An Adaptive, Randomized, Active-controlled, Open-label, Sequential Cohort, Multicenter Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Intravenous Cipargamin (KAE609) in Adult and Pediatric Participants With Severe Plasmodium Falciparum Malaria (KARISMA - KAE609's Role In Severe Malaria)
Phase: PHASE2
Conditions: Severe Malaria
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
KAE609/cipargamin
Clinical Trial Protocol CKAE609B12201 / NCT04675931
An adaptive, randomized, active-controlled, open-label, 
sequential cohort, multicenter study to evaluate the 
efficacy, safety, tolerability, and pharmacokinetics of 
intravenous cipargamin (KAE609) in adult and pediatric 
participants with severe Plasmodium falciparum malaria 
(KARISMA – KAE609’s Role in Severe Malaria)
Document type:
Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
00 (Original Protocol)
Clinical Trial Phase:
II
Release date:
14-Oct-2020 (content final)
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020

Novartis
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Page 2 of 108
Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................19
2
Objectives and endpoints...................................................................................................20
2.1
Primary estimands .................................................................................................21
2.2
Secondary estimands .............................................................................................22
3
Study design ......................................................................................................................23
4
Rationale............................................................................................................................26
4.1
Rationale for study design .....................................................................................26
4.1.1
Rationale for choice of background therapy.........................................27
4.2
Rationale for dose/regimen and duration of treatment ..........................................27
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................29
4.4
Purpose and timing of interim analyses/design adaptations..................................29
4.5
Risks and benefits..................................................................................................30
5
Study Population ...............................................................................................................33
5.1
Inclusion criteria ....................................................................................................34
5.2
Exclusion criteria...................................................................................................34
6
Treatment...........................................................................................................................37
6.1
Study treatment......................................................................................................37
6.1.1
Investigational and control drugs..........................................................37
6.1.2
Additional study treatments ..................................................................38
6.1.3
Treatment arms/group ...........................................................................40
6.1.4
Treatment duration................................................................................40
6.2
Other treatment(s)..................................................................................................40
6.2.1
Rescue medication ................................................................................40
6.2.2
Concomitant therapy.............................................................................41
6.2.3
Prohibited medication ...........................................................................42
6.3
Participant numbering, treatment assignment, randomization ..............................44
6.3.1
Participant numbering...........................................................................44

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Treatment assignment, randomization ..................................................44
6.4
Treatment blinding.................................................................................................45
6.5
Dose escalation and dose modification..................................................................45
6.5.1
Dose modifications................................................................................45
6.6
Additional treatment guidance...............................................................................46
6.6.1
Treatment compliance...........................................................................46
6.6.2
Recommended treatment of adverse events..........................................46
6.7
Preparation and dispensation.................................................................................46
6.7.1
Handling of study treatment and additional treatment..........................46
6.7.2
Instruction for prescribing and taking study treatment .........................47
7
Informed consent procedures ............................................................................................48
8
Visit schedule and assessments .........................................................................................49
8.1
Screening ...............................................................................................................55
8.1.1
Information to be collected on screening failures.................................55
8.2
Participant demographics/other baseline characteristics .......................................55
8.3
Efficacy..................................................................................................................56
8.3.1
Clinical outcome in moderately severe and severe malaria..................56
8.3.2
Parasitemia assessment .........................................................................60
8.3.3
Appropriateness of efficacy assessments..............................................61
8.4
Safety.....................................................................................................................61
8.4.1
Physical Examination............................................................................61
8.4.2
Vital signs..............................................................................................62
8.4.3
Height and Weight ................................................................................62
8.4.4
Laboratory evaluations..........................................................................62
8.4.5
Electrocardiogram (ECG) .....................................................................63
8.4.6
Pregnancy..............................................................................................63
8.4.7
Appropriateness of safety measurements..............................................64
8.5
Additional assessments..........................................................................................64
8.5.1
Pharmacokinetics ..................................................................................64
8.5.2
65
8.5.3
Other Assessments ................................................................................65
9
Study discontinuation and completion ..............................................................................66
9.1
Discontinuation and completion............................................................................66
9.1.1
Study treatment discontinuation and study discontinuation..................66
9.1.2
Withdrawal of informed consent...........................................................67
9.1.3
Lost to follow-up...................................................................................67
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Early study termination by the sponsor.................................................67
9.2
Study completion and post-study treatment ..........................................................68
10 Safety monitoring and reporting........................................................................................68
10.1
Definition of adverse events and reporting requirements......................................68
10.1.1
Adverse events ......................................................................................68
10.1.2
Serious adverse events ..........................................................................70
10.1.3
SAE reporting........................................................................................71
10.1.4
Pregnancy reporting ..............................................................................71
10.1.5
Reporting of study treatment errors including misuse/abuse................72
10.2
Additional Safety Monitoring................................................................................72
10.2.1
Liver safety monitoring.........................................................................72
10.2.2
Renal safety monitoring........................................................................73
10.2.3
Special Hematology monitoring ...........................................................73
10.2.4
Data Monitoring Committee .................................................................74
10.2.5
Adjudication committee........................................................................74
11 Data Collection and Database management......................................................................74
11.1
Data collection.......................................................................................................74
11.2
Database management and quality control............................................................75
11.3
Site monitoring ......................................................................................................75
12 Data analysis and statistical methods ................................................................................76
12.1
Analysis sets ..........................................................................................................76
12.2
Participant demographics and other baseline characteristics.................................76
12.3
Treatments .............................................................................................................76
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................77
12.4.1
Definition of primary endpoint(s)/estimand(s) .....................................77
12.4.2
Statistical model, hypothesis, and method of analysis..........................77
12.4.3
Handling of intercurrent events of primary estimand ...........................77
12.4.4
Handling of missing values not related to intercurrent event ...............78
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................79
12.4.6
Supplementary analysis.........................................................................79
12.4.7
Supportive analyses...............................................................................79
12.5
Analysis of secondary endpoints/estimands..........................................................80
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................80
12.5.2
Safety endpoints....................................................................................85
12.5.3
Pharmacokinetics ..................................................................................88
12.5.4
89
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12.5.5
89
12.6
Analysis of exploratory endpoints and assessments..............................................89
12.7
Interim assessment.................................................................................................90
12.8
Sample size calculation..........................................................................................91
12.8.1
Primary estimand ..................................................................................91
12.8.2
Secondary endpoint(s)...........................................................................91
13 Ethical considerations and administrative procedures ......................................................96
13.1
Regulatory and ethical compliance........................................................................96
13.2
Responsibilities of the investigator and IRB/IEC..................................................96
13.3
Publication of study protocol and results...............................................................96
13.4
Quality Control and Quality Assurance.................................................................96
14 Protocol adherence ............................................................................................................97
14.1
Protocol amendments.............................................................................................97
15 References .........................................................................................................................98
16 Appendices ......................................................................................................................100
16.1
Appendix 1: Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................................100
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up....103
16.3
105
16.4
Appendix 4: Modified version of WHO classification of signs of severe P. 
falciparum malaria...............................................................................................106
16.5
Appendix 5: Approximate amount of blood withdrawn......................................107
16.6
Appendix 6: Coma Scores used in the study .......................................................108
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Table 2-1
Objectives and related endpoints ..........................................................20
Table 3-1
Criteria to temporarily pause the recruitment and initiate 
DMC review..........................................................................................25
Table 4-1
Dose and design adaptations permitted in the study.............................30
Table 6-1
Investigational drugs, control drug and oral standard of care...............37
Table 6-2
Dosing Regimen for IV cipargamin (KAE609) and IV artesunate.......37
Table 6-3
Cohort 1-5: Coartem® (standard of care) dosing per weight (dosing 
as per label) ...........................................................................................38
Table 6-4
Criteria for switch to oral medication (standard of care) ......................39
Table 6-5
Prohibited medications for participants on cipargamin arms................42
Table 6-6
Prohibited medications for participants on IV artesunate arms ............44
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Table 8-1
Assessment Schedule, Cohorts 1-3 .......................................................50
Table 8-2
Assessment Schedule, Cohorts 4-5 .......................................................53
Table 8-3
Definition of clinical success in the study at any time point.................57
Table 8-4
Summary of Neurological assessment ..................................................58
Table 8-5
Details of Laboratory Assessments.......................................................62
Table 8-6
65
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................72
Table 12-1
Handling of other events that may occur and affect derivation of 
primary endpoint ...................................................................................78
Table 12-2
Handling of intercurrent events and other events that may occur 
and affect the derivation of secondary estimand...................................81
Table 12-3
Handling of other events that may occur and affect the derivation 
of clinical success at a visit other than 48 hours...................................82
Table 12-4
Non-compartmental pharmacokinetic parameters ................................88
Table 16-1
Liver event and laboratory trigger definitions ....................................100
Table 16-2
Follow-up requirements for liver laboratory triggers and liver 
symptoms ............................................................................................101
Table 16-3
Specific Renal Alert Criteria and Actions...........................................103
Table 16-4
Normal GFR in children and young adults, as assessed by inulin 
clearance (adapted for pediatric participants included in this study)..104
Table 16-5
105
Table 16-6
Definition of severe malaria................................................................106
Table 16-7
Amount of blood withdrawn per Cohort.............................................107
Table 16-8
Glasgow Coma Scale ..........................................................................108
Table 16-9
Blantyre Coma Score ..........................................................................108
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Figure 3-1
Study design..........................................................................................23
Figure 4-1
 
 
29
Figure 12-1
Plot of probability that half width of 2-sided 90% CIs for a single 
proportion is at most 0.1 for various true proportions ..........................92
Figure 12-2
Plot of probability that half width of 2-sided 90% CIs for 2 
proportion difference is at most 0.1 for various true equal 
proportions ............................................................................................94
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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
Figure 12-3
Probability of observing selected minimal number of events by 
sample size ............................................................................................95

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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
List of abbreviations
AAG
Alpha-1-acid glycoprotein
ACT
Artemisinin-based Combination Therapy
ADME
Absorption, Distribution, Metabolism, Excretion
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASAQ
Artesunate-Amodiaquine
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
ATP
Adenosine Triphosphate
AUC
Area under curve
AV Block
Atrioventricular block
b.i.d. or bd
twice a day
BCS
Blantyre Coma Score
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
Code of Federal Regulation
CI
Confidence Interval
CL/F
The total body clearance of drug from the plasma (volume x time-1)
Cmax
It is the highest concentration of a drug in the blood after a dose is given
CMH
Cochran-Mantel-Haenszel
CMO&PS
Chief Medical Office and Patient Safety
COVID-19
Corona virus disease 2019
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTT
Clinical Trial Team (Novartis)
CV
coefficient of variation
CYP
Cytochrome
DBIL
Direct Billirubin
DHA
Dihydroartemisinin
DMC
Data Monitoring Committee
DNA
Desoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency

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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
mmol/L
Millimoles per Liter(s)
MRI
Magnetic Resonance Imaging
MUAC
Mid-upper arm circumference
NSAIDS
Non-Steroidal Anti-Inflammatory Drugs
P.
Plasmodium
PBPK
Physiology-Based Pharmacokinetic modeling
PCE
Parasite Clearance Estimator
PCR
Polymerized chain reaction
PCT
Parasite clearance time
PD
pharmacodynamic(s)
PfATP4
Plasmodium falciparum ATP4
PI
Prescribing Information
PK
pharmacokinetic(s)
PoC device
Point of Care device
PPS
Per-protocol set
PRR
Parasite reduction ratio
PSW
Premature Study Withdrawal
Q24h
Every 24 hour
QMS
Quality Management System
QRS
The QRS Complex is a group of usually three spikes seen in an ECG 
(electrocardiogram), where each spike represents a depolarization of both heart 
chambers
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
QTc corrected by Fridericia
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RBC
red blood cell(s)
REB
Research Ethics Board
RRT
Renal Replacement Therapy
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SC
subcutaneous
SCr
Serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SMQ
Standardized MedDRA Query
SNPs
Single-Nucleotide Polymorphism
SS
Safety Set

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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1/2
The elimination half-life associated with the terminal slope (lz) of a semi logarithmic 
concentration-time curve (time)
TB
Tuberculosis
TBIL/TBL
Total Bilirubin
ULN
upper limit of normal
US
United States
Vz/F
The apparent volume of distribution during terminal phase (associated with λz) 
(volume)
WBC
white blood cell(s)
WHO
World Health Organization
WWARN
World Wide Antimalarial Resistance Network
µl
Microliter(s)

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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Biomarker
A naturally occurring molecule, gene, or characteristic by which a particular 
pathological or physiological process, disease, etc. can be identified.
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug.
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from paper source forms used at the point of 
care
Enrollment
Point/time of subject entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol).
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors 
and other oversight authorities, as appropriate
Estimand
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under each of the treatment 
conditions being compared. Attributes of an estimand include the population, 
variable (or endpoint) and treatment of interest. It also specifies of how the 
intercurrent events are addressed and provides a population-level summary 
for the variable.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation 
or the existence of the measurements associated with the clinical question of 
interest.
Investigational drug/ 
treatment
The drug whose properties are being tested in the study
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage.

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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.)
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant 
and should be used to identify the participant throughout the study for all 
data collected, sample labels, etc.
Patient
An individual with the condition of interest
PBPK model
Physiologically based pharmacokinetic (PBPK) modeling is a mathematical 
modeling technique for predicting the absorption, distribution, metabolism 
and excretion (ADME) of synthetic or natural chemical substances in 
humans and other animal species.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time 
all study drug administration is discontinued and no further assessments are 
planned
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Screen Failure
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
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 completion
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal.

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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins 
or background therapy.
Study treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
An individual who has consented to participate in this study. The term 
Subject may be used to describe either a healthy volunteer or a patient.
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment.
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
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might 
include whether the participant experiences an intercurrent event.
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a participant does 
not want to participate in the study any longer and does not allow any further 
collection of personal data

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Protocol summary
Protocol number
CKAE609B12201
Full Title
An adaptive, randomized, active-controlled, open-label, sequential cohort, 
multicenter study to evaluate the efficacy, safety, tolerability and 
pharmacokinetics of intravenous cipargamin (KAE609) in adult and pediatric 
participants with severe Plasmodium falciparum malaria (KARISMA –
KAE609’s Role In Severe Malaria)
Brief title
To evaluate efficacy, safety, tolerability and PK of intravenous cipargamin in 
participants with severe Plasmodium falciparum
Sponsor and
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to identify the safe and effective dose of 
intravenous cipargamin in participants with moderately severe and severe 
malaria.
The study also intends to evaluate clinical treatment success using a novel 
clinical endpoint for drug development in severe malaria.
Severe malaria is a medical emergency and is affecting primarily young 
children in Africa. Injectable artesunate is the standard of care for the 
treatment of severe malaria and is highly efficacious. However, the spread of 
artemisinin-resistance in Plasmodium falciparum in Asian countries poses a 
threat for future treatment of patients with this life-threatening disease. To 
mitigate this risk, there is a need of another drug in malaria endemic 
countries. Cipargamin treatment results in rapid clearance of 
parasites including artemisinin resistant parasites.
Primary 
Objective(s) 
The primary objective is to assess the efficacy of different doses of 
intravenous cipargamin vs artesunate by evaluating the proportion of 
participants with ≥ 90% reduction of parasitemia at 12 hours post 
administration of the first dose.
Secondary 
Objective(s)
The key secondary objective is to assess the clinical outcome as measured 
by the proportion of participants with clinical success at 48 hours.
The other secondary objectives are:
1. To assess the presence/absence of severe malaria related individual 
signs over time
2. To evaluate parasite clearance dynamics and proportion of participants 
with recrudescence and reinfection
3. To assess recovery of participants as measured by time (days and hours) 
to discharge from hospital or recovery from prostration
4. To evaluate the safety and tolerability of IV cipargamin
5. To assess the risk of long term neurological sequelae for participants at 
Day 29
6. The assess the risk of hemolysis (early and delayed) during the study 
duration
7. To characterize the plasma pharmacokinetics of IV cipargamin

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Study design
This will be an adaptive, multicenter, randomized, open label, sequential 
cohort study in participants aged ≥ 12 years (Cohorts 1-2) and ≥ 6 months to 
< 12 years (Cohorts 3-5) with a diagnosis of moderately severe and 
severe P. falciparum malaria. This study is investigating the efficacy (parasite 
reduction and clinical outcome), safety, tolerability and pharmacokinetics of 
different injectable dose regimens of cipargamin in comparison to injectable 
artesunate. The first cohort (Cohort 1) will be small, and will include 
participants aged 12 years or over, diagnosed with moderately severe 
malaria and high parasitemia. This cohort will be used for initial evaluation of 
safety and parasite clearance rates before continuing into Cohorts 2-5, which 
will include only severe malaria patients according to WHO criteria. 
Progressively younger participants will be included with each new cohort 
from Cohort 2 onwards. This design aims at minimizing risks for pediatric 
participants < 12 years.
Study population
The study population will consist of male and female participants, including 
pediatric participants aged ≥ 6 months or older. Approximately 252 
participants (60 participants of ≥ 12 years and 192 participants < 12 years) 
will be randomized.
Key Inclusion 
criteria

Cohort 1: Participants aged ≥ 12 years with moderately severe malaria as 
defined in Barnes et al (2004) (prostration and/or repeated vomiting) without 
presence of other signs of severe malaria as per Section 16.4 (and with 
high P. falciparum parasitemia (60,000-250,000 parasites per µl)

Subsequent Cohorts 2 to 5: Participants diagnosed with severe malaria 
as defined in modified version of WHO criteria (Section 16.4) and P. 
falciparum parasite count of ≥ 5000 per µl

Cohort 2: Participants aged ≥ 12 years

Cohort 3: Participants aged 6 - < 12 years

Cohort 4: Participants aged 2 - < 6 years

Cohort 5: Participants aged ≥ 6 months - < 2 years
Key Exclusion 
criteria
Exclusion criteria applying to all Cohorts 1 to 5:
-Mixed Plasmodium infections
-Treatment with quinine or artemisinin derivative or any other antimalarial 
drug or any antibiotic with known antimalarial activity within 12 hours of 
screening.
-Signs/symptoms of severe malnutrition in general accordance with WHO 
guidelines:
1. Under 18 years: <-3 Z-scores of WHO growth standard for weight-for-
height/length (in children < 5 years) or BMI for age (5-18 years), or very low 
mid-upper arm circumference (MUAC < 115 mm in children < 12 years, < 
160mm 12-18 years), or bilateral pitting edema
2. Over 18 years: BMI < 16 kg/m2 or MUAC < 160mm or bilateral pitting 
edema
-Known underlying illness, surgical or medical condition, which is not related 
to ongoing event of severe malaria and which might jeopardize the 
participant's health in case of participation in the study or which might alter 
the distribution, metabolism or excretion of study treatment. For example:
1. neurological or neurodegenerative disorders,
2. cardiac, renal, or hepatic disease, diabetes,
3. epilepsy, cerebral palsy,

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4. known or suspected to be HIV-1 positive and/or receiving antiretroviral 
treatment
5. 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
6. known or suspected cases of active infections or concurrent febrile illness 
such as TB, Typhoid, COVID-19 etc.
Additional exclusion criteria are as follows:
Exclusion criteria for Cohort 1:
-ALT > 5 x the upper limit of normal range (ULN), regardless the level of total 
bilirubin
-Total bilirubin is > 3 mg/dL
-Body weight of < 35 kg or >75 kg
Exclusion criteria for Cohort 2:
-Body weight of < 35 kg or >75 kg
-Participants diagnosed as moderately severe malaria due to repeated 
vomiting without presence of any of the symptoms of severe malaria
Exclusion criteria for Cohorts 3 to 5:
-Body weight of < 5 kg
-Participants diagnosed as moderately severe malaria due to repeated 
vomiting without presence of any of the symptoms of severe malaria
Study treatment
Study treatments:

Cipargamin 10 mg/ml and/or 15mg/ml vial (investigational drug) for 
intravenous administration

Artesunate 60 mg vials (control drug) for intravenous administration
Study treatment will be followed by a full course of oral standard of care 
antimalarial.
Additional treatments:

Oral standard of care: artemether/lumefantrine

Rescue medication: IV artesunate
Treatment of 
interest
IV cipargamin versus IV artesunate
Efficacy 
assessments

Parasitemia

Clinical outcome as measured as normalization of signs of severe malaria
Pharmacokinetic 
assessments
Standard PK parameters of cipargamin and alpha-1-acid glycoprotein level 
over time
Key safety 
assessments

Adverse event monitoring

Physical examination

Vital signs

Laboratory assessments of blood and urine

ECG assessment

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1
Introduction
1.1
Background
Severe malaria is a medical emergency and affects primarily young children in Africa. Severe 
malaria is defined by presence of one or more of the systemic signs such as impaired 
consciousness, respiratory distress in relation to metabolic acidosis, convulsions, prostration, 
severe anemia, hypoglycemia, acidosis, liver and renal impairment, significant bleeding, shock, 
pulmonary edema and hyperparasitemia (WHO 2014). Injectable artesunate is the standard of 
care for the treatment of severe malaria and is highly efficacious. However, the spread of 
artemisinin-resistance Plasmodium falciparum in Asian countries poses a risk for future 
treatment of patients with this life-threatening disease. Treatment of severe malaria with IV 
artesunate should always be followed by a complete treatment course of an appropriate oral 
antimalarial regimen.
Cipargamin is a novel spiroindolone class drug with potent and fast-acting schizonticidal 
activity, which acts by disrupting the malaria parasite Na+ homeostasis by inhibition of the 
ATPase PfATP4. Cipargamin is being currently evaluated as an oral treatment for 
uncomplicated malaria and has demonstrated good efficacy in several clinical studies. Most 
recently, a phase IIa safety study with approximately 190 participants was completed in 2020 
(Investigator`s Brochure). Because of its rapid clearance of parasites (median parasite clearance 
time <12 hours) and because of its activity against artemisinin resistant parasites 
(Naß and Efferth 2019), cipargamin will be evaluated in the treatment of adults and children 
with severe malaria as an injectable treatment followed by a full course of standard oral 
artemisinin-based therapy Coartem®.
In this study, different doses of IV cipargamin will be compared to the standard of care, IV 
artesunate, with the goal of identifying efficacious and safe dose of injectable cipargamin to be 
administered in a subsequent phase III study. Both IV drugs will be followed by a full course 
of Coartem in accordance to WHO treatment guidelines.
1.2
Purpose
The purpose of this study is to identify safe and effective dose of intravenous cipargamin in 
moderately severe (Cohort 1) and severe malaria participants (Cohorts 2-5) in an age-
descending manner (refer Barnes et al 2004 for definition of moderately severe malaria and 
Section 16.4 for the definition of severe malaria). The study also aims to evaluate clinical 
success as a novel clinical outcome endpoint, which will be implemented in the confirmatory 
Phase III study.
The purpose of Cohorts 1 and 2 will be to establish efficacy, PK and safety of IV cipargamin in 
participants aged ≥ 12 years. Two cipargamin dose regimens will be evaluated in each of 
Cohorts 1 and 2. Based on the data obtained, one IV cipargamin dose will be selected for 
pediatric participants in Cohorts 3-5. Participants aged from 6 months to <12 years will be dosed 
using weight bands and age-specific considerations.

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2
Objectives and endpoints
All objectives and endpoints are in comparison of IV cipargamin to IV artesunate in participants 
with moderately severe or severe P. falciparum malaria.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the efficacy of IV 
cipargamin

Proportion of participants with ≥ 90% P. 
falciparum parasite reduction at 12 hours, see Section 2.1 for 
the primary estimand
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess clinical outcome

Proportion of participants with clinical success (see 
Section 8.3.1.1.) over time. Clinical success at 48 hours is 
considered as the key secondary endpoint, see Section 2.2
for the secondary estimand.

To assess the 
presence/absence of individual 
signs of severe malaria

Proportion of participants with individual signs of severe 
malaria over time (see Section 8.3.1.2).

To assess the risk of hemolysis

Proportion of participants developing hemolysis (early and 
delayed) after treatment (see Section 10.2.3)

To assess the risk of long term 
neurological sequelae

Proportion of participants with neurological sequelae at 
Day 29

To evaluate parasite clearance 
dynamics

Proportions of participants with ≥ 90% parasite reduction 
at 24 and 48 hours
PCE slope half-life
Time to P. falciparum parasite clearance (PCT)
P. falciparum parasite reduction ratios (PRR) at 12, 24 and 48 
hours
Proportion of participants with recrudescence and reinfection 
by Day 29

To assess other efficacy 
endpoints

Time (days and hours) to switch to oral therapy
Day of discharge from hospital
Time (hours) to recover from prostration

To evaluate the safety and 
tolerability of IV cipargamin

Standard safety/tolerability assessments (incidence of 
serious adverse events (SAEs), mortality, in-hospital 
mortality, adverse events (AEs), and routine safety and 
laboratory assessments)

To assess the plasma 
pharmacokinetics of IV cipargamin

PK parameters of cipargamin: Cmax, T1/2, AUC, CL and 
Vz
Alpha-1-acid glycoprotein level over time and correlation of 
AAG concentration with cipargamin PK parameters

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An estimand is a precise description of the treatment effect reflecting the clinical question posed 
by the trial objective. It summarizes at a population-level, what the outcomes would be in the 
same patients under each of the treatment conditions being compared. Attributes of an estimand 
include the population, variable (or endpoint) and treatment of interest. It also specifies how 
intercurrent events are addressed and provides a population-level summary for the variable. The 
structured framework of estimand detailed in ICH E9 (R1) was newly adopted by the 
Regulatory Members of the ICH Assembly under Step 4 in Nov-2019.
The clinical question of interest is: What is the difference between IV cipargamin and IV 
artesunate in early reduction of asexual parasite load in participants with severe P. 
falciparum malaria who are treated with at least one dose of IV treatment?
The justification for targeting this treatment effect is that severe P. falciparum malaria is caused 
by asexual parasite burden, leading to sequestration and microvascular obstruction. Rapid 
reduction of P. falciparum asexual parasites by 12 hours should prevent participants from 
further deterioration, and so allow eventual recovery from the disease.
The primary estimand is described by the following attributes:
1. Population: Participants with severe P. falciparum malaria and who have been treated with 
at least one dose of IV study medication (either cipargamin or artesunate). Further details 
about the population are provided in Section 5.
2. Variable: A binary outcome indicating ≥ 90% reduction in P. falciparum parasite at 12 
hours (H12) after first IV dose as compared to baseline.
3. Treatment of interest: IV cipargamin vs IV artesunate. Further details about cipargamin 
and artesunate are provided in Section 6.
4. Intercurrent events: (1) taking IV rescue antimalarial medication prior to H12 parasite 
assessment, or (2) mortality prior to H12 parasite assessment. Details on how to handle the 
intercurrent event are provided in Section 12.4.3.
5. Summary measure: Difference in proportion of participants with ≥ 90% reduction in 
baseline parasite count between IV cipargamin dose regimen and IV artesunate will be 
CCI

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evaluated within each cohort separately except Cohort 1, which will be combined with 
Cohort 2.
2.2
Secondary estimands
The secondary clinical question of interest is: What is the difference between IV cipargamin 
and IV artesunate in clinical success at 48 hours without the need of IV rescue antimalarial 
medication?
The justification for the secondary estimand is that it will reflect the clinical outcome including 
recovery from the most severe symptoms of the disease with IV treatment before earliest 
possible administration of oral antimalarial medication at 48 hours. This objective is being 
evaluated for possible use in Phase III study. Further details can be found in Section 12.
The secondary estimand is described by the following attributes:
1. Population: participants with severe P. falciparum malaria and treated with at least one 
dose of IV study medication. Further details about the population are provided in 
Section 5.
2. Variable: A binary outcome indicating clinical success- participant is alive and 
has absence of asexual parasites and no critical signs of severe malaria (See 
Section 8.3.1.2 for further details) at 48 hours.
3. Treatment of interest: IV cipargamin vs IV artesunate. Further details about cipargamin 
and artesunate are provided in Section 6.
4. Intercurrent event: receive IV rescue antimalarial medication before assessing the clinical 
success prior to H48.
5. Summary measure: Proportion of participants with clinical success with 90% CI within a 
treatment group as well as the difference between the cipargamin and artesunate treatment 
group.

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Study design
Figure 3-1
Study design
This will be an adaptive, multicenter, randomized, open label, sequential cohort study in 
participants aged ≥ 12 years old in Cohorts 1-2 and < 12 years old to ≥ 6 months in Cohorts 3-
5 with a diagnosis of moderately severe and severe P. falciparum malaria (Section 16.4). This 
study is investigating the efficacy (parasite reduction and clinical outcome), safety, tolerability 
and pharmacokinetics of different injectable dose regimens of cipargamin in comparison to 
injectable artesunate. Cohort 1 includes only 18 participants aged ≥ 12 years old. As IV 
cipargamin has not yet been evaluated in patients with severe malaria, this first Cohort includes 
participants that are diagnosed with moderately severe malaria. Cohort 1 participants will have 
a minimum parasite count of 60,000 per µl and these high parasitemia levels will help to
determine parasite clearance rates for the two dose regimen. In Cohorts 2-5 participants with 
severe malaria and a minimum parasite count of 5,000 per µl will be enrolled in an age-
decreasing manner. This design aims at minimizing risks for pediatric participants < 12 years 
and at ensuring sufficient number of participants with severe malaria signs to evaluate their 
clinical improvement in the secondary endpoint. In all cohorts, participants on IV cipargamin 
arms will receive one daily injection of IV cipargamin over a minimum of 2 days and a 
maximum of 3 days; with IV artesunate as rescue medication. Participants in the IV artesunate 
arm will be administered a minimum of 3 doses during the first 2 days of treatment. Participants 
in all arms will receive Coartem bid for 3 days following IV therapy.

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See sections Section 6.1.1, Section 6.1.2.1 and Section 6.2.1 for details of each treatment arm.
Cohorts 1-2:
In Cohorts 1 and 2, 18 and 42 participants ≥ 12 years, who satisfy the inclusion/exclusion 
criteria will be randomized in the ratio 1:1:1 to one of three treatment arms. :

IV cipargamin (KAE609) dose regimen 1

IV cipargamin (KAE609) dose regimen 2

IV artesunate
The two doses of IV cipargamin for Cohorts 1 and 2 have been selected based on the rationale 
described in Section 4.2. The doses might be adjusted before the study start based on results 
obtained from the first in human (FIH) study in healthy volunteers to ensure exposure is 
maintained within the predicted safe and efficacious range (AUC 0-24h of 5-42 μg*hr/ml) in the 
study participants.
Cohorts 3-5:
The results from Cohorts 1 and 2 will be analyzed to determine the safe and efficacious exposure 
range and the corresponding doses (cipargamin (KAE609) dose regimen 3) for the participants 
in Cohorts 3 to 5. In these Cohorts all participants will be pediatric and below 12 years of age. 
Only one dose of IV cipargamin will be selected for use in Cohorts 3-5 (see Section 4.2). For 
the pediatric participants in Cohorts 3 to 5, a convenient dosing regimen based on weight bands 
will be defined (Section 4.2). The results from Cohort 1 and Cohort 2 will be summarized for 
interim assessment (IA), and the data will be reviewed by an Independent DMC before 
continuing to dose pediatric participants < 12 years in Cohorts 3-5. The IA will be performed 
on key efficacy, safety and PK data up to Day 29.
In the age descending Cohorts 3 to 5 the PK exposure will be confirmed in up to 6 participants 
per cohort treated with IV cipargamin before recruiting remaining participants. PK data 
obtained from these initial participants from every cohort may lead to modification of the 
selected dose in order to maintain IV cipargamin exposure within the determined safe and 
efficacious range. At the same time, recruitment in the subsequent younger age Cohort will be 
started for the first 6 participants. In case of a need for dose modification in a particular Cohort, 
additional participants maybe recruited into that cohort to ensure data are available for 
approximately 38 participants at the selected dose level.

Cohort 3: Pediatric participants ≥ 6 y - < 12 y

Cohort 4: Pediatric participants ≥ 2 y - < 6 y

Cohort 5: Pediatric participants ≥ 6 m - <2 y
In Cohorts 3 to 5 approximately 192 participants (aged ≥ 6 months to < 12 years) who satisfy 
the inclusion/exclusion criteria will be randomized in a 1:1 ratio to one of two treatment arms:

IV cipargamin (KAE609) dose regimen 3

IV artesunate
Study conduct
Participants will be admitted to the hospital on Day 1 and screened for inclusion in the study. If 
they meet the eligibility criteria they will be randomized to treatment within 3 hours of 

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admission. Participants will be hospitalized under close supervision for at least 72 hours after 
start of IV treatment and until oral treatment with Coartem has been initiated. Hospitalization 
can be extended, if needed, for participants based on disease signs, until IV treatment has been 
completed and oral treatment with Coartem has been initiated. All participants should be 
followed up until Day 29. Visits to assess safety and efficacy will be scheduled during the 
follow-up period as described in the assessments schedule (Table 8-1, Table 8-2). If malaria 
symptoms re-emerge outside the scheduled study visits or any other adverse events occur, 
participants will be instructed to contact the investigator. Study design and assessments will 
slightly vary between cohorts, details are captured in Section 5 and Table 8-1, Table 8-2. The 
safety of the entire study will be monitored by a Data Monitoring Committee (DMC) and 
stopping criteria (based on safety and lack of efficacy criteria) are in place throughout the study 
(Table 3-1). Recruitment in any treatment arms with cipargamin (KAE609) will be paused 
if stopping criteria are met. In event of recruitment pause, all relevant data will be reviewed in 
an ad-hoc DMC meeting and the next steps to be taken with the relevant IV cipargamin dose 
will be decided by Novartis based on the DMC’s recommendation. Planned DMCs will occur 
at the end of Cohort 2 and at the end of Cohort 4. Additional DMC meetings may be conducted 
depending on the need.
Participants in all cohorts will be closely monitored through parasitological, biochemical, 
hematology, physical and neurological examinations (Table 8-1, Table 8-2 and Section 8.3.1). 
Rich PK sampling will be done in Cohorts 1 - 3 and sparse PK sampling will be done in Cohorts 
4-5 for IV cipargamin participants.
Stopping criteria for the study
Data related to participant's efficacy and safety will be continuously monitored by the sponsor. 
If participants randomized to any IV cipargamin arms meet either the safety criteria or lack of 
efficacy criteria as listed in Table 3-1 below, the study may be paused and a DMC review 
conducted.
Table 3-1
Criteria to temporarily pause the recruitment and initiate DMC review
Cohorts with planned 
recruitment
Number of participants 
meeting the safety criteria*
Number of 
participants meeting the lack 
of efficacy criteria**
Cohort with 6 participants
2
2
Cohort with 14 participants
2
2
Cohort with 20 participants
3
3
Cohort with 38 participants
6
6
Throughout the study ( 116 
participants within a single IV 
cipargamin treatment arm)
14
14
*Safety criteria - All cause death or SAE possibly related to cipargamin
**Lack of efficacy criteria – Use of IV artesunate as rescue medication (as per protocol defined 
criteria) in participants randomized to IV cipargamin

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Rationale
4.1
Rationale for study design
As severe malaria is primarily a disease of young children, children down to 6 months have 
been included in this clinical study to obtain data in the relevant patient population. In order to 
ensure adequate efficacy and safety, pediatric participants will be included in an age descending 
manner with the youngest participant between 6 months and 2 years of age enrolled in the final 
cohort after IA and DMC.
As IV cipargamin has not yet been evaluated in patients with severe malaria, Cohort 1 will start 
with a study population, which is less severely ill and ≥ 12 years old. Participants diagnosed 
with moderately severe malaria and high parasitemia (60,000-250,000 parasites per µl) at 
baseline and without significant elevations in liver function tests (ALT and total bilirubin, see 
Section 5.2) will be randomized to Cohort 1. The selected inclusion criteria should limit the 
variability of the disease signs of participants included in Cohort 1, while allowing for efficacy 
assessment based upon parasite clearance and initial safety monitoring. If stopping criteria 
(Table 3-1 in Section 3) are not met in any of the IV cipargamin arms in Cohort 1, recruitment 
of Cohort 2 will be initiated after LPLV (last patient last visit) of Cohort 1. In case of any 
efficacy/safety concerns identified in Cohort 1, PK data will be analyzed and the following 
actions could be taken in consultation with the data monitoring committee (DMC):

Up to six additional participants per treatment arm may be recruited in Cohort 1 before 
proceeding to Cohort 2

Dose for Cohort 2 may be modified (increased or decreased) to ensure exposure within the 
safe and efficacious range
In Cohort 2, participants in the same age population of ≥ 12 years diagnosed with severe malaria 
(Section 16.4) will be enrolled. Participants in Cohorts 2 to 5 will be enrolled with parasitemia 
levels of at least 5,000 parasites per µl. An interim assessment after Cohort 2 will evaluate 
efficacy, safety and PK results of the two IV cipargamin doses compared to IV artesunate. 
Based on these results, a safe and efficacious exposure range will be defined for the use in 
Cohorts 3-5. The dose for Cohorts 3-5 will be selected to ensure that exposure in children < 12 
years of age remains within the determined safe and efficacious range.
Parenteral artesunate is the first line treatment for severe malaria as recommended by 
WHO 2015. All participants will be treated with IV cipargamin or IV artesunate for at least 24 
h (minimum of 2 doses of IV cipargamin and 3 doses of IV artesunate) and until oral therapy 
can be tolerated. IV therapy will be followed by oral antimalarial therapy as per standard 
treatment practice. The oral treatment is a 3-day course of Coartem to ensure complete 
elimination of parasites in participants.
The open label design is chosen since the dosing frequency and method of administration of 
test drug and comparator is not similar. Hence, blinding the treatment would require multiple 
placebo injections in a double dummy design which is ethically not acceptable considering the 
severity of the disease and need for inclusion of pediatric participants. Furthermore, the risk of 
bias arising out of the open-label design is minimized due to the objectivity of the primary 
endpoint, which is based on reduction of parasitemia.

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Parenteral antimalarial treatment followed by a full course of oral antimalarial therapy is the 
standard of care for management of parasitemia and achieving cure in severe malaria patients 
(WHO 2015). In addition, supportive treatment is required to manage severe malaria. Such 
treatments include but are not limited to blood transfusions, fluid replacement therapy, 
anticonvulsants and glucose transfusions. Supportive treatment for management of severe 
malaria will be administered as per local treatment guidelines and will be documented as 
concomitant medication in the study database. A minimum basic standard of supportive 
treatment will be maintained across all the sites participating in the study. Participants should 
not receive any additional antimalarial drug unless used as rescue medication as per protocol.
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The primary aim of the intravenous antimalarial treatment in severe malaria is a rapid reduction 
of the initial parasite load. The efficacy of oral cipargamin in terms of parasite clearance has 
been demonstrated in previous studies using single doses between 10 mg and 150 mg. In study 
CKAE609A2202, aparasitemia was achieved by as early as 12 hours post-dose in the majority 
of the subjects treated with a single dose of oral cipargamin of ≥ 25 mg and by 24 hours post-
dose in the majority of the subjects treated with oral cipargamin irrespective of dose.
 
 
 
IV artesunate, the standard of care for severe malaria, has reported mean PRR24 values between 
7 and 43 across studies (Newton et al 2001, Nealon et al 2002, Newton et al 2003, 
Maude et al 2014). The 
from four oral cipargamin studies including more than 150 participants with uncomplicated 
malaria (CKAE609X2201, CKAE609X2202, CKAE609A2201 and CKAE609A2202) is 
shown in Figure 4-1. In these studies, participants with baseline parasitemia of up to 60,000 
parasites per μl were included 
 oral cipargamin 
treatment. The full exposure-response relationship in participants with hyperparasitemia, as 
expected in severe malaria, remains to be elucidated.
In the same study CKAE609A2202, no safety concerns in patients with uncomplicated malaria 
were associated with 
 
 The doses of IV cipargamin in this 
study have been selected in order not to exceed these mean exposures from the previous study.
The PK exposures of cipargamin following IV administration were predicted using a population 
PK model based on preliminary data from the first two cohorts of the ongoing phase 1 study 
CKAE609X2111. An adjustment in predicted exposures was made 
 
 (Silamut et al 1991) and the 
impact of 
 observed in studies in uncomplicated 
malaria and in healthy volunteers study,
CKAE609X2111.
Based on the above criteria, selected doses for Cohorts 1-2, i.e. 20 and 40 mg once every 24 
hours, are expected to provide exposures within the safe and efficacious range. Due to the half-
life of cipargamin of approximately 24 hours, cipargamin is expected to accumulate with daily 
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dosing. To limit the total exposure of IV cipargamin in this first study of IV cipargamin in 
malaria patients, participants will receive a maximum of 3 daily doses. For severe cases, the 
total duration of IV therapy (either IV cipargamin followed by IV artesunate or IV artesunate 
alone) will be defined by the medical condition of the participants and the prescribing 
information of IV artesunate.
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The lowest dose selected for Cohorts 1-2 i.e. 20 mg is expected to 
 
 
As such, this dose is expected to provide 
equivalent or faster initial parasite clearance than the standard of care i.e. artesunate and thereby 
minimize the risk for severely ill participants due to slow parasite clearance.
A dose of 40 mg is expected to provide 
 
 observed with oral cipargamin in participants with uncomplicated malaria (refer 
Figure 4-1 below). Hence, a fast parasite clearance rate is expected to be achieved in all the 
participants and a full dose response curve can be obtained to ensure that the appropriate benefit 
risk relationship is established in adolescent and adult participants before dosing children below 
12 years in Cohorts 3-5. The anticipated exposure with 40 mg dose is comparable to the highest 
exposure, which was achieved in oral cipargamin in study CKAE609A2202 without any safety 
issues.
In conclusion, the inclusion of 20 and 40 mg doses in Cohorts 1-2 will cover a wider exposure 
range and facilitate the selection of an appropriate dose for later Cohorts 3-5.
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A single dose level with the best benefit risk potential will be evaluated in participants < 12 
years old based on interim assessment of data from Cohorts 1 and 2. The population PK and / 
or PBPK model will be developed / up-dated with this data to predict exposures in participants 
from Cohort 3-5. If required, the speed of IV bolus administration may be adjusted to keep the 
Cmax within the safe range as determined in Cohorts 1-2. 
 
 
 
 
 
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Parenteral artesunate is the WHO recommended first line treatment for severe malaria 
(WHO 2015). Three IV doses are given over the first 24 h (0, 12 and 24 h) and then q24h until 
oral therapy can be tolerated. A full course of oral treatment (artemisinin based combination 
therapy, Coartem in this study) is given afterwards to ensure elimination of the malaria parasite. 
Other 
treatments 
available 
for 
severe 
malaria 
are 
such 
as 
IM artesunate, 
IV quinine and intramuscular artemether. However, these treatments are only recommended 
when IV artesunate is not available.

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An interim assessment (IA) will be performed after completion of Cohort 2. The study team 
and an independent DMC will review key PK/efficacy/safety data including the proportion of 
participants with ≥ 90% parasite reduction at 12 hours as well as at 24 and 48 hours and parasite 
reduction ratios, relevant safety data and PK data from all participants of Cohorts 1 and 2. Based 
on data from Cohorts 1 and 2, the highest safe and effective exposure will be determined and 
used to select doses for Cohorts 3-5.
For subsequent Cohorts 3-5, randomization will start with the next descending age group. 
Novartis pharmacokineticist will review the PK exposure and AAG (if required) in up to 6 
participants treated with IV cipargamin. After confirming that the exposures are adequate, 
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enrollment of participants will continue in the initial cohort (applicable for Cohorts 3-5) and the 
next lower age cohort will be opened for enrollment. However, enrollment for Cohort 5 will 
only be initiated post completion of Cohort 4 and a DMC meeting. In case, the dose for a 
specific age group has to be adjusted, additional participants with the modified dose may be 
recruited.
Additional IAs may be conducted (for e.g. after Cohort 4) to support decision making 
concerning the current clinical study, the sponsor’s clinical development projects in general, or 
in case of any safety concerns.
Following dose and design adaptations are permitted in the study as per below Table 4-1:
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Severe malaria is a medical emergency and is affecting primarily young children in Africa. With 
currently only one WHO recommended IV treatment, there is considerable medical need for an 
additional treatment option as injectable antimalarial. Based on the preclinical and clinical 
evaluation to date, as presented in the Investigator`s Brochure, oral cipargamin has been 
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generally safe and well tolerated. Healthy subjects have been dosed up to single oral doses of 
300 mg, and repeated oral doses up to 150 mg q24h for 3 days, and patients up to single oral 
doses of 150 mg, and repeated oral doses of 50 mg. The participants in this study will be 
receiving IV cipargamin for the treatment of severe malaria and based on the positive efficacy 
results with the oral formulation in the treatment of uncomplicated malaria, they are expected 
to receive benefit from it. The risk to participants (as per Investigator`s Brochure) will be 
minimized by adherence to the inclusion/exclusion criteria, stopping rules, close clinical 
monitoring (including multiple laboratory evaluations as per the Assessment Schedule), the 
staggered design of the study with PK and safety reviews between cohorts. The exposure 
with selected doses of IV cipargamin is not expected to exceed exposures already 
observed with oral cipargamin.
Cohort 1 of the current study will include participants aged ≥ 12 years suffering from 
moderately severe malaria accompanied by a high parasite count. Younger participants will 
only be enrolled in Cohorts 3-5 of the study in descending age order. There will be safety, 
efficacy and PK assessments after Cohort 2 to confirm the dose for Cohorts 3-5, which will be 
administered to children aged ≥ 6 months to 12 years. Participants will be hospitalized under 
close supervision until they are considered fit to be discharged by the investigator. Stopping 
criteria will be applied as mentioned in Section 3 and all participants will be closely monitored 
on an ongoing basis. Recruitment in a specific treatment arm can be put on hold, as necessary.
Expected benefits of IV cipargamin
Based on available evidence about rapid parasite reduction with oral cipargamin in 
uncomplicated malaria, IV cipargamin is also expected to provide rapid parasite reduction in 
severe malaria patients. Rapid parasite reduction should lead to an improvement in clinical 
symptoms and overall clinical benefit for the patient.
However, overall clinical outcome in severe malaria patients is dependent on the comprehensive 
case management including supportive treatment. Hence, at least a basic minimum standard of 
supportive therapy will be maintained across all the sites in this study.
Potential risks with the use of IV cipargamin
Resistance
The risk of developing resistant strains of parasite is low since IV monotherapy will be followed 
by oral standard of care in all the patients. Any recrudescence or new infection will be managed 
with standard of care pharmacotherapy that should effectively eliminate any parasites.
Delayed hemolysis
Based on prospective studies delayed hemolysis has been detected in 7-27% of the severe 
malaria participants treated with IV artesunate (Rolling et al 2014, Kurth et al 2017). 
Hyperparasitemia in non-immune travelers and young age in the endemic regions are the 
confirmed risk factors. The hemolytic event typically peaks 2-3 weeks after the acute phase of 
malaria. Removal of dead parasites from the erythrocytes in the spleen and leaving behind the 
"once-infected" erythrocytes, which are characterized by a shorter life span, is one of the 
assumed mechanism. Based on the mechanism of action of cipargamin, delayed hemolysis 
might occur also in connection with IV cipargamin therapy. All participants will be followed 
up closely for at least 4 weeks and given supportive treatment as needed.
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Liver safety
Reversible and asymptomatic LFT elevations were observed with 75 mg single dose in a patient 
study in uncomplicated malaria and with 10 mg single dose in a human challenge study 
(Investigator`s Brochure). Increase in LFT levels in these studies could have been influenced 
by the disease condition itself and/or the specific human challenge model (Chughlay et al 2020). 
Changes in LFTs are often associated with malaria but liver function generally improves as the 
patient recovers (Reuling et al 2018, Woodford et al 2018). In Cohort 1 of the study, 
participants with ALT > 5 x ULN (regardless the level of total bilirubin) and total bilirubin is > 
3 mg/dL will be excluded. In this study, all participants will be closely monitored, including 
regular liver function tests, and in addition, it will be ensured that all participants would have 
access to standardized supportive treatment like IV fluid replacement and transfusion.
Semen discoloration
In the Phase I first-in-human study with oral cipargamin (CKAE609X2101), 29 participants at 
high doses of oral cipargamin reported transient yellow discoloration of their ejaculate but no 
other genitourinary symptoms. The symptoms were self-limiting and did not require 
intervention. Screening semen analysis studies did not reveal significant abnormalities in those 
taking cipargamin. As a precautionary measure, participants in this study should wear a condom 
during intercourse for one week following the last dose.
IV preclinical safety risks
To support dosing IV cipargamin to humans, IV toxicology studies with the clinical formulation 
1 have been completed in rat and dog (Investigator`s Brochure). The target organ of toxicities 
identified were mostly comparable to the ones identified in oral toxicity studies performed 
previously and included liver, adrenal glands and bone marrow. The main target organ of 
concern was the adrenal gland (Investigator`s Brochure). Lesions were seen in oral and IV 
toxicology studies in dogs, but so far no clinical correlates have been seen in animals or humans. 
Adrenal function will continue to be monitored in clinical studies.
In addition, signs of inflammation (neutrophil increase) were observed in blood and a few 
tissues in both species and a mild decrease in reticulocytes in dogs. The mechanism is unknown 
and these observations were reversible. Participants in this study will be monitored for any signs 
of increased inflammation.
The clinical formulation 1 (intravenous cipargamin injection) lead to local reaction (thrombus) 
in rat but not in dog. The human relevance is unknown and potential local reaction at injection 
site will be monitored in patients. In this clinical study, clinical formulation 2 (10mg/ml) might 
be used, which is identical to clinical formulation 1 (15mg/ml) with the exception of one 
excipient, which is replaced by structurally similar excipient.
During second week of dosing in the dog IV study, cipargamin-related increase in QTc interval 
was noted. These changes are of unknown relevance, as no changes were observed after single 
IV dose, or in the oral toxicology studies. In patients, QT changes are not expected; nevertheless, 
ECG will be monitored for QTcF and cardiac abnormalities.
Cipargamin is non genotoxic and based on animal reproductive and developmental studies, no 
teratogenicity was noted. However, effects on female fertility and fetotoxicity was seen in rats 
at doses that were associated with maternal toxicity. The effects of cipargamin on the human 

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fetus are not known. Therefore, women of childbearing potential may be enrolled only if they 
have a negative pregnancy test prior to receiving cipargamin. Male and female patients have to 
agree to adhere to contraceptive requirements outlined in the exclusion criteria (Section 5.2).
Weak phototoxicity seen in an in vitro test system did not translate to an in vivo mouse model. 
Nevertheless, participants taking cipargamin are advised to use commonly recommended 
precautions when in the sun (e.g. sunscreen, hat, protective clothing).
Comparator IV artesunate
The most important reported side effect of parenteral artesunate is a rare severe allergic reaction, 
which has involved urticarial rash as well as other symptoms, including hypotension, pruritus, 
edema, and/or dyspnea. More common minor side effects associated with IV administration 
have included dizziness, light-headedness, rash, and taste alteration (metallic/bitter taste). 
Nausea, vomiting, anorexia and diarrhea have also been reported, however it is uncertain 
whether such events have been symptoms of severe malaria (Artesunate PI). Participants will 
be closely monitored, including for the signs and symptoms for delayed hemolytic anemia.
Additional considerations
As is the case with any new compound in clinical development, there are unknown risks to 
cipargamin that may be serious and unforeseen.
The current IV cipargamin formulation should not be administered IM or SC 
(Investigator`s Brochure). For IV administration, monitoring of injection sites is required. If 
extravasation occurs, the IV administration must be stopped. Observe and manage 
conservatively.
In summary, the demonstrated efficacy in uncomplicated malaria with the acceptable safety 
profile in participants from both Phase I and Phase II studies demonstrates an acceptable risk-
benefit to investigate the utility of IV cipargamin in the treatment of severe malaria.
5
Study Population
The study population will consist of male and female participants, including pediatric 
participants ≥ 6 months or older.
The plan is to randomize approximately 252 participants (60 participants of ≥ 12 years or older 
and 192 participants < 12 years) in approximately 20 sites from Africa and Asia. Enrollment 
may be increased due to higher drop out or repeat of cohorts as applicable.

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5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Cohort 1: Participants aged ≥ 12 years with moderately severe malaria as defined in 
Barnes et al (2004) (prostration and/or repeated vomiting) without presence of other signs 
of severe malaria (Section 16.4) and with high P. falciparum parasitemia (60,000-250,000 
parasites per µl).
Subsequent Cohorts 2 to 5: Participants diagnosed with severe malaria as defined in 
Section 16.4 (modified version of severe malaria criteria in WHO 2014) and P. 
falciparum parasite count of ≥ 5000 per µl
Cohort 2: Participants aged ≥ 12 years
Cohort 3: Participants aged 6 - <12 years
Cohort 4: Participants aged 2 - < 6 years
Cohort 5: Participants aged ≥6 months - <2 years
2. Written informed consent form must be obtained prior to any study related procedure. If 
the participant is unable to read and write or otherwise incapable of signing an informed 
consent, then a witnessed consent according to local ethical standards is permitted 
(formally documented and witnessed, ideally via an independent trusted witness). 
Participants aged < 18 years, who are capable of providing assent, must provide assent 
with parental/legal guardian consent or as per local ethical guidelines. The participant or 
parent/legal guardian (in case of pediatric participants) is able to understand and comply 
with protocol requirements, instructions and protocol-stated restrictions for their child and 
is likely to complete the study as planned.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Exclusion criteria applying to all Cohorts 1 to 5:
1. Mixed Plasmodium infections
2. Treatment with quinine or artemisinin derivative or any other antimalarial drug or any 
antibiotic with known antimalarial activity within 12 hours of screening
3. Known underlying illness, surgical or medical condition, which is not related to 
ongoing event of severe malaria and which might jeopardize the participant's health in 
case of participation in the study or which might alter the distribution, metabolism or 
excretion of study treatment, e.g. :

neurological or neurodegenerative disorders,

cardiac, renal, or hepatic disease, diabetes,

epilepsy, cerebral palsy,

known or suspected to be HIV-1 positive and/or receiving antiretroviral treatment

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

known or suspected cases of active infections or concurrent febrile illness such as 
TB, Typhoid, COVID-19 etc.

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4. Known history of ECG abnormalities indicating significant risk of safety for 
participants such as:
a. Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker
b. History of familial long QT syndrome or known family history of Torsades de 
Pointes
c. QTcF > 450 ms in males and QTcF > 460 ms in females aged ≥ 12 years old and 
QTcF > 450 ms in females aged < 12 years.
5. Signs/symptoms of severe malnutrition in general accordance with WHO guidelines:

Under 18 years: <-3 Z-scores of WHO growth standard for weight-for-
height/length (in children < 5 years) or BMI for age (5-18 years), or very low mid-
upper arm circumference (MUAC <115 mm in children < 12 years, <160mm 12-
18 years), or bilateral pitting edema

Over 18 years: BMI < 16 kg/m2 or MUAC < 160mm or bilateral pitting edema
6. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days, whichever is longer; or longer if required by local 
regulations
7. Participants taking prohibited medication defined as per Section 6.2.3
8. Pregnant or nursing (lactating) women
9. Female of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective contraception methods 
(listed below) during dosing and until one week after last IV dose or until start of next 
menstruation after last dose of oral standard of care (Coartem), whichever is later. 
Required highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (i.e., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of 
contraception
b. Male partner sterilization (at least 6 months prior to screening). The 
vasectomized male partner should be the sole partner for that participant
c. Female sterilization (have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone 
level assessment
d. Use of oral (e.g. estrogen, synthetic progestins), 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 hormonal vaginal ring or 
transdermal hormone contraception. In case of use of oral contraception women 
should have been stable on the same pill for a minimum of 3 months before 
taking study treatment. Coartem can reduce the effectiveness of hormonal 

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contraceptives, female participants using oral, transdermal patch, or other 
systemic hormonal contraceptives are required to use an additional non-hormonal 
method of birth control, e.g., barrier contraceptives during dosing of oral 
Coartem and until the start of next menstruation after completion of oral 
treatment.
e. Females 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.
f.
If local regulations deviate from the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF.
10. Sexually active males unless they are using highly effective contraception method as 
listed below:
a. Use of condom during intercourse while taking drug and until one week after last 
IV dose and should not father a child in this period.
b. Use of condom by vasectomized participant in order to prevent delivery of the 
drug via body fluids.
Additional specific exclusion criteria for Cohorts 1-5 are as follows:
2. Exclusion criteria for Cohort 1:
1. ALT > 5 x the upper limit of normal range (ULN), regardless the level of total 
bilirubin
2. Total bilirubin is > 3 mg/dL
3. Body weight of < 35 kg or > 75 kg
3. Exclusion criteria for Cohort 2:
1. Body weight of < 35 kg or >75 kg
2. Participants diagnosed as moderately severe malaria due to repeated vomiting without 
presence of any of the symptoms of severe malaria.
4. Exclusion criteria for Cohorts 3 to 5:
1. Body weight of < 5 kg
2. Participants diagnosed as moderately severe malaria due to repeated vomiting without 
presence of any of the symptoms of severe malaria.

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6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Novartis will supply following study drugs (Investigational and control drug) as open label 
participant specific supplies as per Table 6-1.

Cipargamin (KAE609) 10 mg/ml and / or 15 mg/ml vial (investigational drug) for 
intravenous administration

Artesunate 60 mg vials (control drug) for intravenous administration
Apart from Investigational and control drugs, Novartis will also supply additional treatments as 
rescue medication (Artesunate 60 mg vials) and oral medication as standard of care (Coartem 
20/120 and 80/480 mg tablets).
Table 6-1
Investigational drugs, control drug and oral standard of care
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form 
and Packaging
Route of 
Administration
Supply Type
Sponsor (global 
or local)
KAE609 15 
mg/ml
Solution for 
injection; 1 vial 
per box
Intravenous use
Open label
Novartis global
KAE609 10 
mg/ml
Solution for 
injection; 1 vial 
per box
Intravenous use
Open label
Novartis global
Artesunate 60 
mg/vial*
Powder for 
reconstitution; 1 
vial per box
Intravenous use
Open label
Novartis global
Coartem® 20/120 
mg**
Dispersible tablet; 
6 tablets in a 
blister
Oral
Open label
Novartis global
Coartem® 80/480 
mg**
Tablets; 6 tablets 
in a blister
Oral
Open label
Novartis global
*Control drug and rescue medication
** Oral medication as standard of care
Dosing of study drugs for Cohorts 1-5 are described in below Table 6-2:
Table 6-2
Dosing Regimen for IV cipargamin (KAE609) and IV artesunate
Cohort
Treatment arms
Dosing Regimen
1-2
IV KAE609 20 mg - dose 
regimen 1
Minimum of two doses; q24h 
(to be administered at 0 hour 
and 24 hours) and not 
exceeding three doses (Dose 3 
at 48 hours) followed by oral 
medication (Coartem® bid for 3 
days)

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Cohort
Treatment arms
Dosing Regimen
1-2
IV KAE609 40 mg - dose 
regimen 2
Minimum of two doses; q24h 
(to be administered at 0 hour 
and 24 hours) and not 
exceeding three doses (Dose 3 
at 48 hours) followed by oral 
medication (Coartem® bid for 3 
days)
3-5
IV KAE609 - dose regimen 3
Minimum of two doses; q24h 
(to be administered at 0 hour 
and 24 hours) and not 
exceeding three doses (Dose 3 
at 48 hours) followed by oral 
medication (Coartem® bid for 3 
days).See Section 4.2 for 
process of dose selection for 
Cohorts 3-5
1-5
IV Artesunate 2.4 mg/kg (for 
participants weighing at least 
20 kg)  
IV Artesunate 3 mg/kg (for 
participants weighing less than 
20 kg)
0, 12, and 24 h and q24h for 
maximum 8 doses (7 days) 
according to label and until oral 
medication (Coartem® bid for 3 
days) can be given according 
to label
Coartem is used according to the supplied labels in the study.
The proposed Coartem doses for Cohorts 1-5 are as mentioned in below Table 6-3:
Table 6-3
Cohort 1-5: Coartem® (standard of care) dosing per weight (dosing as 
per label)
Weight
Coartem® dosage
≥ 35.0 kg (and ≥ 12 years)
80/480 mg BID for 3 days
25 to < 35 kg
60/360 mg BID for 3 days
15 to < 25 kg
40/240 mg BID for 3 days
5 to < 15 kg
20/120 mg BID for 3 days
6.1.2
Additional study treatments
6.1.2.1
Oral medication (standard of care)
All sites will receive Coartem as standard of care for oral treatment as per local 
practice. Following criteria are recommended for specified timepoints when switching 
participant from IV therapy to oral therapy as mentioned in below Table 6-4:
First timepoint to switch participant from IV therapy to oral is at 48 hour. However, if a 
participant is not able to tolerate oral therapy then continue with IV treatments and evaluate 
again at 72 hour timepoint.

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Table 6-4
Criteria for switch to oral medication (standard of care)
Time
Decision criteria
Decision
0 hours
Review screening results
Start dosing with IV therapy
24 hours
Assess rescue medication
criteria
Continue IV therapy (and 
assess rescue medication 
criteria for participants on IV 
cipargamin) (see Section 6.2.1)
48 hours (Day 3)
(1st timepoint for a switch to 
oral therapy)
Assess the feasibility of 
administering oral medication
Start Coartem, if switch criteria 
are met as per label. Otherwise 
continue IV therapy (and 
assess rescue medication 
criteria per Section 6.2.1)
72 hours (Day 4) onwards
Assess the feasibility of 
administering oral medication 
at every 24 hours
Start Coartem, if switch criteria 
are met as per label. 
Otherwise continue IV 
artesunate or switch to IV 
artesunate therapy (for 
participants on IV cipargamin 
as per Section 6.2.1).
Hospitalization should be 
extended till the time 
participant has not switched to 
oral therapy and assessments 
to be repeated as Day 4 if 
hospitalization is required 
beyond Day 4 (see Table 8-1, 
Table 8-2)
Intravenous artesunate can be administered to a maximum of 7 days based as per supplied labels.
Most participants after switching to oral therapy will be discharged from hospital with full oral 
course of Coartem for 3 days. Site to instruct participant (or participant's representative) on 
intake of oral therapy per label.
After switching to oral therapy (Coartem), if there are efficacy or safety concerns, the 
participant will be administered another ACT (Section 6.2.1) as per local treatment guidance.
6.1.2.2
Supportive therapies
Supportive treatment is required to manage severe malaria. Such treatments include but are not 
limited to blood transfusions, fluid replacement therapy, anticonvulsants (refer to Section 6.2.2) 
and glucose transfusions. Supportive treatment for management of severe malaria will be 
administered as per local treatment guidelines and will be documented as concomitant 
medication in the study database. A minimum basic standard of supportive treatment will be 
maintained across all the sites participating in the study.

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6.1.3
Treatment arms/group
Cohorts 1-2
Participants in each Cohorts (1 to 2) will be randomized into three treatment arms in 1:1:1 ratios 
to each IV cipargamin (KAE609) arms and IV artesunate:

IV cipargamin 20 mg - dose regimen 1

IV cipargamin 40 mg - dose regimen 2

IV artesunate
Cohorts 3-5
Participants in each Cohorts (3 to 5) will be randomized into two treatment arms in 1:1 ratios 
to IV cipargamin (KAE609) arm and IV artesunate:

IV cipargamin - dose regimen 3 ( See Section 4.2 for process of dose selection for Cohorts 
3-5)

IV artesunate
Dosing regimen as explained in Section 6.1.1
6.1.4
Treatment duration
Participants will be treated with IV cipargamin (KAE609) once daily for at least 24 hours (2 
doses) and a maximum of 48 hours (3 doses). Participants requiring prolonged IV treatment 
will be switched to IV artesunate and treated according to local practice. Participants in control 
arms will receive IV artesunate for at least 24 hours (3 doses) and for a maximum of 7 days if 
necessary as per label or until oral Coartem (standard of care) can be tolerated, whichever is 
earlier (see criteria for switch to oral therapy in Section 6.1.2.1).
6.2
Other treatment(s)
6.2.1
Rescue medication
Management of severe malaria consists of an IV antimalarial (cipargamin or artesunate in the 
study) followed by a full course of oral standard of care (Coartem in this study). Hence, rescue 
medication use will also be either IV medication or oral medication as applicable.
Participants randomized to IV artesunate will not be administered any other IV antimalarial as 
rescue medication since IV artesunate is the only standard of care. Participants randomized to 
IV cipargamin may be rescued with IV artesunate, if they meet the following pre-defined 
criteria:

Parasite clearance < 90% at 24 hours post treatment initiation

Clinical decline of severe malaria symptoms (per Investigator) at any time

Participants not able to take oral antimalarial along with presence of parasites at 72 hour 
post treatment initiation

Participants developing signs or symptoms of severe malaria after shift to oral standard of 
care (Coartem) until end of the study (Day 29).

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In addition, participants developing safety concerns due to cipargamin (Refer also Section 16.1, 
Section 16.2 ) can be rescued with IV artesunate.
After completion of full course of Coartem, participants meeting the following criteria will be 
administered another ACT (as per local guidance) as an oral rescue medication:
!
Parasitemia at any time with or without temperature > 37.5ºC

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Prior medications are defined as drugs taken and stopped prior to the first dose of study 
medication. In this study, all medication administered or taken by the participants up to 72 hours 
prior first dose has to be reported as prior medication in the appropriate Case Report Forms.
Severe malaria is a multisystem disease and requires treatment for the various signs and 
symptoms that occur. These will be treated according to the local clinical practice but should 
not include the administration of additional antimalarials unless the participant meets the 
criteria for rescue medication. The following medications are recommended for commonly 
observed symptoms:
!
Paracetamol < 3g/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.
!
Metopimazine for repeated vomiting (or if not available, any other antiemetic which is not 
known to prolong QT and/or cause torsade de pointes)
!
Beta-lactam antibiotics would be preferred in case of a bacterial infection (with the 
exception of amoxicillin-clavulanic acid because of its potential hepatotoxicity). If needed 
clindamycin can be given. All other antibiotics, new-quinolones included, should be 
avoided where possible.
!
Lorazepam and furosemide. Diazepam should be allowed only when the suggested 
alternative lorazepam would not be available.
!
Supportive therapy (e.g. blood or glucose transfusion, refer Study Manual)
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical/ monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, Novartis should be contacted to determine if the participant should continue 
participation in the study, if the time permits based on participant condition.
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms.

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 Examples of drugs 
metabolized by these enzymes are provided under Section 16.3 in Table 16-5. However, 
assessments including SimCYP simulation suggests that the potential change in the exposure 
of these drugs would be less than two fold and unlikely to be of clinical significance. 
CCI

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Nonetheless, caution should be exercised with drugs as outlined in Table 16-5 following ~12 
hours from the last dose of cipargamin.
Administration of paracetamol/acetaminophen is acceptable, but daily total dose should not 
exceed 3g. As for all concomitant medications dose and time of administration must be 
documented in the Concomitant medications section of the eCRF.

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Following considerations on prohibited list of medications are required for participants 
on cipargamin arms (refer below Table 6-5).
For participants on IV artesunate arms, the applicable current prescribing information should 
be followed, including prohibited medications related to potential adverse events or impact on 
efficacy. For study specific reasons, the following considerations for specific medications must 
be taken into account for participants on IV artesunate (refer below Table 6-6).
Regarding prohibited medications for Coartem refer to the current prescribing information.
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CCI

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Prohibited Medication
Prohibited period
treatment e.g., artesunate-amodiaquine (ASAQ), 
artesunate-pyronaridine, DHA-piperaquine, 
chloroquine, amodiaquine, quinine, quinidine, 
mefloquine, halofantrine, lumefantrine as 
monotherapy, artemisinin and its derivatives 
used as monotherapy: artemether, arteether, 
artesunate, dihydroartemisinin, proguanil, 
chlorproguanil, pyrimethamine, sulfadoxine, 
sulfalene, sulfamethoxazole, dapsone, 
primaquine, atovaquone.
Herbal medication with antimalarial activity
12 hours before study entry and for entire study 
period
Other antimicrobials with antimalarial activity
azithromycin, tigecycline, tetracycline, 
erythromycin, rifampicin, doxycycline, 
trimethoprim
12 hours before study entry and during entire 
study period
Any other investigational treatment
For entire study period
Aspirin and corticosteroids (might increase 
the risk for gastrointestinal bleeding)
For treatment duration and 7 days after last 
dose
Potential hepatotoxic drugs
Alpha-methyldopa, Amoxicillin-clavulanic acid, 
Amiodarone, Bosentan, Carbamazepine, 
Dantrolene, Disulfiram, Etretinate, Fluconazole 
Glyburide, Halothane, Heparin, HMG-Co A 
reductase inhibitors, Isoniazid, Ketoconazole, 
Labetalol, Nicotinic Acid, Nitrofurantoin, NSAIDs 
(except paracetamol), Phenylbutazone, 
Phenytoin, Propylthiouracil, Protease inhibitors, 
Sulfonamides, Terbinafine, Trazadone, 
Troglitazone (withdrawn), Valproic Acid
For treatment duration and 7 days after last 
dose
Potential hepatotoxic herbs and alternative 
medications:Chaparral leaf, Ephedra, Gentian, 
Germander, Ji Bu Huan, Senna, Kava kava, 
Scutellaria (skullcap), Shark cartilage
For treatment duration and 7 days after last 
dose
Illicit drugs: Anabolic steroids, Cocaine, 
Ecstasy (MDMA), Phencyclidine (PCP)
For treatment duration and 7 days after last 
dose
Toxins: Carbon tetrachloride, Chloroform, 
Dimethylformamide, Hydrazine, 
Hydrochlorofluorocarbons, 2-Nitropropane, 
Trichloroethylene, Toluene
For treatment duration and 7 days after last 
dose
For drugs falling in above multiple categories, consider whichever is the longer duration as 
prohibited period.

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Table 6-6
Prohibited medications for participants on IV artesunate arms
Prohibited medication
Prohibited period
Drugs used as antimalarials other than the study 
drug, rescue medication and oral standard 
treatment e.g., artesunate-amodiaquine (ASAQ), 
artesunate-pyronaridine, DHA-piperaquine, 
chloroquine, amodiaquine, quinine, quinidine, 
mefloquine, halofantrine, lumefantrine as 
monotherapy, artemisinin and its derivatives 
used as monotherapy: artemether, arteether, 
artesunate, dihydroartemisinin, proguanil, 
chlorproguanil, pyrimethamine, sulfadoxine, 
sulfalene, sulfamethoxazole, dapsone, 
primaquine, atovaquone.
12 hours before study entry and during entire 
study period except as rescue medication
Other antimicrobials with antimalarial activity
Azithromycin, tigecycline, tetracycline, 
erythromycin, rifampicin, doxycycline and 
trimethoprim
12 hours before study entry and during entire 
study period
Herbal medication with antimalarial activity
12 hours before study entry and during entire 
study period
Any other investigational treatment
For entire study period
Illicit drugs: Anabolic steroids, Cocaine, 
Ecstasy (MDMA), Phencyclidine (PCP)
For treatment duration and 7 days after last 
dose
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the patient is first enrolled for screening and is retained as the primary identifier 
for the participant throughout his/her entire participation in the trial. The Participant No. 
consists of the Center Number (Center No.) (as assigned by Novartis to the investigative site) 
with a sequential participant number suffixed to it, so that each participant is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available.
6.3.2
Treatment assignment, randomization
At Day 1, all eligible participants 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 participant fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the participant, which will be used to link the participant to 
a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 

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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 Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment.
Randomization will be stratified by country and if any pretreatment of antimalarial drugs before 
screening period for each cohort.
The randomization scheme for participant will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
This is an open label study so that treatments will not be blinded for participants and investigator 
staff.
In order to minimize the potential impact of treatment knowledge, treatment allocation, dose 
information, PK/AAG assessment schedule and concentration data, as well as other data that 
may result in systematic unblinding will not be available to the Clinical Trial Team (CTT) 
(particularly clinicians, trial statisticians, trial programmers) until the database is locked after 
IA of Cohorts 1-2. After interim database lock, the CTT would be unblinded with the results, 
however, the blinding will then be continued for Cohorts 3-5 until the final database is locked. 
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 and
AAG data for the entire duration of the study (i.e. Cohorts 1-5). In order to develop suitable 
exposure-response models, pharmacometrician could have early access of PK and selected 
efficacy/safety data prior to interim database lock and database lock. Clinical/medical reviewers 
independent of CTT will have access to unblinded data to review the safety data for decisions 
relating to the stopping criteria of the cipargamin treatment arms.
If required, summaries of results by treatment arm will be prepared for Data Monitoring 
Committee (DMC) assessments. The DMC reports will be prepared by an independent team 
(refer Section 10.2.4).
The bioanalyst will request a copy of the randomization list 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 and will share it only post database locks.
6.5
Dose escalation and dose modification
6.5.1
Dose modifications
Investigational or other study treatment dose adjustments and/or interruptions are not permitted 
at individual participant level. For possible dose adjustments at study level, refer to Table 4-1.

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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Qualified site personnel will be designated, as appropriate, by the investigator for both 
preparation and administration of all doses of study medication for each participant. The exact 
dosages administered (based on the weight bands) will be recorded on the Dosage 
Administration Record CRF, along with any additional comments.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants, as detailed in Section 12.5.3.
Records of study medication used and exact doses administered 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.
6.6.2
Recommended treatment of adverse events
Medication used to treat adverse events (AEs) must be recorded on the appropriate page of the 
CRF. There is no specific recommendations and AEs should be treated as per local guidance.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs (See Section 6.1.1).
For details on drug management including preparation and handling, please refer to the 
Pharmacy Manual prior to administration.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label); immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatments along with Coartem (standard of care) and IV artesunate (rescue) must be 
received by a designated person at the study site, handled and stored safely and properly and 
kept in a secured location to which only the investigator and designated site personnel have 
access. Upon receipt, all treatments must be stored according to the instructions specified on 
the labels and in the Investigator`s Brochure. Clinical supplies are to be dispensed only in 
accordance with the protocol. Technical complaints are to be reported to the respective Novartis 
designee.
For the specific detailed dosage preparation of IV cipargamin or IV artesunate, refer to 
Pharmacy Manual. The current IV cipargamin formulation should not be administered IM or 
SC in humans.

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Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of these 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Participants will be 
requested to return all dispensed used (or unused) Coartem during their follow-up visits or 
before the end of the study.
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 monitor (Novartis or designated CRO) or to the Novartis address 
provided in the investigator folder at each site. If the site has a drug destruction policy, they 
might also be instructed to destroy drugs locally as per their process.
6.7.1.2
Handling of additional treatment
The following additional treatments are to be monitored:

Coartem as standard of care for oral therapy (dispensed via IRT)

IV artesunate as rescue medication (dispensed via IRT)

Other medications including supportive therapies as concomitant medication
Details are described in the CRF completion guidelines.
6.7.2
Instruction for prescribing and taking study treatment
Cipargamin (KAE609)
IV cipargamin should be administered for a minimum of 24 hours (2 doses), regardless of the 
participant’s ability to tolerate oral medication earlier. After at least 2 doses or a maximum of 
3 daily doses of IV cipargamin, the participant should be switched to a complete treatment 
course of oral Coartem or rescue medication (see sections Section 6.1.2.1, Section 6.2.1).
Preparation:
The specified dose of cipargamin should be prepared by withdrawing the calculated volume 
from the 2ml vial containing either 10mg/ml or 15mg/ml KAE609. For dose preparation refer 
to the Pharmacy Manual.
As described in Section 4.2 doses in Cohorts 3-5 might be adjusted during the trial to reach 
optimal exposure in the different age groups.
Administration
Cipargamin should be administered as a slow bolus injection over two minutes by the 
intravenous route. It should not be administered intramuscularly or subcutaneously.

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Artesunate
IV artesunate should be administered for a minimum of 24 hours (3 doses), regardless of the 
participant’s ability to tolerate oral medication earlier. After at least 24 hours of IV artesunate,
the participant should be switched to a complete treatment course of oral Coartem (see 
Section 6.1.2.1).
Artesunate should be prepared according to the supplied instructions in label for IV 
administration and injected by the IV route as a bolus over 1-2 minutes.
Coartem
Coartem® should be administered according to the supplied label and with food/drink (broth, 
sweetened condensed milk, etc.) as appropriate.
All dosages prescribed and dispensed to the participant during the study must be recorded on 
the Dosage Administration Record (DAR) CRF.
All kits of study treatment assigned by the IRT will be recorded in the IRT.
7
Informed consent procedures
Eligible participants may only be included in the study after parents, legal guardians or 
caregivers provide written (witnessed, where required by law or regulation), Institutional 
Review Board/Independent Ethics Committee/ Research Ethics Board (IRB/IEC/REB)-
approved informed consent.
In cases where the participant’s representative gives consent, the participant should be informed 
about the study to the extent possible given his/her understanding. If the participant is capable 
of doing so, he/she should indicate agreement 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 (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the participant source documents. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) and assent form that is considered appropriate for this study and complies with the 
ICH GCP guideline and regulatory requirements. Any changes to this ICF or the assent form as 
suggested by the investigator must be agreed to by Novartis before submission to the 
IRB/IEC/REB, and a copy of the approved version must be provided to the Novartis monitor 
after IRB/IEC/REB approval.
Information about common side effects already known about the investigational drug can be 
found in the Investigator`s Brochure and in the Prescribing Information for marketed drugs. 
This information will be included in the participant informed consent and should be discussed 
with the participant during the study. Any new information regarding the safety profile of the 
investigational drug that is identified between Investigator`s Brochure updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 

Novartis
Confidential
Page 49 of 108
Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
safety finding. New information might require an update to the informed consent and then must 
be discussed with the participant.
The following informed consents are included in this study:

Main Study Consent for parents / legal guardians to give consent for their child

Main Study Consent for participants entering adulthood
Both Main Study Consents include a subsection that requires a separate signature for the 
‘Optional Consent for Additional Research’ to allow future research on data/samples 
collected during this study

Model Participant Information and Adolescent Assent 12-17 years old (≥ 12 years to < 18 
years). 

Model Participant Information and Adolescent Assent 7-11 years old (7 years to < 12 years).
for adolescents to express their understanding of the purpose of this study and what will 
happen to them if their parent(s)/legal guardian(s) give their consent for their participation 
in this study

As applicable, Pregnancy Outcomes Reporting Consent for female pregnant participants
and pregnant partner of male participants

There may be a short initial Consent followed by the Main Study Consent, as this disease is 
to be handled like emergency situations.
Female participants 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 requirements.
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
Assessment schedules lists all of the assessments when they are performed for participants of 
Cohorts 1-3 and Cohorts 4-5 separately in Table 8-1 and Table 8-2 respectively. All data 
obtained from these assessments must be supported in the participant’s source documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
Table 8-1 and Table 8-2. Assessments should be performed as per the assessment schedules or 
as close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Participants who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final follow-up visit (first IV treatment +28 days) will be performed. At this final visit, 
all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the CRF.

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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
8.1
Screening
The investigator or their delegate will contact the IRT when a participant enters screening.
In the case where a safety laboratory assessment at screening/baseline is outside of the range 
specified in the exclusion criteria, the assessment may be repeated once prior to randomization 
and must be completed within 3 hours of the screening period. In this case, another 
consent/assent would not be required and the original participant ID number assigned will be 
used. However, if the repeat value remains outside of the specified ranges, the participant must 
be captured as a screen failure.
Rescreening of a participant with a new episode of malaria who had failed screening 
assessments earlier in the study is allowed per investigator's discretion and/or after consultation 
with the sponsor. In this case, a new consent/assent would be required and new participant ID 
number will be used.
IRT will be recontacted after confirming that the participant fulfills all the inclusion/exclusion 
criteria, to get a unique medication number for the package of study treatment and the dose 
level to be dispensed to the participant.
8.1.1
Information to be collected on screening failures
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to randomization will be considered screen failures. The reason for screen failure should 
be recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see 
Section 10.1.3 for SAE reporting details). If the participant fails to be randomized, the IRT must 
be notified that the participant was screen failed.
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form.
8.2
Participant demographics/other baseline characteristics
Participant demographic and baseline characteristic data to be collected on all participants and 
to be entered in eCRF by site personnel:

Age

Gender

Body weight

Head circumference (for children < 2 years)

Body height

Body temperature

Vital signs

Physical examination (data to be entered only in source notes)

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Neurological examination
!
Other severe malaria symptoms examination
!
Prior and concomitant medications
!
Blood chemistry and hematology
!
Urinalysis
!
Pregnancy test (data to be entered only in source notes)
!
Malaria blood film for parasites and gametocytes count and plasmodium species 
determination
!
Medical history
!
Triplicate 12-lead ECG
The following data are not to be assessed or entered by clinical site, these will be generated by 
third parties:
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
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Efficacy assessments will be based on initial parasite clearance and clinical outcome of severe 
malaria signs (including neurological sequelae).
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Clinical success in study participants will be evaluated at various time points throughout the 
study. Clinical success at 48 hours is considered as a key secondary endpoint. Clinical success 
is a composite endpoint based on the criteria shown below (Table 8-3).
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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
Table 8-3
Definition of clinical success in the study at any time point
Disease criteria
Clinical failure (participant 
meeting any of the criteria)
Clinical success (participant 
has to meet all criteria)
Dead or Alive
Dead#
Alive
Presence of asexual parasites
Yes
No
Presence of any of the key 
signs of severe malaria*
Yes
No
# Death - All in hospital deaths and malaria related deaths (as per adjudication committee) 
occurring after hospital discharge
* Key signs of Severe Malaria defined as
1) Altered consciousness (including prostration) – Prostration (inability to sit or drink or breast 
feed) or Glasgow Coma Score < 11 (in participants > 5 years of age) or a Blantyre coma score of < 
3 in children (≤ 5 years)
2) Renal impairment – SCr ≥ 3x ULN or Absolute SCr >3mg/dL or use of Renal Replacement 
Therapy (RRT)
3) Acidosis – Plasma lactate > 4 mmol/L or Respiratory distress defined as rapid, deep and labored 
breathing (costal indrawing, use of accessory muscles and nasal flaring).
8.3.1.2
Signs of severe malaria
Participants will be monitored for the presence of the following signs of severe malaria during 
the entire study duration:

Altered consciousness - Prostration or GCS < 11 for participants > 5 years / BCS < 3 for 
participants ≤ 5 years of age

Renal Impairment - Serum creatinine > 3xULN or > 3 mg/dL or need for renal 
replacement therapy

Acidosis - Serum lactate > 4 mmol/L

Respiratory distress - present or absent

Severe anemia - Hb < 5 g/dl or Hb < 7g/dl in pediatric and adults respectively or need of 
blood transfusion

Jaundice - Serum bilirubin > 3 g/dl

Hypoglycemia- plasma glucose < 40 mg/dL
8.3.1.3
Neurological assessment
Detailed neurological examination will be conducted and relevant medical history collected 
under the following categories to assess the extent of neurological signs and symptoms at 
baseline and to monitor the extent of neurological sequelae in follow-up visits:

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Table 8-4
Summary of Neurological assessment
Assessment parameter
Type of information in CRF
Consciousness
Glasgow Coma Score (GCS*) 
for participants > 5 years
Blantyre Coma Score (BCS*) 
for participants ≤ 5 years
Score for individual component 
of GCS and BCS
Total GCS or BCS calculated 
centrally based on individual 
components
Prostration
Yes or No
Cranial Nerve Palsy
4th, 6th and 7th Nerve
Palsy – present or absent
If present – Right or Left nerve 
palsy
Motor system
Posturing
Abnormal posture - Yes or No
If yes, Type of posture -
Decerebrate/Decorticate/Opisth
otonus/ Hemiplegic
Cerebellar Ataxia
Present or Absent
Strength
Presence or absence of 
following
- Monoplegia or Monoparesis
- Hemiplegia or Hemiparesis
- Quadriplegia or Quadriparesis
Deep Tendon reflex (Biceps, 
Triceps, Knee and Ankle) 
increased
Yes or No
Increased Tone (Upper Limb 
and Lower Limb)
Yes or No
Convulsions
Type of convulsion
Generalised/Focal/Focal with 
secondary generalisation
Presence of ≥ 2 episodes of 
convulsions excluding febrile 
seizures in the last 24 hours 
(for baseline visit) or since last 
visit (for follow-up visits)
Yes or No
Any episode of convulsion 
lasting ≥ 15 min
Yes or No
Sense organs (Examination 
more useful at time of hospital 
discharge and in follow-up 
visits)
Vision
Check both eyes individually
Graded as:
• Child can see
• Visual impairment 
unilateral/bilateral
• Total blindness 
unilateral/bilateral

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Clinical Trial Protocol (Version No. 00)
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Assessment parameter
Type of information in CRF
Hearing
Check both ears individually
Graded as:
• Can hear well
• Possible hearing impairment 
unilateral / bilateral
• Total deafness 
unilateral/bilateral

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Clinical Trial Protocol (Version No. 00)
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Assessment parameter
Type of information in CRF
Speech
To be checked only for kids > 
18 months
Graded as:
• Normal
• Speech Impairment
• Unable to speak
For details of GCS and BCS refer to Section 16.6
Detailed methodology for each of the neurological assessments will be provided in a 
neurological assessment manual and the relevant site staff will be trained prior to the start of 
the study to maintain uniform standard of neurological examination across the study sites.
Based on the results from the neurological examination of every participant, neurological 
sequelae will be graded by the neurological sequelae adjudication committee. Further details 
about grading of neurological sequelae will be mentioned in adjudication committee charter.
8.3.1.4
Other clinical outcome assessments
In addition to the composite endpoint for clinical success as defined in Section 8.3.1.1, 
individual signs of severe malaria as defined in Section 8.3.1.2 will be closely monitored and 
assessed throughout the study.
Furthermore, participants will be monitored for time to start oral therapy, time to hospital 
discharge and time to recover from prostration also to gather holistic information about the 
clinical outcome of participants across treatment arms.
8.3.2
Parasitemia assessment
Malaria blood films will be prepared to determine parasite counts of asexual and sexual forms 
of P. falciparum at baseline and all visits during the study. This data will be used to assess 
parasite reduction or reappearance over entire study duration. Primary endpoint of proportion 
of participants with at least 90% P. falciparum parasite reduction at 12 hours is based on this 
assessment as well as a number of secondary endpoints related to parasitological response and 
parasite reduction or clearance.
Details of all parasitemia related assessments are outlined in respective manual. Quality checks 
of parasite readings will be part of the process.
Blood samples for molecular diagnostic purposes
Blood will be sampled for parasite genotyping as indicated in the assessment schedule 
(Table 8-1 and Table 8-2).
At screening, a blood sample will be collected in all participants fulfilling eligibility criteria for 
inclusion in the study. A second blood sample will be analyzed only in participants with re-
appearance of parasites. This will allow to distinguish between recrudescence and a new 
infection. Sample analysis will be performed at a pre-selected reference laboratory.

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Clinical Trial Protocol (Version No. 00)
Protocol No. CKAE609B12201
Microscopic identification of Plasmodium species might be confirmed with PCR-based 
methods on blood samples collected at relevant time points.
All parasite samples at baseline and other selected time points including re-appearance of 
parasites will also be screened for specific genes/single-nucleotide polymorphisms (SNPs) that 
are known as markers for P. falciparum drug resistance.
During the analysis process no human DNA will be amplified or analyzed by any means.
8.3.3
Appropriateness of efficacy assessments
Parasite count is a standard assessment in malaria studies as it allows to quantify the efficacy 
of the study drug in eliminating the parasites. In this study parasite reduction ≥ 90% at 12h is 
used as the primary endpoint as it is expected to allow differentiation between IV cipargamin 
and IV artesunate.
The composite clinical endpoint is used in this study for the first time. It is a secondary endpoint 
and if it is demonstrated to capture the patient's clinical course appropriately might be used as 
primary endpoint in phase III studies. Previous studies in severe malaria have used mortality-
based endpoints. Through these studies the current standard of care (IV artesunate) has been 
established and generally demonstrates high efficacy. As such, a very large sample size would 
be required in today's situation to demonstrate statistical significance and exposing large 
numbers of patients to an investigational treatment is not considered appropriate. Additionally, 
mortality as an endpoint does not capture the clinical improvement of the treated patients 
adequately.
The individual assessment of all symptoms of severe malaria as secondary endpoints, will allow 
an in-depth analysis of the drug efficacy.
8.4
Safety
Safety assessments to be conducted in the study include:

Physical examination

Vital signs

Height and weight (including Head circumference of children < 2 years)

Laboratory evaluations

ECG evaluations

Pregnancy assessment
For details on AE collection and reporting, refer to Section 10.1.
8.4.1
Physical Examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological assessment.
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be recorded on the appropriate CRF that captures medical history. Significant findings made 

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after signing informed consent that meet the definition of an Adverse Event must be recorded 
as an adverse event.
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Vital signs will include systolic and diastolic blood pressure, temperature, pulse rate, and 
respiratory rate as per Table 8-1 and Table 8-2. After the participant has been still for five 
minutes (as much as possible), systolic and diastolic blood pressure will be measured three 
times using a standard device, with an appropriately sized cuff. Repeat measurements will be 
made at 1-2 minute intervals and the mean of the three measurements will be used.
Temperature will be taken using a standard thermometer, for 5 minutes before reading.
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Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured as specified in Table 8-1 and Table 8-2.
For children < 2 years, head circumference will be measured at baseline and study completion.
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The following laboratory assessments will be performed as per the schedule mentioned in 
Table 8-1 and Table 8-2. Details of the assessments are mentioned below in Table 8-5.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
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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) for participants in 
Cohorts 1-3. For participants in Cohorts 4-5 ECG should be taken in the supine position if 
feasible and in triplicates if possible. The preferred sequence of cardiovascular data collection 
during study visits is ECG collection first, followed by vital signs, and blood sampling. For 
assessments where PK samples are required at 2 mins post drug administration then in those 
instances after drug administration, first PK sample will be collected followed by ECG, vital 
signs and then remaining blood sampling.
Heart rate-corrected QT interval (QTc) should be calculated by using both Fridericia's and 
Bazett's QT correction formula (QTcF and QTcB, respectively). Fridericia formula (QTcF) 
should be used for making clinical decisions.
Triplicate 12 lead ECGs are to be collected with ECG machines supplied by the central 
laboratory. Initial manual readout will be done locally in order to detect significant safety 
findings and allow for immediate response if needed. Local readout will be used for 
inclusion/exclusion purposes as central readout is not available within 3 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 10.1.2. If the participant 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 participant 
should be assessed at the site and appropriate safety procedures (e.g., blood sampling and 
electrolyte correction) initiated without delay, as required. In addition, two additional ECGs 
should be collected at 2min 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.
Any post-dose average QTcF > 500 ms will result in treatment discontinuation (for details refer 
to Section 6.2.1 and Section 9.1.1).
Assessments will be done as indicated in the study assessment Table 8-1 and Table 8-2. All 
ECGs will be assessed centrally by an independent and blinded (with age of participant 
identified) cardiologist.
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All pre-menopausal female participants who are not surgically sterile will have pregnancy 
testing as per Section 8.1. Serum pregnancy test will be performed at screening and at the end 
of the study. If the screening serum pregnancy test is positive, the participant will not be enrolled 
in the study. Additional pregnancy testing might be performed if required locally. If during the 
study, the participant is found to be pregnant, the participant must contact the investigator 
immediately and study treatment will be discontinued (see details in Section 9.1.1).

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Pregnancy test and associated results will not be collected on the CRF.
Participants of child-bearing potential are defined as all women physiologically capable of 
becoming pregnant. This includes female pediatric participants who are menarchal or become 
menarchal during the study.
The required contraception methods and their duration for women participants are described 
under exclusion criteria.
For sexually active male participants also follow recommendation as per Section 5.2 under 
exclusion criteria.
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PK samples will be collected at the visits defined in the assessment schedule (Table 8-1 and 
Table 8-2). Follow instructions outlined in the laboratory manual regarding sample collection, 
numbering, processing and shipment. See the potential use of residual samples for more 
information.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emerging data.
Pharmacokinetic (PK) samples will be obtained and evaluated in all participants randomized to 
cipargamin (KAE609).
The parent drug concentration in plasma samples will be determined by a validated LC-
MS/MS method; the anticipated Lower Limit of Quantification (LLOQ) is 1 ng/ml or better.
Concentrations will be expressed in mass per volume units and will refer to the free base.
Concentrations below the LLOQ will be reported as “zero” and missing data will be labeled as 
such in the Bioanalytical Data Report.
For standard pharmacokinetic abbreviations and definitions, see the list provided at the 
beginning of this protocol.
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.4 or 
higher) wherever possible: Cmax, Tmax, AUClast, AUCinf, AUC0-t, and T1/2 from the plasma 
concentration-time data. In case of sparse sampling, summary statistics of concentrations-time 
data will be listed.
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the terminal 
plasma elimination phase for the determination of T1/2 will include at least 3 data points after 
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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances:

Participant/guardian decision

Pregnancy

Use of prohibited treatment (see Section 6.2.3)

Use of IV rescue medication (see Section 6.2.1)

Any situation in which study participation might result in a safety risk to the participant 
(eg., see Section 16.1, Section 16.2 )

Diagnosed with COVID-19 infection
If discontinuation of study treatment occurs, then investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the participant/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.

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9.1.1.1
Replacement policy
For any cohort, enrollment of additional participants to the current cohort will be considered if 
there is less than the required number of evaluable participants. If the dose is considered 
unsuitable in the first few participants of the current cohort, enrollment of another set of new 
participants to the cohort to be treated with a different dose will be considered.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore

Does not allow further collection of personal data, and

Does not want any further visits or assessments
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the participant’s study withdrawal should be made as detailed in the 
assessment table (Table 8-1 and Table 8-2).
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a participant’s samples until the time of withdrawal) according to applicable 
law.
All biological samples not yet analyzed at the time of withdrawal will no longer be used, unless 
permitted by applicable law. They will be destroyed according to applicable legal requirements.
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant and/or care giver 
(accompanied with participant), e.g. dates of telephone calls, registered letters, etc. A participant 
should not be considered as lost to follow-up until due diligence has been completed or until 
the end of the study.
9.1.4
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 (including 

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slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, participants must be seen as soon as possible and treated as prematurely withdrawn. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the participant’s interests. The 
investigator or sponsor, depending on the local regulation, will be responsible for informing 
IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Each participant will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.
A participant will be considered to have completed the study when the participant 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.
Participants who discontinue study drug and are put on rescue medication will be followed for 
the entire study duration (i.e., until study Day 29).
The investigator and/or referring physician must provide follow-up medical care for all 
participants who are prematurely withdrawn from the study, or must refer them for appropriate 
ongoing care.
An independent Data Monitoring Committee (DMC) will review participant safety at several 
time points and may recommend stopping a cohort/dose or the study early for safety reasons.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant 
or clinical investigation participant after providing written informed consent for participation 
in the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.

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Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The Common Toxicity Criteria (CTC) AE grade version 5
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version.
2. its relationship to the study treatments (ie IV cipargamin or IV artesunate). If the event is 
due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected.’ The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single participant
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Drug interrupted/withdrawn
6. its outcome (i.e. recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued until the end of study visit.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator`s Brochure. For comparator and oral standard of care treatments, safety-related 
information is listed in the product information.
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 participants 
with the underlying disease.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it was more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition eg hospitalized for follow-up visit without worsening of 
underlying condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).

Protocol specific SAEs

Hepatic: Refer to Table 16-2, including potential Hy's Law cases as defined in 
Table 16-1

Cardiac: Absolute QTcF > 500 ms (confirmed by repeat ECGs)

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All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
(or participant's representative) has provided informed consent and until 30 days following the 
last administration of study treatment must be reported to Novartis safety within 24 hours of 
learning of its occurrence. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator`s Brochure for IV cipargamin or 
Package Insert for IV artesunate (new occurrence) and is thought to be related to the study 
treatment, a CMO & PS Department (Novartis safety department) associate may urgently 
require further information from the investigator for health authority reporting. Novartis may 
need to issue an Investigator Notification (IN) to inform all investigators involved in any study 
with the same study treatment that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced more than 30 days after the last administration of study treatment should 
only be reported to Novartis Safety if the investigator suspects a causal relationship to study 
treatment.
10.1.4
Pregnancy reporting
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. Following delivery, the 
newborn should be followed up for up to 12 months for any development abnormality or any 

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issue not seen at birth as per the standard safety processes concerning follow-up for pregnancy 
outcome and related data in CT cases.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment with 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 16-1 in Appendix 1 for complete definitions of liver laboratory triggers.

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Once a participant is exposed to study treatment, every liver event defined in Table 16-1 should 
be followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-2. Repeat 
liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm elevation.
These liver chemistry repeats should be performed using the local laboratory used by the site. 
Repeated laboratory test results must be reported as appropriate.

If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate

Hospitalization of the participant if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more detailed 
history of symptoms and prior or concurrent diseases, history of concomitant drug use, 
exclusion of underlying liver disease
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.2.2
Renal safety monitoring
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trial staff as summarized 
in Table 16-3 and Table 16-4.
Abnormal renal findings must be confirmed within 24-48 hours after the first assessment.
Renal events in the pediatric population should be defined as 25% decrease in eGFR using age-
specific normal values for eGFR and serum/urinary normal values. The Schwartz age- specific 
eGFR formula (Schwartz and Furth 2007) is commonly used to estimate eGFR in the pediatric 
population. Refer to Section 16.3 for Schwartz formula calculation guidance, and normal age-
related pediatric eGFR values. Due to the low values of serum creatinine, small changes can be 
interpreted as substantial changes in eGFR which can be ignored if eGFR is > 90 ml/min/1.73 
m2.
10.2.3
Special Hematology monitoring
Hematology parameters are closely monitored throughout the study to detect early and delayed 
hemolytic anemia.
Early Hemolytic anemia is defined as 10% or greater decrease in hemoglobin levels and an 
increase of LDH levels to >390 U/L, or an increase of ≥10% above baseline occurring up to 
Day 8 of the study.
Delayed hemolytic anemia might occur > 7 days after initiation of parenteral study drug (IV 
artesunate or IV cipargamin) during the study period. The event is characterized by a 10% or 

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greater decrease in hemoglobin levels accompanied by increase of LDH levels to >390 U/L, or 
an increase of ≥10% compared to the values measured at Day 8 of the study.
Decrease in hemoglobin 10% or greater (compared to baseline up to Day 8 and compared to 
Day 8 values after until the end of study), must be always followed by LDH measurement for 
confirmation of hemolysis and requires close observation, follow-up monitoring and 
contributing factors are to be recorded on the appropriate CRFs.
10.2.4
Data Monitoring Committee
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. Planned DMCs will occur at the end of Cohort 2 and at 
the end of Cohort 4. Additional DMC meetings may be conducted depending on the need per 
study data. The DMC will assess at defined intervals the progress of a clinical trial, safety data, 
and critical efficacy variables and recommend to the sponsor whether to continue, modify, or 
terminate a trial.
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC.
10.2.5
Adjudication committee
Two independent adjudication committees will be set up to assess if deaths reported in the study 
are malaria related and to grade reported neurological sequelae respectively. Further details of 
the adjudication committee's composition, organization and responsibilities will be described 
in the adjudication committee charter.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate.
After final database lock, the investigator can retrieve participant data from a portable document 
format (PDF) generator or will receive copies of participant data for archiving at the 
investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.

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11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis / 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eSource DDE or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of participant 
records, the accuracy of data capture / data entry, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a Novartis/delegated CRO organization.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 

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study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The analysis includes the following data sets:

Randomized set: all participants who are randomized.

Full analysis set (FAS): the FAS will be comprised of all participants from Randomized 
set that have baseline P. falciparum count > 0 and take at least one dose of IV study 
treatment during the treatment period. Following the intent-to-treat principle, participants 
will be analyzed according to the treatment group assigned at randomization.

Per-protocol set (PPS): Participants in the FAS who satisfy the inclusion criterion for 
severe malaria and do not have protocol deviations that impact on efficacy.

Safety set (SS): All participants who take at least one dose of study drug during the 
treatment period. Participants will be analyzed according to treatment received.

PK analysis set: All participants who have at least one valid (i.e. not flagged for exclusion) 
PK concentration measurement, receive at least one dose of study drug, and do not have 
any protocol deviations that impact on PK data.
Full details will be described in the statistical analysis plan (SAP). Important protocol 
deviations for exclusion from PPS or PK analysis set will be identified by the clinical team 
before Cohort 1 and 2 database lock and the final database lock.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed by cohort 
and treatment group and summarized descriptively by treatment group for each cohort, Cohorts 
1 and 2 pooled), and all cohorts pooled for the FAS and Safety set if Safety set is different from 
FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, and treatment group for each cohort, Cohorts 1 and 2 
pooled and all cohorts pooled for the FAS period.
12.3
Treatments
The Safety set will be used for the analysis below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.

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The duration of exposure in number of doses and days to IV cipargamin (KAE609), IV 
artesunate, and Coartem will be summarized by means of descriptive statistics.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by cohort and treatment group and summarized according to the 
Anatomical Therapeutic Chemical (ATC) classification system, by treatment group for each 
cohort and all cohorts pooled.
12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary objective is to show that IV cipargamin is non-inferior to IV artesunate in the 
proportion of participants with ≥ 90% P. falciparum parasite reduction at 12 hours. These will 
be evaluated within each Cohort separately except Cohort 1, which will be combined with 
Cohort 2. The analysis will be performed on the FAS.
12.4.1
Definition of primary endpoint(s)/estimand(s)
A participant is considered as achieving ≥ 90% reduction in P. falciparum parasite from 
baseline at 12 hours (after the first IV dose) if P. falciparum asexual parasite reading at 12 hours 
is either absent or with a positive value that is ≤ 10% of the baseline value. See Section 2.1 for 
detailed definition of estimand.
12.4.2
Statistical model, hypothesis, and method of analysis
The statistical null hypothesis is that the difference in proportion of participants with ≥ 90% 
reduction at 12 hours between a cipargamin dose regimen and artesunate is ≤ -0.1 with the 
alternative hypothesis that the difference is > -0.1.
The statistical hypothesis will be tested at the 2-sided 10% significance level without 
multiplicity adjustment for multiple comparison due to multiple cipargamin dose regimen. 
Two-sided 90% confidence intervals (CI) for the difference between each cipargamin dose 
regimen vs artesunate will be provided using the Wilson uncorrected method based on FAS; a 
cipargamin dose regimen is said to be non-inferior to artesunate if the lower limit of CI is > -
0.1.
The hypothesis will be tested for each Cohort separately except Cohort 1, which will be 
combined with Cohort 2.
Data from participants in Cohorts 1 and 2 will be pooled together to allow evaluation of non-
inferiority to artesunate since both cohorts include participants aged ≥ 12 years although 
participants in Cohort 1 are milder in clinical condition compared to participants in Cohort 2. 
The underlying assumptions are (1) the participants for each treatment group follow a binomial 
distribution separately in each Cohort separately except Cohort 1, which will be combined with 
Cohort 2 (2) participants for each treatment group, follow the same binomial distribution in 
Cohorts 1 and 2.
12.4.3
Handling of intercurrent events of primary estimand
The primary estimand will account for the different intercurrent events as follows:

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
If a participant receives any IV rescue antimalarial medication prior to the P. falciparum
asexual parasite assessment at 12 hours, the participant will be classified as not achieving 
≥ 90% reduction,

If a participant dies prior to the P. falciparum asexual parasite assessment at 12 hours, the 
participant will be classified as not achieving 90% reduction.
Composite strategy is used to handle intercurrent events as the intercurrent events indicate that 
the study IV treatment is not working quickly enough to prevent clinical deterioration.
12.4.4
Handling of missing values not related to intercurrent event
All participants should be hospitalized at the time of 12 hours post treatment unless death or 
discontinuation from the study have occurred. Death is considered as an intercurrent events and 
is handled in Section 12.4.3. Any missing data not related to intercurrent events will be handled 
according to Table 12-1.
Since participants are hospitalized at 12 hours, these missing data should be rare. After 
receiving the IV study medication, a participant's parasite load should decrease over time such 
that the parasite count is lower at 12 hours than at previous visits (6 hours or earlier). That is, 
the probability that a participant achieves at least 90% parasite reduction is higher at 12 hours 
than at 6 hours. Therefore, the imputation of using parasite assessment at the latest visit prior 
to 12 hours is conservative. This imputation may slightly under estimate the proportion of 
participants with at least 90% parasite reduction at 12 hours.
Table 12-1
Handling of other events that may occur and affect derivation of 
primary endpoint
Event
Outcome
Discontinuation of study prior to parasite 
assessment at 12 hours, such as withdrawal of 
consent, COVID-19, etc.
Impute using the latest assessment prior to 12 
hours including baseline. Note: the outcome 
is 'no' if baseline value is used.
Intermediate parasite count missing at 12 hours 
due to other reason (such as missing sample, 
technical reason, etc.)

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12.4.5
Sensitivity analyses for primary endpoint/estimand
After receiving antimalarial medication, a participant's parasite usually decreases log-linearly 
after a lag stage (White 2011, Flegg et al 2011). For artemisinin derivatives, parasitemia starts 
to decline in a log-linear manner almost as soon as parasiticidal drug concentrations are reached 
(White 2011). The Tmax is about 0.5 to 15 minutes for IV artesunate (Artesunate PI). The Tmax 
is about 4 hours for oral cipargamin and should be much shorter for IV cipargamin. Missing 
data of parasite counts at 12 hours could be well estimated using a log linear interpolation of 
the 2 parasite counts immediate before and after 12 hours. Since there are 3 planned parasite 
assessments on or after 2 hours, missing parasite count at 12 hours due to early discontinuation 
could be estimated using participant specific log linear regression if there are at least 2 parasite 
counts prior to the discontinuation. A sensitivity analysis will be performed using interpolation 
for missing data at intermediate time points and extrapolation using a log linear regression if 
there are at least 2 parasite counts prior to discontinuation. In the event that a participant does 
not have at least 2 parasite counts prior to discontinuation, the participant will be imputed as 
not achieving ≥ 90% reduction at 12 hours. Parasite counts below the limit of detection will be 
substituted using the half limit of detection.
The severity of disease is different between Cohort 1 and Cohort 2, which might impact the 
ability to achieve ≥ 90% parasite reduction, ie., resulting in a different binomial distribution 
between Cohorts 1 and 2. Therefore, two-sided 90% confidence intervals (CI) for the difference 
between each IV cipargamin dose regimen vs IV artesunate will be provided for Cohort 1 and 
Cohort 2 separately, using handling of missing values not related to intercurrent events specified 
in Section 12.4.4 and in this section.
12.4.6
Supplementary analysis
For each Cohort (except Cohort 1, which will be pooled with Cohort 2), the difference between 
a cipargamin dose regimen and artesunate in the proportion of participants with ≥ 90% reduction 
in parasite at 12 hours will be performed using the Fisher exact test.
For each cipargamin dose regimen that is selected for Cohorts 3-5, the difference versus 
artesunate in proportion of participants with ≥ 90% reduction in parasite at 12 hours will be 
evaluated by pooling data from all cohorts to show if the IV cipargamin dose regimen is superior 
to IV artesunate. The treatment difference will be evaluated based on 2-sided 95% CIs using a 
Mantel-Haenszel estimate of the common risk difference stratified by cohort (Cohorts 1 and 2 
will be pooled together and used as a single stratum)(SAS manual version 13.2 ). P-values will 
be provided using a Cochran-Mantel-Haenszel test (CMH) stratified by cohort.
Similarly, between treatment difference will be evaluated in children by repeating the above 
supplemental analysis on pooled Cohorts from 3-5 only.
These supplement analyses target a different hypothesis to show superiority of each cipargamin 
dose regimen over artesunate and will be performed using the FAS and handling of missing 
values not related to intercurrent events according to Section 12.4.4 and Section 12.4.5.
12.4.7
Supportive analyses
The analyses specified in Section 12.4.2, Section 12.4.5 and Section 12.4.6, will be repeated 
using the PPS.

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12.5
Analysis of secondary endpoints/estimands
Secondary endpoints will be descriptively presented and tabulated (n, mean, standard deviation, 
median, minimum, and maximum for continuous variables; n and percent for categorical 
variables) by treatment group for each cohort separately. Cohort 2 will be also evaluated 
together with Cohort 1. For stratified analysis, Cohort 1 will be combined with Cohort 2. The 
cipargamin dose regimen that is dropped after reviewing data from Cohorts 1-2 will be included 
only in the by-cohort analyses. For those treatment groups that are selected for Cohorts 3-5, 
descriptive statistics will be provided by treatment group using all pooled Cohorts (1-5) as well 
as separately pooled Cohorts 3-5. When data from different cohorts are pooled, an IV 
cipargamin regimen in Cohorts 3 to 5 (aged < 12 years) will be analyzed together with the 
equivalent IV cipargamin regimen as used in Cohorts 1 and 2 (aged ≥ 12 years). Such an IV 
cipargamin dose regimen will be denoted and labeled using the same cipargamin treatment 
group.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Secondary efficacy endpoints include:

Clinical success at 24 hours, 48 hours, 72 hours, 96 hours, hospital discharge, Day 6, Day 
8, Day 15, Day 22, and Day 29. See Table 8-3 for detailed information of defining clinical 
success. Clinical success at H48 is considered as a key secondary endpoint with a 
secondary estimand.

Individual signs of severe malaria over time

Altered consciousness - Prostration or GCS < 11 for participants > 5 years old or BCS 
< 3 for participants ≤ 5 years old

Renal Impairment- Serum creatinine > 3 x ULN or > 3 mg/dL or need for renal 
replacement therapy

Acidosis- Serum lactate > 4 mmol/L

Respiratory distress – present or absent

Severe anemia- Hb < 5 g/dl or Hb < 7g/dl in pediatric and adults respectively with 
parasite count of > 10,000/μl or need of blood transfusion

Jaundice- Serum bilirubin > 3 g/dl with parasite count of > 100,000/μl

Hypoglycemia- plasma glucose < 40 mg/dL

Proportion of participants with convulsion developing or persisting > 6 hour after start of 
IV study treatment

Proportion of participants developing any new severe malaria signs (as per WHO severe 
malaria criteria) after treatment

Proportion of participants with neurological sequelae at Day 2

Proportions of participants with ≥ 90% P. falciparum asexual parasite reduction from 
baseline at 24 and 48 hours

P. falciparum asexual parasite reduction ratios (PRR) at 12, 24 and 48 hours

Time to P. falciparum asexual parasite clearance (PCT) (in hours), defined as time from 
the first IV study medication until the first total and continued disappearance of asexual 
parasite forms which remained at least a further 48 hours,

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
Time to fever clearance (FCT) (in hours), defined as time from the first IV study 
medication 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,

Time to recover from prostration (in hours)

PCE slope half-life

Proportion of participants with recrudescence and reinfection by Day 29
Analysis of secondary estimand
The clinical success at 48 hours (see Table 8-3) for definition of clinical success and Section 2.2
for definition of estimand) will be evaluated using the FAS with data from all cohorts pooled.
Intercurrent events and other non-intercurrent events including partial missing data that may 
occur and affect the derivation of secondary estimand will be handled in Section 12.2. Note: 
partial data missing should be rare since participants are still hospitalized at 48 hours.
Table 12-2
Handling of intercurrent events and other events that may occur and 
affect the derivation of secondary estimand
Event
Outcome
Receive IV antimalarial rescue medication prior 
to 48 hours
Not clinical success
Discontinue the study prior to 48 hours, such as 
withdrawal of consent, COVID-19, etc.
Not clinical success due to early discharge
Missing parasite assessment at 48 hours$

Not clinical success if asexual parasites 
present in the latest visit prior to 48 hours

Ignored* otherwise
Altered consciousness: missing Prostration, 
missing Glasgow Coma Score or missing 
Blantyre coma score in relevant age groups$
Use the result from the latest visit prior to 48 
hours (including baseline) for each missing item
Renal impairment: missing SCr$

Not clinical success if Renal Replacement 
Therapy is used at 48 hours

Use the latest SCr prior to 48 hours
Acidosis and respiratory distress: missing 
plasma lactate or missing respiratory distress 
assessment$
Use the result from the latest visit prior to 48 
hours (including baseline) for each missing item
* determination of clinical success depends on other assessments.
$ Partial data missing, unlikely since participants are in the hospital
Two-sided 90% confidence intervals (CI) for the proportion of participants with clinical success 
at 48 hours will be provided based on the exact method (Clopper-Pearson method). In addition, 
2-sided 90% CIs for the difference between a cipargamin dose regimen and artesunate will be 
provided using a Mantel-Haenszel estimate of the common risk difference stratified by cohort 
where Cohorts 1 and 2 will be combined. Mantel-Haenszel estimate is a weighted risk 
difference with weight roughly proportional to strata size. It's an unbiased estimation of risk 
difference in the population under the following assumptions either (1) the risk difference is 

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same across different strata or (2) the strata sizes in study resemble the strata size in the disease 
population at large.
For participants who discontinue the study prior to the H48 assessments, such as withdrawal of 
consent, COVID-19, etc, the worst outcome (not clinical success) is used. This may under 
estimate the clinical success rate at 48 hours. A sensitivity analysis will be performed by 
imputing missing outcome using the best outcome as "Clinical success".
Descriptive statistics will be provided by cohort in addition to all cohorts pooled.
Supplementary analysis for secondary estimand
Analysis defined for secondary estimand will be repeated by pooling all participants from 
Cohorts 3-5.
Analysis of clinical success at timepoints other than 48 hours
The clinical success defined in Table 8-3 at Hours 24, 72, and 96, at hospital discharge, Days 
8, 15, 22, and 29 will be evaluated using the FAS and data from all cohorts pooled.
Intercurrent events and non-intercurrent events that may occur and affect the derivation of 
clinical success are handled in Table 12-3.
Table 12-3
Handling of other events that may occur and affect the derivation of 
clinical success at a visit other than 48 hours
Event
During hospital period 
(H24,72, and 96, and hospital 
discharge)$
After discharge from hospital 
(Days 8, 15, 22, and 29)
Receive IV antimalarial rescue 
medication prior to the visit
Not clinical success
Not clinical success
Death not related to malaria (as 
per adjudication committee)
Not applicable
Use the worst clinical success 
outcome between the hospital 
discharge visit and the last 
available visit
Discontinue the study prior to 
the visit due to other reasons, 
such as withdrawal of consent, 
lost to follow-up, COVID-19, 
etc.
Not clinical success due to 
early discharge
Use the worst clinical success 
outcome between the hospital 
discharge visit and the last 
available visit
Skipping the visit
Use the worst clinical success 
outcome from the visit before 
or visit after
Use the worst clinical success 
outcome from the visit before 
or visit after
Missing parasite assessments 
with visit

Not clinical success if 
asexual parasites present in 
the previous visit

Ignored* otherwise

Not clinical success if 
asexual parasites not cleared 
at the hospital discharge or 
parasites reappearance in a 
previous visit

Ignored* otherwise

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Event
During hospital period 
(H24,72, and 96, and hospital 
discharge)$
After discharge from hospital 
(Days 8, 15, 22, and 29)
Altered consciousness: 
missing Prostration, 
missing Glasgow Coma 
Score in adults or missing 
Blantyre coma score in children
Use the latest visit (including 
baseline) prior to the visit for 
each missing item

Not clinical success if 
prostration or coma is reported 
as AEs for the visit

Ignored* otherwise
Renal impairment: missing SCr

Not clinical success if Renal 
Replacement Therapy is used 
at the visit

Use the latest SCr prior to 
the visit

Not clinical success if Renal 
Replacement Therapy is used 
at the visit

Not clinical success if renal 
failure or renal impairment is 
reported as AE for the visit

Ignored* otherwise
Acidosis and respiratory 
distress: missing plasma 
lactate or missing respiratory 
distress assessment
Use the result from the latest 
visit prior to the visit for each 
missing item

Not clinical success if lactic 
acidosis or respiratory distress 
is reported as AE for the visit

Ignored* otherwise
$ Partial data missing is unlikely prior to hospital discharge
* Participant is considered as clinical success unless the participant does not meet clinical success 
due to other criterion
At each visit, 2-sided 90% CIs for the proportion of participants with clinical success for each 
treatment group will be provided based on the exact method. In addition, 2-sided 90% CIs for 
the difference between a cipargamin dose regimen and artesunate will be provided using a 
Mantel-Haenszel estimate of the common risk difference stratified by cohort where Cohorts 1 
and 2 will be combined.
At each visit, 2-sided 90% CIs for the proportion of participants with clinical success for each 
treatment group will be provided based on the exact method and 2-sided 90% CIs for treatment 
difference vs artesunate will be provided using the Wilson uncorrected method by cohort. For 
death not related to malaria and discontinuation of study after the hospital discharge, the 
following 2 sensitivity analyses will be performed:

Use the last available clinical success outcome prior to death or discontinuation.

Use multiple imputation methods, which will be specified in the statistical analysis plan.
Analyses of clinical and laboratory assessments and signs related to severe 
malaria
All analyses described below will be performed using the FAS without imputation for missing 
assessments, ie., missing assessments will be excluded from analysis.
For the following individual signs of severe malaria, the shift table of post-baseline presence 
relative to baseline presence or not will be provided by visit (24 hours, 48 hours, 72 hours, 96 
hours, at hospital discharge, Day 6, Day 8, Day 15, Day 22, and Day 29), cohort, and treatment 
group:

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
Altered consciousness - Prostration or GCS < 11 for age > 5 yrs / BCS < 3 for age <= 5 
years

Renal Impairment- Serum creatinine > 3 x ULN or > 3 mg/dL or need for renal 
replacement therapy

Acidosis- Serum lactate > 4 mmol/L

Respiratory distress – present or absent

Severe anemia- Hb < 5 g/dl or Hb < 7g/dl in pediatric and adults respectively with parasite 
count of > 10,000/μl or need of blood transfusion

Jaundice- Serum bilirubin > 3 g/dl with parasite count of > 100,000/μl

Hypoglycemia- plasma glucose < 40 mg/dL
Number and percent of participants will be provided by cohort and treatment group for the 
following events related to severe malaria:

Convulsion developing or persisting > 6 hour after the IV study treatment. Note: 
“persisting > 6 hour” means that convulsion is present at baseline and again at a visit that 
is > 6 hours after IV study treatment.

New severe malaria signs (as per WHO severe malaria criteria) after the IV study 
treatment

Neurological sequelae (by adjudication) at Day 29
Neurological Examination results will be summarized descriptively by visit, cohort, and 
treatment group.
For the following time to event variables, the first visit with the event will be used to calculate 
the time if a participant experiences the event. If a participant does not experience the event, 
the time will be censored at the last visit assessment for specific type of event (such as last sit 
assessment, etc.) with the exception of date of discontinuation (or death) for time to oral 
antimalarial therapy.

Time to oral antimalarial therapy (in hours),

Time to recover prostration in participants who are prostrated at baseline
Descriptive statistics will provided using the Kaplan-Meier method and Kaplan-Meier curves 
will be presented by cohort and treatment.
Day of discharge from hospital will be summarized descriptively by cohort and treatment group. 
Day of death will be used in case of death during hospitalization.
Analysis of secondary endpoints related to parasite clearance dynamics
All analyses will be performed using the FAS.
Proportions of participants with ≥ 90% P. falciparum asexual parasite reduction from 
baseline at 24 and 48 hours: missing data due to intercurrent and non-intercurrent events will 
be handled similar to the primary efficacy endpoint (See Section 12.4.3, Section 12.4.4). These 
2 variables will be analyzed using the statistical methods specified in Section 12.4.2, 
Section 12.4.5 and Section 12.4.6.

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PRRs at 12, 24 and 48 hours: PRR is defined as the ratio of asexual parasite at baseline divided 
by asexual parasite at post-baseline. If the asexual parasite count at post-baseline is 0, the half 
value of detection limit will be used to calculate the ratio. Missing values will not be imputed. 
For each PRR, 2-sided 90% CIs for each treatment group and for treatment ratio between each 
IV cipargamin regime vs IV artesunate by cohort will be provided using an analysis of 
covariance (ANCOVA) model on the log scale with log baseline value as a covariate and 
treatment group as a factor. For all cohorts pooled, the analysis will be performed with cohort 
as an additional factor in the ANCOVA model.
PCT and FCT: PCT will be calculated based on uncorrected P. falciparum asexual parasite 
counts. If a participant does not experience an event (such as P. falciparum parasite clearance, 
etc.), the time to the event will be censored at the last relevant assessment (such as last P. 
falciparum parasite assessment, etc.) participants who do not have the health condition at 
baseline (eg, fever, etc.) will be excluded from the corresponding time to event analysis (eg., 
FCT, etc.). Descriptive statistics will provided using the Kaplan-Meier method and Kaplan-
Meier curves will be presented by treatment and cohort. For all cohorts pooled, difference for 
the cipargamin regimen vs artesunate will be evaluated using a log-rank test stratified by cohort. 
Two-sided 90% CIs for the hazard ratio will be provided.
PCE slope half-life: PCE slope half-life will be calculated for each participant using the 
WWARN (World Wide Antimalarial Resistance Network) Parasite Clearance Estimator as 
described in Flegg et al 2011. 2-sided 90% CIs for each treatment group and for treatment ratio 
between each IV cipargamin regime vs IV artesunate by cohort will be provided using an 
analysis of covariance (ANCOVA) model on the log scale with log baseline value as a covariate 
and treatment group as a factor. For all cohorts pooled, the analysis will be performed with 
cohort as an additional factor in the ANCOVA model.
Incidence of recrudescence and reinfection during the study
Reinfection is defined as appearance of asexual parasites after clearance of initial infection with 
a genotype different from those parasites present at baseline.
Recrudescence is defined as appearance of asexual parasites after clearance of initial infection 
with a genotype identical to that of parasites present at baseline. Recrudescence must be 
confirmed by PCR analysis.
Incidence rates of recrudescence and reinfection at Study Day 29 will be estimated by Kaplan-
Meier method based on the subset of FAS participants who have clearance of initial infection 
by Study Day 7. Time to recrudescence/reinfection will be calculated from the time of first IV 
study medication to the date of first event if a participant experience the event and be censored 
at the time of last parasite assessment if a participant does not experience the event.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings will be presented by cohort, 
treatment group, participant and visit/time if applicable. Summary tables will be presented by 
cohort (including pooled cohort,) and treatment group.
Secondary safety endpoints include:

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
Standard safety/tolerability assessments (incidence of serious adverse events (SAEs), 
mortality, in-hospital mortality, adverse events (AEs), and routine safety and laboratory 
assessments)

Proportion of participants developing early hemolysis after treatment (as defined in 
Section 10.2.3).

Proportion of participants developing delayed hemolysis after treatment (as defined in 
Section 10.2.3).
Adverse events
All information obtained on adverse events will be displayed by cohort, treatment group and 
participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:

by cohort, treatment, primary system organ class and preferred term.

by cohort, treatment, primary system organ class, preferred term and maximum severity.

by cohort, treatment, Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, mortality, in 
hospital mortality, mortality related to malaria by adjudication, serious adverse events, other 
significant adverse events leading to discontinuation, and adverse events leading to dose 
adjustment. Summaries will also be provided separately for adverse events occurring during the 
IV study period (prior to oral standard of care, Coartem) and for adverse events post the IV 
study period (after taking oral Coartem).
The number (and proportion) of participants with adverse events of special interest/related to 
identified and potential risks will be summarized by cohort and treatment.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs, body height, body weight, and head circumference data will be listed by cohort, 
treatment group, participant, and visit/time. If ranges are available, abnormalities (and relevant 
orthostatic changes) in vital signs will be flagged and listed by cohort, treatment group, 
participant, and visit/time. Summary statistics will be provided by cohort, treatment group, and 
visit/time.
12-lead ECG
Abnormal ECG data will be flagged and will be listed by cohort, treatment group, participant 
and visit/time. Summary statistics may be provided by cohort, treatment group and visit/time.
The analysis results for categorical outliers and T-wave morphology will be summarized in 
frequency tables with counts and percentages for both number of participants and number of 

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timepoints. For categorical outliers, the number of participants (%) and timepoints will be 
determined by treatment group for the following:

increase in QTcF from baseline of ≥ 30 msec and ≥ 60 msec

increase in QTcB from baseline of ≥30 msec and ≥ 60 msec

absolute QTcF values > 450 msec, > 480 msec, and > 500 msec

absolute QTcB values > 450 msec, > 480 msec, and > 500 msec

PR change from baseline > 25% increase resulting in PR > 200 msec

QRS change from baseline > 25% increase resulting in QRS > 120 msec

heart rate change from baseline > 25% decrease resulting in heart rate < 50 beats per 
minute

heart rate change from baseline > 25% increase resulting in a heart rate > 100 beats per 
minute
For T-wave morphology, the analysis will be focused on the treatment emergent changes.
The relationship between change from baseline in QTcF/QTcB and cipargamin plasma 
concentration will be assessed graphically with change from baseline in QTcF/QTcB plotted 
against cipargamin plasma concentrations.
This concentration-QT relationship may also be explored using linear mixed effects model 
(Garnett et al 2018). The change from baseline in QTcF/QTcB will be the dependent variable 
in the model, baseline QTcF/QTcB, cipargamin treatment flag (yes or no) cipargamin plasma 
concentrations as a covariate and time as a categorical variable. A random intercept for each 
participant will be specified. Control (artesunate) participants will be included in the analysis 
with a plasma concentration of 0. The control-corrected change from baseline in QTcF/QTcB 
and the two-sided 90% confidence interval will be extracted from the model at the geometric 
mean maximum plasma concentration for cipargamin.
Clinical laboratory evaluations
If normal ranges are available, abnormalities in laboratory data will be flagged and will be listed 
by cohort, treatment group, participant, and visit/time and. Summary statistics will be provided 
by cohort, treatment, and visit/time. Shift tables using the low/normal/high/ (low and high)
classification will be used to compare baseline to the worst on-treatment value.
The number (and proportion) of participants with early hemolysis and number (and proportion) 
of participants with delayed hemolysis (see Section 10.2.3) will be summarized by visit, cohort, 
and treatment group.
The number (and proportion) of participants with serum lactate < 2 mmol/l will be summarized 
by visit (8, 12, 36, 48, and 72 hours), cohort and treatment group in participants with 
hyperlactemia (serum lactate > 4 mmol/L) at baseline.
The percentage change from baseline in plasma lactate level will be summarized by visit (4, 8, 
12, and 24 hours), cohort and treatment group.
The time to normalized blood lactate level (in hours) in participants with baseline blood lactate 
level above normal will be summarized descriptively using the Kaplan-Meier method by cohort 

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and treatment group. Kaplan-Meier curve will be also presented. If a participant does not 
normalize the blood lactate, the time will be censored at the last blood lactate assessment.
12.5.3
Pharmacokinetics
Only cipargamin pharmacokinetics will be determined in this study. For each cohort, 
cipargamin plasma concentration data will be listed by cohort, treatment, participant, and 
visit/sampling time point. Descriptive summary statistics will be provided by cohort (including 
pooled cohort), treatment and visit/sampling time point, including the frequency (n, %) of 
concentrations below the LLOQ and reported as zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations. For geometric related mean and 
CV, concentrations below LLOQ will be included as half of the LLOQ value.
Table 12-4
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUC0-t
The AUC from time zero to time t (e.g. 24h) (amount x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
Ct
Concentration at time t (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (lz) of a semi logarithmic 
concentration-time curve (time).
CL/F
The total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with λz) 
(volume)
Pharmacokinetic variables:
The following pharmacokinetic parameters will be determined using non-compartmental 
method(s) for IV cipargamin:
AUCinf, AUC0-t, Cmax, C2min, Tmax, T1/2, CL, and Vz.
Bio-fluid concentrations will be expressed in mass per volume units. All concentrations below 
the limit of quantitation or missing data will be reported as such in the concentration data listings. 
Concentrations below the limit of quantitation will be treated as zero in summary statistics.
The pharmacokinetic parameters will also be listed by cohort, treatment and participant.

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An interim assessment (IA) after Cohort 2 will be conducted to decide upon the dosing regimen 
for Cohorts 3-5. All randomized participants in Cohorts 1-2 with key efficacy, safety and PK 
data up to Day 29 will be included in this IA.
An independent Data Monitoring Committee (DMC) will review participant safety at several 
time points during the study. If notable adverse events or safety concerns are found at one of 
the planned dose levels, the DMC may recommend dose and/or age adjustment, stopping a 
cohort or the study early for safety reasons.
An additional IA may be conducted (for e.g. after Cohort 4) to support decision making 
concerning the current clinical study, the sponsor’s clinical development projects in general or 
in case of any safety concerns.
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The clinical team may be communicated interim results (e.g. information needed for 
planning/modifying another study) to relevant Novartis teams for information, consulting 
and/or decision purposes.
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The primary objective is to show that an IV cipargamin dose regimen is non-inferior to the IV 
artesunate in proportion of participants with ≥ 90% P. falciparum parasite reduction at 12 hours 
for each cohort. In the artesunate Phase III studies SEAQUAMAT (Dondorp et al 2005) and 
AQUAMAT 
(Dondorp et al 2010), 
proportion 
of 
participants 
with 
≥ 
90% P. 
falciparum parasite reduction was not reported for both artesunate and quinine. Therefore, a 
non-inferiority margin in proportion of participants with ≥ 90% parasite reduction for IV 
cipargamin vs IV artesunate cannot be derived statistically based on historical data. A non-
inferiority margin of 10% is set based on clinical judgement. The KM plot for time to > 90% 
parasite clearance by Kremsner et al (2016) indicated that the proportion of participants with 90% 
parasite reduction at 12 hours was about 50%, 45%, and 40% for artesunate 3 dose IM (n=341), 
3 dose IV (n=337), and 5 dose IM (n=333), respectively. Therefore, we assume that the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Based on these assumptions, a sample size of 13 participants per treatment group will 
provide 90% power to show that a cipargamin treatment group is non-inferior to artesunate for 
each cohort in the proportion of participants with ≥ 90% P. falciparum parasite reduction at 12 
hours using a non-inferiority margin of 10% absolute difference at the 1-sided 5% significance 
level (nQuery 7.0 Table PTE1a). Considering that 5% of participants that may be excluded from 
the analysis (Kremsner et al (2016)), at least 14 participants will be randomized to each 
treatment arm in each cohort except Cohort 1 to achieve 13 evaluable participants per arm for 
the primary analysis. The sample size for Cohort 1 will be 6 participants in each arm, which is 
not based on the statistical justification (no formal testing will be performed in this Cohort 1) 
but based on clinical judgment to rule out the risk of any potential untoward safety or lack of 
efficacy issues in this small group of moderately severe malaria participants before enrolling 
the severe malaria participants into the study.
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The key secondary estimand of clinical success at 48 hours may be used as a primary efficacy 
endpoint for the Ph.3 study. The key secondary objective is to estimate clinical success rates 
for cipargamin and artesunate individually as well as the difference between two treatment 
groups at 48 hours with good precision. The cipargamin treatment group for this estimation will 
CCI

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be the one, which is used in all the cohorts across the study; participants from this treatment 
group will be pooled from all Cohorts. Similarly, for the artesunate group, participants will be 
pooled from all Cohorts.
The sample size calculation considers the precision of the estimates for the individual treatment 
groups as well as the difference between the two treatment groups; and the precision is 
measured in the form of half width of the associated 90% CI as mentioned below.
Precision of the estimates of single proportion
For a binary endpoint, let X be a number of clinical successes with n participants, X follows a 
binomial distribution Bin(n, p) where p is the true proportion of participants with clinical 
success for a treatment group at a visit. Proportion (p) is estimated by X/n with a 90% CI based 
on the exact method; and the half-width of 90% CI is considered as the precision of the estimate. 
Consider d as the targeted half width of CI and Pl and Pu as lower and upper limits of 90% CI 
based on X and n (exact method), the probability that the observed half width (0.5[Pu - Pl])) is 
at most the targeted half, ie., Pr{0.5(Pu - Pl)≤d|Bin(n,p)) will be used to justify the sample size 
for a single proportion.
Figure 12-1
Plot of probability that half width of 2-sided 90% CIs for a single 
proportion is at most 0.1 for various true proportions
Generated using R 3.4.3
For designated half width d, the sample size, n is chosen so that the probability that the half 
width of 2-sided exact 90% CI for p is at most d is at least 80% at a likely true p.

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Figure 12-1 displays the probabilities that the half width of 2-sided exact 90% CIs for a single 
proportion ≤0.1 for true proportions of 0.5 to 0.9 by 0.1. To maintain the same probability, such 
as 80% represented in the horizontal dash line, the sample size is higher when the true 
proportion is closer to 0.5 and is lower when it is away from the 0.5. For instance, when p =0.5,
n=76 is required to estimate the true proportion with at least 80% probability that the half width 
of 2-sided exact 90% CI is ≤10%. Similarly, when p =0.7, n=70 is required to estimate the true 
proportion with at least 80% probability that the half width of 2-sided exact 90% CI is ≤10%.
Precision of the estimates of difference between two proportions
For estimating the difference between two proportions, the half width of 2-sided 90% CIs 
calculated using Wilson's uncorrected method is considered as the precision of the estimation. 
The probability that the half width of 2-sided 90% CI for difference between 2 proportions is at 
most a targeted width (d) at likely proportions will be considered for the sample size selection.
Figure 12-2 displays the probability that the half width of Wilson's uncorrected 2-sided 90% 
CIs for the difference between 2 proportions is most 0.1 for true equal proportions of 0.5, 0.6, 
0.7, 0.75, 0.8, and 0.9. To maintain the same probability, such as 80% represented in the 
horizontal dash line, the sample size is higher when the two equal true proportions are closer to 
0.5. For instance, when p =0.5 for both treatment groups, n=133 is required in order to have at 
least 80% probability that the half width of 2-sided 90% CIs for the difference is at most 0.1. 
Similarly, when p =0.75 for both treatment groups, n=107 is required in order to have at least 
80% probability that the half width of 2-sided 90% CI for the difference is at most 0.1.
Compared with Figure 12-1, Figure 12-2 shows that the required sample size for the precision 
in estimating the difference between 2 proportions is higher than the corresponding sample size 
required for the precision in estimating a single proportion. Therefore, the sample size for the 
study will be justified based on the half width of 2-sided 90% CIs for the difference between 2 
proportions.
The proportion of participants who were alive without new/worsening complication at the end 
of study for artesunate was 0.679 in SEQUAMAT and 0.791 in AQUAMAT (private 
communication). Therefore, it is estimated that the proportion of participants meeting the 
proposed clinical endpoint is about 0.75 in the artesunate arm. To date, cipargamin has not been 
tested in patients with severe malaria. It is assumed that the proportion in the cipargamin arm 
would be same as that of artesunate.
From Figure 12-2, a sample size of n=107 per arm is required in order to have at least 80% 
probability that the half width of 2-sided 90% CIs for the difference between 2 proportions is 
at most 0.1 if the true proportion is 0.75 for both treatment groups. As participants treated with 
the same treatment from all cohorts will be pooled together for the analysis using the FAS, this 
sample size is considered for the artesunate and the cipargamin dose regimen that is used in all 
cohorts.
Taking account that about 8% participants may be excluded from the FAS, participants from 
all cohorts will be randomized to yield about 116 randomized each for the artesunate and the 
cipargamin dose regimen that is used in all cohorts so that 107 participants per group are 
evaluable for this analysis. The enrollment may be increased if the number of participants 
excluded from the FAS is higher. Considering the required sample size for each cohort for the 

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primary endpoint (see Section 12.8.1) and the potential participant population available for 
recruitment, the 116 randomized for a treatment group will split into 6 participants for Cohort 
1, 14 participants for Cohort 2, 38 participants for Cohorts 3 and 4, and 20 participants for 
Cohort 5.
Figure 12-2
Plot of probability that half width of 2-sided 90% CIs for 2 proportion 
difference is at most 0.1 for various true equal proportions
Generated using R 3.4.3.
Safety events
Safety events will be evaluated using the safety set, which is expected to similar to the 
randomized set. Occurrence of a safety event for a regimen (cipargamin or artesunate) will be 
evaluated by cohort and overall with all participants pooled from all cohorts. The probability of 
observing selected minimal number of events is displayed in Figure 12-3 by sample size. From 
this plot,

for a treatment group in a cohort with 6 participants, the probability of observing at least 2 
events is > 75% if true event rate is ≥ 40% but < 20% if true event rate is ≤ 10%

for a treatment group in a cohort with 14 participants, the probability of observing at least 
2 events is about 80% if the true event rate is ≥ 20% but < 20% if the true event rate is ≤ 
5% ;

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
for a treatment group in a cohort with 20 participants, the probability of observing at least 
3 events is about 80% if the true event rate is ≥ 20% but < 20% if the true event rate is ≤ 
7%

for a treatment group in a cohort with 38 participants, the probability of observing at least 
9 events is about 80% if the true event rate is ≥ 20% but < 20% if the true event rate is ≤ 
10%

for a regimen that is selected for Cohorts 3-5 with 116 participants, the probability of 
observing at least 14 events is > 80% if the true event rate is ≥ 15% but < 20% if the true 
event rate is ≤ 9%.
The minimal number of events mentioned above may be used a guidance to interpret the 
occurrence of safety events in a treatment group in a cohort or pooled cohorts.
Figure 12-3
Probability of observing selected minimal number of events by 
sample size
Generated using R 3.4.3

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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g. 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The study will be registered in a publicly accessible database such as clinicaltrials.gov and as 
required in EudraCT. In addition, after study completion (defined as last participant last visit) 
and finalization of the study report, the results and the protocol of this trial will be submitted 
for publication and posted in a publicly accessible database of clinical trial results, such as the 
Novartis clinical trial results website and all required Health Authority websites (e.g. 
Clinicaltrials.gov, EudraCT etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.

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14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
References
References are available upon request
Artesunate Package Insert. Ipca Laboratories Limited; Sep-2019.
Barnes KI, Mwenechanya J, Tembo M, et al (2004) Efficacy of rectal artesunate compared 
with parenteral quinine in initial treatment of moderately severe malaria in African children 
and adults: a randomised study. Lancet; 363:1598-605.
Chughlay MF, Akakpo S, Odedra A, et al (2020) Liver Enzyme Elevations in Plasmodium 
falciparum Volunteer Infection Studies: Findings and Recommendations. Am. J. Trop. Med. 
Hyg.
Dondorp A, Nosten F, Stepniewska K, et al (2005) Artesunate versus quinine for treatment of 
severe falciparum malaria: a randomised trial. Lancet; 366:717–25.
Dondorp AM, Fanello CI, Hendriksen IC, et al (2010) Artesunate versus quinine in the 
treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, 
randomised trial. Lancet; 376:1647–57.
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.
Garnett C, Bonate PL, Dang Q, et al (2018) Scientific white paper on concentration-QTc 
modeling. J Pharmacokinet Pharmacodyn;45:383-97.
KAE609 Investigator`s Brochure
Kremsner PG, Adegnika AA, Hounkpatin AB, et al (2016) Intramuscular Artesunate for 
Severe Malaria in African Children: A Multicenter Randomized Controlled Trial. PLoS Med; 
13(1):e1001938.
Kurth F, Develoux M, Mechain M, et al (2017) Severe malaria in Europe: an 8-year multi-
centre observational study. Malar J; 16:57.
Maude RJ, Silamut K, Plewes K, et al (2014) Randomized controlled trial of levamisole 
hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia. J 
Infect Dis; 209:120-9.
Naß J, Efferth T (2019) Development of artemisinin resistance in malaria therapy. Pharmacol 
Res; 146:104275
Nealon C, Dzeing A, Müller-Römer U, et al (2002) Intramuscular bioavailability and clinical 
efficacy of artesunate in gabonese children with severe malaria. Antimicrob Agents 
Chemother; 46(12):39339.
Newton PN, Angus BJ, Chierakul W, et al (2003) Randomized comparison of artesunate and 
quinine in the treatment of severe falciparum malaria. Clin Infect Dis; 37:7–16.
Newton PN, Chierakul W, Ruangveerayuth R, et al (2001) A comparison of artesunate alone 
with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria. 
Trans R Soc Trop Med Hyg; 95:519-23.

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Reuling IJ, de Jong GM, Yap XZ, et al (2018) Liver Injury in Uncomplicated Malaria is an 
Overlooked Phenomenon: An Observational Study. EBioMedicine; 36:131–9.
Rolling T, Agbenyega T, Issifou S, et al (2014) Delayed hemolysis after treatment with 
parenteral artesunate in African children with severe malaria--a double-center prospective 
study. J Infect Dis;209:1921–8.
Schwartz GJ, Furth SL (2007) Glomerular filtration rate measurement and estimation in 
chronic kidney disease. Pediatr Nephrol; 22:1839–48.
Silamut K, Molunto P, Ho M, et al (1991) Alpha 1-acid glycoprotein (orosomucoid) and 
plasma protein binding of quinine in falciparum malaria. Br J Clin Pharmac; 32:311-5.
WHO (2014) Severe malaria. Tropical Medicine and International Health; 19 (Suppl 1):7–
131.
WHO (2015) Guidelines for the Treatment of Malaria- Third Edition.
White NJ (2011) The parasite clearance curve. Malar J; 10:278.
Woodford J, Shanks GD, Griffin P, et al (2018) The Dynamics of Liver Function Test 
Abnormalities after Malaria Infection: A Retrospective Observational Study. Am J Trop Med 
Hyg; 98(4):1113–9.

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16
Appendices
16.1
Appendix 1: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin normal at 
baseline:

ALT or AST > 5 × ULN

ALP > 2 × baseline (in the absence of known 
bone pathology)

Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome)

Potential Hy’s Law cases (defined as ALT or 
AST ≥ 3 × ULN and Total bilirubin ≥ 2 × ULN [> 
50% conjugated fraction] with no initial findings 
of cholestasis (i.e. ALP < 2 × ULN at baseline) 
and a hepatocellular pattern of injury at the time 
of liver injury (R ratio ≥ 5)*

Any clinical event of jaundice (or equivalent 
term)

ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a 
liver toxicity
If ALT or AST abnormal at baseline:

ALT or AST > 2x baseline or > 300 U/L 
(whichever occurs first)
*R ratio: ALT / ALP, using factor of elevation over ULN for both enzymes

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Table 16-2
Follow-up requirements for liver laboratory triggers and liver 
symptoms
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase post dose:
If normal at baseline:
ALT > 5 x ULN
Normal TBL
OR
If TBL elevated at 
baseline : no change 
from baseline TBL
None

No change to 
study treatment

Measure ALT, AST, 
ALP, TBIL, DBIL, INR, 
albumin and LDH 
within 48 hours
and at least 1x per 
week thereafter until 
resolved

Follow-up for 
symptoms

Initiate close 
monitoring and workup 
for competing 
etiologies
If elevated at 
baseline:
ALT > 3 x baseline
ALT > 20x ULN
Normal
None

Discontinue IV 
cipargamin and 
switch to IV 
artesunate

Continue IV 
artesunate based on 
benefit risk 
assessment of the 
investigator

Report as SAE

Measure ALT, AST, 
ALP, TBIL, INR, 
albumin and LDH in 48 
hours and at least 1x 
per week thereafter 
until resolved

Follow-up for 
symptoms

Initiate close 
monitoring and workup 
for competing 
etiologies

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ALT
TBL
Liver Symptoms
Action
ALT increase with bilirubin increase post dose:
If normal at baseline:
ALT > 3 x ULN
TBL ≥ 2 x baseline 
AND ≥ 2 x ULN AND
at least doubling of 
conjugated (=direct) 
bilirubin from baseline
None

Discontinue IV 
cipargamin and 
switch to IV 
artesunate

Continue IV 
artesunate based on 
benefit risk 
assessment of the 
investigator

Report as SAE

Measure ALT, AST, 
ALP, TBIL, INR, 
albumin and LDH in 48 
hours and at least 1x 
per week thereafter 
until resolved.

Follow-up for 
symptoms.

Initiate close 
monitoring and workup 
for competing 
etiologies.
If elevated at 
baseline:
ALT > 3 x baseline
Actions related to liver events and laboratory triggers:

Repeat liver chemistry tests should be performed using the local laboratory used by the 
site. Test results must be reported as appropriate.

Hospitalization of the participant if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

investigations based on investigator’s discretion: serology tests, imaging (abdominal 
Ultrasound, CT or MRI as appropriate) and pathology assessments,

hepatologist’s consult,

obtaining more detailed history of symptoms and prior or concurrent diseases,

obtaining history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets

exclusion of underlying liver disease
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.

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16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
Renal event
Actions
Confirmed serum creatinine increase 25 – 49%

Consider causes and possible interventions

Follow-up within 24-48 h
Serum creatinine increase ≥ 50 % +OR
if <18 years old, eGFR ≤ 35 ml/min/1.73 m2

Consider causes and possible interventions

Repeat assessment within 24-48h

Consider drug discontinuation unless other 
causes are diagnosed and corrected

Consider patient hospitalization and 
specialized treatment
New onset dipstick proteinuria ≥ 3+

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm within 24-48h

Consider drug discontinuation unless other 
causes are diagnosed and corrected
New onset hematuria ≥ 3+ on urine dipstick

Repeat assessment to confirm within 24-48h

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury
Follow-up of renal events:
Assess, document and record in CRF:
• Urine dipstick and sediment microscopy: crystals, red blood cells (dysmorphic/glomerular vs. 
non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells
• Blood pressure and body weight
• Serum creatinine, BUN, electrolytes (sodium, potassium, calcium) and bicarbonate
• Urine output
Whenever a renal event is identified, a detailed participant history and examination are indicated 
to identify and potentially eliminate risk factors that may have initiated or contributed to the 
event:

Blood pressure assessment (after 5-minute rest)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

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
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium
Pediatric participants: special considerations
Schwartz formula:

For height in cm and SCr in mg/dL: eGFR (ml/min/1.73 m2) = 0.413 x (height/SCr)

For height in cm and SCr in µmol/L: eGFR (ml/min/1.73 m2) = 36.5 x (height/SCr)
Normal renal GFR values, as measured by inulin clearance (Schwartz and Furth 2007), are 
provided in Table 16-4 below:
Table 16-4
Normal GFR in children and young adults, as assessed by inulin 
clearance (adapted for pediatric participants included in this study)
Age
Mean GFR ± SD (ml/min per 1.73 m2)
Term babies
4-6 months
87.4 ± 22.3
7-12 months
96.2 ± 12.2
1-2 years
105.2 ± 17.3
Children
3-4 years
111.2 ± 18.5
5-6 years
114.1 ± 18.6
7-8 years
111.3 ± 18.3
9-10 years
110.0 ± 21.6
11-12 years
116.4 ± 18.9
13-15 years
117.2 ± 16.1
2.7-11.6 years
127.1 ± 13.5
9-12 years
116.6 ± 18.1
Young adults
16.2-34 years
112 ± 13

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16.4
Appendix 4: Modified version of WHO classification of signs of 
severe P. falciparum malaria
Severe malaria is defined as occurrence of one or more of the following observations, in the 
absence of an identified alternative cause, and in the presence of P. falciparum asexual 
parasitemia (WHO 2014)
Table 16-6
Definition of severe malaria
Signs
Definition
Impaired consciousness
A Glasgow Coma Score < 11 in adults or a Blantyre coma score < 3 
in children
Prostration
Generalized weakness so that the person is unable to sit, stand or 
walk without assistance
Multiple convulsions
More than two episodes within 24 hours
Acidosis*
venous plasma lactate ≥ 4 mmol. Severe acidosis manifests clinically 
as respiratory distress – rapid, deep and laboured breathing
Hypoglycaemia
Blood or plasma glucose < 2.2 mmol (< 40 mg/dL)
Severe malarial anaemia
A haemoglobin concentration < 5 g/dl or a haematocrit of < 15% in 
children < 12 years of age (< 7 g/dl or < 20%, respectively, in adults) 
together with a parasite count > 10,000/µl
Renal impairment (acute 
kidney injury)**
Plasma or serum creatinine > 265 µmol/L (3 mg/dL) or ≥ 3x ULN 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 respiratory rate > 30/min, often with chest indrawing and 
crepitations on auscultation
Significant bleeding
Including recurrent or prolonged bleeding from nose gums or 
venepuncture sites; haematemesis or melaena
Shock
Compensated shock is defined as capillary refill ≥ 3 s or temperature 
gradient on leg (mid to proximal limb), but no hypotension. 
Decompensated shock is defined as systolic blood pressure < 70 mm 
Hg in children or < 80 mm Hg in adults with evidence of impaired 
perfusion (cool peripheries or prolonged capillary refill)
Hyperparasitemia
P. falciparum parasitemia > 10%
* Acidosis definition have been modified to categorize venous plasma lactate ≥ 4 mmol as acidosis .
**Renal impairment definition have been modified to include Serum creatinine value of ≥ 3 ULN in 
the existing WHO definition

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16.5
Appendix 5: Approximate amount of blood withdrawn
Table 16-7
Amount of blood withdrawn per Cohort
Cohort
Age of Participants
Amount of blood withdrawn 
(ml)* from Participants in 
total study duration
1-2
≥ 12 years
~40
3
6 years - < 12 years
~40
4
2 years - < 6 years
~11
5
6 months - < 2 years
~11
*Blood volume indicated are approximate. If for any reason additional blood is withdrawn especially 
due to safety or repeat assessment please ensure to keep it close to micro sampling especially for 
children, per local regulations.

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16.6
Appendix 6: Coma Scores used in the study
Table 16-8
Glasgow Coma Scale
Eye Opening 
(E)
-
Verbal 
Response (V)
-
Best Motor 
Response 
(M)
-
Spontaneous
4
Oriented
5
Obeying 
Commands
6
To speech
3
Confused
4
Localizing
5
To pressure
2
Words
3
Normal flexion
4
None
1
Sounds
2
Abnormal 
flexion
3
-
-
None
1
Extension
2
-
-
-
-
None
1
Table 16-9
Blantyre Coma Score
Eye Opening 
(E)
Verbal 
Response (V)
Best Motor 
Response 
(M)
Able to follow 
the moving 
object
1
Normal cry or 
appropriate 
speech (for 
patients who 
are old 
enough to 
talk) in 
response to 
painful stimuli
2
Localize pain 
stimulus
2
Unable to 
follow the 
moving object
0
Moan or an 
abnormal cry 
in response to 
painful stimuli
1
Withdraw limb 
from pain 
stimulus
1
-
-
No cry with 
painful stimuli
0
No response 
or 
inappropriate 
response to 
pain stimulus
0