or within 4 weeks of screening if half-life is unknown)
29. Patients with prior herbal medication within one week of screening
30. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days or 
until the expected pharmacodynamic (PD) effect has returned to baseline, whichever is 
longer
31. Patients taking medications prohibited by the protocol (see Section 5.5.8, Appendix 4)
32. Previous participation in any malaria vaccine study or received malaria vaccine in any 
other circumstance
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Table 5-1
Dosing scheme
Cohorts
Treatment 
Arm
KAE609 
dose (mg)
Coartem
dose (mg)
Dosing regimen
Available strengths
to achieve 
recommended 
dose
1
1
10
QD 1 day
1 x 10 mg
2
80/480
BID 3 days
80/480 mg or 
4 x 20/120 mg
2
3
25
QD 1 day
1 x 25 mg
4
10
QD 3 days
1 x 10 mg


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5
80/480
BID 3 days
80/480 mg or 
4 x 20/120 mg
3
6
50
QD 1 day
1 x 50 mg
7
25
QD 3 days
1 x 25 mg
8
80/480
BID 3 days
80/480 mg or 
4 x 20/120 mg
4
9
75
QD 1 day
1 x 25 mg
1 x 50 mg
10
50
QD 3 days
1 x 50 mg
11
80/480
BID 3 days
80/480 mg or 
4 x 20/120 mg
5
12
150
QD 1 day
1 x 50 mg
1 x 50 mg
1 x 50 mg
13
80/480
BID 3 days
80/480 mg
6
14
225
QD 1 day
1 x 50 mg
1 x 50 mg
1 x 50 mg
1 x 50 mg
1 x 25 mg
110 (if 
required)
QD 1 day
1 x 50 mg
1 x 50 mg
1 x 10 mg
15
80/480
BID 3 days
80/480 mg
5.1.2
Additional treatment
Antipyretic will be allowed for symptomatic management of fever (see Section 5.5.7). No other 
additional treatment beyond investigational drug and control drug are included in this trial. The 
control drug, Coartem, will be also provided as rescue medication (Section 5.5.6).
5.2
Treatment arms
Patients will be randomized in a 1:1 ratio between KAE609 single dose and Coartem in Cohort 
1. Patients will be randomized in a 1:1:1 ratio between KAE609 single and repeated doses and 
Coartem in Cohort 2. Patients will be randomized in a 2:2:1 ratio between KAE609 single dose 
and repeated dose and Coartem in Cohort 3 and Cohort 4. Patients will be randomized in a 2:1 
ratio between KAE609 single dose and Coartem in Cohort 5 and Cohort 6.


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5.3
Treatment assignment and randomization
Randomization to treatment groups will be performed sequentially, cohort by cohort with a 
pause between cohorts to allow safety review (see Section 3.1 and Section 8.4). Randomization 
may be put on hold within a cohort if there are patients experiencing safety events (see Table 
3-1).
Once a cohort is active for enrollment, clinical sites will be informed and Interactive Response 
Technology (IRT) will be activated to accept patients. At Visit 101, all eligible patients will be 
randomized via the IRT to one of the treatment arms. The investigator or his/her delegate will 
contact the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. The 
IRT will assign a randomization number to the patient, which will be used to link the patient to 
a treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. The randomization number will not be communicated to the caller.
The randomization per cohort may be extended after consultation with the sponsor to cover for 
some early study/treatment discontinuation, for e.g., patient who was randomized but not 
treated by study medication etc.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s). 
No stratified randomization will be used in all the cohorts for this study. 
The randomization scheme for patients/subjects will be reviewed and approved by a member 
of the Randomization Group.
5.4
Treatment blinding 
Treatment will not be blinded to patients, investigator staff, and persons performing the clinical 
assessments since KAE609 is dosed once daily for one day or 3 days while Coartem is dosed 
twice daily for 3 days. Since the primary and secondary objectives of the trial are mainly based 
on objective laboratory assessments, this should not bias the safety endpoint and the efficacy 
assessments. To reduce the selection bias to treatment groups, IRT will be used to randomize 
patients to treatment groups and randomization data are kept strictly confidential until formal 
interim safety review or final analysis. At the time of interim safety review or final analysis, the 
randomization data will be loaded into the statistical programming system for access to 
programmers, trial statisticians, and pharmacokineticists. 
At the time of formal interim safety review, if needed, summaries of results by cohort and 
treatment arm, if necessary, will be prepared only for Novartis internal/external experts to make 
decision for progress to the next cohort. These reports will be performed by the study 
biostatistics team (or deputy Contract Research Organization (CRO)) and pharmacokineticist if 
necessary (see Section 9.7). 


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Since this is open-label study, unblinding is not needed in the case of patient emergencies (see 
Section 5.6). 
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Investigators will screen patients only when a cohort is active for enrollment. Each patient is 
uniquely identified by a Subject Number which is composed by the site number assigned by 
Novartis and a sequential number assigned by the investigator. Once assigned to a patient, the 
Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number by 
the investigator. The investigator or his/her staff will contact the IRT and provide the requested 
identifying information for the patient to register them into the IRT. The site must select the 
case report/record form (CRF) book with a matching Subject Number from the Electronic Data 
Capture (EDC) system to enter data. In case that a patient signs the informed consent form 
during the pause of study, the IRT will inform the investigator that the patient cannot be enrolled.   
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening period
Study Disposition CRF.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drugs in individual packaging for each patient.
The study drug packaging has a 2-part label for KAE609. A unique medication number is 
printed on each part of this label which corresponds to one of the treatment arms and dose.
Coartem will not have 2-part label, the medication number will be printed on the main panel. 
Investigator staff will identify the study drug package(s) to dispense to the patient by contacting 
the IRT and obtaining the medication number(s). Immediately before dispensing the package 
to the patient, investigator staff will detach the outer part of the label from the packaging and 
affix it to the source document (Drug Label Form) for that patient’s unique subject number. 
If a patient vomits study drugs, KAE609 within 30 min or Coartem within 1 hour of intake, a 
replacement dose will be given to the patient and the investigator or designee will notify IRT
(see Section 5.5.4).
Medication number and quantity of treatment drug taken by patients have to be collected by the 
investigator or designee.
5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 


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have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication pack number.
The investigator must maintain an accurate record of the dispensing of study treatment in a drug 
accountability log. The study treatment will be administered to patients under hospital 
supervision. Monitoring of drug accountability will be performed by monitors during site visits 
or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
5.5.3.2
Handling of additional treatment
The following non-study treatment will be provided by the Sponsor and has to be monitored 
specifically:

Coartem as rescue medication
Details are described in the CRF completion guidelines.
5.5.4
Instructions for prescribing and taking study treatment
KAE609
KAE609 can be administered irrespective of the timing of food intake.
Study medication will be administered by the study center personnel with approximately 180-
240 ml of water. Each subject's mouth must be checked to ensure that the medication was 
swallowed. In the case that the patient vomits within 30 minutes of intake a replacement dose 
will be given to the patient and the investigator or designee will notify IRT. If the second dose 
is vomited the patient has to be given Coartem as rescue medication.
Coartem
Patients will be dosed BID for 3 days (at the following time points: 0, 8, 24, 36, 48, and 60 
hours) and must receive a standard meal within 30 min prior to dosing, as per label. In the case 
that the patient vomits within 1 hour of intake a replacement dose will be given to the patient 
and the investigator or designee will notify IRT. If the second dose is vomited the patient has 
to be given non-lumefantrine standard of care. 
Conventional 80/480 mg tablets or 20/120 mg tablets are to be taken orally with a glass of water. 
The dispersible tablet is to be dissolved in 10 mL of water in a small cup, and subsequently 
administered orally under hospital supervision; thereafter the cup will be rinsed with an 
additional 10 mL of water and the content is to be swallowed again.


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Coartem medication should be followed whenever possible by food/drink (broth, sweetened 
condensed milk, etc.) as appropriate.
All dosages prescribed and dispensed to the subject during the study must be recorded on the 
Dosage Administration Record (DAR) CRF.
All kits of study treatment assigned by the IRT will be recorded in the IRT.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Additional doses can be given in case of vomiting (see Section 5.5.4). These changes must be 
recorded on the Dosage Administration Record (DAR) CRF.
Otherwise, investigational or other treatment dose adjustments and/or interruptions are not 
permitted.
5.5.6
Rescue medication
The following circumstances
warrant discontinuation of study treatment and the 
implementation of rescue medication (see Section 6.5.8):
Early treatment failure (ETF)
ETF is defined within this protocol as:
1. Clinical decline or lack of improvement (per Investigator) at 24 hours after first dose of 
treatment.
2. Development of any clinical complications (described in the WHO definition of 
complicated/severe malaria (WHO Guidelines 2010)) in the presence of parasitaemia 
within 72 hours of the first dose of treatment
3. Parasitaemia > 75 000/μL at or after 12 hours post-dose
4. Parasitaemia > baseline with or without fever at 36 hours after first dose of treatment
5. Any parasitaemia based on microscopy with fever, 48 hours post-dose
6. Parasitaemia > 100/ μL based on microscopy with or without fever, 72 hours post-dose
Late Clinical Failure (LCF)
Development of danger signs or severe malaria on any day between Study Day 5 and Day 29
in the presence of parasitaemia without previously meeting any of the criteria of ETF.
Presence of parasitaemia and axillary temperature ≥ 37.5ºC on any day between Study Day 5
and Day 29 without previously meeting any of the criteria of ETF.
Late Parasitological Failure (LPF)
Presence of parasitaemia on any day between Study Day 5 and Day 29 and axillary temperature
< 37.5ºC without previously meeting any of the criteria of ETF or LCF.
Commencement of rescue medication with Coartem may occur after start of trial medications 
and up to Study Day 28 as deemed necessary by the investigator. Any patient on KAE609 who 


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did not need rescue medication up to Study Day 28, will be given Coartem at end of the study 
at Study Day 29. Rescue medication according to local guidance will be used for severe malaria.
Patients randomized to Coartem and meeting treatment failure definition will be further treated 
by rescue medication as per local treatment guidance. 
The patients receiving rescue medication will not be replaced and will not discontinue the study 
(i.e., all the examinations as per the assessment schedule and all CRF pages for this patient will 
need to be completed).
Safety blood tests (Full Blood Count (FBC) and blood chemistry) will be collected on the initial 
day of rescue medication dosing. Blood films and blood sampling for parasite count and 
genotyping must be taken before giving the rescue treatment.
Patients treated with at least one dose of trial medications will continue to be followed-up until 
Study Day 29 according to schedule.
Use of rescue medication (including exact rescue regimen and route of administration) must be 
recorded on the electronic case report form (eCRF).
5.5.7
Prior and concomitant medication
Prior medications are defined as drugs taken and stopped prior to first dose of study medication. 
Concomitant medication is defined as any medication, other than the Investigational Medicinal 
Product (IMP), which is given at least once between the day of first dose of randomized study 
medication and the last day of study visit (including those which were started pre-baseline and 
continued into the treatment period ), including prescription and over-the-counter medicines, 
and any traditional or herbal remedies. 
Paracetamol as an antipyretic, and metopimazine for repeated vomiting (or if not available, any 
other antiemetic which is not known to prolong QT and/or cause torsade de pointes) will be 
allowed. If paracetamol or equivalent drug is given as an antipyretic up to 72 hours prior first 
dose, it has to be reported as prior medication
Metoclopramide is contraindicated from the period prior to first dose to Day 5 post-dose 
(120 hours).
Beta-lactam antibiotics can be given in case of a bacterial infection appearing after 
enrolment. All other antibiotics, new-quinolones included, should be avoided where possible.
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including herbal therapy, physical therapy and blood 
transfusions) administered after the patient was enrolled into the study must be recorded in the 
concomitant medications eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.


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5.5.8
Prohibited medication
Use of the following treatments is NOT allowed as per below recommendation in KAE609 
Cohorts:

Antimalarials other than the study drug and rescue medication (Coartem) are not permitted 
during the entire study period.

Herbal medication should not have been taken within 1 week before the study treatment is 
given and should be avoided until the last study visit.  

Any other investigational treatment for the whole study duration.

KAE609 undergoes CYP3A4 metabolism thus potent and moderate CYP3A inhibitors 
(such as HIV antivirals: e.g., ritonavir miscellaneous: e.g., clarithromycin, itraconazole, 
ketoconazole, grapefruit juice, verapamil, cimetidine) and inducers (such as HIV antivirals: 
e.g., efavirenz miscellaneous: e.g., barbiturates, carbamazepine, phenytoin, rifampin, St. 
John's wort) are not allowed up to 14 days before enrolment in the study or minimum 5 half-
lives of the perpetuator drug (whichever is longer) administration and up to 7 days post 
administration.

KAE609 is a potent inhibitor of CYP2C19 and can potentially increase the exposure of 
drugs which are a substrate of CYP2C19 by many folds (such as Proton pump inhibitors: 
e.g., lansoprazole, omeprazole, anti-epileptics: e.g., phenytoin, miscellaneous: e.g.,
amitriptyline, chloramphenicol, clomipramine, indomethacin, nelfinavir, progesterone
(synthetic progestins used in hormonal contraceptives are not prohibited since they are 
metabolized by CYP3A4), proguanil, propranolol, warfarin). Therefore, these are 
prohibited for the treatment duration and 7 days after last dose.

Drug known to cause QTc prolongation or known to be potentially hepatotoxic (see 
Appendix 4) are prohibited for the treatment duration and 7 days after last dose.
Apart from the above mentioned possible interactions in vitro data suggest KAE609 is inhibitor 
of CYP2B6, CYP2C9, CYP2A6, CYP1A2, CYP2D6, CYP2C8, and CYP3A4, however,
assessment including SimCYP simulation suggests that potential change in the exposure of drug 
substrate of any of these would be less than two fold and unlikely to be of clinical significance. 
Nonetheless caution should be exercised such as staggering the dose of victim drug by ~12 
hours from last dose of KAE609. 
Use of the following treatments is NOT allowed as per below recommendation in 
Coartem/Riamet Cohorts:
Coartem/Riamet prescribing information should be followed in general. Use of any prescription 
drugs (with particular attention to use of CYP3A4 inhibitors, e.g., erythromycin, ketoconazole, 
itraconazole, cimetidine or CYP3A4 inducers e.g., rifampin, phenobarbital etc. Also drugs 
metabolized by CYP2D6 like flecainide, metoprolol, imipramine, amitriptyline, clomipramine, 
neuroleptics and those that increase QTc interval like terfenadine, astemizole, cisapride) is 
prohibited during study and within four (4) weeks prior to dosing. Herbal supplements are also 
prohibited during study and within one week prior to dosing. Medication which may be required 
to treat adverse events can be administered considering the potential interaction. Administration 
of paracetamol (daily total dose not to exceed 3g) / acetaminophen is acceptable, but dose and 
time of administration must be documented in the Concomitant medications / significant non-
drug therapies section of the eCRF.


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5.5.9
Emergency breaking of assigned treatment code
Emergency breaking of assigned treatment code is not needed since this is an open-label trial.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol, and any repeat assessments associated with this visit have 
been documented and followed-up appropriately by the investigator.
Patients who discontinue study drug and/or are put on rescue medication at any time during the 
study will be followed for the entire study duration (i.e., until Study Day 29).
The investigator and/or referring physician must provide follow-up medical care for all patients 
who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care. 
This care may include:

Treatment of their malaria and complications

Treatment of secondary infections

Treatment of associated diseases
A safety review committee will review patient safety at several time points (see Section 8.4) 
and may recommend stopping a treatment arm or the study early for safety reasons.
5.6.2
Discontinuation of study treatment
Patients will be treated under hospital supervision during the treatment period. Discontinuation 
of study treatment for a patient occurs when study drug is stopped earlier than the protocol 
planned duration, and discontinuation can be initiated by either the patient or the investigator. 
For patients assigned to 1-day treatment arm, they will not be considered as treatment 
discontinuation if those discontinuation events occur after they have completed the treatment 
as assigned.
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the participation of the patient in the trial.
Study treatment must be discontinued under the following circumstances: 

Patient request 

Pregnancy (see Section 6.5.6 and Section 7.6)

Use of prohibited treatment as per recommendations in Section 5.5.8

Any situation in which study participation might result in a safety risk to the patient and/or 
any adverse events that in the judgment of the investigator, taking into account the patient’s 
overall status, prevent the patient from continuing participation in the study

Unsatisfactory therapeutic effect (see Section 6.5.8)


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
Emergence of the following adverse events: severe nausea/vomiting, severe pruritus, 
increases in QTcF to >500 ms (based on repeat Electrocardiograms (ECGs), development 
of ventricular arrhythmia or clinically significant (symptomatic) bradycardia (see Appendix 
3)

Any laboratory abnormalities (e.g., LFT increase) that in the judgment of the investigator, 
taking into consideration the patient’s overall status, prevent the patient from continuing 
taking the study medication (see Appendix 2)

Deviation from the planned dose regimen for the study drug
Patients who discontinue study drug for any of the above reasons may be given rescue 
medication at the discretion of the investigator and will be followed for the whole study duration 
until Study Day 29.
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study and should undergo the scheduled study visits. The investigator must determine 
the primary reason for the patient’s premature discontinuation of study treatment and record 
this information on the Treatment Completion eCRF. If the patient completes all the scheduled 
visits in the treatment period, the patient is considered to have completed the treatment period. 
If a patient does not complete the scheduled visits in the treatment period, premature treatment 
discontinuation visit assessments detailed in the assessment schedule table should be completed 
and recorded in the eCRF. The only reason a patient would not complete all these visits is 
because he/she withdrew study consent/ died/ lost to follow up or the sponsor terminated the 
study early.
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient, to collect key 
safety data. This telephone contact should preferably be done according to the study visits 
schedule. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment (this patient will not be replaced). 
5.6.3
Premature Study Withdrawal
Patients are considered to be withdrawn prematurely from the study if they do not complete the 
follow-up visits until Study Day 29.
A patient may voluntarily discontinue participation in this study at any time. The investigator 
may also, at their discretion, discontinue the patient from participating in this study at any time. 
Patients may be prematurely discontinued from the study for any of the following reasons:

Adverse event

Protocol deviation

Study closed/terminated

Loss to follow-up

Consent withdrawal

Study or investigator non-compliance

At the request of the investigator


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
Pregnancy
Patients are not obligated to state the reason for withdrawal from this study. However, the 
reasons for withdrawal, or failure to provide a reason, must be documented by the investigator 
on the Completion/Withdrawal section of the eCRF.
If a patient is withdrawn from the study for any reason, the investigator must make every effort 
to perform the study evaluations for Withdrawal visit as specified in the Table 6-1. Withdrawn 
patients will not be replaced.
5.6.4
Withdrawal of informed consent
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason at 
any time. Withdrawal of consent (WoC) from the study 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 patient’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 patient 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 at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until their time of withdrawal) according to applicable 
law.
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.
5.6.5
Loss 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 patient cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit has passed.
5.6.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 


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must be seen as soon as possible and treated as a prematurely withdrawn patient. 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 patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at which 
time all of the assessments listed for the final visit will be performed. At this final visit, all 
dispensed investigational product should be reconciled and the adverse event and concomitant 
medications reconciled on the eCRF.


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Table 6-1
Assessment schedule
Period
Screen
UNS
299
End of 
Follow up / 
PSW
Study  Day 
4
5
8
11
15
22
29
Window
± 0 day
± 0 day
± 1 day
± 1 day
± 1 day
± 1 day
± 2 day
Time (post first dose) in hours
-6 to < 0
0
1
2
4
6
8
12
24
36
48
50
52
56
60
68
72
96
168
240
336
504
672
Obtain informed consent2
x
Demography
x
Inclusion/Exclusion criteria
x
History of alcohol use and Drug abuse
S
Initial Medical and Treatment history
x
Signs and symptoms of Severe Malaria
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Malaria Blood Film for parasite count
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood sampling for PCR genotyping
x
x
x
x
x
x
x
Vital Signs (blood pressure, pulse)
x
x
x
x
x
x
x
x
x
x
x
x
Body temperature
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Drug Administration Record
x
x10
x11
x10
x11
x10
Rescue Medication (Coartem)3
x
Physical Exam and malaria signs and 
symptoms4
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Prior and concomitant medications
x
x
x
x
x
x
x
x
x
x
x
x
Blood chemistry5
x
x
x
x
x
x
x
x
x
x
x
hematology5
x
x
x
x
x
x
x
x
x
x
x
PK KAE609 Single Dose Cohort (rich PK)6
x
x
x
x
x
x
x
x
x
PK KAE609 Three Dose Cohort (rich PK)6
x
x
x
x
x
x
x
x
x
x
x
x
PK Coartem Cohort6
x
x
x
x
x
Triplicate ECG KAE609 Single Dose Cohort7
x
x
x
x
x
Triplicate ECG KAE609 Three Dose Cohort7
x
x
x
x
x
x
Triplicate ECG Coartem Cohort
x
x
x
x
Urinalysis (Dipstick)
x
x
x
x
x
x
Pregnancy test8
x
x
Adverse events
Meal records9
x
x
x
x
x
x
Contact IRT
x
x
x11
x11
x
Screening period disposition page
x
Treatment completion
x
x10
x11
x10
x11
x10
Treatment period disposition page
x
Follow-up period disposition page
x
1
± 0 day
199
EOT Period / premature 
discontinuation
3
± 0 day
± 0 day
2
102
Visit Numbers1 
1
202
203
205
204
206
201
101
Treatment
Follow-up


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EOT = End of treatment; UNS = Unscheduled visit; PSW = Premature study withdrawal
X = assessment to be recorded on clinical data base
S = assessment to be recorded on source documentation only
β-hCG = The β-subunit of human Chorionic Gonadotropin
1 Visit structure given for internal programming purpose only.
2 Prior to start of any study procedure.
3 Commencement of rescue medication with Coartem may occur after start of trial medications and up to Study Day 28 as deemed 
necessary by the investigator. Any patient on KAE609 who have not been rescued till Study Day 28, will be given Coartem at end of 
the study at Study Day 29.
4 A complete physical examination will be performed by the investigational staff at screening and include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen including splenomegaly, back, lymph nodes, 
extremities, vascular and neurological. Body height and body weight will also be measured at screening and data recorded on clinical 
data base.
An abbreviated physical examination will be performed at all other visits starting from Study Day 1. An abbreviated physical exam will 
include the examination of general appearance, vital signs (blood pressure and pulse) and body temperature. Fever monitoring will be 
done until resolution of fever, defined as being afebrile for 48 hours.
Body weight will also be measured at Study End (Study Day 29 or earlier in case of premature patient discontinuation) and data 
recorded on clinical data base. 
5 Laboratory tests should also be taken at any time of withdrawal/discontinuation. 
6 Missed PK sampling time should be taken as soon as possible and actual time should be recorded. For Scheduled time ≤ 2 h ± 10
min; 2 - ≤24 h ± 30 min; > 24 - ≤ 72 ± 2 h, > 72 h ± 24 h.
7 Will be repeated in case of abnormalities.
8 The patient´s menstrual and contraceptive history will be taken and a serum/plasma β-hCG pregnancy test will be performed at 
screening to exclude pregnancy. A urine β-hCG test will be performed at end of study. Results must confirm negative before dosing. 
9Meals consumed within 30 min prior to dosing and 4 hours post dosing to be documented for Coartem cohort.
10 Comparator only (Coartem).
11 Not applicable to 1-day treatment regimen.
12 ECG’s should be taken in triplicate within 5 min after resting for at least 10 min in the supine position to ensure a stable heart rate 
according to the ECG investigator manual. Also, ECG’s should be taken before any other procedure taken at the same nominal time 
point is performed. For Scheduled time ≤ 2 h ± 10 min; 2 - ≤24 h ± 30 min; > 24 - ≤ 72 ± 2 h, > 72 h ± 24 h.


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6.1
Information to be collected on screening failures
All patients/subjects who have signed informed consent but not entered into the next period will 
have the study completion page for the screening period, demographics, inclusion/exclusion, 
and serious adverse event (SAE) data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: 

Age

Gender

Body weight

Body height

Body temperature

Severe malaria

Vital signs

Prior and concomitant medications

Blood chemistry and hematology

Urinalysis

Pregnancy test

Malaria blood film for parasite

Blood sampling for Polymerase Chain Reaction (PCR) genotyping

Medical history

Triplicate 12-lead ECG
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.3
Treatment exposure and compliance
All study treatment taken must be recorded in the Drug Administration Record (DAR) CRF, 
along with any comments about whether the patients swallowed all or part of the medication, 
whether and when vomiting occurred, and whether replacement medication had to be initiated.
Records of study medication used and exact dosages administration will be kept during the 
study. Drug accountability will be noted by the field monitor during site visits and at the 
completion of the study.
All medication (other than study drug) and significant non-drug therapies administered after the 
patient starts treatment with study drug will be documented on the concomitant 
medications/Significant non-drug therapies (surgical and medical procedures CRF and 
non-surgical procedures CRF) CRF after start of study drug.


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6.4
Efficacy
Efficacy assessments will be based on the PCR-corrected Adequate Clinical and Parasitological 
Response (ACPR) and PCR-Uncorrected ACPR at Study Days 15 and 29 (see Section 6.5.8).
6.4.1
Parasitaemia assessment
Blood sampling for parasitology can be done by means of finger prick except when the timing 
for parasitology assessments coincide with time for clinical laboratory tests, in which case, 
blood sample can be taken from the venous blood collected for clinical laboratory analyses.
Parasite counts:

Giemsa stained thick (and thin) films will be examined. Thin films will be examined only 
if identification of species is needed after malaria (Plasmodium) parasite is detected in a 
thick film 

Examination with binocular microscope and with oil immersion lens

Screening examination (prior to patient inclusion into the trial), thick film:

at least 200 thick film fields are examined. If there is no malaria parasite, the slide is 
declared negative, and the patient is not suitable for inclusion.

if asexual forms of Plasmodia are found, a total of 200 thick film fields are to be 
screened for Plasmodium species other than P. falciparum. 

when it has been ascertained that P. falciparum is present, a count is made of the asexual 
forms against leukocytes, using a tally counter. Counting needs to be done based on at 
least 200 leukocytes according to the WHO standards. If less than 100 parasites, 
counting will be extended to 500 leukocytes. The parasite density will be calculated 
according to the formula:
Number of Plasmodium parasites x actual leukocytes (White 
Blood Cell, WBC)
Parasite density per µl = __________________________________________________ 
Number of leukocytes (WBC) counted (200)

Blood examination during the 29 day trial period:

a total of 200 thick films fields are examined (tally counter) before a slide can be 
pronounced negative

if asexual forms of P. falciparum are present, a parasite count is required

if Plasmodium species other than P. falciparum are found, note species
The count should be made for each species (White et al 2014). Blood film may be potentially 
confirmed by PCR. Thick (and thin blood) films will be taken as specified in the assessment 
schedule table and evaluated by standard techniques (Giemsa stain). This will be the definitive 
test for a positive P. falciparum infection. The parasite counts can also be quantified in ‰ (per 
1000) of red cells in the thin film. 
Further technical details are provided in the laboratory manual. 


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6.4.2
Appropriateness of efficacy assessments
The microscopy examination methods to quantify the malaria parasite in blood are validated 
methods (Sinden et al 2012; White et al 2014). For full details refer to the Study Laboratory 
Procedures Manual.
6.5
Safety
Clinical adverse events will be monitored throughout the study to assess the general safety and 
tolerability of the treatment groups.
6.5.1
Physical examination and malaria signs and symptoms
A complete physical examination will be performed by the investigational staff at screening
and include the examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen including splenomegaly, back, lymph nodes, extremities, 
vascular and neurological. 
An abbreviated physical examination will be performed at all other visits starting from Study 
Day 1 including the examination of general appearance and vital signs. Fever monitoring will 
be done until resolution of fever, defined as being afebrile for 48 hours.
A full assessment of malaria signs and symptoms will be made alongside the physical 
examinations at timepoints described in the assessment schedule for all patients (Table 6-1).
Information for all physical examinations must be included in the source documentation at the 
study site. Body height and body weight must be recorded in the clinical database. Clinically 
relevant findings that are present prior to signing informed consent must be included in the 
Medical History part of the eCRF. Significant findings made after first administration of 
investigational drug which meet the definition of an Adverse Event must be recorded on the 
Adverse Event section of the eCRF.
6.5.2
Vital signs
Vital signs (blood pressure, body pulse) will be monitored as part of the physical exam as 
indicated in the study assessment schedule table and recorded on the clinical database.
After the patient has been in supine position for five minutes, systolic and diastolic blood 
pressure will be measured three times using an automated validated device, e.g., OMRON, with 
an appropriately sized cuff. The repeat measurements will be made at 1 - 2 minute intervals and 
the mean of the three measurements will be used. The same arm must be used throughout the 
study. A sphygmomanometer with an appropriately sized cuff should be used. 
6.5.3
Height and weight
In addition, body height in centimeters (cm) will be measured at screening and body weight to 
the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes will be measured at screening 
and at study end (Study Day 29 or earlier in case of premature patient withdrawal from study 
participation).


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6.5.4
Laboratory evaluations
A local laboratory will be preferably used for analysis of all specimens collected except for 
PCR (parasite identification), ECG and PK measurements where central laboratory will be used. 
Details on the collections, shipment of samples and reporting of results by the central 
laboratories are provided to investigators in the laboratory manuals where applicable. 
Assessments will be done as indicated in the study assessment schedule table.
Clinically notable laboratory findings are defined in Appendix 1.
Hematology, Blood chemistry and Urinalysis assessments will be done as described in the
assessment schedule table (Table 6-1).
6.5.4.1
Hematology
Hemoglobin, hematocrit (packed-cell volume (PCV)), platelets, white blood cell (WBC) count 
with differential (as much as possible, neutrophil, lymphocyte and eosinophils counts will be 
performed while basophils and monocytes can be aggregated as ‘other’) counts will be 
measured. Red blood cell count (RBC), reticulocytes count will be performed in case of 
significant hemoglobin drop > 2 g/dL or hemoglobin levels ≤5 g/dL (will be optional depending 
on site equipment). Assessments will be done as indicated in the study assessment schedule 
table (Table 6-1).
6.5.4.2
Blood chemistry
Routine blood chemistry testing will be performed according to the visit schedule in order to 
monitor the general medical condition of the patient.
This includes: Glucose, creatinine (serum), transaminases (ALT/SGPT and AST/SGOT), 
serum-γ-glutamyl transferase (GGT), Total and conjugated bilirubin, haptoglobin, LDH, ALP, 
BUN, INR, sodium, potassium, magnesium, calcium, chloride, total protein and, albumin, .
6.5.4.3
Urinalysis
Dipstick measurements for specific gravity, protein, glucose and blood will be performed as 
indicated in the study assessment schedule table. Microscopy will be performed and urine 
sediment will be assessed in case of an abnormal dipstick test.
6.5.5
Electrocardiogram (ECG)
ECGs should be taken in triplicate within 5 minutes (after 10 minutes rest in the supine position 
to ensure a stable heart rate according to the ECG investigator manual). The preferred sequence 
of cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. 
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Triplicate 12 lead ECGs are to be collected with ECG machines supplied by the central 
laboratory. Initial manual readout will be done locally in order to detect significant safety 
findings and allow for immediate response if needed. Local readout will be used for 
inclusion/exclusion purposes as central readout is not available within 24 hours.


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In the event that a clinically significant ECG abnormality is identified at the site (e.g., severe 
arrhythmia, conduction abnormality of QTcF > 500 ms) the SAE must be reported according to 
the procedure described in Section 7.2. If the patient is hemodynamically compromised, the 
investigator or a medically qualified person must initiate appropriate safety procedures without 
delay (for example cardioversion).
If QTcF is > 500 ms or QTcF increases ≥60 ms from baseline occur at any time, the patient 
should be assessed at the site and appropriate safety procedures (e.g., electrolyte correction) 
initiated without delay, if required. In addition two additional ECGs should be collected at 
2-min intervals and provided to the central ECG laboratory for confirmation.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF page as appropriate.
For 3 day regimens, any post-dose average QTc ≥500 ms will result in patient discontinuation 
from the treatment if there is a planned subsequent treatment.
Assessments will be done as indicated in the study assessment schedule table. All ECGs will 
be assessed centrally by an independent and blinded (with age of patient identified) cardiologist.
6.5.6
Pregnancy and assessments of fertility
A serum or plasma pregnancy test will be performed at the screening visit and urine pregnancy 
test will be performed at study completion. All female patients in this study must undergo 
obligatory pregnancy testing as per schedule of assessment (Table 6-1).
6.5.7
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
6.5.8
Definition of Treatment Failure
Early treatment failure (ETF)
ETF is defined within this protocol as:
1. Clinical decline or lack of improvement (per Investigator) at 24 hours after first dose of 
treatment.
2. Development of any clinical complications (described in the WHO definition of 
complicated/severe malaria (WHO Guidelines 2010)) in the presence of parasitaemia 
within 72 hours of the first dose of treatment
3. Parasitaemia > 75 000/μL at or after 12 hours post-dose
4. Parasitaemia > baseline with or without fever at 36 hours after first dose of treatment
5. Any parasitaemia based on microscopy with fever, 48 hours post-dose
6. Parasitaemia > 100/ μL based on microscopy with or without fever, 72 hours post-dose
Late Clinical Failure (LCF)
Development of danger signs or severe malaria on any day between Study Day 5 and Day 29
in the presence of parasitaemia without previously meeting any of the criteria of ETF


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Presence of parasitaemia and axillary temperature ≥ 37.5ºC on any day between Study Day 5
and Day 29 without previously meeting any of the criteria of ETF
Late Parasitological Failure (LPF)
Presence of parasitaemia on any day between Study Day 5 and Day 29 and axillary temperature
< 37.5ºC without previously meeting any of the criteria of ETF or LCF
Adequate Clinical and Parasitological Response (ACPR):
Absence of parasitaemia on Study Day 29 irrespective of axillary temperature, without 
previously meeting any of the criteria of ETF or Late Treatment Failure or LPF.
Note: The first day of treatment with study medication is defined as Study Day 1 while the day 
prior to the first day of treatment is defined as Day -1. Compared to WHO (2016) which defined 
Day 0 as the first day of treatment with study medication, days after treatment referred to in this 
protocol are 1 day greater. For example, Study Day 29 in this protocol corresponds to Day 28 
by WHO (2016).
Signs/symptoms indicative of severe/complicated malaria 
Danger signs: 
1. not able to drink 
2. vomiting > twice within preceding 24 hours 
3. one convulsion within preceding 24 hours
4. unconscious state
5. unable to sit or stand
Signs of severe malaria:
Severe falciparum malaria is defined as one or more of the following, occurring in the absence 
of an identified alternative cause and in the presence of P. falciparum asexual parasitaemia:

Impaired consciousness (Glasgow coma score < 11 in adults)

Prostration (generalized weakness i.e., unable to sit, stand or walk without assistance)

Multiple convulsions (more than two episodes within 24 hours)

Acidosis (a base deficit of > 8 mEq/L or if not available a plasma bicarbonate level of 
< 15 mmol/L or venous plasma lactate ≥ 5 mmol/L. severe acidosis manifests clinically as 
respiratory distress i.e., rapid, deep, laboured breathing)

Hypoglycemia (blood or plasma glucose < 2.2 mmol/L; < 40 mg/dL)

Severe malarial anemia (haemoglobin concentration < 7 g/dL or haematocrit of < 20% in 
adults with a parasite count > 10 000/µL)

Renal impairment (plasma or serum creatinine > 265 µmol/L (3 mg/dL) or blood 
urea > 20 mmol/L)

Jaundice (plasma or serum bilirubin > 50 µmol/L (3 mg/dL) with a parasite 
count > 100 000/µL)

Pulmonary edema (radiologically confirmed or oxygen saturation < 92% on room air with 
a respiration rate > 30/min, often with chest indrawing and crepitations on auscultation)


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
Significant bleeding (including recurrent or prolonged bleeding from the nose, gums or 
venipuncture sites, haematemesis or melaena)

Shock (compensated shock i.e., capillary refill ≥ 3s or temperature gradient on leg but no 
hypotension; decompensated shock i.e., systolic blood pressure < 80 mm Hg in adults with 
evidence of impaired perfusion)

Hyperparasitaemia (P. falciparum parasitaemia > 10%)
 
6.6.1
Pharmacokinetics
Details on sample collection, numbering, processing and shipment can be found in the 
Laboratory Manual.
7
Safety monitoring
7.1
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 until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy.
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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.


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Study drug/treatment includes investigational drug KAE609 (10 mg, 25 mg, 50 mg, 75 mg, 150 
mg, 225 mg, or 110 mg) as well as Coartem.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the Common Toxicity Criteria (CTC) AE grade
If Common Toxicity Criteria for Adverse Events (CTCAE) grading does not exist for an adverse 
event, use
1= mild
2= moderate
3= severe
4= life-threatening (see Section 7.2 for definition of SAE)
CTCAE Grade 5 (death) is not used, but is collected as a seriousness criteria and also collected 
in other CRFs (Study Completion, Death/Survival).
There may be cases where a CTCAE with a grade of 4 (life-threatening) may not necessarily 
be an SAE (e.g., certain laboratory abnormalities in the absence of meeting other seriousness 
criteria). 

its relationship to the study treatment and the reference product Coartem (Yes/No)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a SAE (see Section 7.2 for definition of SAE) and which seriousness 
criteria have been met.

action taken regarding (investigational) treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g., further observation only) 

study treatment withdrawn

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving;
recovered/resolved with sequelae; fatal; or unknown)
The action taken to treat the adverse event should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the patient informed consent and should 


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be discussed with the patient during the study as needed. Any new information regarding the 
safety profile of the medicinal product that is identified between IB updates will be 
communicated as appropriate. New information might require an update to the informed 
consent and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
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:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient 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.
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 patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 


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dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse.
Any suspected transmission of an infectious agent via a medicinal product is also considered a 
serious adverse reaction.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and following the last administration of study treatment must be 
reported to Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced 
after the 30 day period after the last study visit should only be reported to Novartis safety if the 
investigator suspects a causal relationship to study treatment. 
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.
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English in the electronic Serious Adverse Event (eSAE) Form within the Oracle 
Clinical/Remote Data Capture (OC/RDC) system (wherever available and/or feasible) or on the 
paper SAE Report Form that should be used as back-up, especially in case where there is no 
feasibility of the use of eSAE Form. The investigator must assess the relationship of each SAE 
to the study treatment (KAE609 or Coartem).
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an existing 
SAE. These data will automatically be submitted to Novartis Chief Medical Office and Patient 
Safety (CMO&PS) immediately after investigator signature or 24 hours after entry, whichever 
occurs first.
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated and whether the patient continued or withdrew 
from study participation.
If the SAE is not previously documented in the IB for KAE609 or Package Insert for Coartem 
(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. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
European Union (EU) Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.


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7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which are considered as medically significant events, i.e., SAEs and 
which consist of marked elevations of LFTs and / or pre-specified adverse events. 
These events will require close observation, follow-up monitoring and completion of 
the standard base liver CRF pages.
Any liver event which meets the criteria for a “medically significant” event should follow the 
standard procedures for SAE reporting as described in Section 7.2.
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or a designated medically qualified person at the trial site as 
summarized below. Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the LFT within 24 hours to confirm elevation.
These LFT repeats can be performed at a local laboratory to monitor the safety of the subject. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the liver CRF pages.
Repeat laboratory tests must be entered on the appropriate unscheduled local laboratory CRF 
page.

If the elevation is confirmed, close observation of the patient will be initiated, 
including consideration of treatment discontinuation if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., 
disease, co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver event 
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7.4
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 3. 
7.5
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, patient or 
consumer (European Medicines Agency (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 DAR 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.
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration 
Record (DAR) 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
7.6
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 


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the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local/regional Novartis CMO & PS Department. Pregnancy follow-up should 
be recorded on the same form and should include an assessment of the possible relationship to 
the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on an eSAE form/paper SAE form (as applicable).
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 female partner.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the eCRFs, the adherence to the protocol and to Good 
Clinical Practice (GCP), the progress of enrollment, and to ensure that study drugs are being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis CRA organization. Additionally, a 
central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents (archival and storage) for each patient in the 
study, consisting of case and visit notes (hospital or clinic medical records) containing 
demographic and medical information, laboratory data, ECGs, and the results of any other tests 
or assessments as per ICH-GCP standards. All information on eCRFs must be traceable to these 
source documents in the patient's file. The investigator must also keep the original informed 
consent form signed by the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 
of SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the patients/subjects will be disclosed.


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8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRFs using 
fully validated software that conforms to 21 US Code of Federal Regulations (CFR) Part 11 
requirements and into the OC/RDC. Designated investigator site staff will not be given access 
to the system until they have been trained. Automatic validation programs check for data 
discrepancies during and after data entry and, by generating appropriate error messages, allow 
the data to be confirmed or corrected online by the designated investigator site staff. The 
Investigator must certify that the data entered into the eCRFs are complete and accurate. After 
database lock, the investigator will receive a CD-ROM or paper copies of the patient data for 
archiving at the investigational site. 
All data captured for this study will have an external originating source (either written or 
electronic), the eCRF is not considered as source.
8.3
Database management and quality control
Novartis staff (or CRO working on behalf of Novartis) review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical (ATC) classification 
system. Concomitant procedures, non-drug therapies and adverse events will be coded using 
the Medical dictionary for regulatory activities (MedDRA) terminology.
For those laboratory samples that will be processed centrally the results will be sent 
electronically to Novartis (or a designated CRO). ECG readings will be processed centrally and 
the results will be sent electronically to Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient will be tracked 
using an IRT. The system will be supplied by a vendor, who will also manage the database. The 
database will be sent electronically to Novartis (or a designated CRO).
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked. Any changes to the database after that time can only be made after written agreement 
by Novartis Development management.
8.4
Safety review committee
A safety review committee will be established for this study to review patient safety at several 
time points. The safety review committee can recommend stopping the study or a specific 
treatment arm in case of serious safety observations especially related to hepatic safety profile. 
The safety review committee will include at least one external hepatologist. Regular interim 
review for patient safety will be performed during the study as specified in the safety review 
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Additional ad-hoc safety review may be requested by the safety review committee or the Study 
Team if needed. 
Details of safety analyses will be specified in the analysis plan for the safety review committee. 
The safety review committee will make recommendations to the Study Team on any safety 
issues that are deemed relevant and any changes in the conduct of the study.
Further details of the safety review committee’s composition, organization and responsibilities 
will be described in the safety review committee charter.
8.5
Adjudication Committee
Not required.
9
Data analysis
At the end of trial, full statistical analyses will be performed by cohort and treatment group. 
Coartem data from all cohorts will also be pooled.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
9.1
Analysis sets 
Randomized set
All patients who are randomized.
Full analysis set (FAS) 
FAS will be comprised of all patients from Randomized set who take at least one dose of study 
treatment during the treatment period and whose baseline parasitaemia count is greater than 0. 
Following the intent-to-treat principle, patients will be analyzed according to the treatment 
group assigned to at randomization.
Safety set (SAF set) 
Safety set includes all patients who take at least one dose of study drug during the treatment 
period. Patients will be analyzed according to treatment received. Full details will be described 
in the statistical analysis plan (SAP).
Per-protocol set (PPS) 
PPS will be comprised of patients in FAS who

did not have any important protocol deviations

took at least 80% of assigned study medication(s). If a patient vomited the original dose but 
did not vomit the replacement dose, the patient is considered as taking the dose of study 
medication. Except for patients who are assigned to Coartem treatment, this requires that all 
patients take all KAE609 dosages as assigned


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
did not take other antimalarial medications prior to Study Day 29 for reasons other than 
rescue medication given for P. falciparum related treatment failure, and

met at least one of the following criteria: (a) classified as treatment failure before Study Day 
8 (see Section 6.5.8), (b) absent from parasitaemia at Study Day 29, or (c) had valid PCR 
evaluations at baseline and at the time point with parasitaemia if parasitaemia is present at 
Study Day 8 or later.
Important protocol deviations for exclusion from PPS will be identified by the clinical team 
before the final database lock.
PK analysis set 
All subjects in the safety analysis set who had evaluable PK parameter data and took at least 
80% of assigned study medication.
9.2
Patient demographics and other baseline characteristics
Demographic data and baseline disease characteristics will be descriptively presented and 
tabulated (n, mean, standard deviation, median, minimum, and maximum for continuous 
variables; n and percent for categorical variables) per cohort and treatment arm, as well as 
overall, using the Randomized set.
9.3
Treatments
All analyses in this section will be performed using the safety set.
9.3.1
Study treatment
Number and percentage of doses taken will be presented by cohort and treatment arm. The 
percentage will be calculated based on the planned number of doses per treatment arm. 
Percentage of patients with study drug vomiting and dose replacement will be presented by 
treatment arm. Average daily dosage and total dosage (in mg or tablet) of each drug (KAE609, 
Coartem) will be summarized by cohort and treatment arm.
9.3.2
Prior and concomitant medication
Medications will be identified using the Novartis drug and therapy dictionary (NovDTD) 
including ATC code.
Prior and concomitant medications will be summarized by cohort and treatment group in 
separate tables. Concomitant rescue and other anti-malarial medications will also be 
summarized by cohort and treatment group. Medications will be presented by ATC class and 
preferred term. Tables will also show the overall number and percentage of subjects receiving 
at least one drug of a particular ATC class.
Prior medications are defined as drugs taken and stopped prior to first dose of study medication. 
Any medication given at least once between the day of first dose of randomized study 
medication and the last day of study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the treatment period.


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9.4
Analysis of the primary variable(s)
The primary variable is a safety related endpoint. Therefore, it will be analyzed primarily using 
the SAF set. Efficacy variables are related to secondary 
and the 
related analyses will be presented in Section 9.5 and Section 9.6. 
9.4.1
Primary Variable(s)
The primary variable is the occurrence of at least 2 CTCAE grades increase from baseline in 
ALT or AST during the 4 weeks study period.
9.4.2
Statistical model, hypothesis, and method of analysis
The study is a Phase II safety study aiming to rule out high incidence of abnormal LFT reported 
in a couple of earlier studies. As the significance of safety related results is determined by both 
the frequency of the event and the severity of the event, there is no pre-defined hypothesis. The 
following analyses will be performed using the SAF set:

Proportion of patients with occurrence of the primary variable by cohort and treatment 
group and the 95% confidence interval based on the exact CI (Pearson-Clopper method).

2-sided Fisher exact test for each KAE609 treatment group compared to the pooled 
Coartem.
These results along with patient narratives will be assessed to make decision about whether a 
KAE609 dosage regiment is safe for further development.
9.4.3
Handling of missing values/censoring/discontinuations
No missing value of the primary variable is expected since the analysis is based on the SAF set 
and all patients in the SAF set should provide safety observation as they are hospitalized for the 
first 3 days. No missing imputation will be done in this study.
9.4.4
Sensitivity analyses
In the past KAE609 studies, peak LFT occurred during the first 2 weeks. For patients who 
discontinued the study during the first 2 weeks, their peak LFT may not be observed. Analyses 
in Section 9.4.2 will be performed by excluding those patient(s) who discontinued the study 
before Study Day 15 and did not experience at least 2 CTCAE grades increase from baseline in 
ALT or AST.  
9.5
Analysis of secondary variables
Descriptive statistics for each secondary variable will be provided by cohort and treatment 
group. Statistical comparison with Coartem will not be performed due to small sample size for 
each treatment group. 
9.5.1
Efficacy variables
Secondary efficacy variables include:

PCR-corrected ACPR at Study Days 15 and 29;

Uncorrected ACPR at Study Days 15 and 29;


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
Proportion of patients with parasitaemia at 12, 24, and 48 hours after treatment;

Parasite clearance time (PCT), defined as time from the first dose until the first total and 
continued disappearance of asexual parasite forms which remained at least a further 48 
hours;

Fever clearance time (FCT), defined as time from the first dose until the first time the 
axillary body temperature decreased below and remained below 37.5°C axillary or 38.0°C 
oral/tympanic/rectal for at least a further 24 hours;

Proportion of patients with ETF;

Proportion of patients with LCF;

Proportion of patients with LPF;

Incidence rate of recrudescence and reinfection at Study Day 29.
Analyses of ACPRs (PCR corrected or uncorrected) will be based on the FAS and PPS. 
Analyses of other secondary efficacy variables will be based on the FAS.
9.5.1.1
PCR-corrected ACPR and uncorrected ACPR
At each visit, the ACPR rate with 95% confidence intervals will be provided using the Pearson-
Clopper method for each treatment group by cohort.
Data will be handled as follows:

Treatment failures after 7 days (i.e., Study Day 8) due to reinfection based on PCR 
genotyping are not considered as failure for PCR-corrected analyses.

For parasitological uncorrected ACPR, patients will be treated as failure on and after the 
visit when a new infection (i.e., reinfection) with P. falciparum or other species is 
detected.

Patients who received rescue medication for the treatment of P. falciparum malaria 
(except for the treatment of a new infection) will be considered treatment failures. Patients 
who received other concomitant medication having an effect on malaria for reasons other 
than rescue therapy e.g., for the treatment of P. vivax (e.g., primaquine, certain antibiotics 
(sulfonamides, tetracycline, etc.)) will be considered in the analysis as if they had not 
taken the drug.

Patients will be counted as failure at a visit (e.g., Study Day 15, etc.) if (a) they did not 
have a parasite count i.e., missing parasite count at that visit unless these patients could be 
classified as cured based on absence of parasitaemia (parasite count = 0) at a later time 
(e.g., Study Day 29), or (b) they did not have valid PCR evaluations at baseline and the 
visit if parasitaemia was present at that time (e.g., Study Day 15).
In addition, PCR-corrected ACPR rate will be calculated and plotted using the Kaplan-Meier 
method (Stepniewska and White 2006; WHO 2016) for each treatment group by cohort in the 
FAS. Treatment failure is the event for analysis and patients without Study Day 29 data and 
treatment failure is considered as censored instead of treatment failure. The PCR-corrected 
ACPR rate at Study Day 29 is estimated by the survival function at Study Day 29. Patients who 
had a new infection (i.e., reinfection) with P. falciparum or other species without P. falciparum
recrudescence on or after Study Day 8 will be censored at the time of the first PCR that indicate 
the infection; patients who took antimalarial medications for reinfection or reasons other than 


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rescue medication given for P. falciparum related treatment failure will be censored at the first 
time of such antimalarial medications; other patients without treatment failure will be censored 
at the time of last parasitaemia assessment.
9.5.1.2
Treatment failure related parameters
For the following parameters, 95% confidence intervals will be provided for each treatment 
group by cohort using the Pearson-Clopper method:

proportion of patients with parasitaemia at 12, 24, and 48 hours after treatment

proportion of patients with ETF

proportion of patients with LCF

proportion of patients with LPF
The above parameters will be determined using the uncorrected parasite counts.
In addition, patients whose outcome status cannot be determined due to incomplete/missing 
data will be excluded from analysis.
9.5.1.3
Parasite clearance time (PCT) and fever clearance time (FCT)
Descriptive statistics (mean, standard error, median, quartiles) will be presented for each 
treatment by cohort using the Kaplan-Meier method. Kaplan-Meier curves will be provided.
PCT will be calculated based on uncorrected parasite counts. Patients without parasite clearance 
for whatever reason will be censored at the time of last parasite assessment. 
Patients who were enrolled on the basis of history of fever and did not subsequently have a 
fever at pre-dose will not be included in the analysis of FCT. Patients without fever clearance 
for whatever reason will be censored at the time of last temperature assessment. In case that a 
patient receives rescue medication before (parasite or fever) clearance, the time to event will be 
censored at the first use of rescue medication.  
9.5.1.4
Recrudescence
Reinfection is defined as appearance of asexual parasites after clearance of initial infection with 
a genotype different from those parasites present at baseline. 
Recrudescence is defined as appearance of asexual parasites after clearance of initial infection 
with a genotype identical to that of parasites present at baseline. Recrudescence must be 
confirmed by PCR analysis.
Incidence rates of recrudescence at Study Day 29 will be estimated by Kaplan-Meier method 
based on the subset of FAS patients who have clearance of initial infection by Study Day 7. 
Time to recrudescence will be calculated from the time of first study medication to the date of 
first event if a patient experience the event and be censored at the time of last parasite 
assessment if a patient does not experience the event.
9.5.2
Safety variables
All safety parameters will be analyzed by cohort and treatment group based on the safety.


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9.5.2.1
Adverse event
The number and percentage of patients who report adverse events will be provided according 
to primary system organ class (PSOC), preferred term, and severity. If a patient reports more 
than one adverse event with the same preferred term, the adverse event with the greatest severity 
will be presented. If a patient reports more than one adverse event within the same PSOC, the 
patient will be counted only once with the greatest severity.
Cause of death, SAEs, adverse event causing study drug discontinuation, adverse events by 
severity and causality will be presented. Listings of these events will be provided.
9.5.2.2
Laboratory evaluations
Summary of laboratory evaluations will be presented with respect to three groups of laboratory 
tests (hematology, blood chemistry, and urinalysis).
Descriptive summary statistics (mean, median, standard deviation, minimum and maximum) 
for the baseline, each study visit, and change from baseline to each study visit will be presented. 
These descriptive summaries will be presented by laboratory test group.
In addition, shift tables will be provided in order to compare a patient’s baseline laboratory 
evaluation relative to each study visit and at the maximum value. For the shift tables, the normal 
laboratory values will be used to evaluate whether a particular laboratory test value is normal, 
low, or high for each visit value relative to whether or not the baseline value is normal, low, or 
high. For liver enzymes (ALT, AST, etc.), the shift table of CTCAE grades relative baseline 
and number and percent of patients with ≥2 x ULN (if baseline is normal) or 2 x baseline (if 
baseline is > ULN) will be provided. These summaries will be presented by laboratory test 
group.
9.5.2.3
Vital signs
Descriptive summary statistics for the baseline, each study visit, and change from baseline to 
each study visit will be presented for each vital sign parameter (pulse rate, systolic/diastolic 
blood pressures).
Number and percentage of patients who have vital sign values that meet the criteria for being 
clinically notable after the first dose of study medication will be presented.
9.5.2.4
ECGs
Descriptive summary statistics for the baseline, each study visit, and change from baseline to 
each study visit will be presented for heart rate, PR interval, QRS interval, RR interval, QT 
interval and QTcF (QT interval corrected for heart rate according to Fridericia). Number and 
percentage of patients with abnormal values (such as QTc > 480 ms and > 500 ms or HR 
< 50 /min) and changes from baseline (such as increases in QTc for ≥30 ms and ≥60 ms) will 
be tabulated at each time point and at the maximum value by treatment group in the form of a 
categorical analysis.


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9.5.3
Resource utilization
Data relating to resource utilization will be used for the purpose of economic evaluation which 
will be carried out and reported as a separate activity.
9.5.4
Pharmacokinetics
PK concentrations below the limit of quantification will be treated as zero in summary statistics 
and for the calculation of pharmacokinetic parameters by non-compartmental analysis. 
Descriptive statistics of pharmacokinetic parameters will include arithmetic mean, geometric 
mean, standard deviation, median, minimum and maximum, etc. Parameters such as AUCinf, 
AUClast, AUC0-t, Cmax and Tmax will be reported using non-compartmental method of 
analysis (using Phoenix 6.4 or higher). 


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9.7
Interim safety review
Safety laboratory data and adverse events will be monitored continuously throughout the study 
using data management’s data review reports. 
If there is no significant LFT elevations observed in a cohort at Day 15 (see Table 3-1), the next 
cohort with escalated KAE609 doses will start after informing the safety review committee 
about the findings.
If any significant LFT elevation is observed at Day 15 in any patient(s) in a cohort (see Table 
3-1), a comprehensive safety data review will be performed after all the patients in the cohort 
have been followed up for 28 days post-treatment. 
The safety review committee can pause recruitment and trigger safety review any time based 
on safety signals. An earlier review of the safety data by the safety review committee/Novartis 
in the middle of a cohort would be initiated based on occurrences of LFT elevations in the
cohort as specified below:

The number of patients meeting the primary safety endpoint in a treatment arm is at least 2 
in Cohorts 1 and 2 or at least 3 in Cohorts 3, 4, 5 and 6.  
Data management’s data review reports will be provided to the safety review committee and 
the appropriate Novartis relevant internal and external people who will make decision about 
whether a KAE609 dosage regiment is safe and can be escalated to the higher dosage. Although 
the randomization data are not included in the data management system, the study drug 
(KAE609 QD 1 day, KAE609 QD 3 days, Coartem) and dosage taken by each patient is 
available in the dosage records. No formal interim safety analysis by treatment group will be 
performed.
In case that more comprehensive safety analyses by treatment group are needed at the end of 
cohort or in the middle of cohort, formal interim safety analyses of selected safety or efficacy 
parameters by treatment group will be provided as described in the safety review charter.
9.8
Sample size calculation
The incidence of patients experiencing at least 2 CTC grade increase from baseline in ALT or 
AST is not consistent among KAE609 patient/human challenge studies:

3 out of 8 (37.5%) patients in a Study with KAE609 at 10 mg QD.

4 out of 11 (36.4%) in a Study with KAE609 at 75 mg QD.

1 out of 25 (4%) in a Study with KAE609 at 10 to 30 mg QD.

1 out of 21 (4.8%) in a Study with KAE609 at 30 mg QD X3. 
9.8.1
Single arm approach
Figure 9-1 and 9-2 present the probability of observing at least 2 and 3 safety events, 
respectively, in a treatment group by various sample sizes and true event rates to assess the 
operational characteristics for the proposed sample sizes.


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Given the proposed sample sizes in the treatment groups within each cohort, the probability of 
observing at least 2 safety events in 10 patients or 3 safety events in 20 patients is at least 80% 
if the true event rate is ≥30% and less than 5% if the true event rate is ≤3%. Specifically:
•
For a sample size of 10 patients per treatment group, the probability of observing ≥2 safety 
events is greater than 80% if the true event rate is ≥30% and less than 5% if the true event 
rate is ≤3% (Figure 9-1).
•
For a sample size of 20 patients per treatment group, the probability of observing ≥ 3 safety 
events is greater than 90% if the true event rate is ≥30% and less than 5% if the true event
rate is ≤3% (Figure 9-2).
Figure 9-1
Probability of observing at least 2 safety events by sample size and 
true event rate


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Figure 9-2
Probability of observing at least 3 safety events by sample size and 
true event rate
9.8.2
Power for comparison of KAE609 with Coartem
The comparison between KAE609 doses/regimen with Coartem will help interpretation of liver 
enzyme elevations in the individual KAE609 treatment arms. In the Pyramax Phase II/III trials
(EMA 2012), the incidence of patients experiencing Grade 2 ALT was 3.4%, which was higher 
than other comparators including Coartem. The incidence rate of adults and adolescents 
experiencing at least 2 CTC grade increase from baseline in ALT or AST in Coartem is about 
3%. To assess the power for between treatment comparisons, a Coartem incidence rate of 5% 
is also considered.


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Table 9-1
Power for comparison with Coartem based on 2-sided Fisher exact test
KAE609 true 
incidence rate
Coartem® true 
incidence rate
n for 
KAE609
N for 
Coartem®
Power for 2-sided testing
5% level
10% level
20% level
50%
3%
10
10
50%
70%
77%
10
20
86%
91%
95%
10
30
91%
95%
97%
10
40
94%
97%
99%
10
50
93%
97%
99%
10
60
94%
98%
99%
50%
3%
20
10
78%
84%
92%
20
20
94%
97%
99%
20
30
99%
99%
>99%
20
40
99%
>99%
>99%
20
50
>99%
>99%
>99%
20
60
>99%
>99%
>99%
50%
5%
10
10
43%
63%
72%
10
20
80%
86%
92%
10
30
85%
92%
95%
10
40
90%
94%
97%
10
50
89%
94%
97%
10
60
90%
95%
97%
50%
5%
20
10
71%
77%
86%
20
20
89%
94%
97%
20
30
96%
98%
99%
20
40
98%
99%
>99%
20
50
99%
99%
>99%
20
60
99%
99%
>99%
40%
3%
10
10
28%
50%
54%
10
20
70%
78%
87%
10
30
77%
87%
91%
10
40
84%
91%
95%
10
50
82%
90%
95%
10
60
83%
92%
95%
40%
3%
20
10
49%
61%
80%
20
20
81%
88%
94%
20
30
93%
94%
98%
20
40
96%
97%
99%
20
50
96%
98%
99%
20
60
98%
99%
99%
40%
5%
10
10
23%
43%
50%
10
20
61%
71%
81%
10
30
69%
80%
86%
10
40
77%
85%
91%
10
50
73%
84%
92%
10
60
76%
87%
91%
40%
5%
20
10
43%
53%
71%


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20
20
72%
81%
89%
20
30
86%
90%
95%
20
40
91%
93%
97%
20
50
93%
95%
98%
20
60
94%
96%
98%
Based on PASS 2011
Given the sample size of 10 to 20 per arm within a cohort, the power to detect treatment 
difference is low even with large treatment differences using a 2-sided statistical significance 
level of 5%. If the true rate is 50% for KAE609 and 3% for the Coartem, the power to detect 
between treatment difference is about 80% using a 2-sided test at the 20% significance level for 
n= 10 per arm or at the 10% significance level for n= 20 for KAE609 and 10 for Coartem. 
If there are at least 2 cohorts at the end of study and the patients treated with Coartem are pooled 
from all cohorts, the power to detect treatment difference is greatly increased. In case that the 
study proceeds to the end with 4 cohorts for a total of 40 patients treated with Coartem, the 
power to detect treatment difference using 2-sided test at the 5% significance level is 77% and 
91% for n=10 and 20 patients treated with KAE609, respectively, if the true rate is 40% for 
KAE609 and 5% for the Coartem. In case that the study proceeds to the end with 6 cohorts for 
a total of 60 patients treated with Coartem, the power to detect treatment difference using 2-
sided test at the 5% significance level is 76% and 94% for n=10 and 20 patients treated with 
KAE609, respectively, if the true rate is 40% for KAE609 and 5% for the Coartem.
10
Ethical considerations
10.1
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 Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after such 
consent has been provided by a legally acceptable representative(s) of the patient. In cases 
where the patient’s representative gives consent, the patient must be informed about the study 
to the extent possible given his/her understanding. If the patient is capable of doing so, he/she 
must indicate assent by personally signing and dating the written informed consent document 
or a separate assent form. 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 patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 


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investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject 
recruitment procedures (e.g., advertisements) and any other written information to be provided 
to patients/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.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be submitted for publication and posted in a publicly accessible database 
of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group 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 standard operating 
procedures (SOPs), and are performed according to written Novartis processes.
11
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 patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 


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investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
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. 
11.1
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 intended to eliminate an apparent immediate hazard 
to patients/subjects 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 patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References
European Medicine Agency (EMA) (2012) Pyramax assessment report, Procedure No.: 
EMEA/H/W/002319.
 
Hamed K and Grueninger H (2012) Coartem(®): a decade of patient-centric malaria 
management. Expert Rev Anti Infect Ther; 10(6):645-59.
Hien T, White N, Thuy-Nhien N et al (2017) Estimation of the in vivo MIC of Cipargamin in 
uncomplicated Plasmodium falciparum malaria, Antimicrobial Agents Chemother;61:e01940-
16. 
Sinden RE, Blagborough AM, Churcher T, et al (2012) The design and interpretation of 
laboratory 
assays 
measuring 
mosquito 
transmission 
of 
Plasmodium. 
Trends 
Parasitol;28(11):457-65.
Stepniewska K and White NJ (2006) Some considerations in the design and interpretation of 
antimalarial drug trials in uncomplicated falciparum malaria. Malaria Journal; 5:127.
White NJ, Ashley EA, Recht J, et al (2014) Assessment of therapeutic responses to 
gametocytocidal drugs in Plasmodium falciparum malaria. Malar J;13:483.
 
 
 
World 
Health 
Organization 
(2016) 
World 
Malaria 
Report 
(http://apps.who.int/iris/bitstream/10665/252038/1/9789241511711-eng.pdf?ua=1).


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13
Appendix 1: Clinically notable laboratory values and vital 
signs
Certain adverse events should be considered medically significant and should be submitted to 
Novartis as SAEs within 24 hours. 
1. Hepatic

ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × baseline value

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, like hepatic failure, 
fibrosis and cirrhosis and other liver damage-related conditions; non-infectious 
hepatitis, liver neoplasms
2. Cardiac

Absolute QTcF > 500 ms (confirmed by repeat ECGs)


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14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
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 (Medically significant 
events to be reported as SAEs)

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 14-2
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

Repeat LFTs within 24hHospitalize, if 
clinically appropriate

Establish causality

Complete liver CRF

Report to Novartis as an SAE
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency twice a 
week until resolution, stabilize or return 
to within baseline values)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Repeat LFTs within 24h

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF

Report to Novartis as an SAE
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency twice a 
week until resolution, stabilize or return 
to within baseline values)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Repeat LFTs within 24h

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF

Report to Novartis as an SAE
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency twice a 
week until resolution, stabilize or return 
to within baseline values)


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Criteria
Actions required
Follow-up monitoring
> 5 to ≤ 8 × ULN

Repeat LFT within 24 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

Report to Novartis as an SAE
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency twice a 
week until resolution, stabilize or return 
to within baseline values)
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Repeat LFT within 24 hours

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF

Report to Novartis as an SAE
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency twice a 
week until resolution, stabilize or return 
to within baseline values)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within 48 hours

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 24 hours

If elevation persists, establish causality

Complete liver CRF

Report to Novartis as an SAE
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 24 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF

Report to Novartis as an SAE
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency twice a 
week until resolution, stabilize or return 
to within baseline values)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 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
Preferred terms
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF

Report to Novartis as an SAE
ALT, AST, TBL, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency twice a 
week until resolution, stabilize or return 
to within baseline values)
Any AE potentially 
indicative of a liver 
toxicity* - severe 
events only SMQ 
AE

Consider study treatment 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF

Report to Novartis as an SAE
Investigator discretion


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Criteria
Actions required
Follow-up monitoring
*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
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.
Alb: albumin; PT: prothrombin time.


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
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 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment discontinuation
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 discontinuation 
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine 
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine 
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.
sCr: serum creatinine.


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16
Appendix 4: Medications, herbs and toxins as cause of 
ALT/AST elevations
Table 16-1
Medications, herbs and toxins as cause of ALT/AST elevations
Medications and drugs 
Herbs and alternative medications 
Chaparral leaf 
Alpha-methyldopa 
Ephedra 
Amoxicillin-clavulanic acid 
Gentian 
Amiodarone 
Germander 
Bosentan 
Ji Bu Huan 
Carbamazepine 
Senna 
Dantrolene 
Kava kava 
Disulfiram 
Scutellaria (skullcap) 
Etretinate 
Shark cartilage 
Fluconazole 
Vitamin A 
Glyburide 
Illicit drugs 
Halothane 
Anabolic steroids 
Heparin 
Cocaine 
HMG-Co A reductase inhibitors 
Ecstasy (MDMA) 
Isoniazid 
Phencyclidine (PCP) 
Ketoconazole 
Toxins 
Labetalol 
Carbon tetrachloride 
Nicotinic Acid 
Chloroform 
Nitrofurantoin 
Dimethylformamide 
NSAIDs 
Hydrazine 
Phenylbutazone 
Hydrochlorofluorocarbons 
Phenytoin 
2-Nitropropane 
Propylthiouracil 
Trichloroethylene 
Protease inhibitors 
Sulfonamides 
Terbinafine 
Trazadone 
Troglitazone 
(withdrawn) 
Valproic Acid 
Toluene 

SAP_001.pdf: 
Novartis
For business use only
Page 1
SAP
CKAE609A2202
Clinical Development
KAE609
CKAE609A2202 / NCT03334747
A Phase 2, multi-center, randomized, open-label, dose-
escalation study to determine safety of single (QD) and 
multiple (3 QD) doses of KAE609, given to adults with 
uncomplicated Plasmodium falciparum malaria
Statistical Analysis Plan (SAP)
Author(s):
Trial Statistician, 
CRO Trial Statistician, 
Document type:
SAP Documentation
Document status:
Addendum 1.0
Release date:
07-Apr-2020
Number of pages:
50
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
CKAE609A2202
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason 
for 
update
Outcome for update
Section and title 
impacted 
(Current)
03-Nov-
2017
final in 
CREDI
N/A
N/A - First version
N/A
21-Jan-
2020
Updates 
prior to 
DBL
Amendm
ent 1
Corrected 
definition 
of 
fever 
temperature for other routes from 
38.3 to 38.0
Section 2.3.2 and 
2.8.3.2
Added note for tail of KM plots
Section 2.1.1
Added 
that 
treatment 
failure 
definitions 
are 
based 
on 
P. 
falciparum asexual counts
Extended definition of LCF and 
LPF
with 
respect 
to 
fever 
definition for other routes
Section 2.1.1.1
Adapted condition of parasite 
clearance by Day 7 from definition 
of cures at Day 15/29 and from 
definition of event date for KM
Section 2.1.1.1 + 
Section 2.7.2.1
Adapted definition of Analysis 
Sets to be consistent with Table 5-
9
Section 2.2
Added 
non-PD 
criterion 
to 
definition of PK analysis set
Section 
5.6, 
Table 5-9
Removed 
category 
'Mixed-
infection' 
from 
demographic 
variable P. falciparum species, as 
mixed infections are not allowed
Section 2.3.2
Removed shift tables
Adding note for handling Lab 
values beyond detection limit
Section 2.8.2
Added 'New' to ECG criteria based 
on absolute values only
Section 2.8.3.1
Harmonized definition of subjects 
excluded from FCT with respect to 
tables/figures
Section 2.7.2.3


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SAP
CKAE609A2202
Date
Time 
point
Reason 
for 
update
Outcome for update
Section and title 
impacted 
(Current)
Adapted visit window for analysis 
timepoint for 4 hrs due to gap
Section 
5.1.4 
(Table 5-6)
Clarified baseline derivation as 
assessments at treatment start 
datetime should be included
Section 2.1.1 & 
Section 
5.1.4 
(Table 5-7)
Changed condition of clearance of 
initial 
infection 
for 
recrudescence/reinfection
Section 
2.7.2.4/2.7.2.5
Removed QTcB
Section 
2.8.1.1/2.8.3.1
Added derivation of study day for 
subjects that are randomized but 
not treated
Section 2.1.1
Added HR to in-text table
Section 2.8.1.1
Removed 
table 
for 
MH 
contributing to liver dysfunction
Section 2.3.1
Changed threshold in step 2 (ii) to 
500 such that algorithm fits to 
inclusion criterion 3
Section 2.13
Added Lumefantrine
Section 2.9
Added 
T1/2 
to 
list 
of 
PK 
parameters
Section 2.9
Removed visit window for time 
point 36 hrs for PK and adapted 
preceding and subsequent visit 
windows
Section 
5.1.4, 
Table 
Protocol 
amendme
nt
Adapted 
section 
according 
to 
protocol amendment; added new 
figure 1-1
Section 1.1
Added two new treatment groups 
to list
Section 2.1.1
Adapted sections according to 
protocol amendment
Section 2.15/3.2
Added link to 
final list of 
prohibited medications
Section 5.2
07-Apr-
Updates 
Addendu
Added subgroup of high baseline Section 2.2.1


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Date
Time 
point
Reason 
for 
update
Outcome for update
Section and title 
impacted 
(Current)
2020
after 
DBL
m 1
parasitaemia
Removed analysis on PPS
Section 2.3.2


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Table of contents
Table of contents..................................................................................................................................... 5
List of abbreviations ............................................................................................................................... 7
1
Introduction............................................................................................................................................. 8
1.1
Study design .............................................................................................................................. 8
1.2
Study objectives and endpoints ............................................................................................... 10
2
Statistical methods ................................................................................................................................ 11
2.1
Data analysis general information........................................................................................... 11
2.1.1
General definitions ............................................................................................... 11
2.2
Analysis sets............................................................................................................................ 15
2.2.1
Subgroup of interest.............................................................................................. 16
2.3
Patient disposition, demographics and other baseline characteristics ..................................... 16
2.3.1
Medical history..................................................................................................... 16
2.3.2
Patient demographics and other baseline characteristics...................................... 16
2.3.3
Patient disposition................................................................................................. 17
2.4
Treatments (study treatment, rescue medication, concomitant therapies, compliance)........... 17
2.4.1
Study treatment / compliance ............................................................................... 17
2.4.2
Prior, concomitant and post therapies................................................................... 18
2.5
Analysis of the primary objective............................................................................................ 18
2.5.1
Primary endpoint .................................................................................................. 19
2.5.2
Statistical hypothesis, model, and method of analysis.......................................... 19
2.5.3
Handling of missing values/censoring/discontinuations....................................... 19
2.5.4
Supportive analyses .............................................................................................. 19
2.6
Analysis of the key secondary objective ................................................................................. 19
2.7
Analysis of secondary efficacy objective(s)............................................................................ 19
2.7.1
Secondary endpoints............................................................................................. 19
2.7.2
Statistical hypothesis, model, and method of analysis.......................................... 20
2.8
Safety Analysis........................................................................................................................ 23
2.8.1
Adverse events (AEs)........................................................................................... 23
2.8.2
Laboratory data..................................................................................................... 27
2.8.3
Other safety data................................................................................................... 28
2.9
Pharmacokinetic endpoints...................................................................................................... 29
2.10
PD and PK/PD analyses .......................................................................................................... 30
2.11
Patient-reported outcomes....................................................................................................... 30
30
30
2.14
Overview of analysis methods................................................................................................. 32
2.15
Interim safety review............................................................................................................... 35
3
Sample size calculation......................................................................................................................... 36
3.1
Single arm approach................................................................................................................ 37


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3.2
Power for comparison of KAE609 with Coartem ................................................................... 38
4
Change to protocol specified analyses.................................................................................................. 40
5
Appendix............................................................................................................................................... 40
5.1
Imputation rules....................................................................................................................... 40
5.1.1
Study drug ............................................................................................................ 40
5.1.2
AE date imputation............................................................................................... 40
5.1.3
Concomitant medication date imputation............................................................. 41
5.1.4
Visit windows....................................................................................................... 42
5.2
Prohibited medications............................................................................................................ 44
5.3
AEs coding/grading................................................................................................................. 48
5.4
Laboratory parameters derivations.......................................................................................... 48
5.5
Statistical models..................................................................................................................... 48
5.5.1
Primary analysis ................................................................................................... 48
5.5.2
Key secondary analysis......................................................................................... 48
5.5.3
Other secondary/
 analysis................................................................... 48
5.6
Rule of exclusion criteria of analysis sets ............................................................................... 49
6
Reference.............................................................................................................................................. 50


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization
ETF
Early treatment failure
LPF
Late parasitological failure
LCF
Late clinical failure
SRC
Safety Review Committee
FCT
Fever clearance time
PCT
Parasite clearance time


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1
Introduction
The purpose of the Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis which is planned in the protocol. The study has 6 cohorts: Cohort 1, 5, 6
with 2 arms and Cohort 2, 3, 4 with 3 arms each. Proceeding to next cohort depends on the 
interim safety review outcome done by the safety review committee (SRC) which will happen 
at predefined time points and is outlined in section 2.15 below. A single database will suffice 
for all the cohorts. The clinical study report will be prepared after the final database lock 
(DBL) at the end of all cohorts on the basis of this SAP. This single SAP will be used for the 
analysis of data collected for each cohort and the pooled analysis of all the cohorts together. 
The statistical method in this SAP will be used to execute a separated SRC TFL shells by 
 for Interim Safety review if required.
1.1
Study design
This will be a multicenter, open label, randomized, dose escalation study to evaluate the 
hepatic safety and tolerability of KAE609 in adult patients (≥18 years and ≥45 kg bodyweight) 
with uncomplicated malaria caused by P. falciparum. 
Starting dose of KAE609 will be a single dose of 10 mg and following acceptable safety 
results in the 10 mg treatment arm, the dose of KAE609 will be increased stepwise up to a 
single dose of 225 mg and multiple doses of 50 mg (QD x 3 days) according to schedule 
below (Figure 1-1).
Based on the safety pattern observed in previous studies with KAE609, liver function test 
(LFT) parameters, if they rise, are expected to peak within 14 days of treatment. Hence, the 
decision to escalate to next cohort with higher doses will be based on the criteria as specified 
in the table below (Table 1-1):
Table 1-1
Decision criteria for dose escalation based on LFT results with KAE 
609
LFT parameter
Baseline
Maximum post baseline value 
Decision to escalate to 
next cohort
ALT/AST
Within ULN
< 2 times ULN (from Day 1 to
Day 15)
Escalate to next cohort 
after notification to safety 
review committee, after 
all the patients in the 
cohort have been 
followed for at least 14 
days post treatment 
(study Day 15).
> 1 to ≤ 1.5 
ULN
< 2 times baseline (from Day 1 to
Day 15)
ALT/AST
Within ULN
≥ 2 to < 3 times ULN (from Day 1 to
Day 15)
Escalate to next cohort 
based on review of liver 
safety (and any other 
relevant data) by safety 
review committee, after 
all the patients in the 
> 1 to ≤ 1.5 
ULN
≥ 2 to < 3 times baseline (from 
Day 1 to Day 15)


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cohort have been 
followed for at least 28 
days  post treatment 
(Study Day 29) 
ALT/AST
Any baseline 
value
≥ 2 Grade (CTCAE grades) 
increase from baseline (at any time 
point during the study) in:
-
2 patients in a 10 patient cohort 
(Cohorts 1 and 2)
           or 
-
3 patients in a 20 patient cohort 
(Cohorts 3 and 4, 5 and 6)
Suspend recruitment and 
initiate review of liver 
safety (and any other 
relevant data) by safety 
review committee.
Any further progression of 
the study is based on the 
decision by the safety 
review committee
In consultation with the safety review committee, Novartis can suspend recruitment and 
trigger safety review any time based on safety signals including any potential Hy’s law case.
Based on the pre-specified criteria (Table 3-1) and the review of the liver safety data by a 
safety review committee, the recruitment in Cohort 5 may be stopped and a lower dose of 
KAE609 i.e. 110 mg may be selected for Cohort 6. The study could be stopped after Cohort 5 
if there is no added advantage for dosing the patients with 225 mg single dose from the 
perspective of future clinical development of KAE609 and its subsequent use in clinical 
practice.
Figure 1-1
Study KAE609A2202 diagram
Given the expected sub-therapeutic efficacy of the doses of KAE609 in the first 2 cohorts, a 
smaller number (N=10) of patients will be included (10 mg Single Dose (SD), 25 mg SD and 
10 mg 3 Days) to detect potential LFT increases. In the subsequent cohorts a higher number 
(N=20) of patients will be included. All patients will be followed up for 4 weeks with close 
monitoring in an inpatient setting for at least the first 3 days (Study Day 4) for efficacy and 
safety followed by outpatient monitoring  up to Study Day 29.
Patients will be randomized to KAE609 vs Coartem in a ratio of 1:1 in cohort 1. In cohort 2, 
SD KAE vs QD KAE609 vs Coartem will be randomized in the ratio of 1:1:1. In Cohorts 3 


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and 4 the SD KAE609 vs QD KAE609 vs Coartem will be randomized in the ratio of 2:2:1. In 
Cohorts 5 and 6 the SD KAE609 vs Coartem will be randomized in the ratio 2:1. There are no 
stratification factors in this study.
Visits to assess safety and efficacy will be scheduled during the follow-up period as described 
in the assessment schedule table in protocol. 
The safety of entire study will be monitored by the Safety Review Committee.
1.2
Study objectives and endpoints
Table 1-2
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To characterize hepatic safety aspects of 
single- and multiple ascending doses of 
KAE609 in adult malaria patients
Endpoint(s) for primary objective(s) 

At least 2 CTCAE grades increase from 
baseline in ALT or AST during the 4 
week study period
Secondary Objective(s)

To evaluate overall safety and tolerability 
of KAE609.

To assess key PK parameters following 
treatment with KAE609.

To assess the efficacy of KAE609 in 
patients with uncomplicated falciparum
malaria.

To assess recrudescence after single and 
multiple doses of KAE609
Endpoint(s) for secondary objective(s)

Standard safety/tolerability assessments 
(AE incidence and severity, vital signs, 
ECG, laboratory abnormalities)

PK parameters such as AUC, Cmax, 
Tmax, T½ etc. 

PCR-Uncorrected adequate clinical and 
parasitological response (ACPR) and 
PCR-Corrected ACPR at Days 15 and 
29 (i.e., 14 and 28 days post-dose)
Parasite and Fever Clearance Times 
(PCT 
and 
FCT) 
before 
rescue 
medication is given

Incidence rate of recrudescence at 
Day 29


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2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by 
 on behalf of Novartis for the interim safety assessment and 
after final DBL using SAS version 9.4 according to the data analysis presented in section 9 of 
the study protocol which will also be available in Appendix 16.1.1 of the CSR.  Important 
information is given in the following sections and details will be provided, as applicable, in 
Appendix 16.1.9 of the CSR.
At the end of trial, full statistical analyses will be performed by cohort and treatment group. 
Coartem data from all cohorts will also be pooled.
Any data analysis carried out independently by the investigator should be submitted to 
Novartis before publication or presentation.
Data analyses required for the study SRC meeting will be analyzed by the third party vendor 
(
). The outline of the SRC Review analysis plan is presented in the SRC charter and 
will be detailed in the SRC TFL shells. A separate SAP for SRC is not needed since the 
statistical methods for SRC are same as those in this SAP. 
Information on visit windows, imputation rules and the methods of efficacy and safety 
analyses is given in the sections to follow and details will be provided, as applicable, in 
Appendix 16.1.9 of the CSR. This SAP covers the methods for both planned interim safety 
review and the final analysis.
Unless otherwise stated, summary tables/figures/listings will be on all patients included in the 
population under consideration. 
Categorical data will be presented as frequencies and percentages. For continuous data, n, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. Additionally, geometric mean will be presented for PK parameters which may be 
better described using the lognormal distribution.
Unless otherwise stated, p-values will be provided for two-sided alternative hypotheses and 
presented with up to 4 significant digits after decimal place; confidence intervals will be 
presented with up to 2 significant digits after decimal place. 
Since the randomization is not stratified, statistical analysis will not be stratified.  For pooled 
analyses, coartem patients will be pooled from all the cohorts and compared with patients 
from different KAE doses. 
2.1.1
General definitions 
Study treatment: KAE609 is the investigation treatment whereas Coartem® will serve as 
control. They are referred to as study treatments in the document.
Summary results will be presented by cohort and treatment group. Besides, a pooled Coartem
group from all cohorts will be presented from all tables as applicable. The following 
abbreviated treatment group labels will be used as the column headers in the CSR outputs:

KAE609 10 mg SD


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
KAE609 10 mg QD 3 days

KAE609 25 mg SD

KAE609 25 mg QD 3 days

KAE609 50 mg SD

KAE609 50 mg QD 3 days

KAE609 75 mg SD

KAE609 150 mg SD

KAE609 225 mg SD or KAE609 110 mg SD

Coartem

Pooled Coartem
Baseline: The last measurement made prior to and including administration of the first dose of 
study treatment. Note this may include measurements taken on the day of randomization (e.g. 
lab, ECG, vital signs). If a patient did not receive any dose of study treatment then the 
randomization date will be used as the date of first dose of study treatment.
Study day: Study day will be calculated with respect to the first dose of study treatment. The 
first day of administration of study treatment (first dose) is defined as Day 1. Day -1 will be 
the day before Day 1. Day 0 does not exist. If a patient did not receive any dose of study 
treatment then the randomization date will be used as the date of first dose of study treatment.
For assessments collected on or after Day 1, study day = date of assessment – date of first 
dose of study treatment + 1.
For assessments collected prior to Day 1, study day = date of assessment - date of first dose of 
study treatment.
At the end of trial, full statistical analyses will be performed by cohort and treatment group. 
Coartem data from all cohorts will also be pooled.
Tail of KM plots: Since the tail of KM plots after the day of last planned assessment is not 
reliable due to small numbers of patients at risk, the time to event will be truncated to
the planned last day (Day 29) regardless of censoring.
2.1.1.1
Definition for treatment failures
All definitions of treatment failures are based on P. falciparum asexual counts.
Early treatment failure (ETF)
Patients will be classified as ETF upon meeting any of the following criteria:

Clinical decline or lack of improvement (per Investigator) at 24 hours after first dose 
of treatment.


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
Development of any clinical complications (described in the WHO definition of 
complicated/severe malaria (WHO Guidelines 2010) in the presence of parasitaemia 
(based on microscopy) within 72 hours of the first dose of treatment

Parasitaemia > 75 000/μL based on microscopy at or after 12 hours post first dose

Parasitaemia > baseline based on microscopy with or without fever at 36 hours after 
the first dose of treatment

Any parasitaemia based on microscopy with fever, 48 hours post first dose

Parasitaemia > 100/ μL based on microscopy with or without fever, 72 hours post first 
dose
Late Clinical Failure (LCF)
Patients will be classified as LCF upon meeting any of the following criteria:

Development of danger signs or severe malaria on any day between Study Day 5 and 
Study Day 29 in the presence of parasitaemia based on microspcopy without 
previously meeting any of the criteria of ETF.

Presence of parasitaemia based on microspcopy and fever (i.e. axillary temperature ≥ 
37.5ºC or other routes >= 38°C) on any day between Study Day 5 and Study Day 29 
without previously meeting any of the criteria of ETF.
Late Parasitological Failure (LPF)
Patients will be classified as LPF upon meeting the following criterion:

Presence of parasitaemia based on microspcopy on any day between Study Day 5 and 
Study Day 29 and no fever (i.e. axillary temperature < 37.5ºC or other routes < 38°C)
without previously meeting any of the criteria of ETF or LCF.
Adequate Clinical and Parasitological Response (ACPR):
Absence of parasitaemia based on microspcopy on Study Day 29 irrespective of axillary 
temperature, without previously meeting any of the criteria of ETF, LCF, or LPF.
Uncorrected ACPR at Day X where X=15 and 29

A patient is considered as non-responder at Day X if the patient experiences an ETF,  
LCF or LPF from Day 5 to Day X. 

A patient is also considered as non-responder if the parasitaemia is not cleared by Day 
X unless the patient discontinues the study prior to Day X without ETF, LCF, or LPF 
in which case the response is considered as missing.


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
A patient is considered as responder (Uncorrected ACPR) at Day X if the patient is not 
classified as a non-responder at Day X and the patient has a malaria blood film 
showing absence of parasitaemia at Day X or later if Day X is missing.

The response for a patient is considered as missing/undertermined if the patient is not 
classified as a non-responder and the malaria blood film result at Day X is missing and 
not followed by a subsequent negative result.
PCR-corrected ACPR at Day X where X=15 and 29

A patient is considered as non-responder at Day X if the patient experiences an ETF,  LCF, 
or LPF from Day 5 to Day 7. 

A patient is also considered as non-responder if the parasitaemia is not cleared by Day X
unless the patient discontinues the study prior to Day X without ETF,  LCF, or LPF, in 
which case the response is considered as missing,

A patient is considered as non-responder at Day X if the patient has a parasite 
recrudescence from Day 8 to Day X

A patient is considered as responder (corrected ACPR) at Day X if the patient is not 
classified as a non-responder by Day 7 and has a new infection from Day 8 to Day X 
based on PCR genotyping unless that the patient did not have parasites cleared prior to the 
new infection, in which case the patient is considered as non-responder.

A patient is considered as responder at Day X if the patient is not classified as a non-
responder at Day X and the patient has a malaria blood film showing absence of 
parasitaemia at Day X or later if Day X is missing.

The response for a patient is considered as missing/undetermined if  

The patient has parasitaemia present from Day 8 to Day X for which the PCR 
genotyping of  recrudescence or new infection is not determined.
The patient is not classified as a non-responder at Day X and the malaria blood film 
result at Day X is missing and not followed by a subsequent negative result.
Note - The outcome of PCR-corrected ACPR and uncorrected ACPR at a given day is 
categorized as responder or non-responder to distinguish from failure used in early treatment 
failure, late clinical failure or late parasitological failure. With this notation, ACPR rate is the 
proportion of responders.
A patient with presence of parasitaemia at more than 7 days after the first dose is considered 
as non-responder for uncorrected ACPR. We reclassify such a patient as responder for PCR-
corrected ACPR if presence of parasitaemia at more than 7 days after the first dose is due to 
new infection. Whether the presence of parasitaemia after 7 days is due to recrudescence or 
new infection is determined and provided by the central laboratory.
The above defintions of ACPRs are purely based on the malaria blood film and PCR results 
without consideration for taking concomitant anti-malaria drugs. In statistical analyses, some 


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responses may be overriden for patients who take concomitant anti-malaria drugs (see 
Sections 2.5 and 2.7). 
Fever Clearance time (FCT), defined as time from the first dose until the first time the 
axillary body temperature decreased below and remained below 37.5°C axillary or 38.0°C 
oral/tympanic/rectal for at least a further 24 hours.
Parasite clearance time (PCT), defined as time from the first dose until the first total and 
continued disappearance of asexual parasite forms which remained at least a further 48 hours.
2.2
Analysis sets
Randomized set (RAN) : All patients who are randomized and not misrandomized if 
identified from IRT and who did not experience any important protocol deviation related to
informed consent.
Full analysis set (FAS) : FAS will be comprised of all patients from Randomized set who 
take at least one dose of study treatment during the treatment period and whose baseline 
parasitaemia count is greater than 0. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment group assigned to at randomization.
Safety set (SAF set) : Safety set includes all patients who take at least one dose of study drug 
during the treatment period. Patients will be analyzed according to treatment received.
Per-protocol set (PPS) : PPS will be comprised of patients in FAS who

did not have any important protocol deviations

took at least 80% of assigned study medication(s). If a patient vomited the original 
dose but did not vomit the replacement dose, the patient is considered as taking the 
dose of study medication. Except for patients who are assigned to Coartem treatment, 
this requires that all patients take all KAE609 dosages as assigned. For Coartem, the 
patient needs to take at least 5 doses of study drug to have taken 80%.

did not take other antimalarial medications prior to Study Day 29 for reasons other 
than rescue medication given for P. falciparum related treatment failure, and

met at least one of the following criteria: (a) classified as treatment failure before 
Study Day 8 (see Section 2.1.1.1), (b) absent from parasitaemia at Study Day 29, or (c) 
had valid PCR evaluations at baseline and at the time point with parasitaemia if 
parasitaemia is present at Study Day 8 or later.
Important protocol deviations for exclusion from PPS are specified in Table 5-9 and all other 
important protocol deviations will be identified by the clinical team before the final database 
lock.


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PK analysis set : All subjects in the safety analysis set who had evaluable PK parameter data
and with at least 80% compliance to study medicationand who did not experience any 
important protocol deviation as mentioned in Table 5-9.
2.2.1
Subgroup of interest
The following subgroups will be used for descriptive summary or figures of the selected 
efficacy and safety analyses. The details will be provided in the corresponding sections.

Sex (male vs female)

Patients with baseline parasitaemia >= 10000/µL
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Medical history
Any condition entered on the Relevant medical history / current medical conditions CRF will 
be coded using the MedDRA dictionary. They will be summarized by primary system organ 
class (SOC) and preferred term (PT) of the MedDRA dictionary. A separate summary will 
also be provided on medical conditions that were active at the time of screening.
Medical conditions that are present after informed consent has been signed but before the first 
dose of study medication is administered are collected in the adverse event panel and will be 
summarized separately from adverse events.
The Medical History conditions captured on the eCRF “Protocol solicited events ” will be 
tabulated separately.
History of use of alcohol will also be summarized.
Unless otherwise specified, analyses will be based on the randomized set.
2.3.2
Patient demographics and other baseline characteristics
Demographic data and baseline disease characteristics will be presented descriptively and 
tabulated (n, mean, standard deviation, median, minimum, and maximum for continuous 
variables; n and percent for categorical variables) by cohort and treatment group, as well as 
overall, using Randomized set. If many patients(Overall > 5%) are excluded from FAS, 
summary will also be provided for the FAS.
Following demographic variables will be summarized

Age and age categories ( <65 vs ≥65 yrs) 

Sex (male, female)

Subject child bearing status (able to bear children, premenarche, post menopausal, sterile 
of child bearing age)

Race 

Ethnicity


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
Body height (cm)

BMI and BMI categories (<16, 16 to 25, >25) (kg/m2)
Following disease characteristics at baseline will be summarized

Body temperature and the number and percentage of patients for categories (<37.5, 37.5 to 
<39, ≥39 ) (°C) for (axillary)  and  < 38.0°C, 38.0 to <39.8, ≥ 39.8 for other routes)

Presence of Falciparum species: (P. Falciparum asexual forms, P. Vivax, P. Ovale, P. 
malariae, P. Knowlesi, n (%)) 

P. falciparum asexual forms density per micro ltr. and the number and percentage of 
patients for categories (<500, 500 to <2,000, 2,000 to <5,000, 5,000 to <15,000, 15,000 to 
<50,000, ≥50,000 parasites /μL)
2.3.3
Patient disposition
The number and percentage of patients screened will be presented for overall. In addition, the 
reasons for screen failures will be provided. The number and percentage of patients who 
completed each epoch (treatment and follow-up) and who discontinued each epoch 
prematurely (including the reason for discontinuation) will be presented by cohort for each 
treatment group and overall.  
For each protocol deviation, the number and percentage of patients for whom the deviation 
applies will be tabulated. 
Randomized set will be used.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Number and percentage of doses taken will be presented by cohort and treatment group. The 
percentage will be calculated based on the planned number of doses per treatment group.
Planned number of doses in a treatment group = planned number of days of dosing x number 
of doses to be administered per day in that treatment group. 
For example, planned number of doses is  1 for ‘KAE609 10 mg and 6 for Coartem in cohort 
1, etc.
Percentage of doses taken will be calculated as  
 	
   
	
   
x 100
Compliance will be categorized by < 80 % and >=80 % of doses taken and summarized by 
treatment group.
Number and percentage of patients with study drug vomiting and dose replacement will be 
presented by treatment group.
Average daily dosage and total dosage (in mg) of each study drug  (KAE609,  Coartem) will 
be summarized by cohort and treatment group.


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Average daily dosage =      

     	 	 
!
"#   $  ###
For Coartem, the tablets taken by patient are converted into mg based on the strength of tablet
separately for the two active components of the drug, i.e., artemether and lumefantrine.
Note- If a patient vomited the original dose but did not vomit the replacement dose, the 
patient is considered as fully dosed.  Doses that were vomited are excluded from the analyses 
although all patients who took at least one dose of study drug regardless of vomit or not are 
included in the Safety set.  
Safety set will be used.
2.4.2
Prior, concomitant and post therapies
Prior and concomitant medications will be summarized in separate tables by cohort and 
treatment group.
Concomitant rescue and other anti-malarial medications will also be summarized by cohort 
and treatment group.
Note – The only rescue medication considered in this study is Coartem. All other antimalarial 
drugs are prohibited and if taken then it will be considered as PD. If Coartem is used after 
discontinuation of study drug due to early treatment failure, late clinical failure or late 
parasitological failure then it should be considered as resue medication,. Rescue medication 
will be captured along with other concomitant medications by the investigators under rescue 
medication category.
Any patient on KAE609 who does not need rescue medication up to Study Day 28 will be 
given Coartem as post therapy at the end of the study (Study Day 29) and will be followed as 
per standard medical care.Prior medications are defined as drugs taken and stopped prior to 
first dose of study medication. Any medication given at least once between the day of first 
dose of study medication and the last day of study visit will be a concomitant medication, 
including those which were started pre-baseline and continued into the treatment period. 
Prior and concomitant medications will be coded according to the latest version of WHO 
Drug Reference List dictionary which employs the ATC. The number and percentage of 
patients taking prior and concomitant medications will be summarized for each cohort and 
treatment by ATC class and preferred term (PT).
Number and percentage of the patients receiving prohibited prior and concomitant drugs will 
be summarized. Details regarding prohibited drugs are mentioned in Table 5-9. PK related 
prohibited medications(the drugs which are prohibited only within first 7 days from first dose)  
and non-PK related prohibited medications will summarized separetly.
Safety set will be used.
2.5
Analysis of the primary objective
The primary objective is to characterize hepatic safety aspects of single and multiple 
ascending doses of KAE609 in adult malaria patients for treatment of uncomplicated malaria 
caused by P. falciparum. 


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2.5.1
Primary endpoint
The primary variable is the occurrence of at least 2 CTCAE grades increase from baseline in 
ALT or AST during the 4 weeks study period.
2.5.2
Statistical hypothesis, model, and method of analysis
The study is a Phase II safety study in African patient population aiming to rule out high 
incidence of abnormal LFT reported in a couple of earlier studies. As the significance of 
safety related results is determined by both the frequency of the event and the severity of the 
event, there is no pre-defined hypothesis. The following analyses will be performed using the 
SAF set:

Proportion of patients with occurrence of the primary variable by cohort and treatment 
group and the 95% confidence interval based on the exact CI (Pearson-Clopper method).

2-sided Fisher exact test for each KAE609 treatment group compared to the pooled 
Coartem.
These results along with patient narratives will be assessed to make decision about whether a 
KAE609 dosage regimen is safe for further development.
2.5.3
Handling of missing values/censoring/discontinuations
No missing value of the primary variable is expected since the analysis is based on the SAF 
set and all patients in the SAF set should provide safety observation as they are hospitalized 
for the first 3 days. No missing data imputation will be done in this study.
2.5.4
Supportive analyses
In the past KAE609 studies, peak LFT occurred during the first 2 weeks after dose 
administration. For patients who discontinued the study during the first 2 weeks after dose 
administration, their peak LFT may not be observed. Analyses in Section 2.5.2 will be 
performed by excluding those patient(s) who discontinued the study before Study Day 15 and 
did not experience at least 2 CTCAE grades increase from baseline in ALT or AST.
2.6
Analysis of the key secondary objective
There is no key secondary objective in this study.
2.7
Analysis of secondary efficacy objective(s)
Descriptive statistics for each secondary variable will be provided by cohort and treatment 
group. Statistical comparison with Coartem will not be performed due to small sample size for 
each treatment group.
2.7.1
Secondary endpoints
All efficacy analyses are secondary. Secondary efficacy variables include:

PCR-corrected ACPR at Study Days 15 and 29;

Uncorrected ACPR at Study Days 15 and 29;


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
Proportion of patients with parasitaemia at 12, 24, and 48 hours after the first dose of 
study drug;

Parasite clearance time (PCT), defined as time from the first dose until the first total and 
continued disappearance of asexual parasite forms which remained at least a further 48 
hours;

Fever clearance time (FCT), defined as time from the first dose until the first time the 
axillary body temperature decreased below and remained below 37.5°C axillary or 38.0°C 
oral/tympanic/rectal for at least a further 24 hours;

Proportion of patients with ETF;

Proportion of patients with LCF;

Proportion of patients with LPF;

Incidence rate of recrudescence and reinfection at Study Day 29.
Analyses of ACPRs (PCR corrected or uncorrected) will be based on the FAS and PPS.
Analyses of other secondary efficacy variables will be based on the FAS.
2.7.2
Statistical hypothesis, model, and method of analysis
There are no pre-specified hypotheses for secondary endpoints. Model and method of analysis 
are presented in the following sub-sections by topic.
2.7.2.1
PCR-corrected ACPR and uncorrected ACPR
At each visit, the ACPR rate with 95% confidence intervals will be provided using the 
Pearson-Clopper method for each treatment group by cohort.
PCR corrected/uncorrected ACPRs at Day 29 will be summarized descriptively by the 
following subgroups

Sex (male vs female)
Handling of missing values/censoring/discontinuations
Data will be handled as follows:

Patients with presence of parasitaemia which was determined to be reinfection on Day 8 
or later will be counted as responders for PCR corrected ACPR and as non-responder for 
PCR uncorrected ACPR from the day of test

Patients with presence of parasitaemia which cannot be determined to be recrudescent or 
reinfection due to missing PCR corrected/uncorrected data will be counted as non-
responders from the day of test

Patients with missing/undetermined responses at a visit due to missing blood smear data at 
the visit will be counted as non-responders (PCR corrected or uncorrected) unless there is 
a later blood smear test indicating no parasitemia

Patients who received non rescue anti-malarial medication will be considered in the 
analysis as if they had not taken the anti-malarial drug.


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In addition, PCR-corrected and uncorrected ACPR rate will be calculated and plotted using 
the Kaplan-Meier method for each treatment group by cohort in the FAS. 
2.7.2.1.1 Analysis of PCR-corrected ACPR using Kaplan-Meier method
For the FAS, the proportion of patients with PCR-corrected ACPR at Day 29 and 95% CI will 
be also estimated using the Kaplan-Meier method (Stepniewska and White 2006 and WHO 
2015) 
Event = PCR-corrected non-responder during the study (same as at Day 29, See Section 2.1). 
The event time is the first time when the patient becomes a non-responder based on PCR-
correction. If a patient parasite is not cleared at all, Day 7 is considered as the event time.
The PCR-corrected responder rate at Day 29 is estimated by the survivor function at Day 29 
using the Kaplan-Meier method. 
Rule for censoring:
The following censoring rules will be applied to the patients who were not non-responder

Patients who had a new infection (i.e., reinfection) with P. falciparum or other species 
without P. falciparum recrudescence on or after Day 8 will be censored at the time of the 
first PCR that indicate the infection; 

Patients who received non-rescue antimalaria medication for other infections, such as P. 
falciparum gametocytes, will be censored at the first time of antimalaria medication; 

Patients who have parasites at Day 8 or later but cannot be determined as recrudescence or 
new infection due to missing PCR genotyping will be censored at the time of the first 
malaria blood film with presence of  parasitaemia on or after Day 8.

other patients not classified as non-responder will be censored at the time of last 
parasitemia assessment.
2.7.2.1.2 Analysis of uncorrected ACPR using Kaplan-Meier method
For the FAS, the proportion of patients with uncorrected ACPR at Day 29 and 95% CI will be 
also estimated using the Kaplan-Meier method (Stepniewska and White 2006 and WHO 2015) 
Event = PCR-uncorrected non-responder during the study (same as at Day 29, See Section 
2.1). The event time is the first time when the patient becomes a non-responder without PCR-
correction. If a patient parasitaemia is not cleared at all, Day 7 is considered as the event time.
The uncorrected ACPR rate at Day 29 is estimated by the survivor function at Day 29. 
Rule for censoring:
The following censoring rules will be applied to the patients who were not non-responders

Patients who received non-rescue anti-malaria medication will be censored at the first time 
of anti-malaria medication; 

other patients will be censored at the time of last parasitemia assessment.


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2.7.2.2
Treatment failure related parameters
For the following parameters, 95% confidence intervals will be provided for each treatment 
group by cohort using the Pearson-Clopper method:

proportion of patients with parasitaemia at 12, 24, and 48 hours after treatment

proportion of patients with ETF

proportion of patients with LCF

proportion of patients with LPF
The above parameters will be determined using the uncorrected parasite counts.
Handling of missing values/censoring/discontinuations
Patients whose outcome status cannot be determined due to incomplete/missing data will be 
excluded from analysis. Especially, the denominator is the number of patients who experience 
treatment failure or have malaria blood film result at Day 29 for LCF and LPF. Patients with 
ETF will be excluded from the analysis of LCF and patients with ETF or LCF will be 
excluded from the analysis of LPF.
2.7.2.3
Parasite clearance time (PCT) and fever clearance time (FCT)
Descriptive statistics (mean, standard error, median, quartiles) will be presented for each 
treatment by cohort using the Kaplan-Meier method. Kaplan-Meier curves will be provided.
PCT will be calculated based on uncorrected parasite counts. 
PCT, and FCT will be summarized descriptively by the following subgroup
Sex (male vs female)
Handling of missing values/censoring/discontinuations
Patients without parasite clearance for whatever reason will be censored at the time of last 
parasite assessment.
Patients who did not have fever at baseline will not be included in the analysis of FCT. 
Patients without fever clearance for whatever reason will be censored at the time of last 
temperature assessment. 
In case that a patient receives rescue medication before (parasite or fever) clearance, the time 
to event will be censored at the first use of rescue medication.
2.7.2.4
Recrudescence
Recrudescence is defined as appearance of asexual parasites after clearance of initial infection 
with a genotype identical to that of parasites present at baseline. Recrudescence must be 
confirmed by PCR analysis.
Incidence rates of recrudescence at Study Day 29 will be estimated by Kaplan-Meier method 
based on the subset of FAS patients who have clearance of initial infection before Day 15. 
Time to recrudescence will be calculated from the time of first study medication to the date of 
first event if a patient experiences the event and be censored at the time of last parasite 


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assessment if a patient does not experiences the event. Patients who experienced a new 
infection will be censored at the first time of new infection.
2.7.2.5
Time to event analysis for reinfection
Reinfection is defined as appearance of asexual parasites after clearance of initial infection 
with a genotype different from those parasites present at baseline. Reinfection must be 
confirmed by PCR analysis.
Incidence rates of reinfection at Day 29 will be estimated by the Kaplan-Meier method based 
on the subset of FAS patients who have clearance of initial infection before Day 15. 
Time to event (reinfection) will be calculated from the time of first study medication to the 
date of first event if a patient experiences the event and will be censored at the time of last 
parasite assessment if a patient does not experience the event. Patients who experienced 
recrudescence will be censored at the first time of recrudescence.
Handling of missing values/censoring/discontinuations
The patient will be censored at the time of last parasite assessment if a patient does not 
experience the event. Undertermined treatment failures due to missing PCR data will be 
considered as censored at the time of treatment failure.
2.8
Safety Analysis
All safety parameters will be analyzed by cohort and treatment group based on the safety. 
2.8.1
Adverse events (AEs)
The number and percentage of patients with treatment emergent adverse events will be 
presented. The treatment emergent adverse events (events started on or after the first dose of 
study medication or events present prior to the first dose of study medication but increased in 
severity based on preferred term) will be summarized by MedDRA primary System Organ 
Class (SOC) and Preferred Term (PT). 
Adverse events will be summarized by presenting, for each cohort and treatment group, the 
number and percentage of patients having at least one AE, having an AE in each primary 
system organ class and having each individual AE (preferred term). Summaries will also be
presented for AEs by severity (CTC Toxicity grade) and for study treatment related AEs. If a 
patient reported more than one adverse event with the same preferred term, the adverse event 
with the greatest severity will be presented. If a patient reported more than one adverse event 
within the same primary system organ class, the patient will be counted only once with the 
greatest severity at the system organ class level, where applicable.
The MedDRA version used for reporting the adverse events will be described in a footnote.
The most common adverse events reported (z % in any group for each preferred term in the 
table by SOC and PT) will be presented in the clinical study report by descending frequency 
according to its incidence in overall group starting from the most common event. Here the 
threshold value z is set to 5 (%) but it may be updated following review of the dry run outputs.


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Separate summaries will be provided for death, serious adverse events, severe malaria, other 
significant adverse events leading to treatment discontinuation and adverse events leading to 
dose adjustment. 
Patients who experienced a grade 3 or grade 4 AE will be summarized.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment emergent adverse events which are not serious adverse events with an incidence 
greater than 5% and on treatment emergent serious adverse events and SAE suspected to be 
related to study treatment will be provided by system organ class and preferred term on the 
safety set.
If for a same patient, 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.
Number of deaths resulting from SAEs suspected to be related to study treatment and  number 
of deaths resulting from SAEs irrespective of causality will be provided. 
The adverse events will be summarized for the following subgroup.

Sex (male vs female)
Algorithms for date imputations is provided in Appendix 5.
2.8.1.1
Adverse events of special interest / grouping of AEs
The adverse events of special interest are defined in the Case retrieval Sheet (CRS) which is 
updated for each MedDRA dictionary. The CRS data are stored in RDCRS SAS  dataset 
corresponding to a subset of eCRS SAS view for which the following filtering criteria are 
applied 
-Drug code = KAE609
-the latest version of MedDRA at the time of final database lock.
-End date is null (this means this is the latest CRS version)). Potential risks based on the 
current CRS are listed in Table 2-1.
The number and percentage of patients with these special AEs will be summarized. In 
addition, listings of related adverse events will be provided.
Newly occurring liver enzyme abnormalities and QTcF (QT interval corrected for heart rate 
according to Fredericia) abnormalities will be summarized. Only QTcF and HR will be 
summarized for the intext table. QTcF  will be summarized in post-text tables and will be 
presented in the listing. (see Sections 2.8.2 and 2.8.3.1). 


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Table 2-1 List of safety topics of interest
Safety Topic Of Interest
SOC
MedDRA 
Code
MedDRA Term
MedDRA 
Level
MedDRA 
Qualifier
QTc prolongation
Investigations
20000001
Torsade de pointes/QT prolongation
SMQ
Broad
Adrenal gland disorder
Endocrine disorders
10001353
Adrenal gland disorders
HLGT
Investigations
10001339
Adrenal cortex tests
HLT 
Metabolism and nutrition 
disorders
10014412
Electrolyte and fluid balance conditions
HLGT
Vascular disorders
10011954
Decreased and nonspecific blood pressure 
disorders and shock
HLGT
Investigations
10001373
Adrenal medulla tests 
HLT 
Hepatotoxicity
Hepatobiliary disorders
20000006
Drug related hepatic disorders-
comprehensive search
SMQ
Broad
Phototoxicity
Skin and subcutaneous 
tissue disorders
10072982
Photosensitivity and photodermatosis 
conditions
HLT 
Skin and subcutaneous 
tissue disorders
10052566
Rashes, eruptions and exanthems NEC
HLT 
Skin and subcutaneous 
tissue disorders
10054786
Skin burning sensation
PT
Skin and subcutaneous 
tissue disorders
10037087
Pruritus
PT
Skin and subcutaneous 
tissue disorders
10015151
Erythemas
HLT 
Anemia
Blood and lymphatic 
system disorders
20000029
Haematopoietic erythropenia
SMQ
Broad
Blood and lymphatic 
system disorders
10002055
Anaemias haemolytic NEC
HLT 
Blood and lymphatic 
system disorders
10002052
Anaemias haemolytic immune
HLT 


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Gastrointestinal disorders 
(e.g., nausea, vomiting, 
diarrhea)
Gastrointestinal disorders
20000140
Gastrointestinal nonspecific symptoms and 
therapeutic procedures
SMQ
Broad
Semen discoloration 
(yellow)
Reproductive system and 
breast disorders
10013358
Spermatogenesis and semen disorders
HLT 
Investigations
10016462
Fertility analyses
HLT 
Hypoglycemia
Metabolism and nutrition 
disorders
90000029
Hypoglycemia (Standard)
NMQ
Narrow
Development of clinical 
resistance to KAE609 in P. 
vivax and P. falciparum
Infections and 
infestations
10035499
Plasmodia infections
HLT 
Investigations
10033903
Parasite identification and serology
HLT 
General disorders and 
administration site 
conditions
90000022
Lack of efficacy (PSUR) [Standard]
NMQ
Broad


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2.8.2
Laboratory data
Descriptive statistics will be generated for all clinical laboratory tests performed (actual 
values and changes from baseline) for three groups of laboratory tests (hematology, clinical 
chemistry and urinalysis) by laboratory test, cohort, and treatment group. Change from 
baseline will only be summarized for patients with both baseline and post baseline values and 
will be calculated as:
change from baseline = post baseline value – baseline value
The following laboratory parameters will be analyzed for hematology test group: hemoglobin, 
platelets, white blood cell count, Reticulocytes, hematocrit, red blood cell (RBC) count,  
lymphocytes, lymphocytes (%),  monocytes, monocytes (%), eosinophils eosinophils (%),  
neutrophils, neutrophils(%) , basophils, and basophils (%) .
The following laboratory parameters will be analyzed for clinical chemistry test group 
creatinine, total bilirubin (TBL), direct bilirubin, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase (ALP), glucose, blood urea nitrogen (BUN). 
sodium, potassium, calcium, uric acid,  gamma glutamyltransferase (GGT),
magnesium, 
phosphate, chloride, haptoglobin, total protein, albumin, INR and LDH. 
For liver enzymes (ALT, AST, etc.), the shift table of CTCAE grades relative to baseline will 
be provided. Summary with frequency and percentage of patients with liver related events as 
defined in Table 2-2 will be provided by cohort and treatment: 
Table 2-2
Liver-related events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN;>10xULN
AST
>3xULN; >5xULN; >8xULN >10xULN;
ALT or AST
>3xULN; >5xULN; >8xULN >10xULN; 
ALT or AST and TBL
ALT or AST > 3 × ULN and TBL > 2 x ULN
ALT or AST > 5 × ULN and TBL > 2 x ULN
ALT or AST > 10 × ULN and TBL > 2 x ULN
TBL
>1.5xULN, >2xULN
ALP
>2xULN, >3xULN
ALP & TBL
ALP >3xULN & TBL >2xULN
(ALT or AST) & TBL & ALP
ALT or AST >3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law)
To support the primary endpoint, the number and percentage of patients with at least 2 
CTCAE grades increase from baseline in ALT or AST at any time during the study will be 
provided by cohort and treatment. This safety endpoint will be analyzed using the method 
specified in Section 2.5.2.
Peak ALT/AST and peak TBL will be ploted using eDISH (evaluation of Drug Induced 
Serious Hepatotoxicity) method and Modified eDISH (mDISH) method, see Lin, et. al. (2012).
If required for SRC, maximum increases in ALT or AST during the first 2 weeks (Day 1 to 
Day 15) will be categorized based on the Protocol Table 3-1 as follows:


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2: ≥2 CTCAE grades increase from baseline in either ALT or AST
1: 1 CTCAE grades increase from baseline if baseline value is normal or ≥ 2 times 
baseline value if baseline value is above normal in either ALT or AST
0: otherwise.
Listing of patients with the following renal related laboratories will be provided:

Serum creatinine increase 25 – 49% compared to baseline

Serum creatinine increase 50% compared to baseline

New dipstick proteinuria 1+

New dipstick hematuria ≥ 1+

New dipstick glycosuria ≥ 1+
For urinalysis, frequency tables will be presented.  Number and percent of patients in each 
category will be presented for each visit.
Urine pregnancy data will be summarized by visit.
Laboratory measurements, which are recorded as below the assay detection limits, will be 
imputed as half of the detection limit; and that above the detection limit will be imputed as 
detection limit, for the summary statistics.
2.8.3
Other safety data
2.8.3.1
ECG and cardiac imaging data
The following quantitative variables will be summarized for averaged triplicate ECG: heart 
rate, RR interval, PR interval, QRS interval, QT interval and QTcF. Summary statistics for 
change from baseline will be presented for ECG variables by timepoint and treatment group.
QT intervals will be summarized categorically by computing the number and percentage of 
patients at each time point and at the maximum post baseline value for the following
categories:

QT, QTcF
-
New > 450 and ≤ 480 ms
-
New > 480 and ≤ 500 ms
-
New > 500 ms
-
Increase from baseline of > 30 ms to ≤  60ms
-
Increase from baseline of > 60 ms

HR
-
Increase from baseline >25% and to a value > 100 bpm
-
Decrease from baseline >25% and to a value < 50 bpm

PR
-
Increase from baseline >25% and  to a value > 200 ms
-
New value of > 200 ms


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
QRS
-
Increase from baseline >25% and  to a value > 120 ms 
-
New > 120 ms
A line plot by patient (Spaghetti plot) will be provided by cohort, visit and treatment group.
In addition, shift tables comparing baseline ECG results (normal, abnormal, not available, 
total) with the post-baseline results will be provided by visit and at the worst post-baseline 
result (normal, abnormal, not available, total). 
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
patient listing of all quantitative ECG parameters.
2.8.3.2
Vital signs
The following quantitative variables will be summarized: Weight (kg), Temperature (oC),  
Pulse (beats/min), Supine systolic blood pressure (mmHg) and Supine diastolic blood pressure 
(mmHg).
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed by vital sign and treatment group. 
Change from baseline will only be summarized for patients with both baseline and post-
baseline values and will be calculated as:
Change from baseline = post-baseline value – baseline value
The number and percentage of patients with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-3 below.
Table 2-3
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg)
≥ 180 mmHg/≤ 90 mmHg with increase/decrease from 
baseline of ≥ 20 mmHg
Diastolic blood pressure (mmHg)
≥ 105 mmHg/≤ 50 mmHg with increase/decrease from 
baseline of ≥ 15 mmHg
Pulse (beats/min)
≥ 120 bpm/≤ 50 bpm with increase/decrease from baseline 
of ≥ 15 bpm
Temperature (oC)
>=37.5 (axillary) or >=38.0 (other routes)
Weight
decrease > 7% from baseline
increase > 7% from baseline
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
patient listing of all vital signs.
2.9
Pharmacokinetic endpoints  
PK concentrations below the limit of quantification will be treated as zero in summary 
statistics and for the calculation of pharmacokinetic parameters by non-compartmental 
`method of analysis. Descriptive statistics of pharmacokinetic parameters will include 
arithmetic and geometric (means, standard deviation (SD), median, minimum and maximum, 
etc). Parameters such as AUCinf, AUClast, AUC0-t, Cmax, T1/2 and Tmax will be reported 


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using non-compartmental method of analysis (using Phoenix 6.4 or higher). 2-sided 90% 
confidence intervals for AUC0-24h, Cmax and Tmax PK parameters of KAE609 and 
Lumefantrine will be calculated by cohort and treatment group using normal or log-normal 
approximation as applicable. 
All the PK data may be pooled for population pharmacokinetics analysis and the broad 
principles outlined in the Food and Drug Administration (FDA) Guidance for Industry: 
Population Pharmacokinetics would be followed.
2.11
Patient-reported outcomes
NA.


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2.14
Overview of analysis methods
An overview of statistical analyses and methods applied to efficacy variables and safety 
variables are given in Table 2-4 and Table 2-5.


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Table 2-4
Overview of analysis methods for baseline data and efficacy variables
Variable(s)
Summary 
statistics for 
binary/
categorical 
data 
Listings
95% CI for each 
treatment group
Summary 
statistics for 
continuous data
Time-to-event 
data analysis
K-M
Graphs
Medical history
X
X
-
-
-
-
Demogrpahics and baseline 
characteristics
X
X
-
X
-
-
Patient disposition
X
X
-
-
-
-
Prior medication use
X
X
-
-
-
-
Concomitant medication use
X
X
-
-
-
-
Concomitant rescue medication use
X
X
-
-
-
-
Non-study drug antimalarial medication 
use
X
X
-
-
-
-
Prior other prohibited medications use
X
X
-
-
-
-
Concomitant other prohibited medications 
use
X
X
-
-
-
-
PCR-corrected ACPR response at Days 
15 and 29
X
X
X
-
-
-
PCR -uncorrected ACPR response at 
Days 15 and 29
X
X
X
-
-
-
Proportion of patients with parasitaemia at 
12, 24, and 48 hours after treatment;
X
X
X
-
-
-
Time to parasite clearance (PCT)
-
X
-
-
X
X
Time to fever clearance (FCT)
-
X
-
-
X
X
Proportion of patients with early treatment 
failure 
X
X
X
-
-
-
Proportion of patients with late clinical 
failure 
X
X
X
-
-
-
Proportion of patients with late 
parasitological failure (LPF)
X
X
X
-
-
-


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Variable(s)
Summary 
statistics for 
binary/
categorical 
data 
Listings
95% CI for each 
treatment group
Summary 
statistics for 
continuous data
Time-to-event 
data analysis
K-M
Graphs
Incidence rate of recrudescence at Days 
29.
X
-
-
-
X
X
Incidence rate of reinfection at Days 29
X
-
-
-
X
X


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Table 2-5
Overview of analysis methods for safety/PK variables
Variable(s)
Summary statistics 
for binary/
categorical data 
Listings
Summary 
statistics for 
continuous 
data
Graphs
Between 
treatment 
comparison
At least 2 CTCAE grades increase 
from baseline in ALT or AST 
X
X
-
-
X*
AE
X
X
-
-
-
SAE
X
X
-
-
-
severe malaria
X
X
-
-
-
Adverse events of special interest 
X
X
-
-
-
Hematology  change from baseline
-
X
X
-
-
Clinical chemistry  change from 
baseline
-
X
X
-
-
Liver abnormalities
X
X
-
X1
-
ECG change from baseline
-
X
X
X2
-
ECG abnormality
X
X
-
-
-
Vital signs change from baseline
-
X
X
-
-
Notable vital signs abnormality
X
X
-
-
-
Drug concentrations
-
X
X
X3
-
PK parameters
X
X
* For comparison with pooled Coartem. 95% confidence interval will be provided.
1 eDISH and mDISH plot.
2 Spaghetti plot.
3 Time vs Concentration line plot.
2.15
Interim safety review
Safety laboratory data and adverse events will be monitored continuously throughout the 
study using data management’s data review reports. 
If there are no significant LFT elevations observed in a cohort at Day 15 (see Table 1-1), the 
next cohort with escalated KAE609 doses will start after informing the safety review 
committee about the findings.
If any significant LFT elevation is observed at Day 15 in any patient(s) in a cohort (see Table 
1-1), a comprehensive safety data review will be performed after all the patients in the cohort 
have been followed up for 28 days post-treatment. 
The safety review committee can pause recruitment and trigger safety review any time based 
on safety signals. An earlier review of the safety data by the safety review committee/Novartis 
in the middle of a cohort would be initiated based on occurrences of LFT elevations in the 
cohort as specified below:

The number of patients meeting the primary safety endpoint in a treatment arm is at least 2 
in Cohorts 1 and 2 or at least 3 in Cohorts 3, 4, 5 and 6.  


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Data management’s data review reports will be provided to the safety review committee and 
the appropriate Novartis relevant internal and external people who will make decision about 
whether a KAE609 dosage regimen is safe and can be escalated to the higher dosage. 
Although the randomization data are not included in the data management system, the study 
drug (KAE609 QD 1 day, KAE609 QD 3 days, Coartem) and dosage taken by each patient is 
available in the dosage records. No formal interim safety analysis by treatment group will be 
performed.
In case that more comprehensive safety analyses by treatment group are needed at the end of 
cohort or in the middle of cohort, formal interim safety analyses of selected safety or efficacy 
parameters by treatment group will be provided as described in the safety review charter.
Below is the outline of the data required for the SRM review.
Table 2-6
Specification of data outputs for SRM data review
Output
Analysis set
Periodic 
safety 
review
Baseline
Demographic characteristics
FAS
Yes
Background disease characteristics
FAS
Yes
Safety
Concomitant medications/significant non-drug 
therapies
Safety
Yes
Relevant medical history/current medical condition
Safety
All adverse events and Serious adverse events 
Safety
Yes
Newly occurring liver enzyme abnormalities 
(categorical analysis)  
Safety
Yes
Clinical chemistry shift table based on CTC grade  
Safety
Yes
ALT & AST meeting specified criteria during first 2 
weeks
Safety
Yes
eDISH and mDISH plots
Safety
Yes
3
Sample size calculation
The incidence of patients experiencing at least 2 CTC grade increase from baseline in ALT or 
AST is not consistent among KAE609 patient/human challenge studies:

3 out of 8 (37.5%) patients in a Study with KAE609 at 10 mg QD.

4 out of 11 (36.4%) in a Study with KAE609 at 75 mg QD.

1 out of 25 (4%) in a Study with KAE609 at 10 to 30 mg QD.

1 out of 21 (4.8%) in a study with KAE609 at 30 mg QD X3.


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3.1
Single arm approach
Figure 3-1 and 3-2 present the probability of observing at least 2 and 3 safety events, 
respectively, in a treatment group by various sample sizes and true event rates to assess the 
operational characteristics for the proposed sample sizes.
Given the proposed sample sizes in the treatment groups within each cohort, the probability of 
observing at least 2 safety events in 10 patients or 3 safety events in 20 patients is at least 80% 
if the true event rate is ≥ 30% and less than 5% if the true event rate is ≤ 3%. Specifically: 
•
For a sample size of 10 patients per treatment group, the probability of observing ≥ 2 
safety events is greater than 80% if the true event rate is ≥ 30% and less than 5% if the 
true event rate is ≤ 3% (Figure 3-1).
•
For a sample size of 20 patients per treatment group, the probability of observing ≥ 3 
safety events is greater than 90% if the true event rate is ≥ 30% and less than 5% if the 
true event rate is ≤ 3% (Figure 3-2).
Figure 3-1
Probability of observing at least 2 safety events by sample size and 
true event rate


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Figure 3-2
Probability of observing at least 3 safety events by sample size and 
true event rate
3.2
Power for comparison of KAE609 with Coartem
The comparison between KAE609 doses/regimen with Coartem will help interpretation of 
liver enzyme elevations in the individual KAE609 treatment arms. In the Pyramax Phase II/III 
trials (EMA 2012), the incidence of patients experiencing Grade 2 ALT was 3.4%, which was 
higher than other comparators including Coartem. The incidence rate of adults and 
adolescents experiencing at least 2 CTC grade increase from baseline in ALT or AST in 
Coartem is about 3%. To assess the power for between treatment comparisons, a Coartem
incidence rate of 5% is also considered.
Table 3-1
Power for comparison with Coartem based on 2-sided Fisher exact test
KAE609 true 
incidence rate
Coartem® true 
incidence rate
n for 
KAE609
N for 
Coartem®
Power for 2-sided testing
5% level
10% level
20% level
50%
3%
10
10
50%
70%
77%
10
20
86%
91%
95%
10
30
91%
95%
97%
10
40
94%
97%
99%
10
50
93%
97%
99%
10
60
94%
98%
99%
50%
3%
20
10
78%
84%
92%


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20
20
94%
97%
99%
20
30
99%
99%
>99%
20
40
99%
>99%
>99%
20
50
>99%
>99%
>99%
20
60
>99%
>99%
>99%
50%
5%
10
10
43%
63%
72%
10
20
80%
86%
92%
10
30
85%
92%
95%
10
40
90%
94%
97%
10
50
89%
94%
97%
10
60
90%
95%
97%
50%
5%
20
10
71%
77%
86%
20
20
89%
94%
97%
20
30
96%
98%
99%
20
40
98%
99%
>99%
20
50
99%
99%
>99%
20
60
99%
99%
>99%
40%
3%
10
10
28%
50%
54%
10
20
70%
78%
87%
10
30
77%
87%
91%
10
40
84%
91%
95%
10
50
82%
90%
95%
10
60
83%
92%
95%
40%
3%
20
10
49%
61%
80%
20
20
81%
88%
94%
20
30
93%
94%
98%
20
40
96%
97%
99%
20
50
96%
98%
99%
20
60
98%
99%
99%
40%
5%
10
10
23%
43%
50%
10
20
61%
71%
81%
10
30
69%
80%
86%
10
40
77%
85%
91%
10
50
73%
84%
92%
10
60
76%
87%
91%
40%
5%
20
10
43%
53%
71%
20
20
72%
81%
89%
20
30
86%
90%
95%
20
40
91%
93%
97%
20
50
93%
95%
98%
20
60
94%
96%
98%
Based on PASS 2011
Given the sample size of 10 to 20 per arm within a cohort, the power to detect treatment 
difference is low even with large treatment differences using a 2-sided statistical significance 


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level of 5%. If the true rate is 50% for KAE609 and 3% for the Coartem, the power to detect 
between treatment difference is about 80% using a 2-sided test at the 20% significance level 
for n= 10 per arm or at the 10% significance level for n= 20 for KAE609 and 10 for Coartem. 
If there are at least 2 cohorts at the end of study and the patients treated with Coartem are 
pooled from all cohorts, the power to detect treatment difference is greatly increased. In case 
that the study proceeds to the end with 4 cohorts for a total of 40 patients treated with 
Coartem, the power to detect treatment difference using 2-sided test at the 5% significance 
level is 77% and 91% for n=10 and 20 patients treated with KAE609, respectively, if the true 
rate is 40% for KAE609 and 5% for the Coartem. In case that the study proceed to the end 
with 6 cohorts for a total of 60 patients treated with Coartem, the power to detect treatment 
difference using 2-sided test at the 5% significance level is 76% and 94% for n=10 and 20 
patients treated with KAE609, respectively, if the true rate is 40% for KAE609 and 5% for the 
Coartem.
4
Change to protocol specified analyses
NA.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The study drug administration date should be complete since it’s taken in the hospital. In case 
missing or partial, the visit date will be used as the study drug administration date.
5.1.2
AE date imputation
The following missing dates will not be imputed

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
For other type of missing dates, rules specified in Tables 5-1 to 5-3 will be used
Table 5-1
AE/Treatment Date Abbreviations
Day
Month
Year
Partial Adverse Event Start Date
<not used>
AEM
AEY
Treatment Start Date (TRTSTD)
<not used>
TRTM
TRTY
Table 5-2 describes the possible combinations and their associated imputations. The upper 
text indicates the imputation (NC, A, B, C etc.) and the lower text the relationship of the AE 
start date to the treatment start date (TRTSTD).
Table 5-2
Imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM


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AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The legend to the above table is shown in Table 5-3.
Table 5-3
Imputation algorithm legends
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date 
to Treatment Start Date
Imputation calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
Few examples are shown in Table 5-4.
Table 5-4
Example scenarios
Partial
AE start date
Treatment
start date
Relationship 
with TRTSTD
Imputation 
Calculation
Imputed Date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001
ddNOV2001
20OCT2001
After
( A )
01NOV2001
5.1.3
Concomitant medication date imputation
Missing concomitant medication dates will be imputed similar as to AE dates.


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5.1.3.1
Prior therapies date imputation
Start date: The same rule which is applied to the imputation of AE/concomitant medication 
start date will be used with the exception that: for scenario (B) the start date will be replaced 
by the randomization date -1.
End date: 

Imputed date = min (reference end date, DEC 31 of the year), if month and day are 
missing.

Imputed date = min (reference end date, last day of the Month), if day is missing. 
where reference end date will be randomization date. 
If the end date is not missing and the imputed start date is after the end date, use the end date 
as the imputed start date. If both the start date and the end date are imputed and if the 
imputed start date is after the imputed end date, use the imputed end date as the imputation for 
the start date.
5.1.3.2
Post therapies date imputation
Start date: 

If Day is missing, then impute to the max (reference start date, first day of the month). 

Day and month are missing then impute to the max(reference start date, Jan 1) 

Reference start date will be last date of study treatment administration + 1. 
End date: No imputation.
5.1.3.3
Other imputations
NA.
5.1.4
Visit windows
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one 
of the visit windows. E.g., if the Day 4 visit of a patient is delayed and occurs on Day 7, say, 
it will be re-aligned to visit window Day 8. In the case of major deviations from the visit 
schedule, or due to unscheduled visits, several assessments of a patient may fall in a particular 
visit window (either scheduled or unscheduled). Statistical approaches to handle multiple 
assessments in a given visit window are specified below. 

Of note, patients are allowed to have gaps in visits. All data collected will be displayed 
in listings.

Lower limit and upper limit of the Day 15 visit is set to be Day 14 and Day 16 
respectively, according to the protocol visit schedule since this is the primary analysis 
timepoint.

The following rules are used to determine the window for other visits post baseline:

“Lower limit” = “upper limit of prior applicable visit” + 1. 

“Upper limit” = “target day of current visit” + integer part of (“target day of 
next applicable visit” – “target day of current visit”)/2 with the exception of 
Day 29


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
No upper limit for Day 29 visit

Upper limit of Day 11 is one day before the lower limit of Day 15 
For assessments that are scheduled to be performed only once on a day, Table 5-5 describes 
the analysis windows mapping to visits (not just scheduled visits) based on study days alone.  
For the assessments that may be performed on multiple timepoints on a day, Table 5-6
describes the analysis windows mapping to visits based on study day and time. Repeat and/or 
unscheduled visits (which will be numbered in the database according to new NCDS 
standards) will be mapped for analysis purposes in the same way. If there are multiple 
measurements within an analysis window, the conventions  defined in Table 5-7 will be used 
to determine the appropriate measurement to be selected for analysis.
The mapped visits will be used in the by visit analyses. However, the listings will show the 
collected data regardless of used in the by visit analyses.
Table 5-5
Analysis visit windows based on study days alone
Analysis Visit
Target 
Day
Analysis window for assessment group
Vital signs/
Chemistry/ 
Hematology
Urinalysis
Pregnancy
Baseline
1
Up to Day 1 
Up to Day 1 
up to day 1
Day 2
2
Day 2
Day 2-3
NA 
Day 3
3
Day 3
NA
NA 
Day 4
4
Day 4
NA
NA 
Day 5
5
Day 5 - 6
Days 4-13
NA
Day 8
8
Day 7 – 9
NA
NA
Day 11
11
Day 10 – 13
NA
NA
Day 15
15
Day 14 – 16
Day 14 – 16
NA
Day 22
22
Day 17 – 25
NA
NA
Day 29/End of 
study
29
Day 26 and 
above
Day 17 and 
above
Day 2 and 
above
Table 5-6
Analysis visit windows based on study day and time
Analysis 
Visit
Analysis 
timepoint
Analysis window for assessment group
Temperature/
Parasite count
ECG
PK
KAE609 
Coartem
Baseline
0 hrs
up to 0 hrs
up to < 0 hrs
up to < 0 hrs
NA 
Day 1
1 hrs
NA 
NA 
NA
>0 to 1.5 hrs
2 hrs
>0 to 3 hrs
NA
NA
>1.5 to 3 hrs
4 hrs
>3 to 6 hrs
>0 to 8 hrs
NA
>3 to 5 hrs
6 hrs
NA
NA
>0 to 37 hrs
>5 to 7 hrs
8 hrs
>6 to 10 hrs 
NA 
NA
>7to 10 hrs 
12 hrs
>10 to 18 hrs
>8 to 18 hrs
NA
>10 to 18 hrs
Day 2
24 hrs
>18 to 30 hrs
>18 to 38 hrs
NA
>18 to 38 hrs
36 hrs
>30 to 42 hrs
NA 
NA
NA
Day 3
48 hrs
>42 to 54 hrs
NA 
NA
>38 to 49 hrs


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50 hrs
NA 
NA 
NA
>49 to 51 hrs
52 hrs
NA
>38 to 56 hrs
NA
>51 to 54 hrs
56 hrs
NA 
NA 
NA
>54 to 58 hrs
60 hrs
>54 to 66 hrs 
>56 to 66 hrs
NA
>58 to 64 hrs
68 hrs
NA 
NA 
>37 hrs to Day13
>64 to 70 hrs
Day 4
72 hrs
>66  hrs to 
Day 4
>66 hrs to 
Day 16
NA
>70 hrs to Day 6
Day 5
NA
Day 5-6
NA 
NA
NA
Day 8
NA
Day 7 – 9
NA 
NA
Day 7 – 9
Day 11
NA
Day 10 – 13
NA 
NA
NA
Day 15
NA
Day 14 – 16
NA 
NA
NA
Day 22
NA
Day 17 – 25
NA 
NA
NA
Day 
29/end of 
study
NA
Day 26 and 
avove
Day 17 and 
above
Day 14 and 
above
NA 
Table 5-7        Rules for flagging variables
Timing of 
measurement
Type of data
Rule
Baseline
All data
The last measurement made prior to and including 
administration of the first dose of study treatment – note this 
may include measurements taken on the day of randomization. 
If a patient did not receive any dose of study treatment then the 
randomization date will be used.
Post-baseline efficacy
All data
The measurement closest to the target day/time will be used. In 
the event that two measurements are taken equally apart (e.g. 1 
day before target date and 1 day after) the first one will be used.
Post-baseline safety
Summary visit 
information (e.g. lab, 
ECG, etc.)
The measurement closest to the target day/time will be used. In 
the event that two measurements are taken equally apart, the 
first one will be used. 
Post-baseline safety 
Notable abnormalities 
(e.g. lab, ECG, VS)
The most extreme measurement in the window will be used.  
Note this means a patient can have a notably high and notably 
low measurement within a window
5.2
Prohibited medications
Table 5-8
Table of prohibited medications with respective ATC codes 
Prohibited 
medication
ATC 
code
Drug
Comments
Antimalarials other 
than the study 
drug and rescue 
medication 
(Coartem)
P01BA
Aminoquinolines
Have not included  codes for plain 
arthemether and 
arthemether/lumefantrine 
combination
P01BB
Biguanides
P01BC
Methanolquinolines
P01BD
Diaminopyrimidines
P01BE
Artemisinin and derivatives, plain
P01BX
Other antimalarials
P01BF02
artesunate and mefloquine        
P01BF03
artesunate and amodiaquine        


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P01BF04
artesunate, sulphamethopyrazine and 
pyrimethamine        
P01BF05
artenimol and piperaquine        
P01BF06
artesunate and pyronaridine
P01BE01 
artemisinin
P01BE03 
artesunate
P01BE04 
artemotil
P01BE05 
artenimol
Herbal medication
Do not have codes for this generic 
class
CYP3A4 
metabolism thus 
potent and 
moderate CYP3A 
inhibitors (such as 
HIV antivirals: e.g. 
ritonavir 
miscellaneous: 
e.g. 
clarithromycin, 
itraconazole, 
ketoconazole, 
grapefruit juice, 
verapamil, 
cimetidine)
J05AR
Antivirals for treatment of HIV 
infections, combinations
do not have code for entire class 
of CYP inhibitors so provided 
codes for examples provided in 
the protocol
clarithromycin, 
itraconazole, 
ketoconazole, 
grapefruit juice, 
verapamil, 
cimetidine
J01FA09
clarithromycin
grapefruit juice: code not available
J02AC02
itraconazole
D01AC08
ketoconazole
G01AF11
ketoconazole
J02AB02
Ketoconazole
C08DA01
verapamil
A02BA01
cimetidine
barbiturates, 
carbamazepine, 
phenytoin, 
rifampin, st.John’s 
wort
N03AA
Barbiturates and derivatives
st.John’s wort code not avaiable
N03AF01
carbamazepine
N03AB02
phenytoin
J04AB02 
rifampicin
Proton pump 
inhibitors: e.g. 
lansoprazole, 
omeprazole, anti-
A02BC
Proton pump inhibitors
Indomethacin= Indometacin
N03
ANTIEPILEPTICS
N06AA09
amitriptyline


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epileptics: e.g. 
phenytoin, 
miscellaneous: 
e.g., amitriptyline, 
chloramphenicol, 
clomipramine, 
indomethacin, 
nelfinavir, 
progesterone, 
proguanil, 
propranolol, 
warfarin
D06AX02
chloramphenicol
D10AF03
chloramphenicol
G01AA05
chloramphenicol
J01BA01
chloramphenicol
S02AA01
chloramphenicol
S03AA08
chloramphenicol
N06AA04
clomipramine
C01EB03
indometacin
M01AB01
indometacin
M02AA23
indometacin
S01BC01
indometacin
J05AE04
nelfinavir
G03DA04
progesterone
P01BB01
proguanil
C07AA05
propranolol
B01AA03
warfarin
Acetaminophen
Alpha-methyldopa 
Ephedra
Amoxicillin-
clavulanic acid
Amiodarone
Senna
Dantrolene 
Disulfiram
Vitamin A
Glyburide
Halothane
Anabolic steroids
Heparin
Cocaine
HMG-Co A 
reductase 
inhibitors
Isoniazid 
Phencyclidine 
(PCP)
Ketoconazole
Labetolol
N02BE01
paracetamol
Paracetamol=acetaminophen
code not available for the 
following:
Amoxicillin-clavulanic acid (co-
amoxiclav) ,
Flucanozole, 
Glyburide, Ectasy (MDMA) , 
Phencyclidine, Labetolol, 
Hydrazine, Trazadone, Ephedra
C02AB
Methyldopa
C01BD01
amiodarone
A06AB06
senna glycosides
M03CA01
dantrolene
N07BB01
disulfiram
P03AA04
disulfiram
A11CA
Vitamin A, plain
N01AB01
halothane
A14A
ANABOLIC STEROIDS
B01AB01
heparin
C05BA03
heparin
S01XA14
heparin
N01BC01
cocaine
R02AD03
cocaine
S01HA01
cocaine
S02DA02
cocaine
C10AA
HMG CoA reductase inhibitors
J04AC01
isoniazid
D01AC08
ketoconazole


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Carbon 
tetrachloride
Nicotinic Acid 
Chloroform
Nitrofurantoin
NSAIDs
Hydrazine
Phenylbutazone 
Phenytoin
Protease inhibitors
Sulfonamides
Terbinafine
Trazadone
Troglitazone
(withdrawn)
Valproic Acid
Bosentan
Propylthiouracil
G01AF11
ketoconazole
J02AB02
ketoconazole
C04AC01
nicotinic acid
C10AD02
nicotinic acid
J01XE01
nitrofurantoin
M01A
NSAID
M01AA01
phenylbutazone
N03AB02
phenytoin
J05AE
Protease inhibitors
A07AB
Sulfonamides
D06BA
Sulfonamides
G01AE
Sulfonamides
S01AB
Sulfonamides
D01AE15
terbinafine
D01BA02
terbinafine
A10BG01
troglitazone
N03AG01
valproic acid
C02KX01
bosentan
D05BB01
etretinate
H03BA02
propylthiouracil
N01AB02
chloroform
N01AB05
trichloroethylene
The prohibited medications listed in Table 5-8 is not an exhausted list. Concomitant 
medications not listed above will be manually checked and will be categorized as Prohibited 
medication or non-prohibited medication.
The final list with all prohibited medications that were determined by medical review before 
database lock can be found in the excel file 'Copy of CKAE609A2202_possible_prohibited 
medications.xlsx'.
Copy of 
CKAE609A2202_poss


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5.3
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. AEs are assessed by investigators according to the most current Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 
5.4
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (specify version used in the 
RAP). The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account. The criteria to assign CTCAE grades are 
given in Novartis internal criteria for CTCAE grading of laboratory parameters. The latest 
available version of the document based on the underlying CTCAE version 4.0 at the time of 
analysis will be used. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. 
5.5
Statistical models
5.5.1
Primary analysis
The primary analysis is detailed in Section 2.
SAS procedure FREQ with EXACT statement for one-way tables will be used to estimate the 
proportion of patients (binary outcome = 1 or “Yes”), along with the associated 95% (=100 × 
(1 – two-sided alpha level)) two-sided Clopper- Pearson CI  [Clopper and Pearson 1934]. SAS 
procedure FREQ with EXACT statement for two-way tables will be used to perform the 
Fisher exact test.
5.5.2
Key secondary analysis
NA.
5.5.3
Other secondary/
 analysis
Kaplan-Meier estimates
An estimate of the survival function in each treatment group will be constructed using 
Kaplan-Meier (product-limit) method as implemented in PROC LIFETEST with 
METHOD=KM 
option. The PROC 
LIFETEST statement will use the option 
CONFTYPE=LOGLOG.
Median survival for each treatment group will be obtained along with 95% confidence 
intervals calculated from PROC LIFETEST output using the method of [Brookmeyer and 
Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% confidence 
intervals at specific time points will be summarized. The standard error of the Kaplan-Meier 
estimate will be calculated using Greenwood’s formula [Collett 1994].


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5.6
Rule of exclusion criteria of analysis sets 
Table 5-9
Protocol deviations and non-PD criteria leading to exclusion from 
analysis sets
Analysis Set
PD (Description and ID) that 
causes Subjects to be excluded
Non-PD criteria that cause Subjects to 
be excluded
Randomized

Informed Consent for study 
participation not obtained and 
subject entered trial (INCL06)

Not randomized 

Misrandomized if identified from 
IRT
FAS
NA

Not in Randomized set;

Baseline parasitaemia count is 0 or 
missing

No study drug taken
PPS

Parasite specie is other than 
Plasmodium 
falciparum 
OR 
mixed infection (EXCL01)

Baseline 
plasmodium 
falciparum 
parasite
count 
<500/uL 
or 
>50000/uL 
at 
screening visit (INCL03)

No fever within the past 24 
hours at baseline (INCL04)

Received non-study 
concomitant antimalarial drugs 
between Day 1 and Day 29 
without experiencing treatment 
failure (COMD02)

Patients who received 
concomitant prohibited 
medication  which found to 
change the exposure that 
impacts efficacy. (COMD01b)  

Not in FAS;

<80% 
of 
randomized 
study 
medication taken 

Not classified as non-responder 
before Day 8, no positive blood 
smear parasite on Day 8 onwards,
and blood smear parasite result is 
missing at Day 29.

Not classified as non-responder 
before Day 8,   have at least one 
positive 
blood 
smear 
parasite 
result between Day 8 and Day 29 
which cannot be determined as 
recrudescent 
or 
new 
infection 
based on PCR genotyping;
SAF
NA

Not in Randomized  set;

No study drug taken
PK
Patients who received concomitant 
prohibited medication  which found 
to change the exposure that 
impacts interaction in PK 
parameters (COMD01c)

Not in SAF

No evaluable pharmacokinetic 
parameter data

<80% of randomized study 
medication taken


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6
Reference
European Medicine Agency (EMA) (2012) Pyramax assessment report, Procedure No.: 
EMEA/H/W/002319.
 
Stepniewska K and White NJ (2006) Some considerations in the design and interpretation of
antimalarial drug trials in uncomplicated falciparum malaria: Malar J; 5:127.
Lin X, et. al. (2012)  Validation of Multivariate Outlier Detection Analyses Used to Identify
Potential Drug-Induced Liver Injury in Clinical Trial Populations. Drug Saf; 35 (10): 865-875.
WHO (2015) Guidelines for the treatment of malaria. 3rd edition.