Clinical trial NCT03167242
Conditions: Acute Uncomplicated Plasmodium Falciparum Malaria
Sponsor: Novartis Pharmaceuticals
Start date: 2017-08-02; Completion date: 2021-06-28
Enrollment: 524 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed to determine the most effective and tolerable dose at the shortest dosing regimen of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in adult/adolescent and pediatric patients with uncomplicated Plasmodium falciparum malaria.

There is unmet medical need for anti-malarial treatment with new mechanism of action to reduce probability of developing resistance, and for duration shorter than 3 days of treatment and/or reduced pill burden.

Detailed description:
This was a Phase 2 multi-center and open-label study with a single cohort pharmacokinetic (PK) Run-in Part followed by 2 randomized parallel-group parts, Part A and Part B, in adults and children with confirmed and uncomplicated Plasmodium falciparum malaria. Each part (PK Run-in, Part A and Part B) had the same design structure: A screening phase of up to 24 hours where participants were evaluated for eligibility and randomized (Part A and B) into different cohorts. A treatment phase of up to 3 days where participants were treated for 1, 2 or 3 consecutive days. Finally, participants were followed up until Day 43, where the rescue medication was the local standard at the discretion of the Investigator and participants

PK Run-in part: Adult/adolescent participants (≥ 12 years old) were dosed with a single dose of 200 mg KAF156 and 960 mg LUM-SDF at Day 1. The purpose of this part was to assess potential PK interactions between the compounds when dosed together.

Part A: Adult/adolescent participants (≥ 12 years old) were randomized into one of seven cohorts in a 2:2:2:2:2:2:1 ratio: six KAF156 and LUM-SDF cohorts at starting doses of 400 mg and 480 mg once daily (QD) for 1 day respectively and a control arm (Coartem twice a day (BID) for 3 days). Upon completion of Part A, all the dosing groups were evaluated in an interim assessment to determine the effective and tolerated KAF156 and LUM-SDF dosing regimen and dosages to be used in Part B.

Part B: Children participants (2 to \< 12 years old) were randomized to three KAF156 and LUM-SDF cohorts at dosages and dosing regimens selected from Part A and the control arm (Coartem) in a 2:2:2:1 ratio.

Arms: arm 1: Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg arm 2: Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg arm 3: Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days arm 4: Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days arm 5: Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days arm 6: Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days arm 7: Participants received Coartem twice daily via oral administration for 3 days arm 8: Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg arm 9: Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg arm 10: Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days arm 11: Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days arm 12: Participants received Coartem twice daily via oral administration for 3 days
Interventions: intervention 1: KAF156 intervention 2: Coartem intervention 3: Lumefantrine Solid Dispersion Formulation
Intervention descriptions: intervention 1: KAF156 comes in 100 mg tablets for oral administration. KAF156 was administered in combination with LUM-SDF once daily (QD) for 1, 2 or 3 days at 200 mg, 400 mg or 800 mg doses. intervention 2: Coartem comes as 20/120 mg dispersible tablets or 80/480 mg tablets for oral administration. Coartem was administered twice daily for 3 days as active comparator. intervention 3: LUM-SDF comes in 240 mg or 480 mg sachets for oral administration. LUM-SDF was administered in combination with KAF156 once daily (QD) for 1, 2 or 3 days at 480 mg or 960 mg doses.

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
KAF156
Clinical Trial Protocol CKAF156A2202 / NCT03167242
A Phase 2 interventional, multicenter, randomized 
open-label study to determine the effective and tolerable 
dose of KAF156 and Lumefantrine Solid Dispersion 
Formulation in combination, given once daily for 1, 2 and 
3-days to adults and children with uncomplicated
Plasmodium falciparum malaria
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
N/A
Version number:
03 Clean
Clinical trial phase:
II
Release date:
13-Apr-2018
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 ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 1 ...........................................................................................................................11
Amendment 2 ...........................................................................................................................12
Protocol summary..............................................................................................................16
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................22
2
Study objectives and endpoints .........................................................................................22
2.1
Objectives and related endpoints...........................................................................22
3
Investigational plan ...........................................................................................................24
3.1
Study design...........................................................................................................24
3.2
Rationale for study design .....................................................................................27
3.3
Rationale for dose/regimen, route of administration and duration of treatment....27
3.4
Rationale for choice of control ..............................................................................30
3.5
Purpose and timing of interim assessments/data reviews......................................30
3.6
Risks and benefits..................................................................................................30
4
Population..........................................................................................................................31
4.1
Inclusion criteria ....................................................................................................31
4.2
Exclusion criteria...................................................................................................32
5
Treatment...........................................................................................................................34
5.1
Study treatment......................................................................................................34
5.1.1
Investigational and control drugs..........................................................34
5.1.2
Additional treatment..............................................................................36
5.2
Treatment arms......................................................................................................36
5.3
Treatment assignment and randomization.............................................................37
5.4
Treatment blinding.................................................................................................37
5.4.1
PK Run-in Part......................................................................................37
5.4.2
Parts A and B ........................................................................................37
5.5
Transition from PK Run-in Part to Part A and from Part A to Part B...................38
5.6
Treating the patient................................................................................................38
5.6.1
Patient numbering .................................................................................38


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5.6.2
Dispensing the study drug.....................................................................39
5.6.3
Handling of study treatment..................................................................39
5.6.4
Instructions for prescribing and taking study treatment........................40
5.6.5
Permitted dose adjustments and interruptions of study treatment ........41
5.6.6
Rescue medication ................................................................................41
5.6.7
Prior and Concomitant medication........................................................42
5.6.8
Prohibited medication ...........................................................................43
5.7
Study completion and discontinuation...................................................................45
5.7.1
Study completion and post-study treatment..........................................45
5.7.2
Discontinuation of study treatment .......................................................45
5.7.3
Premature Study Withdrawal ................................................................47
5.7.4
Withdrawal of informed consent...........................................................47
5.7.5
Loss to follow-up ..................................................................................48
5.7.6
Early study termination by the sponsor.................................................48
6
Visit schedule and assessments .........................................................................................48
6.1
Information to be collected on screening failures..................................................55
6.2
Patient demographics/other baseline characteristics .............................................55
6.3
Treatment exposure and compliance .....................................................................55
6.4
Efficacy..................................................................................................................56
6.4.1
Parasitaemia assessment (details provided in the laboratory 
manual)..................................................................................................56
57
6.4.3
Blood sample for molecular diagnostic purposes .................................57
6.4.4
Appropriateness of efficacy assessments..............................................57
6.5
Safety.....................................................................................................................57
6.5.1
Physical examination and malaria signs and symptoms .......................58
6.5.2
Vital signs..............................................................................................58
6.5.3
Body temperature..................................................................................58
6.5.4
Laboratory evaluations..........................................................................59
6.5.5
Electrocardiogram (ECG) .....................................................................59
6.5.6
Pregnancy and assessments of fertility .................................................60
6.5.7
Appropriateness of safety measurements..............................................60
6.5.8
WHO definition.....................................................................................60
62
7
Safety monitoring..............................................................................................................62
7.1
Adverse events.......................................................................................................62


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7.2
Serious adverse events...........................................................................................64
7.2.1
Definition of SAE .................................................................................64
7.2.2
SAE reporting........................................................................................65
7.3
Liver safety monitoring .........................................................................................66
7.4
Renal safety monitoring.........................................................................................67
7.5
Cardiac Safety Monitoring ....................................................................................67
7.6
Reporting of study treatment errors including misuse/abuse ................................68
7.7
Pregnancy reporting...............................................................................................68
8
Data review and database management.............................................................................69
8.1
Site monitoring ......................................................................................................69
8.2
Data collection.......................................................................................................69
8.3
Data management and quality control ...................................................................70
8.4
Data Monitoring Committee..................................................................................70
9
Data analysis......................................................................................................................71
9.1
Analysis sets ..........................................................................................................71
9.2
Patient demographics and other baseline characteristics.......................................72
9.3
Treatments .............................................................................................................72
9.3.1
Study treatment .....................................................................................72
9.3.2
Prior and concomitant medication ........................................................73
9.4
Analysis of the primary variable(s) .......................................................................73
9.4.1
Primary Variable(s)...............................................................................73
9.4.2
Statistical model, hypothesis, and method of analysis..........................74
9.4.3
Handling of missing values/censoring/discontinuations.......................74
9.4.4
Sensitivity analyses ...............................................................................74
9.5
Analysis of secondary variables ............................................................................75
9.5.1
Efficacy variables..................................................................................75
9.5.2
Safety variables .....................................................................................77
9.5.3
Resource utilization...............................................................................78
9.5.4
Pharmacokinetics ..................................................................................78
.78
79
9.7
Interim assessments ...............................................................................................79
9.8
Sample size calculation..........................................................................................80
10 Ethical considerations........................................................................................................83
10.1
Regulatory and ethical compliance........................................................................83
10.2
Informed consent procedures.................................................................................83


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10.3
Responsibilities of the investigator and IRB/IEC..................................................83
10.4
Publication of study protocol and results...............................................................84
10.5
Quality Control and Quality Assurance.................................................................84
11 Protocol adherence ............................................................................................................84
11.1
Protocol amendments.............................................................................................85
12 References .........................................................................................................................85
13 Appendix 1: Clinically notable laboratory and ECG values .............................................87
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................88
15 Appendix 3: Cardiac Alert Threshold Values and Actions...............................................91
16 Appendix 4: Renal Alert Criteria and Actions ..................................................................92
17 Appendix 5: .......................................................................................................................93
List of tables
Table 2-1
Objectives and related endpoints (PK Run-in Part, Part A and Part 
B)...........................................................................................................22
Table 3-1
Dose adjustment for Part A...................................................................28
Table 5-1
PK Run-in Part: KAF156 and LUM-SDF dosing scheme....................35
Table 5-2
Part A: KAF156 and LUM-SDF dosing scheme* ................................35
Table 5-3
Parts A and B: Coartem® dosing per weight.........................................35
Table 5-4
Part B: Children KAF156 and LUM-SDF dosing per weight...............36
Table 5-5
Prohibited medications..........................................................................44
Table 6-1
Assessment schedule (except PK sampling and ECG 
measurements) for all patients (PK Run-in Part, Part A and Part B)....49
Table 6-2
12-Lead ECG assessments (triplicate) for all patients (PK Run-in 
Part, Part A and Part B).........................................................................51
Table 6-3
PK sampling schedule for patients involved in RICH PK sampling 
(PK Run-in Part and Part A) .................................................................52
Table 6-4
PK sampling schedule for patients NOT involved in RICH PK 
sampling (Part A and Part B) ................................................................53
Table 6-5
Overview of specific CRF pages...........................................................54
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................68
Table 9-1
Sample size and width of 2-sided 90% CI for log AUC0_24h and log 
Cmax .....................................................................................................80
Table 14-1
Liver event and laboratory trigger definitions ......................................88
Table 14-2
Follow up requirements for liver events and laboratory triggers..........88


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Table 15-1
Cardiac alert threshold values and actions............................................91
Table 16-1
Specific renal alert criteria and actions .................................................92
Table 17-1 
Part A: KAF156 and LUM-SDF dosing scheme in case KAF156 
relative exposure factor in PK Run-in vs. the reference mean 
AUC0-24h (4930 ng*h/mL) is <1.4........................................................93
Table 17-2
Part A: KAF156 and LUM-SDF dosing scheme in case KAF156 
relative exposure factor in PK Run-in vs. the reference mean 
AUC0-24h (4930 ng*h/mL) is ≥1.4 to <1.8............................................93
Table 17-3
Part A: KAF156 and LUM-SDF dosing scheme in case KAF156 
relative exposure factor in PK Run-in vs. the reference mean 
AUC0-24h (4930 ng*h/mL) is ≥1.8 to <2.5.............................................94
Table 17-4
Part A: KAF156 and LUM-SDF dosing scheme in case KAF156 
relative exposure factor in PK Run-in vs. the reference mean 
AUC0-24h (4930 ng*h/mL) is ≥2.5 to 4..................................................94
List of figures
Figure 3-1
Study design..........................................................................................26
Figure 3-2
Dose selection for Part B.......................................................................29
Figure 9-1
Power to reject adequate clinical and parasitological response 
(ACPR) rate less than or equal to 80% based on 2-sided 95% CI by 
true rate..................................................................................................82


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List of abbreviations
ACT
Artemisinin-based Combination Therapy
ACPR
ACR
Adequate Clinical and Parasitological Response
Albumin-Creatinine Ratio
AE
Alb
Adverse Event
Albumin
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
AUCinf
AUClast
AUC0-t
Area Under the Curve
Area under plasma concentration-time curve from zero to infinity
Area under the plasma concentration-time curve up to the last measurable 
concentration
Area under plasma concentration-time curve from zero to time t of the last 
measured concentration above the limit of quantification
BID
twice a day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CFR
US Code of Federal Regulations
β-hCG
CI
The β-subunit of human Chorionic Gonadotropin
Confidence Interval
CQ
Cmax
Chloroquine
Maximum Peak Observed Concentration
CMO&PS
Chief Medical Office and Patient Safety
CPO
CRF
sCr
Country Pharma Organization
Case Report/Record Form (paper or electronic)
Serum Creatinine
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome
DAR
Dose Administration Record
DHP/DMP
Data Handling Plan/Data Management Plan
DMC
Data Monitoring Committee
EC50
Half maximal effective concentration
ECG
Electrocardiogram
EDC
Electronic Data Capture
e.g.
For exemple (exempli gratia)
EMA
European Medicines Agency
EOT
End of Treatment
ETF
EU
Early Treatment Failure
European Union
FAS
Full Analysis Set


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FBC
Full Blood Count
FCT
FDA
Fever Clearance Time
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Serum-γ-Glutamyl Transferase
GNF
Genomics Institute of the Novartis Research Foundation
HIV
Human Immunodeficiency Virus
HR
Heart Rate
HTS
High Through-put Screening
IA
Interim Assessment
IB
Investigator Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
i.e.
That is (id est)
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IN
Investigator Notification
INR
International Normalized Ratio (blood clotting test)
IUD/IUS
Intrauterine Device/Intrauterine System
IRB
Institutional Review Board
IRT
LCF
Interactive Response Technology
Late Clinical Failure
LFT
Liver function test 
LPF
LTF
Late Parasitological Failure
Late Treatment Failure
LUM-SDF
Lumefantrine Solid Dispersion Formulation
MedDRA
Medical dictionary for regulatory activities 
MEF
Mefloquine
NITD
NovDTD
Novartis Institute for Tropical Diseases
Novartis Drug and Therapy Dictionary
NSAIDS
OATP1B1
Non-Steroidal Anti-Inflammatory Drugs
Organic Anion Transporting Polypeptide 1B1
P.
Plasmodium
PCT
Parasite Clearance Time
PCR
PCV
Polymerase Chain Reaction
Packed-Cell volume (hematocrit)
PD
Pharmacodynamic
PK
Pharmacokinetic
PPS
Per-Protocol Set
PSOC
PT
Primary System Organ Class
Prothrombin Time
PYR
Pyrimethamine
OC/RDC
Oracle Clinical/Remote Data Capture


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PSW
Premature Study Withdrawal
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
QTcB
QT interval corrected by the Bazett's Correction Formula
QTcF
QT Interval Corrected by the Fridericia Correction Formula
RBC
Red Blood Cell Count
RSI
eRT
Reference Safety Information
eResearch Technology
SAE
Serious Adverse Event (paper or electronic)
SAP
SD
Statistical Analysis Plan
Standard Deviation
SFDX
Sulfadoxine
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
SMQ
SNP
Serum Glutamic Pyruvic Transaminase
Standardized MedDRA query
Single-Nucleotide Polymorphism
SOP
Standard Operating Procedure
SS
Safety Set
SUSAR
Suspected Unexpected Serious Adverse Reactions
Tmax
Time after administration of a drug when the maximum plasma concentration is 
reached
TSH
Thyroid Stimulating Hormone
ULN
uPCR
Upper Limit of Normal range
Urinary Protein-Creatinine Ratio
UNS
US
Unscheduled visit
United States
WBC
White Blood Cell
WHO
World Health Organization 
WoC
WOCBP
WWARN
Withdrawal of Consent
Women Of Child Bearing Potential
World Wide Antimalarial Resistance Network


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Glossary of terms
Cohort 
A specific group of patients fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, assess 
internal study validity.
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)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
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
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient ID
A unique number assigned to each patient upon signing the informed 
consent 
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
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 is defined as when a patient 
does not want to participate in the study any longer, and does not want 
any further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained 
biologic material


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Amendment 1 
---------------------------------------------------------------------------------------------------------------
Amendment rationale

In a recent preclinical in vivo study in dogs KAF156 (10 mg/kg) and LUM-SDF (15 
mg/kg) were administered in combination and preliminary data suggest that exposure of 
both KAF156 and lumefantrine increased in presence of each other. There was around 2-3 
fold increase in KAF156 exposure and around 1.5 fold increase in lumefantrine exposure.

Given the above situation and the fact that the study has not yet started, a PK Run-in Part 
has been included in the amended study protocol. This first part of the study will explore 
the PK and safety of KAF156 given in combination with LUM-SDF to understand the 
impact of LUM-SDF on KAF156 exposure as victim drug. In the unlikely scenario of an 
increase in KAF156 exposure beyond the acceptable limit, doses in Part A of the study 
may be adjusted.
Changes to the protocol

Protocol summary: The PK Run-in Part has been added in the table in the following sub-
sections: Study Design, Population, Key inclusion criteria, Study treatment and Data 
analysis. In addition PK assessments has been added to the list of assessments.

Section 1: The rationale for having a PK Run-in Part has been described in Section 1.1 
and the design of the study has been changed (i.e., now a three-part sequential design 
including the PK run-in Part) in Section 1.2.

Section 2.1: Primary objective for the PK Run-in Part has been added (i.e. Assessments of 
KAF156 exposure in the PK Run-in cohort to understand the impact of LUM-SDF on 
KAF156 exposure).

Section 3: Text describing the PK-Run-in Part has been added to different sub-sections of 
Section 3. Modified sections are :
-
Section 3.1 (study design of the PK-Run-in Part added, Table 3-1 added and Figure 3-
1 modified accordingly)
-
Section 3.3 (Rationale for dose/regimen in PK Run-in Part added)
-
Section 3.5 (Purpose of interim assessments/data reviews for the PK Run-in Part 
added)
-
Section 3.6 (Risks and benefits modified to include the PK Run-in Part)  

Section 4: PK Run-in Part has been added to population description.

Section 5.1: Study treatment for the PK Run-in Part has been included in the text and 
Table 5-1. Also, as doses in Part A of the study may be adjusted, Table 5-2 has been 


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modified to indicate KAF156 dose levels for Part A based on the results of the PK Run-in 
Part.

Section 5.2: Treatment arm for PK Run-in Part added.

Section 5.3: Treatment assignment and randomization for the PK Run-in Part added.

Section 5.4: Treatment blinding for PK Run-in Part added.

Section 5.5: Transition from PK Run-in Part to Part A added.

Section 5.6.5: Procedure for patients who vomit in the PK Run-in Part has been added.

Section 6: Schedule of assessments to be used for the PK Run-in Part has been added (i.e., 
same visit schedule as for Cohorts 1 and 2).

Section 9: Data analysis for the PK Run-in Part has been added to Section 9.4, Section 
9.5.4, Section 9.7, and Section 9.8.

References: Three references added.

Appendix 5: Part A dosing scheme based on the results of the PK Run-in Part added.
Amendment 2 
---------------------------------------------------------------------------------------------------------------
Amendment rationale
This protocol is being amended to correct several errors/inconsistencies, and provide 
clarifications. This includes:

To correct the typographical error regarding oral/tympanic/rectal temperature versus 
axillary temperature.

To correct an inconsistency regarding the requirement for blinding the technician 
performing microscopy readings. Since this is an open label study, blinding of technicians 
is not required.

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.


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
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.

Terms “Biochemistry” and “clinical chemistry” 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.

For further clarification, time window for electrocardiogram (ECG) assessment has been 
added in the table of assessment as ECG and pharmacokinetic (PK) assessments should be 
aligned.

Clarification on how some cardiac alerts should be reported. Resting heart rate < 50/min 
with > 25% decrease from pretreatment baseline verified by ECG should be reported to 
Sponsor as adverse event (AE).
Changes to the protocol

List of abbreviations: has been updated based on the changes implemented in this 
amendment.

Protocol summary and Section 4.1: Reference to the laboratory manual for technical 
details 
about 
microscopy 
has 
been 
added, 
and 
typographical 
error 
on 
oral/tympanic/rectal temperature as compared to axillary temperature has been corrected.

Section 3.2: Blinding laboratory technicians who perform microscopy readings has been 
removed as it is not required for this open label study.

Sections 5.6.6, 6.5.4, 6.5.4.2: Term “Biochemistry” or “clinical chemistry” replaced by 
“blood chemistry” to maintain consistency throughout the protocol.

Section 5.6.7: The terms prior medication and concomitant medication have been 
defined for further clarity to make it consistent with existing information in Section 9.3.2.
Clarification on how paracetamol or equivalent drug should be reported when given as 
an antipyretic up to 72 hours prior first dose has been added.

Section 5.7.2: Information on rescue medication in case of treatment discontinuation 
has been added for clarification purposes.

Table 6-1: To correct typographical errors, the following changes have been done:
-
 
 


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-
Meals have to be recorded on dosing days only (Day 1 to3). Meal record at Day 4 has 
been deleted.
-
Patients are discharged on Day 4, so time window at Day 5 cannot be +/- 1 day, but + 1 
day.
-
The sites are required to contact Interactive Response Technology (IRT) for the control 
drug (coartem) once per day only so they are not required to contact IRT at hour 8, 36 
and 60.
-
Addition of PCR sampling 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.
-
PCR sampling are all shipped to central laboratory, but analyzed only in patients 
showing treatment failure. Footnote corrected.
  

Table 6-2: Time window for ECG assessment has been added.

Section 6.2: Body height included in the list of baseline demographic characteristics to 
make it consistent with the information in Table 6-1, Section 6.5.1.

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 6.4.3: PCR sampling are all shipped to central laboratory, but analyzed only in 
patients showing treatment failure.

Sections 6.5.3, 9.5.1: Typographical error on oral/tympanic/rectal temperature as 
compared to axillary temperature has been corrected.

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 has been corrected to be consistent with 
Section 9.5.2.4: “> 60 ms from baseline” replaced by “≥ 60 ms from baseline”.

Section 6.6: Time points for biomarker assessment added for clarification purposes, and 
it has beenclarified that biomarker is assessed in Part A only.


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
Section 7.1, Section 7.3 and Table 16-1: Deleted “Study treatment dosage 
increased/reduced” and/or “Study treatment interrupted” and/or “interruption” 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, 7.7: DS&E replaced by CMO&PS to reflect the latest terminology for 
Novartis Safety.

Section 8.3: “Dosage changes” deleted as not allowed as per protocol.

Table 15-1: For clarification, how some cardiac alerts should be reported has been 
added.
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.
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 do not affect the Informed Consent.


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Protocol summary
Protocol number
CKAF156A2202
Full Title
A Phase 2 interventional, multicenter, randomized open-label study 
to determine the effective and tolerable dose of KAF156 and 
lumefantrine Solid Dispersion Formulation in combination, given 
once daily for 1, 2 and 3-days to adults and children with 
uncomplicated Plasmodium falciparum malaria
Brief title
Efficacy and safety of KAF156 in combination with LUM-SDF in 
adults and children with uncomplicated Plasmodium falciparum
malaria
Sponsor and Clinical 
Phase
Novartis 
Phase 2 
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This study aims to determine the most effective and tolerable dose 
at the shortest dosing regimen of the investigational drug KAF156 
in combination with a solid dispersion formulation of lumefantrine 
(LUM-SDF) in adult/adolescent
and pediatric patients with 
uncomplicated P. falciparum malaria.
There is unmet medical need for anti-malarial treatment with new 
mechanism of action to reduce probability of developing resistance, 
and for duration shorter than 3 days of treatment and/or reduced pill 
burden.
Primary Objective(s) 
The primary objective of this study is to determine the effective 
doses of KAF156 combined with LUM-SDF given daily over 1, 2 or 
3 days for treatment of uncomplicated malaria caused by 
P. falciparum. The primary efficacy endpoint is the polymerase 
chain reaction (PCR) corrected adequate clinical and parasitological 
response (ACPR) at Day 29.
Secondary Objectives
Objective 1: To evaluate the safety and tolerability of 
KAF156/LUM-SDF.
Objective 2: To further assess the effect of treatment with 
KAF156/LUM-SDF by assessing uncorrected ACPR and corrected 
ACPR at additional time points, as well as fever- and parasite 
clearance times.
Objective 3: To assess key pharmacokinetic (PK) parameters of 
KAF156 and lumefantrine.


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Study design
This will be a multicenter and open-label study with a single cohort 
PK Run-in Part followed by 2 randomized, parallel-group parts in 
adults and children with confirmed and uncomplicated P. falciparum
malaria.
Population
The study population will consist of male and female patients (PK 
Run-in Part and Part A: ≥12 years old and ≥35.0 kg; Part B: 2 to 
<12 years old and ≥10.0 kg) with confirmed and uncomplicated P. 
falciparum malaria. The plan is to enroll and treat 12 patients in PK 
Run-in Part and randomize approximately 500 patients in Parts A 
and B (325 in Part A and up to 175 in Part B) in approximately 15 
sites in Africa and Asia.
Key Inclusion criteria

PK Run-in Part and Part A: male and female patients ≥ 12 years 
and with a body weight ≥ 35.0 kg.
Part B: after determining the effective/tolerated doses and 
regimens in adolescent and adult patients, male and female 
patients ≥2 and < 12 years and with a body weight ≥10.0 kg will 
be included.

Microscopic confirmation of P. falciparum by Giemsa-stained 
thick and thin films (refer to the laboratory manual for details).

P. falciparum parasitaemia of more than 1000 and less than 
150 000 parasites/µL at the time of pre-screening (i.e., Study 
Visit 1).

Axillary temperature ≥
37.5 ºC or oral/tympanic/rectal 
temperature ≥38.0C; or similar history of fever during the 
previous 24 hours (history of fever must be documented).

Written informed consent must be obtained before any 
assessment is performed. If the patient is unable to read and 
write, then a witnessed consent according to local ethical 
standards is permitted. Patients < 18 years old, who are capable 
of providing assent, must provide assent with parental/legal 
guardian consent or as per local ethical guidelines.
Key Exclusion criteria

Mixed Plasmodium infections.

Signs and symptoms of severe malaria according to WHO 
(World Health Organization) 2015 criteria unless characterized 
by high parasitaemia only.

Patients with concurrent febrile illnesses (e.g., typhoid fever).

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 watery stools per day.

Pregnant or nursing (lactating) women.


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
Clinically relevant abnormalities of electrolyte balance which 
require correction, e.g., hypokalemia, hypocalcemia or 
hypomagnesemia.

Anemia (Hemoglobin level < 8 g/dL).

Patients with prior antimalarial therapy or antibiotics with 
antimalarial activity within minimum of their five (5) plasma 
half-lives (or within 4 weeks of screening if half-life is 
unknown).

History or family history of long QT syndrome or sudden cardiac 
death, or any other clinical condition known to prolong the QTc
(heart rate-corrected QT)
interval, such as history of 
symptomatic 
cardiac 
arrhythmias, 
clinically 
relevant 
bradycardia or severe heart disease.

Any surgical or medical condition which might significantly 
alter the absorption, distribution, metabolism, or excretion of 
drugs, or which may jeopardize the patient in case of 
participation in the study. The investigator should make this 
determination in consideration of the patient’s medical history 
and/or clinical or laboratory evidence of any of the following: 

AST/ALT > 2 x the upper limit of normal range (ULN), 
regardless of the level of total bilirubin

AST/ALT > 1.5 and ≤2 x ULN and total bilirubin is > ULN

Total bilirubin > 2 x ULN, regardless of the level of 
AST/ALT
Study treatment
PK Run-in Part (≥ 12 years old, ≥ 35.0 kg):

PK Run-in Cohort: KAF156 200 mg and LUM-SDF 960 
mg - QD for 1 day
Part A (≥12 years old, ≥35.0 kg):

Cohort 1: KAF156 400 mg and LUM-SDF 960 mg once daily
(QD) for 1 day

Cohort 2: KAF156 800 mg and LUM-SDF 960 mg QD for 1 
day

Cohort 3: KAF156 400 mg and LUM-SDF 960 mg QD for 2 
days

Cohort 4: KAF156 200 mg and LUM-SDF 480 mg QD for 3 
days

Cohort 5: KAF156 400 mg and LUM-SDF 480 mg QD for 3 
days

Cohort 6: KAF156 400 mg and LUM-SDF 960 mg QD for 3 
days

Cohort 7: Coartem®  twice a day (BID) for 3 days


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The above dosages may be adjusted based on the results of PK 
Run-in Part.
Part B (2 to < 12 years, ≥10.0 kg):

KAF156 and LUM-SDF (up to 3 cohorts selected depending on 
the outcome of Part A)

Coartem® BID for 3 days
Efficacy assessments

Parasitaemia

Blood sample for molecular diagnostic purposes
PK assessments

PK parameters of study drugs (measured by AUC0-24h, 
AUClast, AUCinf, Cmax, Tmax, T½)
Key safety 
assessments

Physical examination and malaria signs and symptoms

Vital signs

Body temperature

Monitoring of laboratory parameters in blood and urine

Electrocardiogram

Adverse event (AE) monitoring
Other assessments

Additional back-up blood samples for certain specific safety 
biomarkers (e.g., miR122) will be collected  and analyzed if 
required
Data analysis
For the PK Run-in Part, the primary objective is to investigate the 
pharmacokinetic interaction potential between KAF156 and 
lumefantrine-SDF. 2-sided 90% confidence intervals for PK 
parameters of KAF156 and lumefantrine will be calculated.  
Subsequent statistical analyses for Part A and Part B will be 
performed separately and similarly. For ACPRs (PCR corrected and 
uncorrected ACPR at Days 15, 29, and 43), 2-sided 95% confidence 
intervals for each treatment group will be constructed using the exact 
(Pearson-Clopper) method. For parasite clearance time and fever 
clearance time, descriptive statistics (mean, standard error, median, 
quartiles) for each treatment group will be presented using the 
Kaplan-Meier method.
Key words
Plasmodium falciparum malaria, KAF156, LUM-SDF, adults, 
children


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1
Introduction
1.1
Background
Malaria is one of the most important infectious diseases which threatens about 3.2 billion people, 
almost half of the world’s population. Despite increasing international efforts for malaria 
control, in 2015, there were 214 million cases worldwide of malaria and 438 000 deaths 
according to the latest World Health Organization estimates (WHO 2015). Sub-Saharan Africa 
carries a disproportionately high share of the global malaria burden. In 2015, the region was 
home to 88% of malaria cases and 90% of malaria deaths. Also, in areas with high transmission 
of malaria, children under 5 are particularly susceptible to infection, illness and death; more 
than two thirds (70%) of all malaria deaths occur in this age group (306 000 estimates deaths in 
2015; see WHO 2015).
Malaria is caused by Plasmodium parasites. There are five parasite species that cause malaria 
in humans, and two of these species – P. falciparum and P. vivax – pose the greatest threat. 
P. falciparum is the most prevalent malaria parasite on the African continent. It is responsible 
for most malaria-related deaths globally. P. vivax is the dominant malaria parasite in most 
countries outside of sub-Saharan Africa (WHO 2015).
Standard antimalarial drugs such as chloroquine (CQ), pyrimethamine (PYR), sulfadoxine 
(SFDX) and mefloquine (MEF) have become largely ineffective in many malaria endemic 
regions. The only exceptions are the artemisinin-based combination therapies (ACTs) such as 
Novartis’ Coartem®/Riamet® and Eurartesim®, current standard-of-care for P. falciparum
malaria. Unfortunately, some recent reports (Ashley et al 2014; Menard et al 2016) suggest that 
decades of continuous use of artemisinin and bisquinoline derivatives as monotherapies may 
have fostered the emergence of drug resistance in Plasmodium species in Southeast Asia. 
Reduced in vitro susceptibility of P. falciparum to artemisinin in this region has been 
documented (Dondorp 2009). Recent studies showed that artemisinin resistance extends over 
more of Southeast Asia than had previously been known, and is now present close to the border 
with India (Menard et al 2016). If widespread artemisinin drug resistance was to occur, malaria 
pharmacotherapy would be severely impaired. This finding signifies that spread of resistance is 
inevitable, thus there is urgent need for new antimalarials with new mechanism of actions (Tun 
et al 2015).
In addition, current falciparum malaria treatments require at least a 3-day dosing regimen which 
may contribute to therapeutic non-compliance in some patients. Indeed, patients often have 
resolution of clinical symptoms within 1 to 2 days and may neglect taking final doses. This may 
contribute to the development of drug resistance. 
There is therefore a strong medical need for new chemical entities with a new mode of action 
as additional treatment options for this very common disease with substantial morbidity and 
mortality. Simplifying regimens by developing treatments that can be used in a once daily dose 
for less than 3-day administration can improve treatment success and reduce probability of 
developing resistance via improved adherence and thus accelerate malaria eradication. 
The purpose of this study is to determine the effective and tolerable dose of KAF156, a new 
antimalarial molecule that can be administered in combination with a Solid Dispersion 
Formulation of lumefantrine (LUM-SDF) for the shortest treatment duration possible.


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KAF156 is the first drug from a different and novel class of drugs called imidazolepiperazines 
and was developed by the Novartis Institute for Tropical Diseases (NITD) following a high 
through-put screening (HTS) of the Novartis compound library by the Genomics Institute of the 
Novartis Research Foundation (GNF). KAF156 is structurally distinct from currently marketed 
antimalarial drugs and other experimental antimalarial compound classes currently in 
development. The mechanism of action of KAF156 is still being characterized, but may be 
related to a previously uncharacterized gene (Plasmodium falciparum cyclic amine resistance 
locus, Pfcarl). KAF156 kills/inhibits the erythrocytic replication life cycle stages (blood stages) 
of the two main causative agents of human malaria, P. falciparum and P. vivax, both at low 
nanomolar EC50s (in vitro). In addition, KAF156 has shown activity in liver stage models of 
Plasmodium infection, conferring causal prophylactic protection in animal infection models. 
Limited evidence of gametocyticidal activity may confer transmission blocking activity. 
KAF156 has not demonstrated activity against liver hypnozoites and therefore has a low 
probability to be used for a radical cure for P. vivax. Also, KAF156 is equally potent against 
drug-sensitive and a broad panel of drug resistant malaria strains (Kuhen et al 2014).
KAF156, when combined in a fixed-dose formulation with an anti-malarial partner drug, could 
offer a much needed new treatment for malaria, including in areas where resistance to ACTs is 
emerging. A fixed-dose formulation with a single-dose regimen to ensure patient adherence to 
the full treatment would be an ideal option. However, the development of such single-dose 
regimens are more challenging in terms of maintaining adequate blood levels during 6-7 days 
(3 parasite replication cycles). Considering the impending risk of resistance to existing 
antimalarials and higher risk of therapeutic failure with a single- or two day regimen, a three 
day regimen will also be evaluated with the simultaneous exploration of one and two day 
treatment regimen in order to reduce the overall development risk and address the critical unmet 
medical need due to emerging resistance to standard therapy.
Lumefantrine-Solid Dispersion Formulation (SDF) will be used as partner drug in this study. In 
contrast to the conventional lumefantrine formulation, lumefantrine-SDF has an improved 
absorption profile and less food effect, leading to exposure which allows for a once-daily 
regimen. LUM-SDF is expected to have a similar safety profile to conventional LUM used as 
partner drug in Coartem®.
KAF156 and lumefantrine will be administered as combination for the first time in this study. 
Based on their metabolism, no clinically relevant interaction is expected between KAF156 and 
lumefantrine. However, in a recent preclinical in vivo study in dogs KAF156 (10 mg/kg) and 
LUM-SDF (15 mg/kg) were administered in combination and preliminary data suggest that 
exposure of both KAF156 and lumefantrine increased in presence of each other. There was 
around 2-3 fold increase in KAF156 exposure and around 1.5 fold increase in lumefantrine 
exposure. 
A slightly increased lumefantrine exposure is not considered of clinical significance as it was 
anticipated, based on potential metabolic interaction. KAF156 is a weak CYP3A4 inhibitor 
based on an interaction study with piperaquine and can potentially increase lumefantrine 
exposure slightly. However, in clinical interaction studies of lumefantrine with strong CYP3A4 
inhibitors such as ketoconazole (Lefevre et al 2002) and lopinavir/ritonavir-based antiretroviral
(Kredo et al 2016) despite up to 5 fold increase in lumefantrine exposure it was concluded that 


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this interaction did not result in lumefantrine exposures above seen in patients following a 
standard dose of Coartem (Lefevre et al 2001).
On the other hand, increased KAF156 exposure was unanticipated and there is no sufficient 
data to cover for exposure for the highest doses of KAF156 in this study, should KAF156 
exposure increase by 2 fold. The dog data suggest that increased KAF156 exposure potentially 
occurs because of interaction of LUM-SDF with KAF156 at absorption-level which in turn 
suggest that interaction may not lead to more than 2 fold increase in KAF156 exposure in human 
given its estimated bioavailability of at least 50% in humans. There is no experience of KAF156 
exposure beyond that of 1200 mg single dose or 600 mg daily for 3 days. Given the above 
situation, the first part of the study will explore the PK and safety of KAF156 given in 
combination with LUM-SDF to understand the impact of LUM-SDF on KAF156 exposure as 
victim drug. In the unlikely scenario of an increase in KAF156 exposure beyond the acceptable 
limit, doses in Part A of the study may be adjusted (as described in Section 3.3).
1.2
Purpose 
This Phase 2 study aims to determine the most effective and tolerable dose at the shortest dosing 
regimen of the investigational drug KAF156 and a Solid Dispersion Formulation of 
lumefantrine (LUM-SDF) in combination in adult/adolescent and pediatric patients with 
uncomplicated P. falciparum malaria. Different dose combinations and dosing regimens (i.e., 
3-, 2-, and 1-day regimens) of KAF156 and LUM-SDF in combination and a reference product 
Coartem® will be assessed.
This study is set up in a three-part sequential design. Following the PK Run-in Part, Part A of 
the study will determine in adults and adolescents (greater than or equal to 12 years of age and
with a body weight ≥35.0 kg) the most effective and tolerated dose regimens to be carried 
forward into Part B which will be conducted in pediatric (2 to < 12 years old and with a body 
weight ≥10.0 kg) population. Combined data obtained from Parts A and B will then form the 
basis for identifying the dose regimen(s) that should be further investigated in Phase 3 
development in adults and children down to 2 years of age.
Coartem® will be used as a control for trial sensitivity in Parts A and B so as to evaluate if any 
significant safety issues or low efficacy results observed in the experimental treatment groups 
for both adults/adolescents and children are due to treatment or population. It will also provide 
preliminary relative efficacy for experimental treatment groups compared to the control 
although it’s not statistically powered to show non-inferiority or superiority. 
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints (PK Run-in Part, Part A and Part B)
Objective(s)
Endpoint (s)
Primary Objective(s)

To determine the effective doses of 
KAF156 combined with LUM-SDF given 
Endpoint(s) for primary objective(s)  

PCR-corrected adequate clinical and 
parasitological response (ACPR) at Day 


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Objective(s)
Endpoint (s)
daily over 1, 2 or 3 days for treatment of 
uncomplicated malaria caused by P.
falciparum.
29 (i.e., 28 days post-dose) in Parts A 
and B.

Assessments of KAF156 exposure in 
the PK Run-in cohort to understand the 
impact of LUM-SDF on KAF156 
exposure.
Secondary Objective(s) 

To evaluate the safety and tolerability of 
KAF156/LUM-SDF.
Endpoint(s) for secondary objective(s)

Standard safety/tolerability 
assessments: AE incidence and 
severity, liver and kidney function tests 
and electrocardiogram (ECG) 
abnormalities.

To further assess the effect of treatment 
with KAF156/LUM-SDF by assessing 
uncorrected ACPR and corrected ACPR
at additional time points, as well as 
fever- and parasite clearance times.

PCR-Uncorrected ACPR at Days 15, 29 
and 43 (i.e., 14, 28 and 42 days post-
dose).
PCR-corrected ACPR at Days 15 and 
43 (i.e., 14 and 42 days post-dose).
Incidence rate of recrudescence and 
reinfection at Days 15, 29 and 43.
Parasite and Fever Clearance Times 
(PCT and FCT).
Proportion of patients with parasitaemia 
at 12, 24, and 48 hours after treatment.

To assess the key PK parameters of 
KAF156 and lumefantrine.

PK assessments


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3
Investigational plan
3.1
Study design
This will be a multicenter, open-label, randomized, parallel-group study in adults and children 
with confirmed and uncomplicated P. falciparum malaria. 
Screening of patients for inclusion in the study consists of two parts: a Pre-Screening Part and 
a Screening Part.

Pre-Screening Part (Study Visit 1): Pre-screening is a key element to successfully identify 
the correct patients to be screened for this clinical study. Study Visit 1 should be used to 
obtain a P. falciparum parasite count (see Section 6.4.1), which is to be conducted locally.
Patients should have a P. falciparum parasitaemia of more than 1000 and less than 150 000 
parasites/µL at the time of Study Visit 1 to be further screened.

Screening Part (Study Visit 99): Further screening assessments will take place as soon as 
the pre-screening P. falciparum parasitaemia outcome is available and only if outcome is in 
the pre-defined range (more than 1000 and less than 150 000 parasites/µL).
Pre-screening parasite count should be used as baseline count. In case parasite count has 
been done > 6 hours before Visit 99, then it should be repeated and the outcome of the 
repeated test should be considered as baseline parasite count.
The study has a PK Run-in Part and two main parts: Part A and Part B.
PK Run-in Part;
Male and female adult/adolescent patients (≥ 12 years old and ≥ 35.0 kg) will be enrolled in the 
PK Run-in Part. 12 patients will be dosed with a single dose of 200 mg KAF156 and 960 mg
LUM-SDF. Study procedures and assessments are the same as in the 1-day cohorts in Part A 
with rich PK.
The drug-exposure results of the PK Run-in Part will be evaluated by the sponsor and trigger 
the start of Part A with KAF156 dosing as planned, or lead to a dose adaptation in Part A in 
case an interaction is shown between LUM-SDF and KAF156. Following this evaluation of 
drug-exposure, all investigators will be informed of the results and IRT/dosing will be 
implemented as specified in Table 3-1 and Appendix 5.
Patients in the PK Run-in cohort in whom the drug exposure cannot be established due to 
vomiting or drop-out, will be replaced by additional patients in order to achieve a total of 12 
patients with evaluable exposure results in the PK Run-in Part.
Part A:
Approximately 325 male and female adult/adolescent patients (≥12 years old and ≥35.0 kg) 
will be enrolled in Part A of the study.
At screening, eligible patients will be randomized into one of the seven cohorts, i.e., six 
KAF156 and LUM-SDF dose combinations and a control arm (see Figure 3-1), in 2:2:2:2:2:2:1 
ratios. The standard doses of KAF156 as shown below may be corrected according to Table 3-
1 in case of increased exposure in the PK Run-in Part (see Appendix 5).


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
Cohort 1: KAF156 400 mg and LUM-SDF 960 mg once daily (QD) for 1 day

Cohort 2: KAF156 800 mg and LUM-SDF 960 mg QD for 1 day

Cohort 3: KAF156 400 mg and LUM-SDF 960 mg QD for 2 days

Cohort 4: KAF156 200 mg and LUM-SDF 480 mg QD for 3 days

Cohort 5: KAF156 400 mg and LUM-SDF 480 mg QD for 3 days

Cohort 6: KAF156 400 mg and LUM-SDF 960 mg QD for 3 days

Cohort 7: Coartem®  twice a day (BID) for 3 days (dosing as per product label)
Patients will be admitted to the hospital on Day 1. They will be dosed on either a) Day 1 alone 
or b) Days 1 and 2 or c) Days 1, 2 and 3 depending on the assigned study arm, and will remain 
in the hospital under close supervision until they are discharged by the investigator or designee 
on Day 4. At the discretion of the investigator, patients may stay additional days if needed. The 
patients will then be followed up until Day 43. Visits to assess safety and efficacy will be 
scheduled during the follow-up period as described in the schedule of assessments tables (Table 
6-1, Table 6-2, Table 6-3 and Table 6-4). If malaria symptoms re-emerge outside the scheduled 
study visits, patients will be instructed to contact the investigator.
Rich pharmacokinetic (PK) sampling will be done in 6 patients each in cohorts 1-4 and 6, and 
in 12 patients in Cohort 5 (see Table 6-3), and sparse PK sampling will be done in the rest of 
the patients as well as in Cohort 7 (see Table 6-4).
Upon completion of Part A, all the dosing groups will be evaluated in an interim assessment 
(IA) to determine the effective and tolerated KAF156/LUM-SDF dose combination for 3 days 
and for 1 to 2 days. The IA will be performed on selected endpoints which include, Polymerase 
Chain Reaction (PCR) corrected and uncorrected adequate clinical and parasitological response
(ACPR) at Day 29, KAF156 and LUM-SDF blood exposures, incidence of adverse events
(AEs), QTc, laboratory abnormalities, serious adverse events (SAEs), or any other endpoint that 
is deemed important for the IA. Dosing regimen and dosages in Part B will be informed by 
results from Part A.
Part B:
Approximately up to 175 children (2 to < 12 years old and ≥10.0 kg) with uncomplicated 
P. falciparum malaria will be randomized to up to three KAF156 and LUM-SDF dose 
combinations and the control arm in 2:1 ratios (2 patients for each KAF156 and LUM-SDF 
dose combination and 1 patient for control) depending on the outcome of the interim assessment 
in Part A.
Eligible patients will be enrolled into one out of the up to four dosing cohorts i.e., up to three 
investigational drug dosing arms and a control arm (see Figure 3-1). Dosing will be adjusted 
based on children’s body weight similar to the adjustment of Coartem®.

KAF156 and LUM-SDF: up to 3 cohorts selected depending on the outcome of Part A

Coartem® BID for 3 days
Initially, 4-6 children in the age range of 6 to < 12 years will be included in Part B to confirm 
that KAF156 and LUM-SDF PK/drug exposure is consistent with Part A and that the 
assumption in dosing is correct in these cohorts. Following confirmation of drug exposure in 
these children, the additional patients will be included in Part B of the study.


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Study design, procedures and assessments are the same in Part A and Part B (see above). The 
safety of entire study will be monitored by an Independent Data Monitoring Committee (DMC).
Figure 3-1
Study design


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3.2
Rationale for study design
This will be a multicenter, open-label, randomized, parallel-group study in adults and children 
with confirmed and uncomplicated P. falciparum malaria.
The use of a combination regimen with two drugs is well established for evaluation of anti-
malaria therapy and is recommended by WHO guidelines (WHO 2015). As specified in 
Section 1, there is unmet medical need for anti-malarial treatment with new mechanism of 
action to reduce probability of developing resistance, and for shorter duration of treatment 
and/or reduced pill burden.
The objective of this dose finding (Phase 2) study design is to identify the most effective and 
tolerated dose regimen of KAF156 and LUM-SDF in combination with the shortest duration in 
adults/adolescents (Part A) and in children (Part B) with uncomplicated P. falciparum malaria.
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 chosen study design is the most efficient one to achieve the study goals (i.e., determine 
optimal dose, combination and duration in adults, adolescents and pediatrics down to age of 2).
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 
Rationale for dose/regimen in PK Run-in Part:  
The objective of the PK Run-in cohort is to assess the maximum potential increase in KAF156 
exposure as victim due to LUM-SDF with sufficient safety margins. Therefore, the lowest dose
of KAF156 (200 mg) will be administered with the highest dose of LUM-SDF (960 mg) to 
understand the worst case scenario. 
The highest single dose and multiple dose planned in Part A of this study are 800 mg and 400 
mg, respectively which is 2/3 of the highest previously tested dose of 1200 mg as single dose 
and the 600 mg as highest multiple dose (with acceptable safety profiles).
Therefore, an increase in KAF156 exposure of <1.4 fold observed in the PK Run-in Part is not 
considered to be of clinical concern. For higher increases in exposure the doses of KAF156 in 
Part A will be adjusted as detailed in Table 3-1 below. The subsequent doses in Part B will be 
as planned in Table 5-4. 
In the PK Run-in cohort AUC0-24h will be used as main parameter for the comparison with 
historical data as it covers the full absorption profile and is a more stable parameter than Cmax.
Cmax and AUC are expected to be proportional. Given the straightforward interpretation of this 
PK analysis, the sponsor will subsequently make the decision on dose adaptation in Part A 
according to Table 3-1 below.


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Table 3-1
Dose adjustment for Part A
Standard Dose KAF156 in Part A
200 mg
400 mg
800 mg
KAF156 relative exposure factor in PK Run-in vs. 
the reference mean AUC0-24h (4930 ng*h/mL)*
Correction
Factor
Adapted Doses (mg)
<1.4
1.0
200
400
800
≥1.4 to <1.8
0.75
150
300
600
≥1.8 to <2.5
0.50
100
200
400
≥2.5 to 4
0.25
50
100
200
*The reference value of AUC0-24h for 200 mg is extrapolated from the mean value (9860 ng*h/mL) after the first dose of 
400mg in P. falciparum patients 
No clinically significant interaction is anticipated for the lumefantrine exposure. Although the 
safety margin of lumefantrine is high, in the PK Run-in cohort lumefantrine levels will 
nevertheless be analyzed for confirmation.
Rationale for dose/regimen in Part A:
A range of doses and regimens of KAF156 combined with LUM-SDF was selected based on 
expected exposure, efficacy and safety outcomes, and supported by clinical as well as 
pre-clinical data (Kuhen et al 2014; Leong et al 2014). 
As a general principle, the drug combination should provide adequate parasiticidal serum levels 
over a period of at least 6-7 days (3 parasite life-cycles approximately) in order to achieve cure 
in a patient. It is known that lumefantrine Day 7 serum concentrations above 200 ng/mL 
correlate strongly with treatment success (WWARN 2015). From initial experience with 
KAF156, Day 6 concentrations above 58 ng/mL (2 times EC99) correlate with treatment 
success (Kuhen et al 2014; Leong et al 2014). 
The highest tolerated doses identified in healthy volunteer and proof of concept studies were: 
KAF156 400 mg for multiple days, KAF156 800 mg for single dosing, LUM-SDF 960 mg for 
single dosing. Total exposure and Cmax for LUM-SDF 960 mg QD for 3 days is expected not 
to exceed total exposure and Cmax following dosing with the conventional lumefantrine
formulation.
Preliminary pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to assess 
the percentage of patients in whom threshold concentration of lumefantrine (above 200 ng/mL) 
and KAF156 (above 58 ng/mL) will be maintained over 6-7 days. Simulations from these 
models suggest that under fasting conditions, the 3-day doses and the 2-day doses of KAF156 
and LUM-SDF combinations have a relatively high likelihood to be effective; the 1-day doses 
have a lower likelihood of being effective. Testing the proposed dose/regimens allows for a 
more complete characterization of the dose-response relationship.


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Rationale for dose/regimen in Part B:  
Upon completion of Part A, all dose cohorts will be evaluated according to the following 
success/failure criteria:
Table 3-2
Cohort Success Criteria
Efficacy
The lower limit of 2-sided 95% exact confidence interval for PCR corrected ACPR at 
Day 29 is greater than 80%
Safety
A comprehensive assessment of AEs, SAEs, lab data and ECG for investigational and 
reference product (Coartem®) by DMC/Novartis will determine the tolerability success 
criteria for the cohorts
If needed, secondary efficacy parameters can also be evaluated to discriminate between cohorts 
in Part A.
Selected cohorts that pass the efficacy/safety hurdles will be further evaluated in Part B.
Figure 3-2
Dose selection for Part B
The number of cohorts to be assessed in pediatric population (Part B) will depend on the 
outcome of the interim assessment. Up to 4 cohorts will be assessed in Part B (i.e., up to 3 
cohorts with KAF156/LUM-SDF and 1 cohort with Coartem®). The selected adult doses from 
Part A will be adjusted to the pediatric population in Part B using the proven body weight bands 
for Coartem® (see Table 5-4). Initially, 4-6 children in the age range of 6 to < 12 years will be 
included in Part B to confirm that KAF156 and LUM-SDF PK/drug exposure is consistent with 
Part A and that the assumption in dosing is correct in these cohorts. Following confirmation of 
drug exposure in these children, the additional patients will be included in Part B of the study.
Due to the fact that their metabolizing cytochrome (CYP) enzymes are not yet fully matured, 
children < 2 years will not be included in this study. 
Patients must be fasted 3 hours before and for 4 hours after KAF156/LUM-SDF administration.
Coartem® will be administered with food and doses will be based on patient’s body weight as 
per product label.


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Rationale for duration of treatment:
With LUM-SDF as partner drug for KAF156, the goal is to provide at least the same efficacy 
as current standard treatment, but with lower dosing frequency and pill burden compared to 
Coartem®: from a 3-day twice a day treatment regimen (for ≥35.0 kg patient 4 tablets per dose 
for total of 6 doses i.e. 24 tablets) to a 3, 2 or 1-day single daily dose treatment regimen.
3.4
Rationale for choice of control
The control treatment used in Parts A and B of this study is Coartem®, the artemisinin-based 
combination therapy artemether-lumefantrine. Coartem® is widely used for P. falciparum
malaria and has a well-characterized safety and efficacy profile (Hamed and Grueninger 2012). 
In addition, Coartem® tablets contain the same partner drug as in the current study 
(lumefantrine). For these reasons, Coartem® is considered the appropriate comparator treatment 
for this study. 
3.5
Purpose and timing of interim assessments/data reviews
For the PK Run-in Part the first 24 hours of PK samples will be analyzed for KAF156 and 
lumefantrine blood levels in order to confirm doses of KAF156 for Part A. In case of unexpected 
increase in exposure of KAF156 doses in Part A will be adjusted according to Table 3-1.
An interim assessment (IA) will be conducted after completion of Part A. The purpose of this 
assessment is to assess key parameters of efficacy and tolerability of KAF156 and LUM-SDF 
dose combinations for each dosing regimen (3 days vs. 2 days vs. 1 day) in adolescent/adult 
patients (see Section 3.3). Upon determining the preferred dose combinations, children 2 to 
< 12 years will be treated with these dose combinations adjusted for their body weight (Part B). 
In addition, the pharmacokinetic data will be reviewed as available, to ensure that exposures of 
KAF156 and lumefantrine are not considerably different than expected, however 
pharmacokinetic data alone will not lead to any change in conduct of the study. Before fully 
enrolling patients in Part B, 4-6 children in the age range of 6 to < 12 years will be included to 
confirm that KAF156 and LUM-SDF PK/drug exposure is consistent with Part A and that the 
assumption in dosing is correct. Following confirmation of drug exposure in these children, the 
additional patients will be included in Part B of the study.
Additional interim safety review of study data will be conducted by the independent Data 
Monitoring Committee (DMC, see Section 8.4). These reviews may also be conducted to 
support decision making concerning the current clinical study, or in case of any safety concerns. 
3.6
Risks and benefits
Based on the preclinical and clinical evaluation to date as presented in the respective 
Investigator Brochures (IB) for KAF156 and LUM-SDF, the combination of KAF156 and 
LUM-SDF is expected to be generally safe and well tolerated. The risk to patients in this trial 
will be minimized by compliance with the eligibility criteria and study procedures, close clinical 
monitoring and minimal treatment duration. Patients will be hospitalized under close 
supervision until they are discharged by the investigator or designee on Day 4. At the discretion 
of the investigator, patients may stay additional days if needed.


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In the current study, KAF156 will be given to patients with uncomplicated P. falciparum
malaria. KAF156 is expected to reduce the number of circulating malaria parasites in the blood 
of patients and consequently improve their clinical symptoms over the first 48 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 group. Any early treatment failure (ETF) (see 
Section 6.5.8), recrudescence or new infection will be managed with standard-of-care 
pharmacotherapy. This may minimize the likelihood of resistance emergence or spread. Any 
recrudescing parasites will be analyzed for standard markers of resistance. 
Following confirmation of drug exposure in the PK Run-in Part, the current study will initially 
include adolescents from 12 to < 18 years and adults (Part A), followed by children 2-11 years 
(Part B) after an effective/safe dose has been established for adults and adolescents. PK/drug 
exposure will be also confirmed first in 4-6 children in the age range of 6 to < 12 years before 
the additional patients will be included in Part B of the study.
This is the first time that KAF156 and lumefantrine-SDF will be tested in patients as a 
combination treatment. All previous studies involved KAF156 alone. Whereas lumefantrine in 
the conventional formulation has been fully characterized and widely used as partner drug in 
Coartem®, lumefantrine-SDF has been produced in pilot-scale only. LUM-SDF is expected to 
have an improved bioavailability and similar safety profile to conventional LUM used as the 
partner drug in Coartem®. 
4
Population
The study population will consist of male and female patients (PK Run-in Part and Part A: ≥12 
years old and ≥35.0 kg; Part B: 2 to < 12 years old and ≥10.0 kg) with confirmed and 
uncomplicated P. falciparum malaria.
Only patients with malaria symptoms and P. falciparum counts more than 1000 and less than 
150 000 parasites/µL will be included in the study.
The plan is to enroll and treat 12 patients in PK Run-in Part and to randomize approximately 
500 patients (325 in Part A and up to 175 in Part B) in approximately 15 sites in Africa and 
Asia. Expected recruitment in Africa is approximately 85% for both Parts A and B with the rest 
of the patients expected to be recruited in Asia. The expected drop-out rate is 16% (Held et al
2015).
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
Demography
1.
PK Run-in Part and Part A: male and female patients ≥ 12 years and with a body weight ≥ 
35.0 kg
Part B: after determining the effective/tolerated doses and regimens in adolescent and adult 
patients, male and female patients ≥2 and < 12 years and with a body weight ≥10.0 kg 
will be included


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Health status
2.
Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films (refer 
to the laboratory manual for details)
3.
P. falciparum parasitaemia of more than 1000 and less than 150 000 parasites/µL at the 
time of pre-screening (i.e., Study Visit 1) 
4.
Axillary temperature ≥37.5 ºC or oral/tympanic/rectal temperature ≥38.0ºC; or similar 
history of fever during the previous 24 hours (history of fever must be documented)
5.
Negative pregnancy test for women of child bearing potential (WOCBP)
Regulations
6.
Written informed consent must be obtained before any assessment is performed. If the 
patient is unable to read and write, then a witnessed consent according to local ethical 
standards is permitted. Patients < 18 years old, who are capable of providing assent, must 
provide assent with parental/legal guardian consent or as per local ethical guidelines
7.
The patient or his/her parent/legal guardian (in case of pediatric patients) is able to 
understand and comply with protocol requirements, instructions and protocol-stated 
restrictions and is likely to complete the study as planned
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 Plasmodium infections
2.
Signs and symptoms of severe malaria according to WHO 2015 criteria unless 
characterized by high parasitaemia only
3.
Active infections including tuberculosis  
4.
Patients with concurrent febrile illnesses (e.g., typhoid fever)
5.
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
6.
Known relevant liver disease e.g. chronic hepatitis, cirrhosis, compensated or 
decompensated, history of hepatitis B or C, hepatitis B or A vaccination in last 3 months, 
known gallbladder or bile duct disease, acute or chronic pancreatitis
7.
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including human immunodeficiency virus (HIV) infection
8.
Severe malnutrition (body mass index (BMI) < 16.0 for patients ≥ 12 years, and less than 
70% of median normalized WHO reference weight for children < 12 years)
9.
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 watery stools per day
10. Pregnant or nursing (lactating) women
11. Sexually active patients not willing to practice effective contraception


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12. Women of child bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for the duration of the study. Highly effective contraception methods 
include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking 
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 patients on the 
study, the vasectomized male partner should be the sole partner for that patient

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking 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
13. Sexually active males must use a condom during intercourse while taking drug and for 
the duration of the study 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
14. Active duodenal ulcer, ulcerative colitis, Crohn’s disease, chronic (i.e., > 2 weeks) use 
of non-steroidal anti-inflammatory drugs (NSAIDs)
15. Clinically relevant abnormalities of electrolyte balance which require correction, e.g., 
hypokalemia, hypocalcemia or hypomagnesemia.
16. Anemia (Hemoglobin level < 8 g/dL)
17. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the patient in 
case of participation in the study. The investigator should make this determination in 
consideration of the patient’s medical history and/or clinical or laboratory evidence of 
any of the following: 

AST/ALT > 2 x the upper limit of normal range (ULN), regardless of the level of  
total bilirubin

AST/ALT > 1.5 and ≤2 x ULN and total bilirubin is > ULN


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
Total bilirubin > 2 x ULN, regardless of the level of AST/ALT
18. Resting QTcF > 450 ms (males), QTcF > 460 ms (females) at screening
19. Creatinine > 2 x ULN in the absence of dehydration. In the case of dehydration, the 
creatinine should be < 2 x ULN after oral/parenteral rehydration
20. 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
21. Known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, 
or hepatic impairment
22. Known active or uncontrolled thyroid disease
23. Inability to tolerate oral medication (in tablet and/or liquid form)
Interfering substances
24. Patients with prior antimalarial therapy or antibiotics with antimalarial activity within 
minimum of their five (5) plasma half-lives (or within 4 weeks of screening if half-life is 
unknown)
25. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days or 
until the expected pharmacodynamic effect has returned to baseline, whichever is longer
26. Patients taking medications prohibited by the protocol (see Section 5.6.8, Table 5-5)
27. Previous participation in any malaria vaccine study or received malaria vaccine in any 
other circumstance
Specific to the study
28. History or family history of long QT syndrome or sudden cardiac death, or any other 
clinical condition known to prolong the QTc interval, such as history of symptomatic 
cardiac arrhythmias, clinically relevant bradycardia or severe heart disease
29. Use of agents known to prolong the QT interval unless it can be permanently 
discontinued for the duration of study
30. History of hypersensitivity to any of the study drugs or its excipients or to drugs of 
similar chemical classes
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Novartis will supply the following investigational products as open label patient specific 
supplies (see Table 5-1, Table 5-3, Table 5-4 and Appendix 5).

For PK Run-in Part:

KAF156 50 mg and/or 100 mg and/or 200 mg (Tablets in bottles)

Lumefantrine 480 mg (SDF in sachets)


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
For Part A:

KAF156 100 mg and/or 200 mg (Tablets in bottles)

Lumefantrine 480 mg (SDF in sachets)

Coartem® 20/120 mg and 80/480 mg (tablets in blister pack)

For Part B:

KAF156 (Tablets in bottles). Dose strengths based on Table 5-4 to be confirmed

Lumefantrine (SDF in sachets). Dose strengths based on Table 5-4 to be confirmed

Coartem® 20/120 mg (dispersible tablets in blister pack)
Table 5-1
PK Run-in Part: KAF156 and LUM-SDF dosing scheme
Cohort
Treatment
Dose (mg)
Dosing regimen
Daily dosing based on 
available strengths
PK Run-in
KAF156
LUM-SDF
200
960
QD 1 day
1 x 200 mg or 2 x 100 mg
2 sachets
Table 5-2
Part A: KAF156 and LUM-SDF dosing scheme*
Cohort
Treatment
Dosing regimen
1
KAF156
LUM-SDF
QD 1 day
2
KAF156
LUM-SDF
QD 1 day
3
KAF156
LUM-SDF
QD 2 days
4
KAF156
LUM-SDF
QD 3 days
5
KAF156
LUM-SDF
QD 3 days
6
KAF156
LUM-SDF
QD 3 days
*KAF156 dose levels are based on the results of the PK Run-in Part and will be adjusted 
according to Table 3-1 (see also Appendix 5 for dosing details).
Table 5-3
Parts A and B: Coartem® dosing per weight
Artemether/Lumefrantine
≥12 years and 
≥35.0 kg 
80/480 mg BID  during 3 days
25.0 to < 35.0 kg
60/360 mg BID during 3 days
15.0 to < 25.0 kg
40/240 mg BID during 3 days
10.0 to < 15.0 kg
20/120 mg BID during 3 days


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Table 5-4
Part B: Children KAF156 and LUM-SDF dosing per weight
KAF156 and LUM-SDF
25.0 to < 35.0 kg
0.75 of the adult dose
15.0 to < 25.0 kg
0.50 of the adult dose
10.0 to < 15.0 kg
0.25 of the adult dose
The selected adult doses from Part A will be adjusted to the pediatric population in Part B using 
the proven body weight bands for Coartem®. Specific details on medication will be 
communicated to relevant internal and external stakeholders before the start of Part B.
5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial. 
Rescue medication will be provided by the investigator according to local practices 
(Section 5.6.6).
5.2
Treatment arms
Following confirmation of exposure in the PK Run-in Part, patients will be randomized in 
2:2:2:2:2:2:1 ratios between six KAF156 and LUM-SDF dose combinations and the Coartem®
cohort in Part A. In Part B, patients will be randomized in 2:1 ratios (2 for each KAF156 and 
LUM-SDF dose combination and 1 for Coartem) to one of up to three KAF156 and LUM-SDF 
dose combinations and the Coartem® cohort depending on the outcome of Part A interim 
assessment. 
PK Run-in Part (≥ 12 years old, ≥ 35.0 kg):

PK Run-in Cohort: KAF156 200 mg and LUM-SDF 960 mg - QD for 1 day
Part A (≥12 years old, ≥35.0 kg)*: 

Cohort 1: KAF156 400 mg and LUM-SDF 960 mg - QD for 1 day

Cohort 2: KAF156 800 mg and LUM-SDF 960 mg - QD for 1 day

Cohort 3: KAF156 400 mg and LUM-SDF 960 mg - QD for 2 days

Cohort 4: KAF156 200 mg and LUM-SDF 480 mg - QD for 3 days

Cohort 5: KAF156 400 mg and LUM-SDF 480 mg - QD for 3 days

Cohort 6: KAF156 400 mg and LUM-SDF 960 mg - QD for 3 days

Cohort 7: Coartem®  BID for 3 days
*KAF156 dose levels are based on the assumption of non-significant drug-drug interaction 
in the PK Run-in Part and will be adjusted according Table 3-1 in case of increased 
exposure to KAF156 in the PK Run-in cohort.
Part B (2 to < 12 years, ≥10.0 kg):

KAF156 and LUM-SDF (up to 3 cohorts selected depending on the outcome of Part 
A)

Coartem® BID for 3 days


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5.3
Treatment assignment and randomization
PK Run-in Part
At Visit 101, the investigator or his/her delegate will contact the IRT after confirming that a 
patient fulfills all the inclusion/exclusion criteria. If the enrollment for this part is still open, the 
eligible patient will be assigned to receive KAF156 200 mg and LUM-SDF 960 mg QD 1 day 
via Interactive Response Technology (IRT). The IRT will specify medication number(s) and 
amount (e.g., number of tablets, etc.) to the patient. The medication number(s) and the 
appropriate amount for each medication number will be communicated to the caller so that the 
corresponding investigational drug(s) can be dispensed to the patient. 
Parts A and B
Following completion of the PK Run-in Part, at Visit 101, all eligible patients will be 
randomized via Interactive Response Technology (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 (cohort) and will specify medication 
number(s) and amount (e.g., number of tablets, etc.). The medication number(s) and the 
appropriate amount for each medication number will be communicated to the caller so that the 
corresponding investigational drug(s) can be dispensed to the patient. The randomization 
number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from Novartis Clinical Trial Team. 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.
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group. Randomization will be stratified by country in Part A and by country 
and age category at screening in Part B (2 to < 6, 6 to < 12 years).
5.4
Treatment blinding
5.4.1
PK Run-in Part
Treatment blinding in the PK Run-in Part is not applicable since the part is a single cohort.
5.4.2
Parts A and B
Treatment will not be blinded to patients and investigators since dose frequency and dosages 
for KAF156 and LUM-SDF may change from cohort to cohort and double-blinding will require 
triple dummies for 3 different drugs (KAF156, LUM-SDF, and Coartem®). Double-blinding is 
further complicated by the food requirement where patients assigned to KAF156 and 
LUM-SDF combinations are required to be fasted while patients assigned to Coartem® are 


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required to be fed. KAF156, LUM-SDF, and Coartem® will be provided to investigators who 
will dispense the correct dosage to patients based on IRT's instruction. However, since the 
primary and secondary objectives of the trial are mainly based on objective, laboratory 
assessments, this should not bias the efficacy and the safety endpoint assessments. Moreover, 
the lab technician performing these efficacy assessments will not have knowledge of the 
treatment arms to which the patients are assigned. 
In order to minimize the potential impact of treatment knowledge, treatment allocation, dose 
information, electrocardiogram (ECG), and PK assessment schedule and concentration data, as 
well as other data that may result in systematic unblinding will not be uploaded into any 
Novartis analysis or data review system that is available to the Clinical Trial Team (particularly 
clinicians, statisticians, programmers) until the database is locked for each part. Further details 
on data handling are documented in the appropriate data handling plan (DHP)/data management 
plan (DMP). The pharmacokineticist will be unblinded for PK/drug exposure data only for the 
whole duration of the study (i.e., Part A and Part B).
During the conduct of Part A and during Part B, summaries of results by treatment arm will be 
prepared only for Data Monitoring Committee (DMC) assessments. The DMC reports will be 
performed by an independent team (see Section 9.7).
The bioanalyst will request a copy of the randomization to facilitate analysis of the samples. 
The bioanalyst will provide the sample data to the team under blinded conditions. The 
bioanalyst will keep this information confidential until the final clinical database lock for each 
part.
5.5
Transition from PK Run-in Part to Part A and from Part A to Part 
B
Following the PK results from the PK Run-in cohort, the sponsor will set up IRT/dosing of 
KAF156 for Part A as specified in Table 3-1 and Appendix 5. All investigators will be informed
accordingly. 
After completion of Part A, the database will be cleaned and locked for Part A. Interim 
assessment of selected efficacy and safety endpoints will be performed to determine the most 
effective and safe dose of KAF156 and LUM-SDF combination for each tested dosing regimen 
and assess the dosage to be used in children in Part B for the selected dosing regimen. The 
results from Part A and the doses to be used for Part B will be communicated to relevant internal 
and external stakeholders.
5.6
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.6.1
Patient numbering
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. 


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Upon signing the pre-screening 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. 
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 epoch 
Study Disposition CRF.
5.6.2
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. A unique medication number is printed on each 
part of this label which corresponds to one of the treatment drugs and dose. 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 within 1 hour of intake a replacement dose will be given to the 
patient and the investigator or designee will notify IRT. 
Medication number and quantity of treatment drug taken by patients have to be collected by the 
investigator or designee.
5.6.3
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 
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. Technical complaints are to be reported to the respective Novartis country pharma 
organization (CPO) Quality Assurance.
Medication labels will be in the locally accepted 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 Study monitor or to the Novartis address provided in the investigator 
folder at each site.


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5.6.4
Instructions for prescribing and taking study treatment
KAF156 and LUM-SDF
Patients must be fasted 3 hours before and 4 hours after KAF156/LUM-SDF administration. 
Water can be provided ad-libitum. In Part B, pediatric patients may be given non-fatty liquids 
such as orange juices prior to 1 hour of dosing and 1 hour after dosing and recorded. Patients 
may receive some food at the time they arrive at the hospital and then be fasted for 3 hours 
minimum before they receive KAF156/LUM-SDF.
Administration of LUM-SDF and KAF156 must be under staff supervision. Patients will take 
the KAF156 and LUM-SDF according to the assigned dose level and dosing regimen (once 
daily for either 1, 2 or 3 days) of the KAF156 and LUM-SDF combination. 
The content of LUM-SDF sachet(s) should be emptied in mouth directly and then patients 
should drink some water. This will ensure that the complete dose is administered without any 
loss. A pair of scissors is needed to open the LUM-SDF sachets. Subsequently (preferably in 
2 min, but in any case < 15 min), KAF156 will be administered orally. Tablet(s) to be swallowed 
with water. 
For the pediatric population in Part B specific strength of the KAF156 tablet and LUM-SDF 
sachet will be available. These children will be given LUM-SDF as dispersible powder in mouth 
directly and then patients should drink some water. Subsequently (preferably in 2 min, but in 
any case < 15 min), KAF156 will be given as film-coated tablets that could be dissolved in pre-
specified amount of liquid. Administration of LUM-SDF and KAF156 must be under study 
staff supervision.
Each patient’s mouth must be checked to ensure that the medications were swallowed. 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. 
Food intake information will be collected only on dosing day, i.e., time of last food intake before 
dosing, time of first food intake after dosing, amount of meal consumed (%) and type of food 
based on the following 6 categories:
1. none (=no meal)
2. liquid only (zero fat)
3. minimal meal (estimate of < 200 calories, ~ 1 g of fat)
4. light meal (estimate of 200-300 calories, 5-10 g of fat)
5. Standard meal (estimate of 400-500 calories, 20-30 g of fat)
6. high fat meal (estimate of 800-1000 calories, > 50 g of fat)
In Part B, a low fat vehicle may be used for drug administration in children < 6 years old if they 
are unable to take the medication normally with water, depending on the outcome of Part A.
Coartem®
With respect to 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 less than 30 min prior to dosing, 
as per label. Dosages will be administered according to weight group as described in Table 5-
3.


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Conventional 20/120 mg and 80/480 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. This procedure will be 
repeated as necessary in order to administer the amount of doses indicated.
Coartem® medication should be followed whenever possible by food/drink (mother’s milk, 
broth, sweetened condensed milk, etc.) as appropriate. 
All kits of study treatment assigned by the IRT will be recorded in the IRT and IMP 
accountability log.
Food intake information will be collected on each dosing day, i.e., time of last food intake 
before dosing, time of first food intake after dosing, amount of meal consumed (%) and type of 
food based on the following 6 categories:
1. none (=no meal)
2. liquid only (zero fat)
3. minimal meal (estimate of < 200 calories, ~ 1 g of fat)
4. light meal (estimate of 200-300 calories, 5-10 g of fat)
5. Standard meal (estimate of 400-500 calories, 20-30 g of fat)
6. high fat meal (estimate of 800-1000 calories, > 50 g of fat)
5.6.5
Permitted dose adjustments and interruptions of study treatment
No dose adjustments other than according to body weight group as described above (see Section 
5.1.1) are permitted.
Additional doses can be given in case of vomiting (see Section 5.6.4). 
The changes must be recorded on the electronic Dosage Administration Record (eCRF).
For both Parts A and B, patients who vomit within 1 hour of trial drug administration will be 
given a replacement dose, and IRT must be notified.
For the PK Run-in Part, patients who vomit within 1 hour of trial drug administration will not 
be assessed in the PK analysis. In such case, additional patients will be dosed to compensate for 
the missing PK data and to achieve the total number of 12 patients with evaluable PK data in 
the PK Run-in Part.
5.6.6
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)

Development of danger signs or severe malaria on Day 2, Day 3, Day 4 in the presence of 
parasitaemia.

Parasitaemia on Day 3 higher than Day 1 count irrespective of axillary temperature

Parasitaemia on Day 4 with axillary temperature ≥37.5°C


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
Parasitaemia on Day 4 equals to or more than 25% of count on Day 1
Late Clinical Failure (LCF) 

Development of danger signs or severe malaria on any day from Day 5 to Day 43 in the 
presence of parasitaemia without previously meeting any of the criteria of early treatment 
failure

Presence of parasitaemia and axillary temperature ≥37.5oC on any day from Day 5 to Day 
43 without previously meeting any of the criteria of Early Treatment Failure
Late Parasitological Failure (LPF)

Presence of parasitaemia on any day from Day 8 to Day 43 and axillary temperature 
< 37.5oC without previously meeting any of the criteria of Early Treatment Failure or Late 
Clinical Failure 
Commencement of rescue medication with a combination antimalarial product (local standard 
at the discretion of the investigator or a medically qualified person) may occur after start of trial 
medications and up to 43 days after the last dose of KAF156/LUM-SDF as deemed necessary 
by the investigator. Lumefantrine-based treatment must be avoided in case of early treatment 
failure (ETF). Patients will be monitored, either in clinic, by telephone, or via home visits for 
three days to ensure adherence to the rescue medication therapy. These patients 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 established anti-malarial treatment.
Patients treated with at least one dose of trial medications will continue to be followed-up until 
Day 43 according to schedule.
Use of rescue medication (including exact rescue regimen and route of administration) must be 
recorded on the Concomitant medications/Significant non-drug therapies after start of study 
drug.
5.6.7
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.


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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 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.
5.6.8
Prohibited medication
5.6.8.1
Drug with potential impact on efficacy & safety
Drugs with antimalarial effect: Drugs/supplements which are known to have antimalarial 
effects are NOT allowed within minimum of their five (5) plasma half-lives (or minimum of 
4 weeks if half-life is unknown) prior to enrollment and during the entire study period. They 
may be used in the course of managing a patient which has developed early or late treatment 
failure (ETF or LTF) or failed to respond to standard-of-care.
Lumefantrine-based treatments should not be used even in the case of treatment failure, at least 
up to Day 28 post last dose.
Drug with QTc Potential: Drugs/supplements which have potential to increase QTc interval 
such as but not limited to antiarrhythmic drugs, neuroleptics and antidepressant agents, 
metoclopramide, macrolides and fluoroquinolones antibiotics, imidazole and triazole antifungal 
agents, certain non-sedating antihistamines (terfenadine, astemizole), and cisapride, should be 
avoided during the study and within minimum of their five (5) plasma half-lives of last dose (or 
minimum of 14 days if unknown ) prior to dosing. Furthermore, drugs that slow the heart rate
(HR), like digitalis and beta blockers should be avoided.
Drugs with potential liver safety concerns: Drugs which are known to have potential 
hepatotoxicity should not be used during study and within minimum of their five (5) plasma 
half-lives of last dose (or minimum of 14 days if half-life is unknown) prior to dosing. This
includes NSAIDs (also over-the-counter medicines) and herbal medicines. Paracetamol 
< 4g/day (or equivalent pediatric dosage; 10 to 15 mg/kg orally every 4 to 6 hours) may be used 
however, exact doses and time should be recorded appropriately.
5.6.8.2
Drug with potential for pharmacokinetic interaction: 
Drugs/supplements impacting KAF156 and lumefantrine exposure: drugs or supplements 
which are known CYP3A inhibitors (e.g., erythromycin, ketoconazole, itraconazole, cimetidine) 
or CYP3A inducers (e.g. rifampin, phenobarbital) etc. should not be used during study and 
within 14 days prior to dosing.


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Drugs/Supplements which can be impacted by KAF156 and lumefantrine: KAF156 and 
lumefantrine both have strong potential for inhibition of CYP2D6 enzyme and KAF156 also 
has strong potential for inhibition of CYP3A enzyme. It has relatively lower inhibition potential 
for CYP2C8, CYP2C9 and CYP2B6 enzyme and OATP1B1 transporter. The following table 
(Table 5-5) lists drugs which have either been shown to increase 5-fold or higher when 
co-administered with a known CYP inhibitor or whose exposure-response relationship 
indicated that small increases in their exposure levels by the concomitant use of CYP inhibitors 
may lead to serious safety concerns. These drugs should not be used within 14 days or at least 
within their 5 half-lives of last dose prior to dosing. These drugs should also not be used during 
the study period or at least up to Day 29 post last dose even in the course of treating an adverse 
event. If this cannot be avoided, extreme caution is advised and dosing and monitoring should 
be adjusted to account for the possible CYP enzyme inhibition. Drugs outside of this list may 
be used to treat adverse events unless they are recognized as falling into either of the two 
categories listed in the table.
Table 5-5
Prohibited medications
CYP 
Enzymes/transporter 
Sensitive substratesa 
Substrates with narrow 
therapeutic rangeb
CYP2D6 
Atomoxetine, desipramine,
dextromethorphan, metoprolol,
nebivolol, perphenazine, tolterodine,
venlafaxine
Thioridazine, neuroleptics, 
flecainide, metoprolol, and 
tricyclic antidepressants 
such as imipramine, 
amitriptyline, clomipramine
CYP3A
Alfentanil, aprepitant, budesonide, 
buspirone,conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, 
eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, 
midazolam, nisoldipine, quetiapine, 
saquinavir, sildenafil, simvastatin, sirolimus, 
tolvaptan, tipranavir, triazolam, vardenafil
Alfentanil, astemizole, 
cisapride, cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus, tacrolimus, 
terfenadine
CYP2B6c
Bupropion, efavirenz
CYP2C8 
Repaglinided 
Paclitaxel
CYP2C9 
Celecoxib
Warfarin, phenytoin
OATP1B1
Bosentan, pravastatin
a Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a known CYP inhibitor.


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b CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates 
that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (e.g., Torsades de Pointes).
c The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they represent 
the most sensitive substrates studied with available inhibitors evaluated to date. 
d Repaglinide is also a substrate for OATP1B1, and KAF156 potentially inhibits therapeutic OATP1B1 as well.
Except for medication which may be required to treat adverse events, no new medication other 
than study drugs will be allowed from the first dosing until up to completion of Day 7 
evaluations.
Should a patient have an incidental and limited need for a medication to be taken within the 
restricted pre-dose timeframe (e.g., antibiotic prophylaxis prior to dental surgery, etc.), the 
sponsor should be advised, as administration of any concomitant medication may require the 
patient to be withdrawn from the study. Decisions regarding withdrawal from study 
participation will be discussed with the sponsor on a case-by-case basis. Administration of 
paracetamol < 4 g/day (or equivalent pediatric dosage; 10 to 15 mg/kg orally every 4 to 6 hours) 
as an antipyretic is acceptable. If within 36 hours of study drug administration, infections other 
than malaria require the administration of drugs with antimalarial activity (such as
co-trimoxazole, tetracycline, doxycycline, etc.), with the exception of the use of topical 
antibiotics, the patient will be followed up until the end of the study.
5.7
Study completion and discontinuation 
5.7.1
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 are put on rescue medication will be followed for the 
entire study duration (i.e., until Day 43).
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
An independent Data Monitoring Committee (DMC) will review patient safety at several time
points (see Section 8.4) and may recommend stopping a cohort or the study early for safety 
reasons.
5.7.2
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 


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planned duration, and discontinuation can be initiated by either the patient or the investigator. 
For patients assigned to 1-day and 2-day cohorts, 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 patient’s risk of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient request 

Pregnancy (see Section 6.5.6 and Section 7.7)

Use of prohibited treatment as per recommendations in Table 5-5

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)

Emergence of the following adverse events: severe nausea/vomiting, severe pruritus, 
increases in QTcF to > 500 ms (based on repeat ECGs), development of ventricular 
arrhythmia or clinically significant (symptomatic) bradycardia (see Appendix 3)

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevent the patient from continuing participation 
in the study (e.g., increase in liver enzymes > 3 times the upper limit of normal (see 
Appendix 2)

Deviation from the planned dose regimen for the study drug (e.g., vomiting of the 
replacement dose within 2 hours of intake)
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 Day 43.
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 Epoch, the patient is considered to have completed the treatment Epoch. 
If a patient does not complete the scheduled visits in the treatment Epoch, premature treatment 
discontinuation visit assessments detailed in the table of assessment should be completed and 
recorded in the eCRF.
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).


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5.7.3
Premature Study Withdrawal
Patients are considered to be withdrawn prematurely from the study if they do not complete the 
follow-up visits until Day 43.
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 patient, investigator, or sponsor

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.
5.7.4
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent (WoC) from the study is defined as when a patient:

Does not want to participate in the study anymore
and/or

Does not want any further visits or assessments
and/or

Does not want any further study related contacts
and/or

Does not allow analysis of already obtained biologic material 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine 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.


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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 below.
5.7.5
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.
5.7.6
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 
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 in the Epoch will be performed. At this final 
visit, all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications recorded on the eCRF. An overview of the specific CRF pages are 
listed on Table 6-5 (for database development purposes). The PK Run-in Part will follow the 
same visit schedule as for Cohorts 1 and 2 which have QD dosing for 1 day.


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Table 6-1
Assessment schedule (except PK sampling and ECG measurements) for all patients (PK Run-in Part, Part A and 
Part B)
Epoch
UNS
299
End of 
Follow up 
/ PSW
Study  Day 
4
5
8
15
29
43
Window
± 0 day
+ 1 day
± 1 day
± 2 day
± 4 days
± 4 days
Time (post-dose) in hours
0
1
3
6
8
12
18
24
27
30
36
48
51
54
60
68
72
96
168
336
672
1008
Obtain pre-screening informed consent
x
Obtain informed consent
x
Demography
x
Inclusion/Exclusion criteria
x
Initial Medical and Treatment history
x
Signs and symptoms of Severe Malaria
x
x
x
x
x
x
x
x
x
x
x
Vital Signs (blood pressure, pulse)
x
x
x
x
x
x
x
x
x
x
x
Body temperature3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Drug Administration Record
x
x4
x5
x4
x6
x4
Physical Exam and malaria signs and 
symptoms7
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
x
x
x
x
x
Blood chemistry, hematology and 
x
x
x
x
x
x
x
x
x
Thyroid function
x
x
x
Urinalysis (Dipstick)
x
x
x
x
x
x
x
x
x
Pregnancy test9
x
x
Malaria Blood Film for parasite and 
gametocyte count
x10
x10
x
x
x
x
x
x
x
x
x
x
x
x
Blood sampling for PCR Genotyping and 
resistance markers11
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Meal records13
x
x4
x5
x4
x6
x4
Contact IRT14
x
x
x5
x6
x
-24 to < 0
1
101
102
2
3
± 0 day
± 0 day
± 0 day
Visit Numbers2 
99
201
202
203
204
205
Treatment1
199
EOT Epoch / premature 
discontinuation
Follow-up
1
Screen15


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UNS = Unscheduled visit
EOT = End of Treatment
PSW = Premature Study Withdrawal
X = assessment to be recorded on clinical database
S = assessment to be recorded on source documentation only
1 Patients will be admitted to the hospital on Day 1 and will remain in the hospital under close supervision until they are discharged by the investigator or 
designee on Day 4.
2 Visit structure given for internal programming purpose only.
3 Fever monitoring will be done every 6 hours until resolution of fever, defined as being afebrile for 24 hours.
4 Comparator only (Coartem®). Coartem® will be given at 0, 8, 24, 36, 48 and 60 hours. For all drug administrations actual time should be recorded.
5 Not applicable to 1-day treatment regimen.
6 Not applicable to 1 and 2-day treatment regimens.
7 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. Malaria signs and symptoms, body height and body weight will also be recorded at screening as part of the complete physical examination.
An abbreviated physical examination will be performed at all other visits starting from Day 1. An abbreviated physical exam will include the examination 
of general appearance and malaria signs and symptoms. Body weight will also be measured at End of Study Visit (Day 43 or earlier in case of premature 
patient discontinuation). 
8 Laboratory tests should also be taken at any time of withdrawal/discontinuation.
9 The patient´s menstrual and contraceptive history will be taken and a urine β-hCG pregnancy test will be performed at screening to exclude pregnancy 
and at end of study. Results must confirm negative before dosing.
10 Pre-screening parasite count should be used as baseline count. In case parasite count has been done > 6 hours before Study Visit 99 then it should 
be repeated at Study Visit 99 and the outcome of the repeated test should be considered as baseline parasite count
11 PCR will be used for genotyping to establish malaria recrudescence/reinfection. PCR blood samples will be used for reviewing resistance markers. At 
screening, blood sample will be collected in all patients fulfilling eligibility criteria for inclusion in the study. A second blood sample collected as per Table 
above will be analyzed only in patients showing treatment failure before standard-of-care is administered.
 
13 Meals within 3 hours prior to dosing and within 4 hours post-dosing to be documented.
14 IRT has to be notified at Study Visit 1, at each study drug dispensing and at the completion or discontinuation of study treatment, upon completion of 
study or premature withdrawal from study participation. Also, if a patient vomits study drugs and needs to take a replacement medication, the site staff 
need to notify IRT.


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15 Screen Epoch has 2 parts: a Pre-Screening Part (Study Visit 1) to successfully identify the correct patients to be screened for this clinical study, and a 
Screening Part (Study Visit 99) in which further assessments will take place.
Table 6-2
12-Lead ECG assessments (triplicate) for all patients (PK Run-in Part, Part A and Part B)
Note: ECG’s should be taken in triplicate within 5 minutes after resting for at least 10 minutes 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 to < 24 h ± 30 min; ≥ 24 to 72 h ± 2 h; > 72 h ± 24 h.
UNS = Unscheduled visit
EOT = End of Treatment
PSW = Premature Study Withdrawal
X = assessment to be recorded on clinical data base
1 Patients will be admitted to the hospital on Day 1 and will remain in the hospital under close supervision until they are discharged by the investigator or 
designee on Day 4.
2 Visit structure given for internal programming purpose only.
3 ECG assessment at this time point to be done for patients in Part A only, ECG assessments will be repeated in case of abnormalities.
Epoch
UNS
299
End of 
Follow up 
/ PSW
Study  Day 
4
5
8
15
29
43
Window
± 0 day
+ 1 day
± 1 day
± 2 day
± 4 days
± 4 days
Time (post-dose) in hours
0
1
3
6
8
12
18
24
27
30
36
48
51
54
60
68
72
96
168
336
672
1008
KAF-LUM SDF 1D cohort
x
x
x
x3
x
x3
x
x
KAF-LUM SDF 2D cohort
x
x3
x
x
x
x
x
x
KAF-LUM SDF 3D cohort
x
x3
x
x
x
x
x
x
x
Coartem cohort
x
x3
x
x
x
± 0 day
± 0 day
± 0 day
Treatment1
Follow-up
101
102
1
2
3
201
199
EOT Epoch / premature 
discontinuation
202
203
205
204
Visit Numbers2 
99
Screen
1
-24 to < 0


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Table 6-3
PK sampling schedule for patients involved in RICH PK sampling (PK Run-in Part and Part A)
Notes: A) Each PK sample will be 1mL blood. Further details on sample collection, numbering, processing and shipment can be found in the 
Site Operations Manual. B) 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 to < 24 h ± 30 min; ≥ 24 to 72 h ± 2 h; > 72 h ± 24 h.
UNS = Unscheduled visit
EOT = End of Treatment
PSW = Premature Study Withdrawal
X = assessment to be recorded on clinical data base
1 Patients will be admitted to the hospital on Day 1 and will remain in the hospital under close supervision until they are discharged by the investigator or 
designee on Day 4.
2 Visit structure given for internal programming purpose only.
3 PK sampling at Visit 101 should be done in a range of 15 min to 1 min prior to dosing.
Epoch
UNS
299
End of 
Follow up 
/ PSW
Study  Day 
4
5
8
15
29
43
Window
± 0 day
+ 1 day
± 1 day
± 2 day
± 4 days
± 4 days
Time (post-dose) in hours
0
1
3
6
8
12
18
24
27
30
36
48
51
54
60
68
72
96
168
336
672
1008
KAF-LUM SDF 1D cohort
x3
x
x
x
x
x
x
x
x
x
x
KAF-LUM SDF 2D cohort
x3
x
x
x
x
x
x
x
x
x
x
x
x
KAF-LUM SDF 3D cohort
x3
x
x
x
x
x
x
x
x
x
x
x
x
± 0 day
± 0 day
± 0 day
2
3
1
EOT Epoch / premature 
discontinuation
Treatment1
Visit Numbers2 
Follow-up
199
101
102
205
201
202
203
204
Screen
1
-24 to < 0
99


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Table 6-4
PK sampling schedule for patients NOT involved in RICH PK sampling (Part A and Part B)
Note: 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 
to < 24 h ± 30 min; ≥ 24 to 72 h ± 2 h; > 72 h ± 24 h.
UNS = Unscheduled visit
EOT = End of Treatment
PSW = Premature Study Withdrawal
X = assessment to be recorded on clinical data base
1 Patients will be admitted to the hospital on Day 1 and will remain in the hospital under close supervision until they are discharged by the investigator or 
designee on Day 4.
2 Visit structure given for internal programming purpose only.
3 PK sampling at these time points to be done only for patients in Part A.
Epoch
UNS
299
End of 
Follow up 
/ PSW
Study  Day 
4
5
8
15
29
43
Window
± 0 day
+ 1 day
± 1 day
± 2 day
± 4 days
± 4 days
Time (post-dose) in hours
0
1
3
6
8
12
18
24
27
30
36
48
51
54
60
68
72
96
168
336
672
1008
KAF-LUM SDF 1D cohort
x
x
x3
x
x3
x
KAF-LUM SDF 2D cohort
x3
x3
x
x
x
x
x
KAF-LUM SDF 3D cohort
x3
x3
x
x
x
x
x
x
Coartem cohort
x3
x
x
x
x
± 0 day
± 0 day
± 0 day
199
EOT Epoch / premature 
discontinuation
1
2
3
Treatment1
101
102
201
Visit Numbers2 
99
203
Follow-up
204
205
202
Screen
1
-24 to < 0


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Table 6-5
Overview of specific CRF pages
UNS = Unscheduled visit
EOT = End of Treatment
PSW = Premature Study Withdrawal
X = assessment to be recorded on clinical data base
1 Patients will be admitted to the hospital on Day 1 and will remain in the hospital under close supervision until they are discharged by the investigator or 
designee on Day 4.
2 Visit structure given for internal programming purpose only.
3 To be completed at the last study drug administration.
4 Comparator only (Coartem®).
5 Not applicable to 1-day treatment regimen.
6 Not applicable to 1 and 2-day treatment regimens.
7 To be completed at End of Treatment (EOT) Epoch (end of Day 3 or at the time of treatment Epoch discontinuation).
8 To be completed at end of follow-up Epoch (Day 43 or at the time of follow-up Epoch discontinuation).
9 The Screen Epoch disposition page is completed at Visit 1 if a patient is a screen failure at Visit 1 and at Visit 99 otherwise.
Epoch
UNS
299
End of 
Follow up 
/ PSW
Study  Day 
4
5
8
15
29
43
Window
± 0 day
+ 1 day
± 1 day
± 2 day
± 4 days
± 4 days
Time (post-dose) in hours
0
1
3
6
8
12
18
24
27
30
36
48
51
54
60
68
72
96
168
336
672
1008
Screening Epoch disposition page9
x
x
Treatment completion3
x
x4
x5
x4
x6
x4
Treatment Epoch disposition page7
x
Follow-up Epoch disposition page8
x
± 0 day
± 0 day
± 0 day
Visit Numbers2 
99
101
102
199
EOT Epoch / premature 
discontinuation
1
2
3
Treatment1
Follow-up
201
202
203
204
205
-24 to < 0
Screen
1


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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 
epoch/period will have the study completion page for the screening epoch/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

Initial medical and treatment history

Severe malaria

Vital signs

Physical exam

Prior and concomitant medications

Blood chemistry and hematology

Thyroid function

Urinalysis

Pregnancy test

Malaria blood film for parasite and gametocyte count

Blood sampling for 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
Compliance will be assessed by the investigator and/or study personnel at each visit using 
pill/sachet counts. This information should be captured in the source document at each visit. All 
study treatment taken must be recorded in the Dosage Administration Record 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.


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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 CRF after start of study drug.
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.
6.4
Efficacy
Efficacy assessments will be based on the PCR-corrected Adequate Clinical and Parasitological 
Response (ACPR) at Day 29 (see Section 6.5.8).
6.4.1
Parasitaemia assessment (details provided in the laboratory manual)
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

Pre-screening/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 (WBC)
Parasite density per µl = __________________________________________________ 
Number of leukocytes (WBC) counted (200)

Blood examination during the 43 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


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
if P. falciparum gametocytes are seen, perform a gametocyte count against 1000 
leukocytes 
The count should be made for each species and for the P. falciparum gametocytes (White 
et al 2014). Blood film will be used for gametocyte count, and 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. 
 
 
 
 
 
6.4.3
Blood sample for molecular diagnostic purposes
Blood will be sampled for parasite genotyping as indicated in the assessment schedule (Table 
6-1). At screening, blood sample will be collected in all patients fulfilling eligibility criteria for 
inclusion in the study. A second blood sample collected as per Table 6-1 will analyzed only in 
patients showing treatment failure. This will distinguish between recrudescence and new 
infection. Analysis will be done by a pre-selected central laboratory.
Microscopic species identification (parasitaemia) will be confirmed and determined with PCR-
based methods on blood retained from samples collected at the time of withdrawal.
All parasite samples at baseline will also be screened for specific genes/single-nucleotide 
polymorphisms (SNPs) that are known as markers for P. falciparum resistance.
During the analysis process no human DNA will be amplified or analyzed by any means.
6.4.4
Appropriateness of efficacy assessments
The microscopy examination methods to quantify the malaria parasite and gametocyte 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.


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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. In addition, body height in centimeters (cm) and body weight to the 
nearest 0.1 kilogram (kg) in indoor clothing, but without shoes will be measured during the 
complete physical examination at screening.
An abbreviated physical examination will be performed at all other visits starting from Day 1 
including the examination of general appearance and vital signs. Body weight to the nearest 
0.1 kilogram (kg) in indoor clothing, but without shoes will be measured at Study End only 
(Day 43 or earlier in case of premature patient withdrawal from study participation). 
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 (Table 6-
1).
In particular in Part B pediatric patients need to be examined for signs of dehydration.
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
Body temperature
Body temperature will be monitored as indicated in the study assessment schedule table and 
recorded on the clinical data base. Fever monitoring will be done every 6 hours until resolution 
of fever, defined as being afebrile for 24 hours.
Fever Clearance is defined (in patients with an increased temperature at baseline) as the time 
of the first measurement of axillary temperature of < 37.5°C (or < 38.0°C for alternative routes). 
Fever clearance will be concluded following confirmation of temperature < 37.5°C (or < 38.0°C 
for alternative routes) on the subsequent measurement for at least 24 hours.
Patients who entered in the study on the basis of history of fever and did not subsequently have 
an increased body temperature measurement indicating presence of fever pre-dose will not be 
included in the analysis of fever clearance time (FCT).


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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 and resistance markers), 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 at screening, 24 and 48 
hours post-dose, Day 5 and then at each following Study visit up to end of study.
6.5.4.1
Hematology
Hemoglobin, hematocrit (packed-cell volume - PCV), 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’). Red blood cell count 
(RBC), reticulocytes count and haptoglobin levels will be performed in case of significant 
hemoglobin drop > 2g/dL or hemoglobin levels ≤5g/dL (will be optional depending on site 
equipment). Assessments will be done as indicated in the study assessment schedule table.
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, ALP, BUN, INR, sodium, 
potassium, magnesium, calcium, chloride, total protein and albumin.
Thyroid Stimulating Hormone (TSH) and free thyroxine T4 are tested at screening, after 
336 hours, and at study completion only.
At screening, results of the thyroid test are not mandatory for eligibility into the study.
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, except for 
children ≤ 6 years, when Bazett formula (QTcB) is recommended.


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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.
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 2-3 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 pregnancy test in urine will be performed at the screening visit and at study completion. Any 
female aged 8 years and above is considered a woman of child-bearing potential (WOCBP), 
and must be included among female patients undergoing obligatory pregnancy testing during 
the study.
6.5.7
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
6.5.8
WHO definition
Definition of treatment failures
Early Treatment Failures (ETF)

Development of danger signs or severe malaria on Day 2, Day 3, Day 4 in the presence of 
parasitaemia.

Parasitaemia on Day 3 higher than Day 1 count irrespective of axillary temperature.

Parasitaemia on Day 4 with axillary temperature ≥37.5°C.

Parasitaemia on Day 4 equals to or more than 25% of count on Day 1.


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Late Clinical Failure (LCF)

Development of danger signs or severe malaria on any day from Day 5 to Day 43 in the 
presence of parasitaemia without previously meeting any of the criteria of early treatment 
failure.

Presence of parasitaemia and axillary temperature ≥37.5oC on any day from Day 5 to 
Day 43 without previously meeting any of the criteria of Early Treatment Failure.
Late Parasitological Failure (LPF)

Presence of parasitaemia on any day from Day 8 to Day 43 and axillary temperature 
< 37.5oC without previously meeting any of the criteria of Early Treatment Failure or Late 
Clinical Failure 
Adequate Clinical and Parasitological Response (ACPR):
Absence of parasitaemia on Day 43 irrespective of axillary temperature, without previously 
meeting any of the criteria of Early Treatment Failure or Late Treatment Failure or Late 
Parasitological Failure.
In this study, “absence of parasitaemia on Day 43” has been adapted to “absence of parasitaemia 
on Day 29” based on the short half-life of the study drugs.
Note: The first day of treatment with study medication is defined as Day 1 while the day prior 
to the first day of treatment is defined as Day -1. Compared to WHO (2015) 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, Day 29 in this protocol corresponds to Day 28 by WHO 
(2015).
Signs/symptoms indicative of severe/complicated malaria 
Danger signs: 
1. not able to drink or breast feed
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 or Blantyre coma score < 3 in 
children)

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)


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
Hypoglycemia (blood or plasma glucose < 2.2 mmol/L; < 40 mg/dL)

Severe malarial anemia (haemoglobin concentration ≤5 g/dL or a haematocrit of ≤15% in 
children < 12 years of age (< 7 g/dL and < 20% respectively 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)

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 < 70 mm Hg in children or 
< 80 mm Hg in adults with evidence of impaired perfusion)

Hyperparasitaemia (P. falciparum parasitaemia > 10%)
 
 
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. 


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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.
Study drug/treatment includes investigational drugs i.e. KAF156 (200 mg, 400 mg and 800 mg), 
LUM-SDF (480 mg and 960 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 Terminology 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 criterion 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 serious adverse event (SAE - see Section 7.2 for definition of 
SAE) and which seriousness criteria have been met.

action taken regarding study 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 given 

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)


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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 Investigator Brochure (IB). This information will be included in the patient 
informed consent and should 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, for example, via an Investigator Notification (IN) 
or an Aggregate Safety Finding. 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 (e.g., blood transfusion for the treatment of anemia due to 
malaria) 

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.


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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 (please refer to Annex IV, ICH-E.2D Guideline).
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 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
Expectedness assessment
Since KAF156 and LUM-SDF will be administered to the patients on the same day, it would 
only be possible to assess the suspectedness of the reported SAEs to the combination (i.e., 
KAF156 and LUM-SDF). Hence, the expectedness of the reported SAEs will also be assessed 
for the combination. KAF156 and LUM-SDF have separate Investigator Brochure (IB) and the 
respective reference safety information (RSI) will be used. If the reported SAE/s is/are listed in 
the RSI of either of the product’s IB, those will be considered as expected adverse events to the 
combination product (i.e., KAF156 and LUM-SDF) for reporting purposes. RSI in the 
LUM-SDF IB is based on the safety profile of Coartem®.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit 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 Serious Adverse Event 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 to the study treatment (KAF156/lumefantrine combination 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 


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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 Investigator Brochure(s) (IB) or Package Insert 
(new occurrence) and is thought to be related to the study treatment a CMO&PS Department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
European Union (EU) Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
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 will require close observation, follow-up monitoring, completion of the 
specific liver CRF pages and reported as SAE (Section 7.2.2).
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 designated personal 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 liver function test (LFT) within 24 hours to confirm elevation.
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.


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
Discontinuation of the investigational/study 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).

Report to Novartis as SAE.

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 pre-defined checklist. All follow-up information, and the 
procedures performed must be recorded on appropriate CRF pages, including the liver event 
overview CRF pages.
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 (uPCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 16-1 in Appendix 4 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 4.
7.5
Cardiac Safety Monitoring
To ensure patient safety and fully characterize the cardiovascular safety of the investigational 
drug, a standardized process for identification, monitoring and evaluation of cardiac events is 
followed.
The following categories of notable ECG changes will be assessed during the course of the 
study (irrespective of whether classified/reported as (S)AE):

QTcF increase from pretreatment baseline ≥60 ms (QTcB for children ≤ 6 years)

QTcF > 500 ms (QTcB for children ≤ 6 years)
Resting heart rate:

ECG of HR < 50/min with > 25% decrease from pretreatment baseline or

HR < 50/min associated with symptoms
Cardiac rhythm: 

Any cardiac arrhythmia associated with hemodynamical compromise

Sustained ventricular tachycardia ≥ 30 sec, or ventricular fibrillation 


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Every cardiac event as defined in Table 15-1 in Appendix 3 should be appropriately documented 
in the eCRF (both AE and SAE) and followed up by the investigator or designated personnel at 
the trial site as summarized in Appendix 3.
7.6
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 dose administration record (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 
(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
7.7
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 
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.


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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 drug is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
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 will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 US Code of Federal 
Regulations (CFR) Part 11 requirements. Designated investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies and, by generating appropriate error messages, allow the data to be 
confirmed or corrected. The Investigator must certify that the data entered into the Electronic 
Case Report Forms are complete and accurate. After database lock, the investigator will receive 
a CD-ROM or paper copies of the subject 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.
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they have 
been trained. 
Automatic validation procedures within the system 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 electronic Case Report Forms are complete and accurate. After 


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database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Data management and quality control
Novartis staff (or Contract Research Organization (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. If the electronic query system 
is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete and 
sign the faxed copy and fax it back to Novartis staff or designee that will make the correction 
to the database. The signed copy of the Data Query Form is kept at the investigator site.
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 Interactive Response Technology (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 for each part separately. After 
these actions have been completed and the database has been declared to be complete and 
accurate, it will be locked and the treatment codes will be unblinded and made available for 
data analysis for each part. Any changes to the database after that time can only be made after 
written agreement by Novartis Development management.
8.4
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be established for this study to review 
patient safety at several time points. The DMC can recommend to stop the study or a specific 
cohort in case of serious safety observations which can include a non-acceptable rate of early 
treatment failures. The DMC will consist minimally of an external clinician with expertise in 
tropical diseases and external statistician. Regular formal interim assessment to review patient 
safety will be performed during the study as specified in the DMC charter.
Additional ad-hoc safety review may be requested by DMC or Novartis if needed.
Details of safety analyses will be specified in the analysis plan for the DMC. The DMC will 
make recommendations to Novartis on any safety issues that are deemed relevant. 


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The DMC is accountable to the Sponsor for appropriate monitoring of the study data. Although 
the DMC may make recommendations to the Sponsor about changes in the conduct of the study, 
final decisions will be made by Novartis Clinical Development senior management. In the case 
of 
early 
termination, 
consultation 
with 
Health 
Authorities 
may 
be 
required.
Further details of the DMC’s composition, organization and responsibilities will be described 
in the DMC charter.
9
Data analysis
Statistical analyses for PK Run-in Part, Part A and Part B will be performed separately. For key 
efficacy and safety outcomes, pooled analysis will be performed by pooling Part B with 
corresponding cohorts in Part A. Unless described separately otherwise, same statistical method 
will be used for separate analysis and pooled analysis.
For each cohort in Part B, a corresponding cohort in Part A will exist with matching dose and 
regimen. For statistical analyses and clinical study reporting, treatment group name, instead of 
cohort number, will be used for both parts and the pooled analysis which will include only those 
treatment groups with patients in both parts. The following treatment groups will be used (doses 
for KAF156 in Part A may be adapted according to Table 3-1):

KAF156 400 mg/LUM-SDF 960 mg QD 1 day

KAF156 800 mg/LUM-SDF 960 mg QD 1 day

KAF156 400 mg/LUM-SDF 960 mg QD 2 days

KAF156 200 mg/LUM-SDF 480 mg QD 3 days

KAF156 400 mg/LUM-SDF 480 mg QD 3 days

KAF156 400 mg/LUM-SDF 960 mg QD 3 days

Coartem®
Efficacy data from the PK Run-in Part will not be pooled with the data from other cohorts. The 
PK analysis will be performed separately for this cohort.
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.


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Safety set (SS)
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) 
Per-protocol set will be comprised of patients in FAS who

did not have any important protocol deviations

took at least 80% of randomized 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® cohort, this requires that all 
patients take all KAF156 and LUM-SDF dosages as assigned

did not take other antimalarial medications prior to Day 29 for reasons other than rescue 
medication given for signs and symptoms of infection with P. falciparum or unsatisfactory 
therapeutic effect, and

met at least one of the following criteria: (a) classified as treatment failure before Day 8 (see 
Section 6.5.8), (b) absent from parasitaemia at Day 29 or later, or (c) had valid PCR 
evaluations at baseline and at the time point with parasitaemia if parasitaemia is present at 
Day 8 or later.
Important protocol deviations for exclusion from PPS will be identified by the clinical team 
before database lock for each part.
PK analysis set
All subjects in the safety analysis set who had evaluable pharmacokinetic parameter data. 
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 treatment group, as well as overall, using 
the FAS and PPS.
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 treatment group and drug (KAF156, 
LUM-SDF, or Coartem®). The percentage will be calculated based on the planned number of 
doses per treatment group. 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 drug (KAF156, LUM-SDF, Coartem®) will be summarized by treatment group.


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9.3.2
Prior and concomitant medication
Medications will be identified using the Novartis drug and therapy dictionary (NovDTD)
including Anatomical Therapeutic Chemical (ATC) code.
Prior and concomitant medications will be summarized by treatment group in separate tables. 
Concomitant rescue and other anti-malarial medications will also be summarized by treatment 
group. Medications will be presented in alphabetical order, by ATC codes and grouped by 
anatomical main group (the first level of the ATC codes). Tables will also show the overall 
number and percentage of subjects receiving at least one drug of a particular ATC code and at 
least one drug in a particular anatomical main group.
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. 
9.4
Analysis of the primary variable(s)
The PK Run-in Part will be separately analyzed. The primary objective for the PK Run-in Part 
is to investigate the pharmacokinetic interaction potential between KAF156 and LUM-SDF. 
The analyses of PK parameters of KAF156 and LUM-SDF are detailed in Section 9.5.4.
The primary efficacy objective in Part A is to determine the effective dose of KAF156 combined 
with LUM-SDF given daily over 1, 2, 3 days for treatment of uncomplicated malaria caused by 
P. falciparum in adults/adolescents. If there are multiple KAF156 and LUM-SDF dose 
combinations that are effective, tolerable and safe, the most effective dose combination(s) in 
the less frequent 1 to 2 days regimen and the most effective dose combination(s) in the 3 days 
regimen will be carried over to Part B. Up to 3 KAF156 and LUM-SDF dose combinations may 
be carried over to Part B.
The primary efficacy objective in Part B is to determine if the selected dose combination 
regimens from Part A is effective in children down to 2 years.
Data in Part B will be pooled with the corresponding cohort data in Part A to determine which 
KAF156 and LUM-SDF dose combination can be carried forward to Phase 3 studies.
9.4.1
Primary Variable(s)
The primary efficacy variable is the PCR corrected Adequate Clinical and Parasitological 
Response (ACPR) at Day 29.
A patient is considered as PCR-corrected ACPR at Day 29 if the patient does not meet any of 
the criteria of early treatment failure (up to Day 4), late clinical failure (Day 5 to Day 29) or late 
parasitological failure (Day 8 to Day 29), and is absence of parasitaemia on Day 29 irrespective 
of axillary temperature unless the presence of parasitaemia after 7 days is due to reinfection 
based on PCR.
A presence of parasitaemia after 7 days of treatment initiation (Day 8 or later) is considered as 
a reinfection only if the parasitaemia is clear before Day 8 and none of the parasite strain(s) 
detected on Day 8 or later matche with the parasite strain at baseline based on PCR genotyping.


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Treatment failures after 7 days due to reinfection based on PCR genotyping are not considered 
as failure for PCR-corrected analyses but will be considered as failure for PCR uncorrected 
analyses.
9.4.2
Statistical model, hypothesis, and method of analysis
The statistical null hypothesis is that the ACPR rate at Day 29 is at most 80% with the alternative 
hypothesis that the ACPR rate at Day 29 is greater than 80%. The statistical hypothesis will be 
evaluated using the lower limit of 2-sided 95% exact confidence interval (CI) (Pearson-
Clopperr method) for the ACPR rate at Day 29. If the lower limit of 2-sided 95% exact 
confidence interval for the ACPR rate at Day 29 is greater than 80%, the null hypothesis will 
be rejected. The statistical hypothesis testing will be evaluated separately for each KAF156 and 
LUM-SDF combination in each part based on the PPS. There is no adjustment for multiplicity 
since this is an exploratory study.
For exploratory purpose, 2-sided 95% confidence intervals for the difference in ACPR at Day 
29 between each KAF156/LUM-SDF treatment group and Coartem® will be constructed using 
the Wilson uncorrected method.
9.4.3
Handling of missing values/censoring/discontinuations
No missing data are expected for the primary efficacy analysis based on PPS since patients who 
are not evaluable for the primary efficacy variable are excluded from PPS. See Section 9.4.4
for missing data handling for the supportive analysis using FAS.
9.4.4
Sensitivity analyses
The primary efficacy variable will be performed based on the FAS using the statistical method 
specified in Section 9.4.2. Missing primary efficacy variable will be handled as follows:

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 (from 
the day of rescue use onwards).

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 or for the treatment 
of P. falciparum gametocytes (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 if (a) they did not have a parasite count at Day 29 
unless these patients could be classified as cured based on absence of parasitemia at 
later time, or (b) they did not have valid PCR evaluations at baseline and Day 29 if 
parasitemia was present at Day 29.
In addition, 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) which uses treatment failure as the event and treats missing data as censored 
instead of treatment failure. The PCR-corrected ACPR rate at Day 29 is estimated by the 
survival function at Day 29. 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 took antimalarial 


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medications for reinfection or reasons other than rescue medication given for signs and 
symptoms of infection with P. falciparum or unsatisfactory therapeutic effect will be censored 
at the first time of such antimalarial medications; other patients without treatment failure will 
be censored at the time of last parasitemia assessment.
A two-sided 95% CI for the difference in proportion between each KAF156/LUM-SDF 
combination treatment group and Coartem® will be calculated based on the variance of 
individual proportion using the Greenwood formula.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
Secondary efficacy variables include:
1. PCR-corrected ACPR at Days 15 and 43;
2. Uncorrected ACPR at Days 15, 29, and 43;
3. Proportion of patients with parasitaemia at 12, 24, and 48 hours after treatment;
4. Time to parasite clearance (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;
5. Time to fever clearance (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;
6. Proportion of patients with early treatment failure (ETF);
7. Proportion of patients with late clinical failure (LCF);
8. Proportion of patients with late parasitological failure (LPF);
9. Incidence rate of recrudescence and reinfection at Days 15, 29 and 43.
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 mean ACPR rate with 95% confidence intervals will be provided using 
Pearson-Clopper method for each treatment group.
Data will be handled as follows:

Treatment failures after 7 days (i.e., 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 (from 
the day of rescue use onwards). 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 or for the treatment of P. falciparum gametocytes (e.g. primaquine, certain 


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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., Day 15, etc.) if (a) they did not have 
a parasite count at that visit unless these patients could be classified as cured based on 
absence of parasitaemia at a later time (e.g., 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., 
Visit Day 15).
In addition, PCR-corrected ACPR rate will be calculated and plotted using the Kaplan-Meier 
method for each treatment group in the FAS (see Section 9.4.4).
9.5.1.2
Treatment failure related parameters
For the following parameters, 95% confidence intervals will be provided for each treatment 
group using the Pearson-Clopper method:

proportion of patients with parasitaemia at 12, 24, and 48 hours after treatment

proportion of patients with early treatment failure (ETF)

proportion of patients with late clinical failure (LCF)

proportion of patients with late parasitological failure (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 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.
9.5.1.4
Recrudescence and 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.
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 and reinfection at Days 15, 29 and 43 will be estimated by 
Kaplan-Meier method based on the subset of FAS patients who have clearance of initial 
infection by Day 7. Time to event (recrudescence or reinfection) will be calculated from the 


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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.
The following additional analyses will be performed for each part and the pooled Part A and 
Part B:

For PCR corrected and uncorrected ACPR rates, the 95% confidence intervals for the 
difference between each test group (KAF156/LUM-SDF combination) and the control 
(Coartem®) will be provided using the Wilson uncorrected method. For the pooled analysis, 
the treatment differences versus control will be evaluated using a Mantel-Haenszel estimate 
of the common risk difference stratified by Part (see SAS manual version 13.2 Pages 2681-
2682, 2014).

For PCT and FCT, the difference between each test group and control will be evaluated 
using a log-rank test. Patients who did not experience a clearance will be censored at the 
time of last relevant assessment (parasite or fever). For the pooled analysis, the log-rank test 
will be stratified by Part.
9.5.2
Safety variables
All safety parameters will be analyzed based on the safety.
9.5.2.1
Adverse event
The number and percentage of patients who report adverse events will be summarized by 
treatment group 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, serious adverse events, adverse event causing study drug discontinuation, 
adverse events by severity and causality will be presented by treatment group. 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 and treatment group.
In addition, shift tables will be provided in order to compare a patient’s baseline laboratory 
evaluation relative to each study visit. 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 a 
categorical analysis will be provided. These summaries will be presented by laboratory test 
group and treatment group.


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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) for each treatment group.
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 by treatment group.
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, QTcB (QT interval corrected for heart rate according to Bazett) and QTcF (QT interval 
corrected for heart rate according to Fredericia) for each treatment group. 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.
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 and geometric 
(means, standard deviation (SD), median, minimum and maximum, etc). In the study rich PK 
data will be collected from subset of patients whereas all other patient will provide sparse PK 
samples. A separate PK analysis will be performed for patients providing rich PK data. 
Parameters such as AUCinf, AUClast, AUC0-t, Cmax and Tmax will be reported for the 
patients with rich PK data using non-compartmental method of analysis (using Phoenix 6.4 or 
higher). For the PK Run-in cohort, 2-sided 90% confidence intervals for AUC0-24h, Cmax and 
Tmax PK parameters of KAF156 and lumefantrine will be calculated by part and treatment 
group using normal or log-normal approximation as applicable. Non-compartmental PK 
analysis for patients with sparse data will also be conducted and feasible PK parameters will be 
reported. A descriptive statistics for concentration at nominal time point of 168 hours post dose 
or any other time point identified critical for the cure would also be reported for all the patients.
All the PK data will 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.
 


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9.7
Interim assessments
PK Run-in Part: For the patients in the PK Run-in KAF156 200 mg/LUM-SDF 960 mg cohort, 
PK analyses will be performed on the samples collected in the first 24 hours. AUC0-24, for 
KAF156 and lumefantrine will be calculated and compared with the expected values when one 
drug was given alone. Dosing in Part A will subsequently proceed according to the algorithm 
specified in Table 3-1. 12 patients with evaluable PK data are needed in the PK Run-in cohort.


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End of Part A: After the last patient has completed the last visit in Part A, the clinical database 
will be cleaned and locked.
An interim assessment will be performed to evaluate if any KAF156 and LUM-SDF 
combination is effective and safe and which KAF156 and LUM-SDF dose regimen(s) will be 
carried forward in Part B. Only the primary efficacy endpoint, selected secondary efficacy, PK, 
and safety endpoints (all adverse events, serious adverse events and laboratory results) will be 
analyzed by the study biostatistics team.
The results will be communicated to relevant internal and external people who will contribute 
to the selection of effective and safe dose regimen.
DMC reports: At selected time points during the study, DMC reports will be provided by a 
CRO team not involved in the study conduct. The unblinded DMC reports will be reviewed by 
the DMC.
Additional ad-hoc safety review may be requested by DMC or Novartis if needed. Only the 
decision or information needed for planning/modifying the trial (such as continuation of study, 
dosing information for new patients, etc.) will be communicated to the blind clinical trial team 
involved in trial conduct. No further dissemination of DMC reports should occur.
9.8
Sample size calculation
Sample size for PK run-in cohort
The objective of this part is to assess the effect of LUM-SDF in the exposure of KAF156 in 
patients and to see if the current planned dosages for KAF156 in Part A should be modified or 
how to modify KAF156 dosages in Part A. Therefore, the sample size is calculated/justified 
based on the precision of estimating KAF156 exposure. The key variables for exposure of 
KAF156 are AUC0-24h and Cmax. It’s well known that the distribution of AUC or Cmax is best 
described by log normal distribution. The half width of 2-sided 90% confidence interval for the 
log AUC0-24h or log Cmax is the target for sample size calculation. The relevant historical data 
for sample size calculation are the standard deviations of log AUC0-24h and log Cmax, which are 
usually invariant to the dosage. 
In a POC Study, the standard deviation for log AUC0-24h was 0.26 and 0.27 for 10 P. falciparum
patients treated with KAF156 400 mg QD 3 days and for 18 P. falciparum patients treated with 
KAF156 800 mg QD, respectively. The corresponding standard deviation for log Cmax was 
0.205 and 0.215, respectively.
Table 9-1
Sample size and width of 2-sided 90% CI for log AUC0_24h and log 
Cmax
Standard deviation 
(in log)
n
Target half width 
of 2-sided 90% CI
Half width in 
terms of ratio 
(anti-log)
Probability that observed half 
width of 2-sided 90% CI is ≤ 
the target
0.21
9
0.153
1.17
0.80
0.21
12
0.126
1.13
0.80
0.21
10
0.150
1.16
0.80


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Standard deviation 
(in log)
n
Target half width 
of 2-sided 90% CI
Half width in 
terms of ratio 
(anti-log)
Probability that observed half 
width of 2-sided 90% CI is ≤ 
the target
0.26
9
0.200
1.22
0.80
0.26
12
0.155
1.17
0.80
0.26
13
0.150
1.16
0.80
0.26
12
0.150
1.16
0.70
0.27
9
0.200
1.22
0.80
0.27
12
0.161
1.17
0.80
0.27
14
0.150
1.16
0.80
0.27
12
0.150
1.16
0.68
Based on nQuery Table MOC1-1.nqa. 
A sample size of 12 patients will provide 80% probability that the observed half width of 2-
sided 90% CI for log AUC0_24h is ≤0.155 or 1.17 in terms of ratio. A sample size of 12 patients 
will provide 80% probability that the observed half width of 2-sided 90% CI for log Cmax is 
≤0.126, or 1.13 in terms of ratio. The target half widths of 2-sided 90% CI in Table 9-1 are 
about 1.2 in terms of ratio, which is smaller than 1.4 used for dose adjustment in Table 3-1.
Part A
The primary efficacy objective for this part is to determine the effective dose(s) of KAF156 
combined with LUM-SDF for treatment of uncomplicated malaria caused by P. falciparum in 
adolescents and adults. The primary efficacy endpoint is the PCR corrected ACPR rate at Day 
29 based on the per-protocol analysis set. The statistical null hypothesis is that the ACPR rate 
is at most 80% with the alternative hypothesis that the ACPR rate is greater than 80%. The 
statistical hypothesis will be evaluated using the lower limit of 2-sided 95% exact confidence 
interval for the ACPR rate. If the lower limit of 2-sided 95% exact confidence interval for ACPR 
rate is greater than 80%, the null hypothesis will be rejected. 
Rejecting the null hypothesis of at most 80% ACPR rate is equivalent to showing non-inferiority 
to a ACPR rate of 90% with a non-inferiority margin of 10%. 90% is specified in the 2015 
WHO guidelines as the ACPR rate cutoff-threshold for a change in treatment policy and a 10% 
non-inferiority margin is considered as acceptable for early-phase trials (Held, et al 2015). 
Figure 9-1 plots the power to reject the null hypothesis of at most 80% ACPR rate versus sample 
size by various true ACPR rates (90%, 93%, 95%, and 97%). Due to the discrete property of 
binomial distribution, the power increases zigzag with jump at 26, 34, 41, 48, 55, 62, and 68 as 
the sample size increases. When the sample size is at least 41, the power to reject the null 
hypothesis of at most 80% ACPR rate is about 80% or higher if the true rate is 95% or higher. 
Since there is a 2:1 ratio among different treatment groups, the sample size in the per-protocol 
analysis set will be targeted to be 42 patients for each KAF156/LUM-SDF dose combination 
group and 21 patients for the comparator (Coartem®) cohort. This sample size will provide at 
least 80% power to reject the null hypothesis of at most 80% ACPR rate for the 6 KAF156 dose 
combinations if the true ACPR rate is at least 95%. If there are multiple KAF156/LUM-SDF 
dose combinations that are all effective, the less frequent or/and highest KAF156/LUM-SDF 


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dose combination(s) that is tolerable may be selected for further evaluation. The PK/PD 
modeling may be used to assist the selection of appropriate dose combination(s) for Part B. 
Assuming that about 16% of patients will be excluded from the per-protocol analysis set, about 
325 patients (50:50:50:50:50:50:25) will be randomized to yield 42 patients for each 
KAF156/LUM-SDF dose combinations and 21 patients for the Coartem® cohort in the per-
protocol analysis set.
Figure 9-1
Power to reject adequate clinical and parasitological response (ACPR)
rate less than or equal to 80% based on 2-sided 95% CI by true rate
Part B
The primary objective for this part is to assess the safety and efficacy of the selected 
KAF156/LUM-SDF dose combination(s) adjusted for body weight in pediatric patients. For the 
primary efficacy variable of PCR corrected ACPR rate at Day 29 based on the per-protocol 
analysis set, a sample size of at least 41 patients will provide about 80% power or higher to 


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reject the null hypothesis of at most 80% ACPR rate based on the lower limit of 2-sided 95% 
exact confidence interval if the true rate is 95% or higher for a KAF156/LUM-SDF dose 
combination. Since there is a 2:1 ratio between a KAF156/LUM-SDF dose combination group 
and the Coartem® cohort, the sample size in the per-protocol analysis set will be targeted to be 
42 patients for each KAF156/LUM-SDF dose combination group and 21 patients for the 
Coartem® cohort. Assuming that 16% of patients will be excluded from the per-protocol 
analysis set, about 50 pediatric patients will be randomized to yield 42 patients for each KAF156 
and LUM-SDF combination and 21 patients for the Coartem® cohort in the per-protocol 
analysis set.
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, United States (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 
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 Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 


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written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. 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 either submitted for publication and/or 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 
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. 


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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 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
Ashley EA, Dhorda M, Fairhurst RM et al (2014) Spread of artemisinin resistance in 
Plasmodium falciparum malaria. N Engl J Med;371(5):411-23.
Dondorp AM, Nosten F, Yi P et al (2009) Artemisinin resistance in Plasmodium falciparum 
malaria. N Engl J Med.;361(5):455-67.
Flegg JA, Guerin PJ, White NJ, et al (2011) Standardizing the measurement of parasite 
clearance in falciparum malaria: the parasite clearance estimator. Malar J; 10:339.
Hamed K and Grueninger H (2012) Coartem(®): a decade of patient-centric malaria 
management. Expert Rev Anti Infect Ther;10(6):645-59.
Held J, Supan C, Salazar CL et al (2015) Ferroquine and artesunate in African adults and 
children with Plasmodium falciparum malaria: a phase 2, multicentre, randomised, double-blind, 
dose-ranging, non-inferiority study. Lancet Infect Dis;15(12):1409-19. 
Kredo T, Mauff K, Workman L, et al. (2016) The interaction between artemether-lumefantrine 
and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients. BMC Infect Dis; 
16:30.
Kuhen KL, Chatterjee AK, Rottmann M, et al (2014) KAF156 is an antimalarial clinical 
candidate with potential for use in prophylaxis, treatment, and prevention of disease 
transmission. Antimicrob. Agents Chemother;58(9):5060-7. 
Lefevre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, Gathmann I, Mull 
R, Bakshi R. 2001. A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine 
for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 
64:247–256.
Lefevre G, Carpenter P, Souppart C, et al. (2002) Pharmacokinetics and electrocardiographic 
pharmacodynamics of artemether-lumefantrine (Riamet) with concomitant administration of 
ketoconazole in healthy subjects. Br J Clin Pharmacol; 54:485-92.
Leong FJ, Zhao R, Zeng S et al (2014) A first-in-human randomized, double-blind, placebo-
controlled, single- and multiple-ascending oral dose study of novel Imidazolopiperazine 
KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. 
Antimicrob. Agents Chemother; 58(11):6437-43. 


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Ménard D, Khim N, Beghain J et al KARMA Consortium (2016) A Worldwide Map of 
Plasmodium falciparum K13-Propeller Polymorphisms. N Engl J Med;374(25):2453-64.
SAS Institute Inc. (2014) SAS/STAT® 13.2 User’s Guide. Cary, NC: SAS Institute Inc.
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.
Tun KM, Imwong M, Lwin KM et al (2015) Spread of artemisinin-resistant Plasmodium 
falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect 
Dis;15(4):415-21.
White NJ, Ashley EA, Recht J et al (2014) Assessment of therapeutic responses to 
gametocytocidal drugs in Plasmodium falciparum malaria. Malar J;13:483.
WorldWide Antimalaria Resistance Network (WWARN) (2015) Artemether-lumefantrine 
treatment of uncomplicated Plasmodium falciparum malaria: a systemic review and meta-
analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient 
data. BMC Med; 13:227. doi: 10.1186/s12916-015-0456-7. 
World 
Health 
Organization 
(2015) 
World 
Malaria 
Report 
(http://apps.who.int/iris/bitstream/10665/200018/1/9789241565158_eng.pdf?ua=1).


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13
Appendix 1: Clinically notable laboratory and ECG values
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

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 drug 
immediately

Repeat LFTs within 24h

Hospitalize, if clinically appropriate

Establish causality

Report to Novartis as an SAE

Complete Liver CRF
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 drug 
immediately

Repeat LFTs within 24h

Hospitalize if clinically appropriate

Establish causality

Report to Novartis as an SAE

Complete Liver CRF
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 drug 
immediately
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc


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Criteria
Actions required
Follow-up monitoring

Repeat LFTs within 24h

Hospitalize, if clinically appropriate

Establish causality

Report to Novartis as an SAE

Complete Liver CRF
(frequency twice a week until 
resolution, stabilize or return to 
within baseline values)
> 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

Report to Novartis as an SAE

Complete Liver CRF
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 drug 
immediately

Repeat LFT within 24 hours

Hospitalize if clinically appropriate

Establish causality

Report to Novartis as an SAE

Complete Liver CRF
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 24 hours

If elevation is confirmed, initiate 
close observation of the patient
Monitor LFT until resolutionc
(frequency twice a week until 
resolution, stabilize or return to 
within baseline values)
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 24 hours

If elevation persists, establish 
causality

Report to Novartis as an SAE

Complete Liver CRF
Monitor LFT until resolutionc
(frequency twice a week until 
resolution, stabilize or return to 
within baseline values)
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

Report to Novartis as an SAE

Complete Liver CRF
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
Jaundice

Discontinue the study drug 
immediately

Hospitalize the patient
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency twice a week until 


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Criteria
Actions required
Follow-up monitoring

Establish causality

Report to Novartis as an SAE

Complete Liver CRF
resolution, stabilize or return to 
within baseline values)
Any AE potentially 
indicative of a 
liver toxicity* 
severe events 
only SMQ AE

Consider study drug discontinuation 

Hospitalization if clinically 
appropriate

Establish causality

Report to Novartis as an SAE

Complete Liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency twice a week until 
resolution, stabilize or return to 
within baseline values
* 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
a Elevated 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 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.


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Protocol No. CKAF156A2202
15
Appendix 3: Cardiac Alert Threshold Values and Actions
Table 15-1
Cardiac alert threshold values and actions
Values
Actions
If confirmed by two repeat 
ECG, check and correct the 
patient’s serum potassium 
and magnesium immediately.
Report as SAE to Sponsor 
and transmit to eRT 
immediately for prompt 
review.
Discontinue patient from 
study therapy. 
Monitor ECG hourly until at 
least 2 consecutive hourly 
ECGs performed are back to 
baseline
QTcF (QTcB for 
children ≤ 6 years)
QTcB > 500 ms (< 6 years); 
QTcF> 500 (≥6 years).
Cardiac rhythm
Sustained ventricular 
tachycardia lasting 30 sec or 
more, or ventricular 
fibrillation, or any 
hemodynamically 
compromising cardiac 
arrhythmia
QTcF (QTcB for 
children ≤ 6 years)
Resting heart rate
Increase from baseline ≥ 60 
ms
HR < 50/min with > 25% 
decrease from pretreatment 
baseline verified by ECG
If confirmed by two repeat 
ECG, check and correct the 
patient’s serum potassium 
and magnesium immediately.
Report to Sponsor as AE 
(unless it meets the SAE 
criteria as described in 
Section 7.2.1) and transmit to 
eRT immediately for prompt 
review.


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Protocol No. CKAF156A2202
16
Appendix 4: Renal Alert Criteria and Actions
Table 16-1
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 ≥150 mg/g or > 15 
mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment discontinuation 
New dipstick hematuria ≥1+ not due to trauma
or menstruation
Urine sediment microscopy
Perform serum creatinine, ACR 
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.


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17
Appendix 5: 
Table 17-1
Part A: KAF156 and LUM-SDF dosing scheme in case KAF156 relative 
exposure factor in PK Run-in vs. the reference mean AUC0-24h (4930 
ng*h/mL) is <1.4
Cohort
Treatment
Dose (mg)
Dosing regimen
Daily dosing based on 
available strengths
1
KAF156
LUM-SDF
400
960
QD 1 day
4 x 100 mg or 2 x 200 mg
2 sachets
2
KAF156
LUM-SDF
800
960
QD 1 day
8 x 100 mg or 4 x 200 mg
2 sachets
3
KAF156
LUM-SDF
400
960
QD 2 days
4 x 100 mg or 2 x 200 mg
2 sachets
4
KAF156
LUM-SDF
200
480
QD 3 days
2 x 100 mg or 1 x 200 mg
1 sachet
5
KAF156
LUM-SDF
400
480
QD 3 days
4 x 100 mg or 2 x 200 mg
1 sachet
6
KAF156
LUM-SDF
400
960
QD 3 days
4 x 100 mg or 2 x 200 mg
2 sachets
Table 17-2
Part A: KAF156 and LUM-SDF dosing scheme in case KAF156 relative 
exposure factor in PK Run-in vs. the reference mean AUC0-24h (4930 
ng*h/mL) is ≥1.4 to <1.8
Cohort
Treatment
Dose (mg)
Dosing regimen
Daily dosing based on 
available strengths
1
KAF156
LUM-SDF
300
960
QD 1 day
3 x 100 mg
2 sachets
2
KAF156
LUM-SDF
600
960
QD 1 day
6 x 100 mg or 3 x 200 mg
2 sachets
3
KAF156
LUM-SDF
300
960
QD 2 days
3 x 100 mg
2 sachets
4
KAF156
LUM-SDF
150
480
QD 3 days
3 x 50 mg 
1 sachet
5
KAF156
LUM-SDF
300
480
QD 3 days
3 x 100 mg
1 sachet
6
KAF156
LUM-SDF
300
960
QD 3 days
3 x 100 mg
2 sachets


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Protocol No. CKAF156A2202
Table 17-3
Part A: KAF156 and LUM-SDF dosing scheme in case KAF156 relative 
exposure factor in PK Run-in vs. the reference mean AUC0-24h (4930 
ng*h/mL) is ≥1.8 to <2.5
Cohort
Treatment
Dose (mg)
Dosing regimen
Daily dosing based on 
available strengths
1
KAF156
LUM-SDF
200
960
QD 1 day
2 x 100 mg or 1 x 200 mg
2 sachets
2
KAF156
LUM-SDF
400
960
QD 1 day
4 x 100 mg or 2 x 200 mg
2 sachets
3
KAF156
LUM-SDF
200
960
QD 2 days
2 x 100 mg or 1 x 200 mg
2 sachets
4
KAF156
LUM-SDF
100
480
QD 3 days
2 x 50 mg or 1 x 100 mg
1 sachet
5
KAF156
LUM-SDF
200
480
QD 3 days
2 x 100 mg or 1 x 200 mg
1 sachet
6
KAF156
LUM-SDF
200
960
QD 3 days
2 x 100 mg or 1 x 200 mg
2 sachets
Table 17-4
Part A: KAF156 and LUM-SDF dosing scheme in case KAF156 relative 
exposure factor in PK Run-in vs. the reference mean AUC0-24h (4930 
ng*h/mL) is ≥2.5 to 4
Cohort
Treatment
Dose (mg)
Dosing regimen
Daily dosing based on 
available strengths
1
KAF156
LUM-SDF
100
960
QD 1 day
2 x 50 mg or 1 x 100 mg
2 sachets
2
KAF156
LUM-SDF
200
960
QD 1 day
2 x 100 mg or 1 x 200 mg 
2 sachets
3
KAF156
LUM-SDF
100
960
QD 2 days
2 x 50 mg or 1 x 100 mg
2 sachets
4
KAF156
LUM-SDF
50
480
QD 3 days
1 x 50 mg
1 sachet
5
KAF156
LUM-SDF
100
480
QD 3 days
2 x 50 mg or 1 x 100 mg
1 sachet
6
KAF156
LUM-SDF
100
960
QD 3 days
2 x 50 mg or 1 x 100 mg
2 sachets

SAP_001.pdf: 
Global Clinical Development - General Medicine
KAF156
CKAF156A2202 / NCT03167242
A Phase 2 interventional, multicenter, randomized 
open-label study to determine the effective and tolerable 
dose of KAF156 and Lumefantrine Solid Dispersion 
Formulation in combination, given once daily for 1, 2 and 
3-days to adults and children with uncomplicated
Plasmodium falciparum malaria
Statistical Analysis Plan (SAP) Addendum
Author:
Trial Statistician, 
; 
Document type:
SAP Documentation
Document status:
Final 3.0
Release date:
8-November-2021
Number of pages:
61
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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CKAF156A2202
Document History – Changes compared to previous final version of SAP
Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
28-
May-
2017
final 
in 
CREDI
N/A
N/A - First version
N/A
02-
Jul-
2018
Amendment 
1
Updates during 
Mock 
shell 
finalization
Tail of KM plots
Definition of treatment failure 
and ACPR: Only  P. falciparum 
asexual form is used 
Section 2.1.1
Subgroup categories defined in 
one section only
Section 2.2.1, 
2.7.2.6
Weight categroies define for 
each part separately. Body 
temperature using other than 
axilarry
Section 2.3.2
Censoring rule for Patients 
reinfected with other species 
than P. falciparum added
Section 
2.5.4.2
Shift tables of LAB are deleted
Section 2.8.2
 
09-
Aug-
2018
Amendment 
2
Updated prior to 
interim dry run
Worst 
assessment 
will 
be 
selected for efficacy if multiple 
assessment 
within 
a 
visit 
window
Make 
axillary 
equivalent 
temperature 
by 
subtracting 
0.50C from a value and cut off 
as 38.0 0C for different routes  
Closest assessment will be 
selected for efficacy variables
Section 5.1.4
All applicable 
section 
Section 5.1.4
Section 2.2


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Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
15-
Oct-
18
6-
Nov-
18
6-
Nov-
18
3-
Jan-
19
No direct SAS 
procedure 
is 
available 
for 
calculating the 
treatment 
difference 
and 
95% CI for K-M 
estimate
Tables 
using 
summary 
of 
change 
from 
baseline in ECG 
variables 
is 
removed
To consider the 
partial
dosing 
for calculating 
the compliance
Handling 
Lab 
values
beyond 
detection limit
Length exceeds 
the limit
To be consistent 
with conversion 
of 
body 
temperature 
from axillary to 
other routes
Compliance 
is 
on full doses
Clarified PPS - Valid PCR 
assessment required for late 
treatment failures between Day 
8 and Day 29 
Clarification is added
Note is added
Section 
2.5.4.2 
is 
updated
Section 2.8.3
Section 2.4.1
Section 2.8.2


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CKAF156A2202
Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
7-1-
2019
Section 2.1.1 is updated for the 
treatment header for PK run in 
cohort
Section 2.3.2 is updated for 
Body   temperature categories
Compliance definition is further 
clarified
Section 2.1.1
Section 2.3.2
Sction 2.4.1
11-
01-
2019
LAB 
notable 
abnormality 
criterion 
to 
matched 
with 
standard 
templates
Table 2-2 updated to include 
additional notable criterion 
Section 2.8.2
13-
02-
2019
20-
02-
2019
Post 
Dry 
run 2
Post 
Dry 
run 2
To allow the 
possibility 
for 
patients 
with
late 
parasite 
clearance 
or 
missing data on 
Days 8, 9, or 15 
to be classified 
as 
cured 
(clinical 
success)
Due 
to 
the 
multiple 
assessments/day  
in 
treatment 
Removed the condition that the 
parasite must be cleared by Day 
7. Accordingly, changed the 
condition for the analyses of 
recrudescence and reinfection at 
Days 15, 29, and 43 from 
“parasite clearnce by Day 7” to 
“parasite clearance before Day 
15”. 
Study day     calculation is based 
on dosing date and time during 
treatment period 
Sections 
2.1.1, 
2.5.4, 
2.7.2
Section 2.1


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Date
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Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
26-
02-
2019
5-03-
2019
10-
03-
2019
27-
03-
2021
Post dry run 
2
Post dry run 
2
Post dry run 
2
Before final 
DBL
period the study 
day calulcation 
is updated
PD 
ID 
INCL01B 
corresponds to 
ascent form for 
adolescent 
patients 
have 
been retired 
Ngeative 
PCR 
results 
for 
positive 
blood 
smear sample
Exclude 
the 
patients 
from 
PPS
received 
non antimalarial 
drugs 
which 
may impact on 
efficacy. 
Exclude 
patients having 
compliance 
<80% from PK 
set
PD ID is removed from the 
criterion for exclusion from the 
randomized set
Negative PCR will categorize 
the patient as PCR corrected 
responder
Definition of PPS/PK SET and 
criterion for patients exclusion 
from PPS/ PKSET is updated
5-<10 kg category removed
Average daily dosage = sum of 
actual  doses taken in mg / 
planned number of days of 
treatment.
Section deleted
Table 5-10 is updated to clarify 
Section 5.7
2.1.1.2
2.2, 5.7
2.3.2
Patient
demographics 
and 
other 


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Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
20-
08-
21
30-
Oct-
21 
Post 
final 
DBL
All 
patients 
are >=10 Kgs. 
5-<10 
Kg 
category is not 
applicable 
Formula 
for 
average 
daily 
dose is revised 
using 
planned 
number of days
Imputation 
of 
missig 
prior/post 
therapies  dates 
is 
combined 
with 
the 
concomitant 
medication 
dates 
Anti 
malarial 
drugs between 
Day1 and Day 
29 should be 
changed prior to 
Day 
29 
to 
include Day 1
In Part A, 4 
patients with 
Age category of <12 years is 
added
 
 
Sensitivity analysis is added
Sensitivity analysis is added
baseline 
characteristics
2.4.1
Study 
treatment 
/ 
compliance
5.13.1
and 
5.1.3.2
Prior 
and 
post 
therapies 
dates 
imputation
5.7
Rule of 
exclusion  
criteria 
of 
analysis sets
Section 2.3.2 
Patient
demographics 
and 
other 
baseline 
characteristics
Section 2.2.1,
Subgroup of 
interest
Section 2.3.2 
Patient 
demographics 
and 
other 
baseline 
characteristics


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Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
age <12 years 
were recruited
Replace patients 
with patients
 
 
 
 
 
 
 
To assess the 
impact 
of 
administration 
non-study 
antimalarial 
drugs 
on 
the 
PCR 
uncorrected 
response rate at 
D29
To assess the 
impact of new 
infections on the 
PCR corrected 
ACPR rate at 
D29
 
 
2.7.2.2
Treat
ment 
failure 
related 
parameters
2.5.4
Suppo
rtive analyses


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Table of contents
Table of contents .................................................................................................................8
List of tables ........................................................................................................................9
List of abbreviations..........................................................................................................11
1
Introduction .......................................................................................................................12
1.1
Study design...........................................................................................................12
1.2
Study objectives and endpoints .............................................................................16
2
Statistical methods.............................................................................................................17
2.1
Data analysis general information .........................................................................17
2.1.1
General definitions................................................................................18
2.2
Analysis sets ..........................................................................................................21
2.2.1
Subgroup of interest ..............................................................................22
2.3
Patient disposition, demographics and other baseline characteristics ...................23
2.3.1
Medical history......................................................................................23
2.3.2
Patient demographics and other baseline characteristics ......................23
2.3.3
Patient disposition.................................................................................24
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................24
2.4.1
Study treatment / compliance................................................................24
2.4.2
Prior, concomitant and post therapies...................................................25
2.5
Analysis of the primary objective..........................................................................26
2.5.1
Primary endpoint...................................................................................26
2.5.2
Statistical hypothesis, model, and method of analysis..........................26
2.5.3
Handling of missing values/censoring/discontinuations for primary 
endpoint analysis...................................................................................26
2.5.4
Supportive analyses...............................................................................26
2.6
Analysis of the key secondary objective ...............................................................29
2.7
Analysis of secondary efficacy objective(s)..........................................................29
2.7.1
Secondary endpoints .............................................................................29
2.7.2
Statistical hypothesis, model, and method of analysis..........................30
2.8
Safety analyses.......................................................................................................33
2.8.1
Adverse events (AEs)............................................................................33
2.8.2
Laboratory data .....................................................................................38
2.8.3
Other safety data ...................................................................................39
2.9
Pharmacokinetic endpoints....................................................................................41
2.10
PD 
 analyses.........................................................................................42


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2.11
Patient-reported outcomes .....................................................................................42
42
.42
2.14
Overview of analysis methods...............................................................................44
2.15
Interim analysis......................................................................................................47
3
Sample size calculation .....................................................................................................48
4
Change to protocol specified analyses ..............................................................................51
5
Appendix ...........................................................................................................................51
5.1
Imputation rules.....................................................................................................51
5.1.1
Study drug.............................................................................................51
5.1.2
AE date imputation ...............................................................................51
5.1.3
Concomitant medication/non-drug therapy date imputation.................52
5.1.4
Visit windows........................................................................................53
5.2
Non-study drug antimalarials ................................................................................56
5.3
Prohibited medications ..........................................................................................57
5.4
AEs coding/grading ...............................................................................................58
5.5
Laboratory parameters derivations ........................................................................58
5.6
Statistical models...................................................................................................59
5.6.1
Primary analysis....................................................................................59
5.6.2
Key secondary analysis.........................................................................59
59
5.7
Rule of exclusion criteria of analysis sets..............................................................60
6
Reference...........................................................................................................................61
List of tables
Table 1-1
Objectives and related endpoints (PK Run-in Part, Part A and Part 
B)...........................................................................................................16
Table 2-1 List of safety topics of interest.................................................................................35
Table 2-2
Liver-related events...............................................................................38
Table 2-3
Normal heart rates (resting) by age.......................................................40
Table 2-4
Criteria for notable vital sign abnormalities..........................................41
Table 2-5
Normal blood pressure by age...............................................................41
Table 2-6
Overview of analysis methods for baseline data and efficacy 
variables ................................................................................................45
Table 2-7
Overview of analysis methods for safety/PK variables ........................47
Table 2-8
Specification of data outputs for DMC data review..............................48


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Table 3-1
Sample size and width of 2-sided 90% CI for log AUC0_24h and log 
Cmax .....................................................................................................49
Table 5-1
AE/Treatment Date Abbreviations........................................................51
Table 5-2
Imputation algorithm.............................................................................52
Table 5-3
Imputation algorithm legends ...............................................................52
Table 5-4
Example scenarios.................................................................................52
Table 5-5
Analysis visit windows based on study days alone..............................54
Table 5-6
Analysis visit windows based on study day and time..........................55
Table 5-7
Rules for flagging variables ..................................................................56
Table 5-8
Table of non-study drug antimalarials with respective ATC codes......56
Table 5-9
Prohibited medication with respective ATC codes...............................57
Table 5-10
Protocol deviations and non-PD criteria leading to exclusion from 
analysis sets...........................................................................................60


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List of abbreviations
AE
Adverse event
ACPR
Adequate clinical and parasitological response
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
DBL
Data base lock
ETF
Early treatment failure
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
LCF
Late clinical failure
L.O.S.
Level of significance
LPF
Late parasitalogical failure
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
PK
Pharmacokinetics
PPS
Per-Protocol Set
qd
Qua’que di’e / once a day
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
The purpose of Statistical Analysis Plan (SAP), is to describe the implementation of the 
statistical analysis which is planned in the protocol. The study has three parts: PK Run-in Part, 
Part A, and Part B. A single database for run-in part and Part A will be locked after the last 
patient last visit (LPLV) in Part A and before the first patient first visit (FPFV) in Part B. The 
interim assessment in Part A will be performed and is outlined in section 2.15 below. The 
clinical study report will be prepared after the final database lock (DBL) at the end of Part B on 
the basis of this SAP. This single SAP will be used for the analysis of data collected for the run-
in part, Part A, Part B, and the pooled analysis of Part A and Part B together. A separate analysis 
plan will be prepared and executed by 
 for DMCs based on this SAP.
1.1
Study design
This will be a multicenter, open-label, randomized, parallel-group study in adults and children 
with confirmed and uncomplicated P. falciparum malaria. 
The study has a PK Run-in Part and two subsequent parts: Part A and Part B.
PK Run-in Part:
Male and female adult/adolescent patients (≥ 12 years old and ≥ 35.0 kg) will be enrolled in the 
PK Run-in Part. 12 patients will be dosed with a single dose of 200 mg KAF156 and 960 mg 
LUM-SDF. Study procedures and assessments are the same as in the 1-day cohorts in Part A 
with rich PK.
Interim assessment after PK Run-in Part
For the patients in the PK Run-in KAF156 200 mg/LUM-SDF 960 mg cohort, PK analyses will 
be performed on the samples collected in the first 24 hours. The results will trigger the start of 
Part A with dosing as planned, or lead to a dose adaptation in Part A in case an interaction is 
shown between LUM-SDF and KAF156.
Part A:
Approximately 325 male and female adult/adolescent patients (≥ 12 years old and ≥ 35.0 kg) 
will be enrolled in Part A of the study.
At screening, eligible patients will be randomized into one of the seven cohorts, i.e., six 
KAF156 and LUM-SDF dose combinations and a control arm (see Figure 1-1), in 2:2:2:2:2:2:1 
ratios:

Cohort 1: KAF156 400 mg and LUM-SDF 960 mg once daily (QD) for 1 day

Cohort 2: KAF156 800 mg and LUM-SDF 960 mg QD for 1 day

Cohort 3: KAF156 400 mg and LUM-SDF 960 mg QD for 2 days

Cohort 4: KAF156 200 mg and LUM-SDF 480 mg QD for 3 days

Cohort 5: KAF156 400 mg and LUM-SDF 480 mg QD for 3 days

Cohort 6: KAF156 400 mg and LUM-SDF 960 mg QD for 3 days


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
Cohort 7: Coartem®  twice a day (BID) for 3 days (dosing as per product label)
Randomization will be stratified by country in Part A. 
Patients will be admitted to the hospital on Day 1. They will be dosed on either a) Day 1 alone 
or b) Days 1 and 2 or c) Days 1, 2 and 3 depending on the assigned study arm, and will remain 
in the hospital under close supervision until they are discharged by the investigator or designee 
on Day 4. At the discretion of the investigator, patients may stay additional days if needed. The 
patients will then be followed up at Days 5, 8, 15, 29 (primary analysis time point), and 43. 
Visits to assess safety and efficacy will be scheduled during the follow-up period as described 
in the schedule of assessments tables (Table 6-1, through Table 6-4) in the protocol. If malaria 
symptoms re-emerge outside the scheduled study visits, patients will be instructed to contact 
the investigator.
Rich pharmacokinetic (PK) sampling will be done in 6 patients each in Cohorts 1-4 and 6, and 
in 12 patients in Cohort 5 (see protocol Table 6-3), and sparse PK sampling will be done in the 
rest of the patients as well as in Cohort 7 (see protocol Table 6-4).
Interim assessment after Part A:
Upon completion of Part A, all the dosing groups will be evaluated in an interim assessment 
(IA) to determine the effective and tolerated KAF156/LUM-SDF dose combination for 3 days 
and for 1 to 2 days. The IA will be performed on selected endpoints which include, Polymerase 
Chain Reaction (PCR) corrected and uncorrected adequate clinical and parasitological response 
(ACPR) at Day 29, KAF156 and LUM-SDF blood exposures, incidence of adverse events 
(AEs), QTc, laboratory abnormalities, serious adverse events (SAEs), or any other endpoints
that are deemed important for the IA. Dosing regimen and dosages in Part B will be informed 
by results from Part A.
Part B:
Approximately up to 175 children (2 to < 12 years old and ≥ 10.0 kg) with uncomplicated 
P. falciparum malaria will be randomized to up to three KAF156 and LUM-SDF dose 
combinations and the control arm in 2:1 ratios (2 patients for each KAF156 and LUM-SDF 
dose combination and 1 patient for control) depending on the outcome of the interim assessment 
in Part A. 
Randomization will be stratified by country and age category at screening in Part B (2 to < 6, 6 
to < 12 years).
Eligible patients will be enrolled into one out of the up to four dosing cohorts, i.e., up to three 
investigational drug dosing arms and a control arm (see protocol Figure 1-1). Dosing will be 
adjusted based on children’s body weight similar to the adjustment of Coartem®.

KAF156 and LUM-SDF: up to 3 cohorts selected depending on the outcome of Part A

Coartem® BID for 3 days
Before fully enrolling patients in Part B, 4-6 children in the age range of 6 to < 12 years will be 
enrolled first in Part B to confirm that KAF156 and LUM-SDF PK/drug exposure is consistent 


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with Part A and that the assumption in dosing is correct in these cohorts. Following confirmation 
of drug exposure in these children, the additional patients will be included in Part B of the study.
Study design, procedures and assessments are the same in Part A and Part B as described in 
Section 6 in the protocol.
The safety of entire study will be monitored by an Independent Data Monitoring Committee 
(DMC).


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Figure 1-1
Study design


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1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints (PK Run-in Part, Part A and Part B)
Objective(s)
Endpoint (s)
Primary Objective(s)

To determine the effective doses of 
KAF156 combined with LUM-SDF given 
daily over 1, 2 or 3 days for treatment of 
uncomplicated malaria caused by P. 
falciparum.
Endpoint(s) for primary objective(s)  

PCR-corrected adequate clinical and 
parasitological response (ACPR) at Day 
29 (i.e., 28 days post-dose) in Parts A 
and B.

Assessments of KAF156 exposure in the 
PK Run-in cohort to understand the 
impact 
of 
LUM-SDF 
on 
KAF156 
exposure.
Secondary Objective(s) 

To evaluate the safety and tolerability of 
KAF156/LUM-SDF.
Endpoint(s) for secondary objective(s)

Standard 
safety/tolerability 
assessments: AE incidence and severity, 
liver and kidney function tests and 
electrocardiogram (ECG) abnormalities.

To further assess the effect of treatment 
with KAF156/LUM-SDF by assessing 
uncorrected ACPR and corrected ACPR 
at additional time points, as well as fever-
and parasite clearance times.

PCR-Uncorrected ACPR at Days 15, 29 
and 43 (i.e., 14, 28 and 42 days post-
dose).

PCR-corrected ACPR at Days 15 and 43 
(i.e., 14 and 42 days post-dose).

Incidence rate of recrudescence and new 
infection at Days 15, 29 and 43.

Parasite Clearance time and Fever 
Clearance Times (PCT and FCT).

Proportion of patients with parasitemia at 
12, 24, and 48 hours after treatment.

To assess the key PK parameters of 
KAF156 and lumefantrine.

PK assessments.


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2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by Novartis for the interim assessment and after final DBL using SAS 
version 9.4 according to the data analysis presented in section 9 of the study protocol which is 
also available in Appendix 16.1.1 of the CSR.  Important information is given in the following 
sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR.
Statistical analyses for PK run-in cohort, Part A, and Part B will be performed separately. For 
key efficacy and safety outcomes, pooled analysis will be performed by pooling Part B with 
corresponding cohorts in Part A to determine which KAF156 and LUM-SDF dose combination 
can be carried forward to Phase 3 studies. Unless described separately otherwise, the same 
statistical method will be used for separate analysis and pooled analysis.
For each cohort in Part B, a corresponding cohort in Part A will exist with matching dose and 
regimen. For statistical analyses and clinical study reporting, treatment group name (see Section 
2.1.1), instead of cohort number, will be used for both parts and the pooled analysis which will 
include only those treatment groups with patients in both parts.
Data analyses required for the study Data Monitoring Committee (DMC) will be analyzed by 
the third party vendor 
. The outline of the DMC analysis plan is presented in the 
DMC charter and will be detailed in a separate SAP based on this SAP. 
Information on visit windowing, 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: DMC meetings, planned interim 
analysis, 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.


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Unless otherwise stated, p-values will be provided for two-sided alternative hypotheses and 
presented up to 4 significant digits after decimal place; confidence intervals will be presented 
up to 2 significant digits after decimal place. 
Although randomization is stratified by country in part A and stratified by country and age 
category in part B, statistical analysis will not be stratified accordingly due to small sample 
sizes in each country/age category.  For pooled analyses, study part (part A, part B) will be used 
as stratum.
2.1.1
General definitions 
Study treatment: KAF156, Lumefantrine solid dispersion formulation (LUM-SDF), and 
Coartem®. KAF156 and LUM-SDF are part of investigation treatments whereas Coartem® will 
be served as control. They are referred to as study treatments in the document.
Treatment group name, instead of cohort number, will be used in statistical analyses and outputs. 
The following abbreviated treatment groups will be used as the headers in the CSR outputs:

KAF200 mg/LUM960 mg-1D (for PK run-in part) or KAF200 mg/LUM960 mg-1D in 
case the description is too long

KAF400 mg/LUM960 mg-1D

KAF800 mg/LUM960 mg-1D

KAF400 mg/LUM960 mg-2D

KAF200 mg/LUM480 mg-3D

KAF400 mg/LUM480 mg-3D

KAF400 mg/LUM960 mg-3D

Coartem
Baseline: The last measurement made prior to administration of the first dose of study treatment. 
Note this may include measurements taken on the day of randomization (e.g. lab, ECG, vitals). 
If a patient did not receive any dose of study treatment then the date at 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. Due to the multiple assessments collecetd more than 
once for a day in the treatment phase for some variables, the study day calulcation is based on 
the treatment start date and time.
For the assessments that are performed more than once for a day:
On or after Day 1 up to Day 3, study day =Integer (datetime of assessment – datetime of 
first dose of study treatment)/(60*60*24) + 1.
For assessments collected  after Day 3, study day =date of assessment – date of first dose 
of study treatment + 1.


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For assessments that are performed once for a day: 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.
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 reset to planned last 
day regardless of censoring.
2.1.1.1
Definition of treatment failures
Early Treatment Failures (ETF)
Patient will be classified as ETF upon meeting any of the following criterion

Development of danger signs or severe malaria on Day 2, Day 3, Day 4 in the presence of 
parasitemia.

Parasitemia on Day 3 higher than Day 1 count irrespective of axillary temperature.

Parasitemia on Day 4 with axillary temperature ≥ 37.5°C.

Parasitemia on Day 4 equals to or more than 25% of count on Day 1.
Late Clinical Failure (LCF)
Patient will be classified as LCF upon meeting any of the following criterion

Development of danger signs or severe malaria on any day from Day 5 to Day 43 in the 
presence of parasitemia without previously meeting any of the criteria of early treatment 
failure.

Presence of parasitemia and axillary temperature ≥ 37.5oC on any day from Day 5 to Day 43 
without previously meeting any of the criteria of Early Treatment Failure.
Late Parasitological Failure (LPF)

Presence of parasitemia on any day from Day 8 to Day 43 and axillary temperature < 37.5oC 
without previously meeting any of the criteria of Early Treatment Failure or Late Clinical 
Failure. Missing body temperature assessment in presence of parasitemia will be classified 
as LCF.
Note: If the temperature is measured using other routes, such as oral/tympanic/rectal, the 
corresponsding threshold for fever is 38.0oC. Danger signs or severe malaria is recorded as 
adverse events. The adverse event start date of danger signs or severe malaria will be used in 
the determination of ETF and LCF. Only P. Falciparum asexual form is used for 
parasitemia/parasite in the assssments of treatment failure and ACPR in Section 2.1.1.2 below.
The body temperature assessment closest to the blood smear assessment date will be used. 


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2.1.1.2
Definition of ACPRs
Uncorrected ACPR at Day X where X=15, 29, or 43

A patient is considered as non-responder at Day X if the patient experiences an ETF,  LCF
from Day 5 to Day X, or LPF from Day 8 to Day X. 

A patient is also considered as non-responder if the parasite is not cleared  by Day X unless 
the patient discontinues the study prior to Day X without ETF or LCF or LPF, in which case 
the response is considered as missing.

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 parasite 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, 29, or 43

A patient is considered as non-responder at Day X if the patient experiences an ETF or LCF
from Day 5 to Day 7. 

A patient is also considered as non-responder if the parasite is not cleared by Day X unless 
the patient discontinues the study prior to Day X without ETF or 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 or negative results 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 parasite at 
Day X or later if Day X is missing.

The response for a patient is considered as missing/undertermined if  

The patient, not classified as non-responder at Day X, has parasite 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 


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failure, late clinical failure or late parasitological failure. With this notation, ACPR rate is the 
proportion of responders.
Recurrence of parasitemia after 7 days is considered as non-responder for uncorrected 
ACPR. We reclassify such patient as responder for PCR-corrected ACPR if recurrence of 
parasitemia after 7 days is due to new infection. Whether the recurrence of parasitemia after 7 
days is due to recrudescence or new infection is determined and provided by the central 
laboratory. Negative PCR will catgeorize the patient as PCR corrected responder.
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 
responses may be overriden for patients who take concomitant anti-malaria drugs (see Sections 
2.5 and 2.7). 
Fever Clearance is defined (in patients with axillary temperature of >= 37.5°C at baseline) as 
the time of the first measurement of at least 2 consecutive axillary temperatures of < 37.5°C (or 
< 38.0°C for alternative routes) measured at least 24 hours apart.
Time to parasite clearance (PCT) is 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
All patients who are enrolled in the PK run-in cohort or randomized in Parts A and B. Unless 
otherwise specified, misrandomized patients will be excluded from the randomized set. For the 
PK run-in part, this set includes all patients with informed consent and treated with study 
medication.
Misrandomized patients, if identified from IRT, include patients who are screen-failures, but 
have been randomized by the investigator before eligibility was finally assessed or mistakenly, 
and  have not been treated. If patients were re-screened and successfully randomized, they will 
be included in the randomized set according to the treatment assigned in the last randomization.
Note: There is no randomization in the PK run-in cohort. For this cohort, the more appropriate 
terminology is “Enrolled set”. However, ‘Randomized set’ is used for simplicity.  
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 P. Falciparum asexual  parasitemia
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) 
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. In particular, patient will be 


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analyzed in the same treatment group as randomized if s/he receives at least one dose of the 
study medication of that group.
Per-protocol set (PPS) 
Per-protocol set will be comprised of patients in FAS who

did not have any important protocol deviations

took at least 80% of randomized 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. Since a partial compliance, such as 83%, etc., can be calculated based on the 
actual dosage taken (see Section 2.4.1), this allows patients assigned to KAF156 and LUM-
SDF arms to take partial dosages which slightly deviates from the protocol. 

did not take non-study drug antimalarial medications prior  to Day 29 unless experiencing 
any treatment failure (ETF, LCF, LPF) (e.g new infections between Day 8 and Day 29), and

met at least one of the following criteria: (a) classified as treatment failure (including 
parasite not cleared) before Day 8 (see Section 2.1.1), (b) absent from parasitemia at Day 
29 or later, (c) had valid PCR evaluations at baseline and at the time point with parasitemia
using malaria blood film if parasitemia is present between Day 8 and Day 29, or (d) had 
parasitemia present  on Day 8 or later without parasite clearance before Day 8.
Important protocol deviations for exclusion from PPS are specified in Table 5-9 and will be 
identified by the clinical team before database lock for each part.
PK analysis set 
All patients in the safety analysis set who had evaluable pharmacokinetic parameter data and 
with at least 80% compliance to study medication and did not receive the concomitant prohibited 
medication  which found to be change in the exposure that impacts interaction in PK parameters. 
2.2.1
Subgroup of interest
The following subgroups will be used for descriptive summary of the selected efficacy and 
safety analyses . The details will be provided in the corresponding sections.

Age groups as per section 2.3

Baseline weight groups as per section 2.3

Sex (male vs female)

Region


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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 system organ class (SOC) 
and preferred term (PT) of the MedDRA dictionary. 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 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 medical history or 
medical history possibly contributing to liver dysfunction” will be tabulated separately.
History of use of alcohol will also be provided.
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 descriptively presented and 
tabulated per treatment group, as well as overall, using randomized set and PPS. If many 
patients are excluded from randomized set, summary will also be provided for the FAS.
Following demographic variables will be summarized

Age and age categories (for Part B: 2 to <6, 6 to <12 ; for PK run-in cohort and and Part A: 
<12, 12 to <18,  18 to <65, and ≥ 65, <18 vs ≥18 yrs ) 

Sex (male, female)

Patient child bearing status (able to bear children, premenarche, post menopausal, sterile of 
child bearing age)

Race (Caucasian, black, Asian, native american, pacific islander, unknown, other)

Ethnicity

Body weight and weight categories (  <35, 35 to <75 and >=75 kg  for Part A and PK run-
in cohort); (10 to <15, 15 to <25, 25 to <35 and  >= 35 kg for Part B);( <15 , 15 to <25, 25 
to <35, 35 to 75, >75 kg for Parts A+B)

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 categories (<37.5, 37.5 to <39, ≥39 ) (°C) for (axillary)  and < 38.0°C,  
38.0 to 39.5, ≥ 39.5 for other routes)


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
Falciparum species: (P. Falciparum asexual forms, P. Falciparum gametocytes, P. Vivax, P. 
Ovale, P. malariae, P. Knowlesi, and Mixed-infection , n (%)) 

P. falciparum density per micro ltr. and its categories (<1,000, 1,000 to <2,000, 2,000 to 
<5,000, 5,000 to <15,000, 15,000 to <50,000, 50,000 to <100,000, 100,000 to 
<150,000, >=150,000 parasites/µL; <100,000 /μL,  ≥100,000 parasites /μL)

Gametocytes counts /μL. 
2.3.3
Patient disposition
The number  of patients who screened and screening failures will be presented. In addition, the 
reasons for screen failures will be provided. The number and percent of patients who completed 
each epoch (treatment and follow up) and who discontinued each epoch prematurely (including 
the reason for discontinuation) will be presented for each treatment group and overall.  
For each protocol deviation, the number and percent 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 percent of doses taken will be presented by treatment group and drug (KAF156, 
LUM-SDF, or Coartem®). 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  3 for ‘KAF156 400 mg and LUM-SDF 480 mg QD 
for 3 days’ group, 6 for Coartem, etc.
In the percent calculation for KAF156/LUM-SDF based treatment groups, patient is considered 
to be dosed if s/he took any study drug regardless of vomiting or not. 
Percent of doses taken (i.e. compliance) on a day will be calculated as actual  dose administered 
/planned   dose x 100% capped at 100% (if a compliance on a given day exceeds 100%, use 
100%). Average compliance for a study drug will be calcualted as sum of the compliance for 
all days and divide by the number of day’s. For KAF/LUM, compliance for combined dose will 
be the average compliance of both drugs. 
In addition, percent of full doses taken will be calculated as actual number of full doses 
administered /planned  number of doses x 100% where a patient is considered to be fully dosed 
if s/he took all study drug(s) in full dose.
Compliance will be categorized by < 80 % and >=80 % of full doses taken and summarized by 
treatment group.


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Number and percent 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  (KAF156, LUM-SDF, 
Artemether,  Lumefantrine) will be summarized by treatment group. If a patient vomited the 
original dose and took a replacement dose, the replacement dose will be used to calculate the 
average. 
Average daily dosage = sum of actual  doses taken in mg / planned number of days of treatment. 
For Coartem, the tablets taken by the patient are converted into mg based on the strength of 
tablet.
Note- If a patient vomited the original dose but did not vomit the replacement dose, the patient
is considered as fully dosed. If a patient vomited the original dose and did not have a 
replacement dose or vomited both the original dose and the replacement dose, the patient is not 
considered as fully dosed. 
Safety set will be used.
2.4.2
Prior, concomitant and post therapies
Prior and concomitant medications will be summarized in separate tables by treatment group.
Concomitant rescue and other anti-malarial medications will also be summarized by treatment 
group.
Note – rescue medications and non-study antimalarial drugs are the same. If they are used after 
discontinuation of study drug due to early treatment failure, late clinical failure or late 
parasitological failure then they should be considered as resue medications, otherwise, they are 
considered as other non-study drug antimalarial medications. Rescue medications will be 
captured along with other concomitant medications by the investigators under rescue 
medication category.
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 treatment by ATC class 
and preferred term (PT).
Number and percentages of the patients received prohibited prior and concomitant drugs will 
be summarized
Safety set will be used.


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2.5
Analysis of the primary objective
The PK Run-in Part will be separately analyzed. The primary objective for the part is to 
investigate the pharmacokinetic interaction potential between KAF156 and LUM-SDF. The 
analyses of PK parameters of KAF156 and LUM-SDF are detailed in Section 2.9.
The primary efficacy objective in Part A is to determine the effective dose of KAF156 combined 
with LUM-SDF given daily over 1, 2, 3 days for treatment of uncomplicated malaria caused by 
P. falciparum in adults/adolescents. If there are multiple KAF156 and LUM-SDF dose 
combinations that are effective, tolerable and safe, the most effective dose combination(s) in 
the less frequent 1 to 2 days regimen and the most effective dose combination(s) in the 3 days 
regimen will be carried over to Part B. Up to 3 KAF156 and LUM-SDF dose combinations may 
be carried over to Part B.
The primary efficacy objective in Part B is to determine if the selected dose combination 
regimens (adjusted for body weight) from Part A are effective in children down to 2 years.
2.5.1
Primary endpoint
The primary efficacy variable is the PCR corrected Adequate Clinical and Parasitological 
Response (ACPR) at Day 29 (see Section 2.1).
2.5.2
Statistical hypothesis, model, and method of analysis
The statistical null hypothesis is that the ACPR rate at Day 29 is at most 80% with the alternative 
hypothesis that the ACPR rate at Day 29 is greater than 80%. The statistical hypothesis will be 
evaluated using the lower limit of 2-sided 95% exact confidence interval (CI) (Pearson-Clopper 
method) for the ACPR rate at Day 29. If the lower limit of 2-sided 95% exact confidence 
interval for the ACPR rate at Day 29 is greater than 80%, the null hypothesis will be rejected. 
The statistical hypothesis testing will be evaluated separately for each KAF156 and LUM-SDF 
combination in each part based on the PPS. There is no adjustment for multiplicity since this is 
an exploratory study.
2.5.3
Handling of missing values/censoring/discontinuations for primary 
endpoint analysis
Parasite assessments obtained within the protocol specified visit window for Day 29 (Day 25 
to Day 33) will be considered as the assessment for Day 29.
No missing data are expected for the primary efficacy analysis based on PPS since patients who 
are not evaluable for the primary efficacy variable are excluded from PPS. See Section 2.5.4 
for missing data handling for the supportive analysis using FAS.
2.5.4
Supportive analyses
The primary efficacy variable will be performed based on the FAS using the statistical method 
specified in Section 2.5.2.
Primary efficacy variable will be handled additionally for those patients who are excluded from 
the PPS as follows:


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
Presence of parasitemia which cannot be determined to be  recrudescent or reinfection due 
to missing PCR data will be counted as non-responders (from the day of test)

Missing/undertermined responses at Day 29 due to missing blood smear data at the visit 
will be counted as non-responders 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 antmalarial drug. 

Note: These patients did not experience any treatment failure (ETF, LFT, or LPF). In 
case that non-PPS patients who experienced treatment failure, they will be included as 
non-responders if they received rescue medication for the treatment of P. falciparum 
malaria due to recrudescent  or as responder for PCR corrected ACPR if they received 
rescue medication for treatment of a new infection on Day 8 or later.  
For exploratory purpose, 2-sided 95% confidence intervals for the difference in ACPR at Day 
29 between each KAF156/LUM-SDF treatment group and Coartem® will be constructed using 
the Wilson uncorrected method.
Let 
a = # patients with responders in  investigational arm
c = # non-responders in investigational arm
m = sample size of investigational arm (a+c)
b = # responder in control arm
d = #  in control arm
n = sample size of control arm (b+d)
 =  −	  is the treatment difference

 =  
⁄
− 
   is estimated treatment difference 
where z is the standard normal deviate associated with 5% level of significance (l.o.s.) two 
sided. 


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In planned analysis of PCR corrected ACPR at Day 29, PCR corrected ACPR rate at Day 29 
was to be calculated by considering patients with new infections prior to Day 29 as PCR 
corrected ACPR.  In order to assess the impact of new infections on the PCR corrected ACPR 
rate, two sensitivity analysis will be performed. In the first analysis, PCR corrected ACPR rate 
will be recalculated by excluding the patients with new infections occurring prior to Day 27. It 
is seen that new infections were reported more on Day 29 visit compared to prior to Day 29 
visit. In another sensitivity analysis, patients with new infections occurring up to Day 29 will 
be excluded and PCR corrected ACPR rate will be recalculated in the remaining patients. 
Analyses will be based on Per-protocol set for PK Run-in, Part A and B.
2.5.4.1
Analysis of PCR-corrected ACPR rate 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 15, Day 43, 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 first time of 
the PCR that indicate the infection or blood smear with other species; 

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  parasites on or after Day 8.

other patients not classified as non-responder will be censored at the time of last parasitemia 
assessment.
A two-sided 95% CI for the difference in proportion of responders between each 
KAF156/LUM-SDF combination treatment group and Coartem® will be calculated based on 
the variance of individual proportion using the Greenwood formula.
2.5.4.2
Analysis of uncorrected ACPR rate 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) 


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Event = PCR-uncorrected non-responder during the study (same as at Day 15, Day 43, See 
Section 2.1). The event time is the first time when the patient becomes a non-responder without 
PCR-correction. If a patient parasite 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 cleared the initial infection by Day 7 and are re-infected with species different 
than P. Falciparum will be censored at the time of re-infection.

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.
An asymptotic two-sided 95% CI for the difference in proportion of responders between each 
KAF156/LUM-SDF combination treatment group and Coartem® will be calculated from the z-
test statistic distribution based on the variance of individual proportion using the Greenwood 
formula.
The confidence interval will be constructed as: (rk – rC) ± Zα/2 * SEd,
where,
rT = Kaplan-Meier estimate for the investigational group at time t,
rC = Kaplan-Meier estimate for the control group at time t,
SEd = √(SEk2+ SEC2),
SET = estimated standard error for the investigational group based on Greenwood’s formula,
SEC = estimated standard error for the control group based on Greenwood’s formula,
Zα/2
= z-statistic = probit(1-α/2) from a normal distribution function,
α = 0.05.
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)
2.7.1
Secondary endpoints
Secondary efficacy variables include:
1. PCR-corrected ACPR at Days 15 and 43;
2. Uncorrected ACPR at Days 15, 29, and 43;


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3. Proportion of patients with parasitemia at 12, 24, and 48 hours after treatment;
4. Time to parasite clearance (PCT), defined as time from the first dose until the first total and 
continued disappearance of (P. Falciparum) asexual parasite forms which remained at least 
a further 48 hours;
5. Time to fever clearance (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;
6. Proportion of patients with early treatment failure (ETF);
7. Proportion of patients with late clinical failure (LCF);
8. Proportion of patients with late parasitological failure (LPF);
9. Incidence rate of recrudescence and reinfection at Days 15, 29 and 43.
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, method of analysis, and 
handling of missing values/censoring/discontinuations 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 Pearson-
Clopper method for each treatment group.
Handling of missing values/censoring/discontinuations
Data will be handled as follows for ACPRs (PCR corrected or uncorrected):

Presence of parasitemia which were 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

Presence of parasitemia which cannot be determined to be recrudescent or reinfection due 
to missing PCR data will be counted as non-responders from the day of test

Missing/undertermined 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 antmalarial drug
In addition, PCR-corrected and uncorrected ACPR rate will be calculated and plotted using the 
Kaplan-Meier method for each treatment group in the FAS (see Section 2.5.4).


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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 using the Pearson-Clopper method:

proportion of patients with parasitemia at 12, 24, and 48 hours after treatment

proportion of patients with early treatment failure (ETF)

proportion of patients with late clinical failure (LCF)

proportion of patients with late parasitological failure (LPF)
The above parameters will be determined using the uncorrected asexual parasite counts.
In addition, 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 43 for LCF and LPF.
In planned analysis of PCR uncorrected ACPR at Day 29, administration of non-study 
antimalarial drugs without treatment failures was not considered. A sensitivity analysis will be 
performed to assess the impact of administration non-study antimalarial drugs on the PCR 
uncorrected response rate. Proportion of patients with PCR uncorrected ACPR at Day 29 with 
95% CI will be re-calculated by considering the patients receiving non-study antimalarial drugs 
if received before Day 29 without being treatment failures as non-responder using FAS for PK 
Run-in, Part A and B. Patients who received concomitant prohibited non-malaria medications 
with potential impact on efficacy/antimalarial activity (PROH01b) before the Day 29 visit
without being treatment failures will be considered as as non-responder also.
2.7.2.3
Parasite clearance time (PCT) and fever clearance time (FCT)
Descriptive statistics (mean, standard error, median, quartiles) will be presented using the 
Kaplan-Meier method. Kaplan-Meier curves will be provided.
PCT will be calculated based on uncorrected asexual 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. Patients who received any 
antimalarial medication (including rescue medication) before (parasite or fever) clearance will 
be censored at the first use of antimalarial medication. The difference between each test group 
and control will be evaluated using a log-rank test. Patients who did not experience a clearance 
will be censored at the time of last relevant assessment (parasite or fever). For the pooled 
analysis, the log-rank test will be stratified by Part.
2.7.2.4
Time to event analysis for 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. 


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Incidence rates of recrudescence at Days 15, 29 and 43 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 (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.Undertermined treatment failures due to 
missing PCR data will be considered as censored at the time of treatment failure. 
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 Days 15, 29 and 43 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 be censored at the time of last parasite 
assessment if a patient does not experience the event. Indetermite treatment failures due to 
missing PCR data will be considered as censored at the time of treatment failure.
2.7.2.6
Pooled efficacy analyses
PK run-in part will not be pooled in the pooled efficacy analysis. The following additional 
analyses will be performed on pooled Part A and Part B (and pooled PK run-in cohorts, if 
available):

For PCR corrected and uncorrected ACPR rates, the treatment differences versus control 
will be evaluated using a Mantel-Haenszel estimate of the common risk difference stratified 
by Part (see SAS manual version 13.2 Pages 2681-2682, 2014).

For PCT and FCT, the difference between each test group and control will be evaluated 
using a stratified log-rank test (stratified by part). 

In addition, between treatment differences among the following KAF156 and LUM-SDF 
combinations will be evaluated to support the contribution of individual component for Part 
A:

KAF800 mg/LUM 960 mg-1D vs KAF400 mg/LUM 960 mg-1D

KAF200 mg/LUM 480 mg-3D vs KAF400 mg/LUM 480 mg-3D

KAF800 mg/LUM 960 mg-1D vs KAF400 mg/LUM 960 mg-2D

KAF400 mg/LUM 960 mg-3D vs KAF400 mg/LUM 480 mg-3D


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PCR corrected/uncorrected ACPRs at Day 29, PCT, and FCT will be summarized descriptively 
by the following subgroups

Age groups as per section 2.3

Baseline Weight groups as per section 2.3

Sex (male vs female)

Region
2.8
Safety analyses
All safety analyses will be performed using the safety set. Safety data for PK run-in cohort will 
be summarized separately. Part A and Part B will be pooled for selected safety analysis.
2.8.1
Adverse events (AEs)
The number and percent 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 primary System Organ Class (SOC) and 
Preferred Term (PT). 
Adverse events will be summarized by presenting, for each  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 (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 threshold 
value z is set to 5 (%) but it may be updated following review of the dry run outputs.
Separate summaries will be provided for deaths, serious adverse events, severe malaria, other 
significant adverse events leading to treatment discontinuation and adverse events leading to 
dose adjustment. 
Serious adverse events in screening phase will be flagged in data listing due to rare frquency.
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.


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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 and SAEs pooled from Parts A and B will be summarized overall and for 
the following subgroups.

Age groups as per section 2.3

Baseline Weight groups as per section 2.3

Sex (male vs female)

Region
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 = KAF156
-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 percent of patients with these special AEs will be summarized. In addition, 
listings of related arverse events will be provided.
Newly occurring liver enzyme abnormalities and QTcF abnormalities will be summarized (see 
Sections 2.8.2 and 2.8.3.1) 


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Table 2-1 List of safety topics of interest


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Safety 
Topic 
Of Interest
SOC
Search Criteria Details
MedDRA 
Code
MedDRA Term
MedDRA 
Level
MedDRA 
Qualifier
Gastrointestinal 
tolerability
Gastrointestinal 
disorders
20000140
Gastrointestinal 
nonspecific 
symptoms 
and 
therapeutic 
procedures (SMQ)
MQ2
BROAD
Bradycardia
Cardiac 
disorders
90003924
Bradycardia 
[KAF156] 
(CMQ)
NMQ1
Gastrointestinal 
bleeding 
and 
ulceration
Gastrointestinal 
disorders
90003929
Gastrointestinal bleeding 
and ulceration [KAF156] 
(CMQ)
NMQ1
Renal 
tubular 
necrosis
Renal 
and 
urinary 
disorders
90003925
Renal tubular necrosis 
[KAF156] (CMQ)
NMQ1
Thyroid 
hypertrophy 
and 
hyperplasia
Endocrine 
disorders
90003926
Thyroid hypertrophy and 
hyperplasia 
[KAF156] 
(CMQ)
NMQ1
Hepatotoxicity 
(GenMed)
Hepatobiliary 
disorders
ALT/AST > 3 ULN; ALP > 2 ULN; 
TBL>1.5 ULN; ALP >3 ULN and 
TBL>2 ULN; ALT/ AST > 3  ULN and 
TBL>2 ULN; ALT/AST > 3 ULN and  
TBL >= 2 ULN and  ALP <2 ULN’
20000006
Drug 
related 
hepatic 
disorders 
–
comprehensive 
search 
(SMQ)
MQ2
BROAD
QTc 
prolongation
Cardiac 
disorders
Number of pts with notable QTcF, 
those with QTcF>500 msecs, or 
increase by >=60 msecs over 
baseline.
Sustained ventricular tachycardia 
lasting 30 sec or more, or ventricular 
fibrillation
20000001
Torsade de pointes/QT 
prolongation (SMQ)
MQ1
BROAD


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Hematological 
disorders
Blood 
and 
lymphatic 
system 
disorders
20000027
Haematopoietic 
cytopenias (SMQ)
MQ1
BROAD
Antimalarial 
drug resistance
Infections and 
infestations
90003928
Anti-malarial 
drug 
resistance 
[KAF156] 
(CMQ)
NMQ1
Drug –
Drug 
Interactions
General 
disorders 
and 
administration 
site conditions
90000024
Interactions 
(PSUR) 
[STANDARD] (NMQ)
NMQ1


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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 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, Haptoglobin, 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 Biochemistry 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, creatinine, uric acid,  gamma glutamyltransferase (GGT),
magnesium, phosphate, chloride, and total protein, albumin, INR, Thyroid Stimulating hormone 
(TSH), Thyroxine Free T4.
Box plot for direct platelet count normalized using ULN (upper limit of normal) will be 
provided by timepoint and treatment group. Similarly, box plot for biochemistry parameters 
will also be provided by timepoint and treatment group. These Box plots will be presented 
using normalized values based on ULN and LLN (lower limit of normal) for all parameters with 
the exception of GGT, ALT, ALP, AST, BUN, direct bilirubin, total bilirubin Creatinine, and 
Urate, which are normalized using ULN only.
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 treatment: 
Table 2-2
Liver-related events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN;>10xULN; > 20XULN
AST
>3xULN; >5xULN; >8xULN >10xULN; >20XULN
ALT or AST
>3xULN; >5xULN; >8xULN >10xULN>20XULN
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, >3XULN
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)
Listing of patients with the following renal related laboratories will be provided:

Serum creatinine increase 25 – 49% compared to baseline


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
Serum creatinine increase 50% compared to baseline

New dipstick proteinuria ≥ 1+

New dipstick hematuria ≥ 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 recordred as below the assay detection limits, will be 
imputed as half of the detection limit; and that above the detection limit will be impued 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, QTcB (QT interval corrected for heart rate 
according to Bazett) and QTcF (QT interval corrected for heart rate according to Fredericia). 
Descriptive summary statistics for the change from baseline for each post-baseline visit will be 
performed by ECG parameters and treatment group.
Patients with notably high QT, HR and fever (≥37.5 °C for axillary  or ≥ 38.3°C for other routes)
will be provided. 
To assess the temporal correlations mean change of QTcF over time, mean change of ECG HR 
over time, mean change of temperature over time, and PK concentration of KAF156 and 
lumefantrine over time will be plotted with all panels aligned on the x-axis (Time after dosing).
QTc will be summarized categorically by computing the number and percentage of patients at 
each time point and at the maximum post baseline value with following:

QT, QTcF, or QTcB
-
> 450 and ≤ 480 ms
-
> 480 and ≤ 500 ms
-
> 500 ms
-
Increase from Baseline of ≥30 ms to <  60ms
-
Increase from Baseline of ≥60 ms

HR for age ≥18 years 
-
Increase from baseline >25% and to a value > 100 bpm
-
Decrease from baseline >25% and to a value < 50 bpm

HR for age  <18 years 
-
> upper limit of normal (ULN) defined in Table 2-3
-
< lower limit of normal (LLN) defined in Table 2-3

PR


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-
Increase from baseline >25% and  to a value > 200 ms
-
New value of > 200 ms

QRS
-
Increase from baseline >25% and  to a value > 120 ms 
-
> 120 ms
Table 2-3
Normal heart rates (resting) by age
Age (years)
Normal range bpm
1 - ≤ 3 
70 - 110
3 - ≤ 6
65 -110
6 - ≤12
60 -95
>12
55 -85
Source: Nelson Textbook of Pediatrics, 18th Edition
A line plot by patient (Spaghetti plot) will be provided by 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 as compared with baseline 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
As body temperature is being measured using different routes, in order to harmonize all 
temperature values, for summaries a correction will be made to methods other than axillary as 
follows.
Body temperature (axillary equivalent) = value (oral/tympanic/rectal) - 0.5 degrees (oC). 
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 2-4 below.


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Table 2-4
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg) for 
age ≥18 years
≥ 180 mmHg/≤ 90 mmHg with increase/decrease from 
baseline of ≥ 20 mmHg
Systolic blood pressure (mmHg) for 
age <18 years
>  ULN or < LLN  defined in Table 2-5
Diastolic blood pressure (mmHg) for 
age ≥18 years
≥ 105 mmHg/≤ 50 mmHg with increase/decrease from 
baseline of ≥ 15 mmHg
Diastolic blood pressure (mmHg) for 
age <18 years
>  ULN or < LLN  defined in Table 2-5
Pulse (beats/min) for age ≥18 years
≥ 120 bpm/≤ 50 bpm with increase/decrease from baseline 
of ≥ 15 bpm
Pulse (beats/min) for age <18 years
>  ULN or < LLN  defined in Table 2-3
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 as compared with baseline will be 
provided, as well as a by-patient listing of all vital signs.
Table 2-5
Normal blood pressure by age
Age (years)
Normal range systolic 
(mmhg)
Normal range diastolic (mmhg)
1 - ≤ 3 
90-105
55-70
3 - ≤ 6
95-110
60-75
6 - ≤12
100-120
60-75
>12 - <18
110-135
65-85
Source: Nelson Textbook of Pediatrics, 18th Edition
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 analysis. 
Descriptive statistics of pharmacokinetic parameters will include arithmetic and geometric 
(means, standard deviation (SD), median, minimum and maximum, etc). In the study rich PK 
data will be collected from subset of patients whereas all other patient will provide sparse PK 
samples. A separate PK analysis will be performed for patients providing rich PK data. 
Parameters such as AUCinf, AUClast, AUC0-t, Cmax and Tmax may be reported for the 
patients with rich PK data 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 
KAF156 and lumefantrine will be calculated by part and treatment group using normal or log-
normal approximation as applicable. Non-compartmental PK analysis for patients with sparse 
data will also be conducted and feasible PK parameters will be reported. A descriptive statistics 
for concentration at nominal time point of 168 hours post dose or any other time point identified 


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critical for the cure may also be reported for all the patients. These PK parameters/ PK 
concentration may also be explored graphically.
All the PK data may be pooled for population pharmacokinetics analysis across studies 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 2-6 and Table 2-7. 


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Table 2-6
Overview of analysis methods for baseline data and efficacy variables
Variable(s)
Summary 
statistics 
for binary/
categorical 
data 
Listings
Between 
treatment 
comparison 
95% CI for 
each treatment 
group
Summary 
statistics for 
continuous 
data
Time-to-
event data 
analysis
K-M
Graph
s
Pooled 
analysis (Part 
A +Part B)
Medical history
X
X
-
-
-
-
-
-
Demogrpahics and baseline 
characteristics
X
X
-
-
-
-
-
X
Patient disposition
X
X
-
-
-
-
-
X
Prior medication use
X
X
-
-
-
-
-
-
Concomitant medication use
X
X
-
-
-
-
-
-
Concomitant rescue medication use
X
X
-
-
-
-
-
-
Concomitant Non-study drug antimalarial 
medication use
X
X
-
-
-
-
-
-
Prior other prohibited medications use
X
X
-
-
-
-
-
-
Concomitant other prohibited medications 
use
X
X
-
-
-
-
-
-
PCR-corrected Response at Day 29
X
X
X
X
-
X
X
X
PCR-corrected response at Days 15 and 
43
X
X
X
X
-
X
X
X
Uncorrected ACPR response at Days 15, 
29, and 43
X
X
X
X
-
X
X
X
Proportion of patients with parasitemia at 
12, 24, and 48 hours after treatment;
X
X
X
-
-
-
-
Time to parasite clearance (PCT)
X
X
-
-
X
X
X
Time to fever clearance (FCT)
X
X
-
-
X
X
X
Proportion of patients with early treatment 
failure 
X
X
-
X
-
-
-
-


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Variable(s)
Summary 
statistics 
for binary/
categorical 
data 
Listings
Between 
treatment 
comparison 
95% CI for 
each treatment 
group
Summary 
statistics for 
continuous 
data
Time-to-
event data 
analysis
K-M
Graph
s
Pooled 
analysis (Part 
A +Part B)
Proportion of patients with late clinical 
failure 
X
X
-
X
-
-
-
-
Proportion of patients with late 
parasitological failure (LPF)
X
X
-
X
-
-
-
-
Incidence rate of recrudescence at Days 
15, 29 and 43
X
-
-
-
-
X
X
-
Incidence rate of reinfection at Days 15, 
29 and 43
X
-
-
-
-
X
X
-
Proportion of infected mosquitoes
-
-
-
-
X
-
-
-


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Table 2-7
Overview of analysis methods for safety/PK variables
Variable(s)
Summary statistics 
for binary/
categorical data 
Listings
Summary 
statistics 
for 
continuous 
data
Graph
s
Pooled 
analysis 
(Part A 
+Part B)
AE
X
X
-
-
X
SAE
X
X
-
-
X
severe malaria
X
X
-
-
Adverse events of special interest 
X
X
-
-
X
Hematology  change from baseline
-
X
X
X
X
Biochemistry  change from baseline
-
X
X
X
X
Liver abnormalities
X
X
-
-
X
ECG abnormality
X
X
-
-
X
Vital signs change from baseline
-
X
X
-
X
Notable vital signs abnormality
X
X
-
-
X
Drug concentrations
-
X
X
-
-
2.15
Interim analysis
PK Run-in Part: For the patients in the PK Run-in KAF156 200 mg/LUM-SDF 960 mg cohort, 
PK analyses will be performed on the samples collected in the first 24 hours. AUC0-24, for 
KAF156 and lumefantrine will be calculated and compared with the expected values when one 
drug was given alone. Dosing in Part A will subsequently proceed according to the algorithm 
specified in protocol, Table 3-1.  
End of Part A: After the last patient has completed the last visit in Part A, the clinical database 
will be cleaned and locked.
An interim assessment will be performed to evaluate if any KAF156 and LUM-SDF 
combination is effective and safe and which KAF156 and LUM-SDF dose regimen(s) will be 
carried forward in Part B. Only the primary efficacy endpoint, selected secondary efficacy 
(uncorrected ACPR at Day 29, PCT, and FCT), PK, and safety endpoints (all adverse events, 
serious adverse events and laboratory results) will be analyzed by the study biostatistics team. 
Other efficacy and safety endpoints will be analyzed if deemed necessary.
The results will be communicated to relevant internal and external people who will contribute 
to the selection of effective and safe dose regimen.
DMC reports: At selected time points during the study, DMC reports will be provided by a 
CRO team not involved in the study conduct. The unblinded DMC reports will be reviewed by 
the DMC.
Additional ad-hoc safety review may be requested by DMC or Novartis if needed. Only the 
decision or information needed for planning/modifying the trial (such as continuation of study, 
dosing information for new patients, etc.) will be communicated to the blind clinical trial team 
involved in trial conduct. No further dissemination of DMC reports should occur. 


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Below is the outline of the data required for the DMC review.
Table 2-8
Specification of data outputs for DMC data review
Output
Analysis set
Periodic 
safety 
review
End of Part A 
interim 
analysis
Baseline
Patient disposition
Randomized
Yes
Yes
Recruitment by country and center
Randomized
Yes
Yes
Demographic characteristics
Randomized
Yes
Yes
Background disease characteristics
Randomized
Yes
Yes
Safety
Concomitant medications/significant non-drug 
therapies
Safety
Yes
Yes
All adverse events and Serious adverse events 
(including narratives)
Safety
Yes
Yes
General, liver, and renal specific safety 
laboratories (categorical analysis)  
Safety
Yes
Yes
ECG (Categorical analysis)
Safety
Yes
Yes
Vital signs (clinical notable)
Safety
Yes
Yes
Early treatment failures
Safety
Yes
Yes
Efficacy
PCR corrected and uncorrected cure rates at Day 
29
Per-Protocol
No
Yes
PCR corrected and uncorrected cure rates at Day 
43
Per-Protocol
No
Yes
PCT, FCT
FAS
No
Yes
KAF156 and LUM-SDF PK
PK 
No
Yes
3
Sample size calculation
Sample size for PK run-in cohort
The objective of this part is to assess the effect of LUM-SDF in the exposure of KAF156 in 
patients and to see if the current planned dosages for KAF156 in Part A should be modified or 
how to modify KAF156 dosages in Part A. Therefore, the sample size is calculated/justified 
based on the precision of estimating KAF156 exposure. The key variables for exposure of 
KAF156 are AUC0-24h and Cmax. It’s well known that the distribution of AUC or Cmax is best 
described by log normal distribution. The half width of 2-sided 90% confidence interval for the 
log AUC0-24h or log Cmax is the target for sample size calculation. The relevant historical data 
for sample size calculation are the standard deviations of log AUC0-24h and log Cmax, which are 
usually invariant to the dosage. 
In POC Study X2202, the standard deviation for log AUC0-24h was 0.26 and 0.27 for 10 P. 
falciparum patients treated with KAF156 400 mg QD 3 days and for 18 P. falciparum patients 


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treated with KAF156 800 mg QD, respectively. The corresponding standard deviation for log 
Cmax was 0.205 and 0.215, respectively.
Table 3-1
Sample size and width of 2-sided 90% CI for log AUC0_24h and log Cmax
Standard deviation 
(in log) 
n
Target half width 
of 2-sided 90% CI
Probability that observed half width 
of 2-sided 90% CI is ≤ the target
0.21
9
0.153
0.80
0.21
12
0.126
0.80
0.21
10
0.150
0.80
0.26
9
0.200
0.80
0.26
12
0.155
0.80
0.26
13
0.150
0.80
0.26
12
0.150
0.70 
0.27
9
0.200
0.80
0.27
12
0.161
0.80
0.27
14
0.150
0.80
0.27
12
0.150
0.68
Based on nQuery Table MOC1-1.nqa. 
A sample size of 12 patients will provide 80% probability that the observed half width of 2-
sided 90% CI for log AUC0_24h is ≤0.155. A sample size of 12 patients will provide 80% 
probability that the observed half width of 2-sided 90% CI for log Cmax is ≤0.126.
Part A
The primary efficacy objective for this part is to determine the effective dose(s) of KAF156 
combined with LUM-SDF for treatment of uncomplicated malaria caused by P. falciparum in 
adolescents and adults. The primary efficacy endpoint is the PCR corrected ACPR rate at Day 
29 based on the per-protocol analysis set. The statistical null hypothesis is that the ACPR rate 
is at most 80% with the alternative hypothesis that the ACPR rate is greater than 80%. The 
statistical hypothesis will be evaluated using the lower limit of 2-sided 95% exact confidence 
interval for the ACPR rate. If the lower limit of 2-sided 95% exact confidence interval for ACPR 
rate is greater than 80%, the null hypothesis will be rejected. 
Rejecting the null hypothesis of at most 80% ACPR rate is equivalent to showing non-inferiority 
to a ACPR rate of 90% with a non-inferiority margin of 10%. 90% is specified in the 2015 
WHO guidelines as the ACPR rate cutoff-threshold for a change in treatment policy and a 10% 
non-inferiority margin is considered as acceptable for early-phase trials (Held, et al 2015). 
Figure 3-1 plots the power to reject the null hypothesis of at most 80% ACPR rate versus sample 
size by various true ACPR rates (90%, 93%, 95%, and 97%). Due to the discrete property of 
binomial distribution, the power increases zigzag with jump at 26, 34, 41, 48, 55, 62, and 68 as 
the sample size increases. When the sample size is at least 41, the power to reject the null 
hypothesis of at most 80% ACPR rate is about 80% or higher if the true rate is 95% or higher. 
Since there is a 2:1 ratio among different treatment groups, the sample size in the per-protocol 
analysis set will be targeted to be 42 patients for each KAF156/LUM-SDF dose combination


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group and 21 patients for the comparator (Coartem®) cohort. This sample size will provide at 
least 80% power to reject the null hypothesis of at most 80% ACPR rate for the 6 KAF156 dose 
combinations if the true ACPR rate is at least 95%. If there are multiple KAF156/LUM-SDF 
dose combinations that are all effective, the less frequent or/and highest KAF156/LUM-SDF 
dose combination(s) that is tolerable may be selected for further evaluation. The PK/PD 
modeling may be used to assist the selection of appropriate dose combination(s) for Part B. 
Assuming that about 16% of patients will be excluded from the per-protocol analysis set, about 
325 patients (50:50:50:50:50:50:25) will be randomized to yield 42 patients for each 
KAF156/LUM-SDF dose combinations and 21 patients for the Coartem® cohort in the per-
protocol analysis set.
Figure 3-1
Power to reject adequate clinical and parasitological response (ACPR) 
rate less than or equal to 80% based on 2-sided 95% CI by true rate


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Part B
The primary objective for this part is to assess the safety and efficacy of the selected 
KAF156/LUM-SDF dose combination(s) adjusted for body weight in pediatric patients. For the 
primary efficacy variable of PCR corrected ACPR rate at Day 29 based on the per-protocol 
analysis set, a sample size of at least 41 patients will provide about 80% power or higher to 
reject the null hypothesis of at most 80% ACPR rate based on the lower limit of 2-sided 95% 
exact confidence interval if the true rate is 95% or higher for a KAF156/LUM-SDF dose 
combination. Since there is a 2:1 ratio between a KAF156/LUM-SDF dose combination group 
and the Coartem® cohort, the sample size in the per-protocol analysis set will be targeted to be 
42 patients for each KAF156/LUM-SDF dose combination group and 21 patients for the 
Coartem® cohort. Assuming that 16% of patients will be excluded from the per-protocol 
analysis set, about 50 pediatric patients will be randomized to yield 42 patients for each KAF156 
and LUM-SDF combination and 21 patients for the Coartem® cohort in the per-protocol 
analysis set.
4
Change to protocol specified analyses
None
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The study drug administatrtion 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 administatrtion 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 partial missing start 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).


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Table 5-2
Imputation algorithm
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/non-drug therapy date imputation
Missing concomitant dates will be imputed similar as to AE dates.


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5.1.3.1
5.1.3.2
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 29 visit is set to be Day 25 and Day 33 
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

No upper limit for Day 43 visit

Upper limit of Day 15 is one day before the lower limit of Day 29
For assesments 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.


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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
Thyroid function
Membrane 
feed 
assay/ pregnancy
Baseline
1
Up to Day 1 
Up to Day 1 
up to day 1
Day 2
2
Day 2
NA 
NA 
Day 3
3
Day 3
NA 
NA 
Day 4
4
Day 4
NA 
NA 
Day 5
5
Days 5 -  6
NA
NA
Day 8
8
Day 7 - 11
NA
NA
Day 15
15
Day 12 - 24
Day 2 - 29
NA
Day 29
29
Day 25 - 33
NA
NA
Day 43/End of 
study
43
Day 34 and above
Day 
30 
and 
above
Day 2 and above


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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
Rich and Sparse PK
Baseline
0 hrs
up to 0 hrs
up to 0 hrs
up to 0 hrs 
up to 0 hrs 
Day 1
1 hrs
NA 
NA 
NA 
> 0 - 2 hrs
3 hrs
NA 
NA 
>0 - 4 hrs
> 2 - 4 hrs
6 hrs
>0 - 9 hrs
>0 - 9 hrs
>4 - 12 hrs
>4 - 9 hrs
8 hrs
NA 
NA 
NA 
NA 
12 hrs
>9 - 15 hrs
>9 - 18 hrs
NA 
>9 - 15 hrs
18 hrs
>15 - 21 hrs
NA 
>12 - 21 hrs
>15 - 21 hrs
Day 2
24 hrs
>21 - 27 hrs
>18 hrs to 30 hrs
>21 - 25 hrs
>21 - 25 hrs
27 hrs
NA 
NA 
>25 – 28 hrs
>25 - 28 hrs
30 hrs
>27 - 33 hrs
NA 
>28 - 39 hrs
>28 - 33 hrs
36 hrs
>33 - 42 hrs
>30 - 42 hrs
NA 
>33 - 42 hrs
Day 3
48 hrs
>42 - 60 hrs
>42 - 60 hrs
>39 – 49 hrs
>42 - 49 hrs
51 hrs
NA 
NA 
>49 – 52 hrs
>49 - 52 hrs
54 hrs
NA 
NA 
>52 – 61 hrs
>52 - 63 hrs
60 hrs
NA 
NA 
NA 
NA 
68 hrs
NA 
NA 
>61 – 70 hrs
NA 
Day 4
72 hrs
>60  hrs to Day 4
>60 hrs to Day 4
>70 hrs to Day 5 
>63hrs to Day 4
Day 5
NA
Day 5 - 6
Day 5 - 6
NA 
Day 5 - 6
Day 8
NA
Day 7 – 11
Day 7 – 11
Day 6 -25
Day 7 – 11
Day 15
NA
Day 12 - 24
Day 12 - 24
NA 
Day 12 and above
Day 29
NA
Day 25 - 33
Day 25 - 33
NA 
NA 
Day 43/End of study
NA
Day 34 and above
Day 34 and above
Day 26 and above 
NA


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Table 5-7
Rules for flagging variables
Timing of 
measurement
Type of data
Rule
Baseline
All data
The last measurement made prior to 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
parasite count and 
temperature
The measurement closest to the target day/time  will be used.
In the event two measurements are taken equally apart, 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 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
Non-study drug antimalarials
Table 5-8
Table of non-study drug antimalarials with respective ATC codes 
Non-study drug antimalarials
ATC code
ATC name
Aminoquinolines
P01BA01 
Chloroquine
P01BA02 
Hydroxychloroquine
P01BA03 
Primaquine
P01BA06 
Amodiaquine
Biguanides
P01BB01 
Proguanil
P01BB02 
Cycloguanil embonate
P01BB51 
Proguanil, combinations
Methanolquinoline
P01BC01 
Quinine
P01BC02 
Mefloquine
Diaminopyridimidines
P01BD01 
Pyrimethamine
P01BD51 
Pyrimethamine, combinations
Artemisinin and derivatives, plain
P01BE01 
Artemisinin
P01BE02 
Artemether
P01BE03 
Artesunate
P01BE04 
Artemotil
P01BE05 
Artenimol
Artemisinin and derivatives, 
combinations
P01BF02 
Artesunate and mefloquine
P01BF03 
Artesunate and amodiaquine
P01BF04 
Artesunate, sulphamethopyrazine and pyrimethamine
P01BF05 
Artenimol and piperaquine
P01BF06 
Artesunate and pyronaridine
Other Antimalarials
P01BX01 
Halofantrine
P01BX02 
Arterolane and Piperaquine
Coartem*
P01BF01
Artemether and lumefantrine
*in case used by patients receiving KAF156/Lum-SDF


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5.3
Prohibited medications
Table 5-9
Prohibited medication with respective ATC codes 
Prohibited medication
ATC code
ATC name
ANALGESICS
N02CC06
Eletriptan
N02CA01
Dihydroergotamine
N02CA02
Ergotamine
N02AB03
Fentanyl
ANESTHETICS
N01AH02
Alfentanil
N01AH02
Alfentanil
N01AH01
Fentanyl
ANTIARRHYTHMICS
C01BD07
Dronedarone
C01BC04
Flecainide
C01BA01
Quinidine
N06AA01
Desipramine
N06AX16
Venlafaxine
N06AX12
Bupropion
N06AA02
Imipramine
N06AA09
Amitriptyline
N06AA04
Clomipramine
ANTIEMETICS AND 
ANTINAUSEANTS
A04AD12
Aprepitant
ANTIEPILEPTICS
N03AB02
Phenytoin
ANTIHISTAMINES FOR 
SYSTEMIC USE
R06AX11
Astemizole
R06AX12
Terfenadine
ANTIINFLAMMATORY AND 
ANTIRHEUMATIC PRODUCTS
M01AH01
Celecoxib
ANTINEOPLASTIC AGENTS
L01CD01
Paclitaxel
ANTIPSYCHOTICS
N05AB03
Perphenazine
N05AE05
Lurasidone
N05AH04
Quetiapine
N05AC02
Thioridazine
N05AG02
Pimozide
N05
Neuroleptics
ANTITHROMBOTIC AGENTS
B01AA03
Warfarin
ANXIOLYTICS
N05BE01
Buspirone
BETA BLOCKING AGENTS
C07AB02
Metoprolol
C07AB12
Nebivolol
C07AB02
Metoprolol
CALCIUM CHANNEL BLOCKERS
C08CA02
Felodipine
C08CA07
Nisoldipine
CORTICOSTEROIDES
R01AD08
Fluticasone
COUGH SUPPRESSANTS
R05DA09
Dextromethorphan
DIRECT ACTING ANTIVIRALS
J05AE10
Darunavir
J05AE02
Indinavir
J05AR10
Lopinavir
J05AX09
Maraviroc


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J05AE01
Saquinavir
J05AE09
Tipranavir
J05AG03
Efavirenz
DIURETICS
C03DA04
Eplerenone
C03XA01
Tolvaptan
DRUGS FOR FUNCTIONAL 
GASTROINTESTINAL 
DISORDERS
A03FA02
Cisapride
HYPNOTICS AND SEDATIVES
N05CD08
Midazolam
N05CD05
Triazolam
IMMUNOSUPPRESSANTS
L04AA18
Everolimus
L04AA10
Sirolimus
L04AD01
Ciclosporin
L04AA10
Sirolimus
L04AD02
Tacrolimus
INTESTINAL 
ANTIINFLAMMATORY AGENTS
A07EA06
Budesonide
LIPID MODIFYING AGENTS
C10AA02
Lovastatin
C10AA01
Simvastatin
C10AA03
Pravastatin
OTHER ANTIHYPERTENSIVES
C02KX01
Bosentan
OTHER ANTINEOPLASTIC 
AGENTS
L01XE06
Dasatinib
L01XE10
Everolimus
L01XX33
Celecoxib
OTHER BLOOD GLUCOSE 
LOWERING DRUGS
A10BX02
Repaglinide
OTHER DERMATOLOGICAL 
PREPARATIONS
D11AH01
Tacrolimus
OTHER DIURETICS
C03XA02
Conivaptan
OTHER OPHTALMOLOGICALS
S01XA18
Ciclosporin
S01XA23
Sirolimus
PSYCHOSTIMULANTS
N06BA09
Atomoxetine
UROLOGICALS
G04BD07
Tolterodine
G04BD10
Darifenacin
G04BE03
Sildenafil
G04BE09
Vardenafil
5.4
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
5.5
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 


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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. For laboratory tests that are graded for both low and high values,
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
5.6
Statistical models
5.6.1
Primary analysis
The primary analysis of ACPR at Day 29 is detailed in Section 2.
SAS procedure FREQ with EXACT statement for one-way tables will be used to estimate the 
proportion of responders (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].
5.6.2
Key secondary analysis
NA
5.6.3
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 survivor 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].
Difference in responder rates stratified by part using Mantel-Hanszel estimate
For PCR corrected and uncorrected ACPR rates, the treatment differences versus control will 
be evaluated using a Mantel-Haenszel estimate of the treatment difference in responder rates 
stratified by Part using PROC FREQ with RISKDIFF(COMMON) option in the TABLES
statement).


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Difference in responder rates using the Wilson uncorrected method
For PCR corrected and uncorrected ACPR rates, the treatment differences versus control will 
be evaluated using a Wilson uncorrected method using PROC FREQ with RISKDIFF ( CL= 
WILSON)  option in the TABLES statement.
5.7
Rule of exclusion criteria of analysis sets 
Table 5-10
Protocol deviations and non-PD criteria leading to exclusion from 
analysis sets
Analysis Set
PD (Description and ID) that causes 
Patients to be excluded
Non-PD criteria that cause Patients to 
be excluded
Randomized

Informed Consent for study 
participation 
or 
parental 
consent 
not 
obtained 
and 
patient entered trial (INCL01)


Not randomized (Parts A and B)

Misrandomized if identified from 
IRT (Parts A and B)

Not treated with study medication 
(PK run-in part)
FAS
NA

Not in Randomized set;

Baseline parasitemia count is 0 or 
missing

No study drug taken
PPS

Parasite specie is other than 
Plasmodium 
falciparum 
OR 
mixed infection (INCL04)

Baseline 
plasmodium 
falciparum 
parasite 
count 
<1000/uL or >=150000/uL at 
screening visit (INCL05)

No fever within the past 24 
hours at baseline (INCL07)

Prohibited 
non-antimalarial 
medications that may have 
effect on efficacy (PROH01b) if 
received before the Day 29 visit
without being treatment failures

Not in FAS;

<80% 
of 
randomized 
study 
medication taken 

Received non-study concomitant 
antimalarial drugs prior to Day 29 
without 
experiencing 
treatment 
failure 

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 and later (early 
discontinued)

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 and  
have parasites cleared prior to the 
positive blood smear parasite;


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
Not classified as non-responder 
before Day 8, no positive blood 
smear parasite before Day 29, 
blood smear parasite result is 
missing at Day 29,  and blood 
smear 
parasite 
result 
is 
not 
negative at Day 43 (intermediate 
missing)
SAF
NA

Not in Randomized set;

No study drug taken
PK
Patients who received concomitant 
prohibited medication  which found 
to be change in the exposure that 
impacts 
interaction 
in 
PK 
parameters; will be reviewed case 
by case for exclusion from the PK 
set

Not in SAF

No 
evaluable 
pharmacokinetic 
parameter data

Compliance is <80% of randomized 
study medication taken 
6
Reference
Nelson Textbook of Pediatrics, 18th Edition
Clopper, C. J. and Pearson, E. S. (1934), “The Use of Confidence or Fiducial Limits 
Illustrated in the Case of the Binomial,” Biometrika, 26, 404–413. 
Collett, D. (1994), Modeling Survival Data in Medical Research, London: Chapman & Hall. 
SAS/STAT ® 9.1 User’s Guide. Cary, NC: SAS Institute Inc.