Clinical trial NCT04300309
Conditions: Plasmodium Falciparum Malaria
Keywords: Plasmodium falciparum malaria artemether lumefantrine neonates infants
Sponsor: Novartis Pharmaceuticals
Start date: 2020-12-21; Completion date: 2024-05-10
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate PK, safety, tolerability and efficacy of a new formulation of artemether-lumefantrine dispersible tablet in neonates and infants \<5 kg body weight with acute uncomplicated Plasmodium falciparum malaria.

Detailed description:
This was a multicenter, open-label, single-arm, adaptive design with dose adaptation (deescalation or escalation) study in infants and neonates \<5 kg body weight with P. falciparum malaria. There were two sequential and age-descending cohorts of participants, all \<5 kg: Cohort 1 of infants \>28 days of age, and Cohort 2 of neonates ≤ 28 days of age.

Arms: arm 1: Artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days
Interventions: intervention 1: artemether:lumefantrine (2.5 mg:30 mg)
Intervention descriptions: intervention 1: Two oral dispersible tablets twice daily for three consecutive days. Each tablet contained artemether-lumefantrine 2.5 mg:30 mg.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
COA566 
Clinical Trial Protocol CCOA566B2307 / NCT04300309
A multicenter, open-label, single-arm study to evaluate the 
PK, safety, tolerability and efficacy of a new artemether-
lumefantrine (2.5 mg:30 mg) dispersible tablet in the 
treatment of infants and neonates <5 kg body weight with 
acute uncomplicated Plasmodium falciparum malaria 
Document type: 
Amended Protocol Version (global) 
Version number: 
01 Clean 
Clinical Trial Phase: 
II/III 
Release date: 
29-Jun-2023
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018 


Novartis 
Confidential 
Page 2 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 1 .................................................................................................................... 10 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 16 
1.1 
Background ............................................................................................................ 16 
1.2 
Purpose .................................................................................................................. 17 
2 
Objectives and endpoints ................................................................................................... 17 
3 
Study design ...................................................................................................................... 18 
4 
Rationale ............................................................................................................................ 22 
4.1 
Rationale for study design ..................................................................................... 22 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 22 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 25 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.5 
Rationale for public health emergency mitigation procedures .............................. 25 
4.6 
Risks and benefits .................................................................................................. 26 
5 
Population .......................................................................................................................... 27 
5.1 
Inclusion criteria .................................................................................................... 28 
5.2 
Exclusion criteria ................................................................................................... 28 
6 
Treatment ........................................................................................................................... 29 
6.1 
Study treatment ...................................................................................................... 29 
6.1.1 
Investigational and control drugs .......................................................... 29 
6.1.2 
Additional study treatments .................................................................. 30 
6.1.3 
Treatment arms/group ........................................................................... 30 
6.1.4 
Treatment duration ................................................................................ 30 
6.2 
Other treatment(s) .................................................................................................. 31 
6.2.1 
Concomitant therapy ............................................................................. 31 
6.2.2 
Prohibited medication ........................................................................... 32 
6.2.3 
Rescue medication ................................................................................ 34 
6.3 
Subject numbering, treatment assignment, randomization .................................... 35 
6.3.1 
Subject numbering ................................................................................ 35 
6.3.2 
Treatment assignment, randomization .................................................. 35 


Novartis 
Confidential 
Page 3 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
6.4 
Treatment blinding ................................................................................................ 35 
6.5 
Dose escalation and dose modification.................................................................. 36 
6.5.1 
Dose escalation guidelines .................................................................... 36 
6.5.2 
Dose modifications ................................................................................ 36 
6.5.3 
Follow-up for toxicities ......................................................................... 36 
6.6 
Additional treatment guidance ............................................................................... 36 
6.6.1 
Treatment compliance ........................................................................... 36 
6.6.2 
Recommended treatment of adverse events .......................................... 37 
6.6.3 
Emergency breaking of assigned treatment code .................................. 37 
6.7 
Preparation and dispensation ................................................................................. 37 
6.7.1 
Handling of study treatment and additional treatment .......................... 37 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 38 
7 
Informed consent procedures ............................................................................................ 38 
8 
Visit schedule and assessments ......................................................................................... 39 
8.1 
Screening ............................................................................................................... 40 
8.1.1 
Information to be collected on screening failures ................................. 41 
8.2 
Subject demographics/other baseline characteristics............................................. 41 
8.3 
Efficacy .................................................................................................................. 41 
8.3.1 
Appropriateness of efficacy assessments .............................................. 43 
8.4 
Safety ..................................................................................................................... 43 
8.4.1 
Laboratory evaluations .......................................................................... 44 
8.4.2 
Other safety evaluations ........................................................................ 44 
8.4.3 
Appropriateness of safety measurements .............................................. 44 
8.5 
Additional assessments .......................................................................................... 45 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 45 
8.5.2 
Pharmacokinetics .................................................................................. 45 
9 
Study discontinuation and completion .............................................................................. 46 
9.1 
Discontinuation ...................................................................................................... 46 
9.1.1 
Discontinuation of study treatment ....................................................... 46 
9.1.2 
Withdrawal of informed consent ........................................................... 47 
9.1.3 
Lost to follow-up ................................................................................... 47 
9.1.4 
Early study termination by the sponsor ................................................. 48 
9.2 
Study completion and post-study treatment .......................................................... 48 
10 Safety monitoring and reporting ........................................................................................ 48 
10.1 
Definition of adverse events and reporting requirements ...................................... 48 
10.1.1 
Adverse events ...................................................................................... 48 
10.1.2 
Serious adverse events .......................................................................... 50 


Novartis 
Confidential 
Page 4 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
10.1.3 
SAE reporting........................................................................................ 51 
10.1.4 
Pregnancy reporting .............................................................................. 51 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 51 
10.2 
Additional Safety Monitoring ................................................................................ 52 
10.2.1 
Data Monitoring Committee ................................................................. 52 
11 Data Collection and Database management ...................................................................... 53 
11.1 
Data collection ....................................................................................................... 53 
11.2 
Database management and quality control ............................................................ 53 
11.3 
Site monitoring ...................................................................................................... 54 
12 Data analysis and statistical methods ................................................................................ 54 
12.1 
Analysis sets .......................................................................................................... 54 
12.2 
Subject demographics and other baseline characteristics ...................................... 55 
12.3 
Treatments ............................................................................................................. 55 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 55 
12.4.1 
Definition of primary endpoint(s) ......................................................... 55 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 56 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 56 
12.4.4 
Sensitivity and supportive analyses ...................................................... 56 
12.5 
Analysis of secondary endpoints ........................................................................... 56 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 56 
12.5.2 
Safety endpoints .................................................................................... 58 
12.5.3 
Pharmacokinetics .................................................................................. 59 
12.5.4 
PK/PD relationships .............................................................................. 60 
12.5.5 
Patient reported outcomes ..................................................................... 60 
 
 60 
12.7 
Interim analyses ..................................................................................................... 61 
12.8 
Sample size calculation.......................................................................................... 61 
12.8.1 
Primary endpoint(s) ............................................................................... 61 
12.8.2 
Secondary endpoint(s) ........................................................................... 62 
13 Ethical considerations and administrative procedures ...................................................... 63 
13.1 
Regulatory and ethical compliance ........................................................................ 63 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 63 
13.3 
Publication of study protocol and results............................................................... 64 
13.4 
Quality Control and Quality Assurance ................................................................. 64 
14 Protocol adherence ............................................................................................................ 64 
14.1 
Protocol amendments............................................................................................. 64 
15 References ......................................................................................................................... 66 


Novartis 
Confidential 
Page 5 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
16 Appendices ........................................................................................................................ 69 
16.1 
Appendix 1: Clinically notable laboratory values and reference ranges (vital 
signs, head circumference) .................................................................................... 69 
16.2 
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ......................................................................................................... 74 
16.3 
Appendix 3: Pharmacokinetic sampling ................................................................ 76 
16.4 
Appendix 4: Signs and symptoms indicative of severe P. falciparum malaria 
(WHO 2015) .......................................................................................................... 76 
16.5 
Appendix 5: IMCI guidelines ................................................................................ 77 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 17 
Table 4-1 
Historical exposure values from previous studies ................................. 23 
Table 4-2 
PBPK modeled exposures based on a 5:60 mg (A:L) dose regimen .... 24 
Table 6-1 
Investigational and control drug ............................................................ 29 
Table 6-2 
Prohibited medication ........................................................................... 32 
Table 6-3 
Provisional dose levels .......................................................................... 36 
Table 8-1 
Schedule of assessments ....................................................................... 40 
Table 8-2 
Assessments & Specifications............................................................... 43 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 52 
Table 12-1 
Standard deviation for log Cmax in Coartem studies A2102 and 
B2306 .................................................................................................... 62 
Table 16-1 
Normal Vital Signs according to Age ................................................... 69 
Table 16-2 
Reference ranges for magnesium (mg/dL) by age range (male-
female)................................................................................................... 69 
Table 16-3 
Reference ranges for potassium (mmol/L) by age range (male-
female)................................................................................................... 69 
Table 16-4 
Follow up requirements for liver events and laboratory triggers .......... 74 
Table 16-5 
PK Sampling scheme ............................................................................ 76 
List of figures 
Figure 3-1 
Patient participation overview ............................................................... 19 
Figure 3-2 
Study flow chart .................................................................................... 20 
Figure 16-1 
Reference ranges for head circumference in males (0-13 weeks) ......... 70 
Figure 16-2 
Reference ranges for head circumference in males (0-2 years) ............ 71 
Figure 16-3 
Reference ranges for head circumference in females (0-13 weeks) ..... 72 
Figure 16-4 
Reference ranges for head circumference in females (0-2 years) ......... 73 
 


Novartis 
Confidential 
Page 6 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
List of abbreviations 
ACPR 
Adequate Clinical and parasitological Response  
ACT 
artemisinin-based combination therapy 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ART 
artemether 
ARV 
antiretroviral 
ASAQ 
artesunate-amodiaquine 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
b.i.d. 
twice a day 
BMI 
Body Mass Index 
BW 
body weight 
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
Cmax 
in the context of this study, Cmax is meant as the higher concentration between those at 
1 hour or 2 hours post first dose 
CMO 
Chief Medical Office (Novartis) 
CNS 
Central Nervous System 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTT 
Clinical Trial Team 
CV 
coefficient of variation 
DBP 
Diastolic Blood Pressure 
DHA 
Dihydroartemisinin 
DMC 
Data Monitoring Committee 
e.g. 
For example 
EC 
Ethics committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
ETF 
Early Treatment Failure 
FAS 
full analysis set 
FCT 
Fever clearance Time 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
HIV 
Human Immunodeficiency Virus 
i.e. 
That is to say 


Novartis 
Confidential 
Page 7 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
IB 
Investigator's Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMCI 
Integrated Management of Childhood Illness 
IN 
Investigator Notification 
INR 
International normalized ratio of prothrombin time of blood coagulation 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LAR 
Legally Acceptable Representative  
LCF 
Late Clinical Failure 
LLOQ 
lower limit of quantification 
LPF 
Late Parasitological Failure 
MedDRA 
Medical dictionary for regulatory activities 
PBPK 
Physiology-Based Pharmacokinetic modeling 
PCR 
polymerase chain reaction 
PCT  
time to parasite clearance 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PPS 
per protocol set 
PS 
Patient Safety (Novartis) 
QMS 
Quality Management System 
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 
RBC 
red blood cell(s) 
SAE 
serious adverse event 
SBP 
Systolic Blood Pressure 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SMQ 
Standardized MedDRA Query  
 
 
SNPs 
Single-Nucleotide Polymorphisms 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBIL/TBL total bilirubin 
ULN 
upper limit of normal 
WBC 
white blood cell(s) 
WHO 
World Health Organization 


Novartis 
Confidential 
Page 8 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
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) 
Enrollment 
Point/time of subject entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the screening procedures 
described in the protocol) 
Investigational drug 
The study drug whose properties are being tested in the study 
Investigational 
Product/ 
Investigational 
Medicinal product 
A pharmaceutical form of an active ingredient or placebo being tested or 
used as a reference (such as an active comparator) in a clinical trial, 
including a product with a marketing authorization when used or 
assembled (formulated or packaged) in a way different from the approved 
form, or when used for an unapproved indication, or when used to gain 
further information about an approved use. 
Medication pack 
number 
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system 
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.) 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease. 
Patient 
An individual with the condition of interest 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, treatment, follow-up, etc. 
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. 
Recruitment 
Point/time of subject selection for the study: the point at which screening is 
completed and eligibility has been fully confirmed so that the patient can 
receive first dose of treatment. 
Screen Failure 
A subject who is screened but is not treated or randomized 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, 
etc. 
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 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 
A trial participant (can be a healthy volunteer or a patient) 


Novartis 
Confidential 
Page 9 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
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 number 
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study 
Withdrawal of consent 
(WoC) 
Withdrawal of consent from the study is defined as when a subject does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study related 
contact, and does not allow analysis of already obtained biologic material 


Novartis 
Confidential 
Page 10 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Amendment 1 
Amendment Rationale 
This study has completed enrollment for Cohort 1 (22 patients, > 28 days old) and Cohort 2.1 
(3 patients, 15-28 days old). As of 29-Jun-2023, recruitment for Cohort 2.2 (patients 1-28 days 
old) is ongoing, 2 patients have been enrolled since recruitment for Cohort 2.2 has started in 
November 2022.  
The protocol is being amended to enable additional optional PK checks for artemether and 
lumefantrine and additional interim assessments by the DMC to be able to read out and provide 
relevant clinical data as soon as possible for this difficult to recruit patient population. In 
addition, errors/inconsistencies have been corrected, clarifications provided, and text related to 
public health emergencies and safety reporting has been updated. The key changes include: 
• To allow for a PK check during Cohort 2.2, after the first 9 patients in the 1-28 days age 
group have been recruited in Cohort 2 (from Cohort 2.1 and 2.2 combined)  
• To allow for an additional optional PK check after the first 9 patients in the 15-28 days 
age group have been recruited in Cohort 2 (from Cohort 2.1 and 2.2 combined) 
• To allow for additional interim assessments with DMC reviews throughout the study to 
assess PK, safety and efficacy to support identification of appropriate dose(s) for the 
population under study  
• To allow for determination of appropriate dose(s) for the population under study using 
data from the ongoing study and PBPK modeling 
• To update text about public health emergencies and safety reporting  
Changes to the protocol 
• List of abbreviations: has been updated based on the changes implemented in the 
amendment 
• Glossary of terms: Definition of “Investigational medicinal product” and clarification of 
“Investigational drug” have been added. 
• Protocol Summary, Section 3, 10.2.1: Population is clarified to include approximately 44 
patients in the study (approximately 22 patients in each cohort).  
• Section 3, 4.2, 4,4, 6.5.1.2, 10.2.1; 12.5.3, 12.7: Editorial changes have been done to 
streamline text in these sections to: 
• Clarify that PK check during Cohort 2.2 to occur when first 9 patients in the 1-28 
days age group are recruited from Cohort 2.1 and 2.2. An additional optional PK 
check may occur after the first 9 patients in the 15-28 days age group are recruited 
from Cohort 2.1 and 2.2.  
• Clarify that two planned interim assessments will be done in the study.  
• Section 4.2, 4,4: Language added to enable periodic update of PBPK model to support 
dose recommendation if data permits.  
• Section 4.5: Text added for public health emergency mitigation procedure.  
• Section 5:  


Novartis 
Confidential 
Page 11 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
• Clarification added to enable use of PBPK modeling to support dose 
recommendation. 
• Number of sites and countries updated to reflect the current status of the study. 
• Text added in Section 5.2 to clarify that Appendix 1 is an example for reference for 
electrolyte balance 
• Table 6-1: Modified as per latest requirements 
• Section 6.1.3: Editorial changes done to remove redundant duplicate text since details are 
already provided in Section 3. 
• Section 9.1.4: Clarification added to reflect that early study termination may also occur on 
DMC recommendation  
• Section 10.1.3: Additional clarification text added about SAE reporting in eCRF 
• Section 10.2.1, 12.7: Clarification added about optional additional interim assessments 
along with DMC reviews to support decision making for dose recommendation. 
• Section 12.8.2:  
• Typographical error rectified to reflect the correct probability calculation for power 
consideration for Day 8 lumefantrine concentration 
• Clarification added that enrolment may stop after 16 evaluable patients for PK 
analyses are recruited in any of the cohorts, as 16 evaluable patients are sufficient as 
per original protocol.  
• Clarification added about criterion for observed half width of 2 sided 90% CI for the 
log concentration in case of early readout of the study 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through colored font for deletions and colored underlined for insertions. 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC and Health Authority approval according to local 
regulations prior to implementation. 
 
The changes herein do not affect the Informed Consent.   


Novartis 
Confidential 
Page 12 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Protocol summary 
Protocol number 
CCOA566B2307 
Full Title 
Multicenter, open-label, single-arm study to evaluate the PK, safety, 
tolerability and efficacy of a new artemether:lumefantrine (2.5 mg:30 mg) 
dispersible tablet in the treatment of infants and neonates <5 kg body weight 
with acute uncomplicated Plasmodium falciparum malaria. Acronym: CALINA 
Brief title 
Pharmacokinetics, safety, tolerability and efficacy of a new artemether-
lumefantrine dispersible tablet in infants and neonates <5 kg body weight with 
acute uncomplicated Plasmodium falciparum malaria 
Sponsor and 
Clinical Phase 
Novartis 
Phase II/III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
This study aims to evaluate PK, safety, tolerability and efficacy of a new 
formulation of artemether-lumefantrine dispersible tablet in neonates and 
infants <5 kg body weight with acute uncomplicated Plasmodium falciparum 
malaria. 
Malaria is a disease that has a much higher prevalence and severity in infants 
and children. Although relatively infrequent as compared to the number of 
cases in infants and children ≥5 kg, confirmed malaria in neonates and infants 
<5 kg does exist in certain endemic countries and calls for evaluation of 
appropriate treatment. It is still a significant unmet medical need as there are 
no approved treatments for this vulnerable group of patients. 
A previous clinical study with a similar design found that artemether exposure 
in patients <5 kg body weight following administration of dispersible tablets 
(artemether:lumefantrine 20 mg:120 mg; i.e. 1:6) was around 2-3 fold higher 
than anticipated safe exposures, whereas exposure to lumefantrine was as 
expected. Given the potential neurotoxicity of artemether at high exposures, 
this is undesirable and therefore, following detailed Physiology-Based 
Pharmacokinetic modeling (PBPK), new doses, using a dispersible tablet with 
a lower amount of artemether relative to lumefantrine (2.5 mg:30 mg, i.e.1:12) 
have been selected for investigation in this study. 
Primary 
Objective(s)  
The primary objective of this study is to assess the key PK parameter of 
artemether Cmax (ART Cmax; represents the higher concentration between the 
concentrations at 1 hour and 2 hours after first dose) in infants and neonates 
<5 kg body weight dosed with the new formulation of artemether-lumefantrine 
dispersible tablet 
Secondary 
Objectives 
Secondary objectives are: 
To determine efficacy by assessing: 
• 
PCR-corrected Adequate Clinical and parasitological Response (ACPR) 
at Days 15, 29, and 43, and uncorrected ACPR at Days 8, 15, 29, and 
43. 
• 
Incidence rate of recrudescence and new infections at Days 15, 29 and 
43. 
• 
Parasite and Fever clearance Times (PCT and FCT). 
To evaluate its safety and tolerability by collecting serious adverse events 
(SAEs), adverse events (AEs), and routine safety laboratory assessments.  


Novartis 
Confidential 
Page 13 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
To assess other key PK parameters, i.e. Lumefantrine Day 8 concentration 
(C168h), Artemether AUC, DHA and Lumefantrine Cmax and AUC as 
appropriate.  
Study design 
This will be a multicenter, open-label, single-arm, adaptive study with two 
sequential and age-descending cohorts in infants and neonates <5 kg body 
weight with acute uncomplicated P. falciparum malaria. There will be a core 
study period of 43 days followed by a long term safety follow up at one year 
of age. 
Population 
This study will consist of male and female patients <5 kg body weight with 
acute uncomplicated P. falciparum malaria. Cohort 1: infants >28 days of 
age, and Cohort 2: neonates ≤28 days of age. The plan is to enroll and treat a 
minimum of approximately 44 patients (approximately 22 in each of the two 
sequential cohorts). Additional patients may be enrolled if the 
artemether/lumefantrine exposure is inadequate according to the periodic PK 
checks as per the protocol (with a maximum of 98 patients overall). 
Key Inclusion 
criteria 
1. Male or female neonates/infants 
2. Body weight <5 kg but ≥ 2 kg 
3. In Cohort 1, infants aged >28 days; in Cohort 2, neonates aged 1 to ≤28 
days (3 subgroups: 1-7 days; 8-14 days; 15-28 days) 
4. Microscopically confirmed diagnosis of P. falciparum malaria (or mixed 
infections): 
• 
in Cohort 1 of ≥500 and <100,000 parasites/µL asexual P. falciparum 
parasitemia 
• 
in Cohort 2 of ≥100 and <100,000 parasites/µL asexual P. falciparum 
parasitemia 
• 
in Cohort 2, either congenital or neonatal 
• 
either symptomatic or asymptomatic 
Key Exclusion 
criteria 
1. Head circumference < - 2 SD z-score in cm following WHO age and sex-
specific reference curves (suspicion of microcephaly) 
2. Presence of severe malaria (according to WHO 2015 definition) 
3. HIV status:  
• 
in Cohort 1, patient’s or patient's mother's current treatment with 
ARV 
• 
in Cohort 2, mother’s known HIV positive status at patient's birth or 
mother's current treatment with ARV 
4. Presence of the following signs of a critical condition: apnea-bradycardia, 
sustained bradycardia, tachycardia, desaturation, hypotension, 
hypothermia; or other severely deteriorated general condition (based on 
IMCI criteria in sick infants) (WHO 2005) 
5. Presence of any clinically significant neurological condition:  
• 
any episode of convulsion during the present illness (in keeping with 
the IMCI list of general danger signs) 
• 
known neurological disorders (e.g. chronic seizure disorders, 
cerebral palsy) 
6. Presence of clinically significant abnormality of the hepatic and renal 
systems 
7. Patients unable to swallow or whose drinking is impaired 


Novartis 
Confidential 
Page 14 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
8. Known hypersensitivity of the patient or either patient's parent to 
artemether, lumefantrine, any of the excipients of Coartem®/Riamet® 
Dispersible tablet, or to drugs of similar chemical classes 
9. History of malabsorption or previous gastrointestinal surgery, or history of 
radiation therapy that could affect drug absorption or metabolism, or any 
other disorder or history of a condition that could interfere with drug 
absorption, distribution, metabolism, or excretion 
10. Known family history of congenital prolongation of the QTc interval or 
sudden death or with any other clinical condition known to be associated 
with prolongation of the QTc interval such as history of symptomatic 
cardiac arrhythmias, with clinically relevant bradycardia or with severe 
cardiac disease 
11. Disturbances of electrolyte balance (e.g. hypokalemia or 
hypomagnesaemia) 
12. Presence of any age-adjusted clinically or hematologically relevant 
laboratory and blood chemistry abnormalities 
13. Patients who received any antimalarial drug, including antibiotics with 
antimalarial activity, within 14 days of trial start, or any other prohibited 
drug (see Table 6-2) 
14. Patients who received an investigational drug within 5 half-lives of 
enrollment or participated in an investigational study or within 30 days, 
whichever is longer 
NOTE: Where information is either not available or insufficient (e.g. from 
medical history, charts, etc.) to assess whether a patient meets a specific 
exclusion criterion, the study site team shall use its best medical judgement to 
make an inclusion/exclusion decision for the patient. 
Study treatment 
artemether:lumefantrine 2.5 mg:30 mg dispersible tablet 
Efficacy 
assessments 
Parasitemia determinations in peripheral blood and body temperature 
measurement, as well as signs and symptoms of early treatment failure. 
Pharmacokinetic 
assessments  
5 blood samples (500 μL each) will be obtained from each subject at the 
scheduled time points indicated in one of the 2 possible sample schemes in 
order to assess artemether, dihydroartemisinin and lumefantrine in every 
sample. 
Key safety 
assessments 
Adverse event monitoring, Physical examinations, Vital signs, monitoring of 
hematology and blood chemistry. 
Other 
assessments  
Follow up of liver events.  
 
Data analysis 
Artemether Cmax (ART Cmax ; higher concentration between the concentrations 
at 1 hour and 2 hours after first dose) is the primary endpoint. Day 8 (168 h) 
lumefantrine concentration is a key secondary endpoint. Ninety percent (90%) 
confidence intervals for artemether Cmax and Day 8 (168 h) lumefantrine 
concentration will be calculated based on the log normal distribution by cohort 
and treatment group using the PK analysis set. For PCR corrected ACPR 
rates at Days 15, 29, and 43 and uncorrected ACPR rates at Days 8, 15, 29, 
and 43, 95% confidence intervals will be provided using the Pearson-Clopper 
method for each treatment group by cohort using PPS for PCR-corrected 
ACPR and FAS for uncorrected ACPR. For PCT and FCT, descriptive 
statistics (mean, standard error, median, quartiles) will be presented for each 
treatment by cohort using the Kaplan-Meier method based on the FAS. 


Novartis 
Confidential 
Page 15 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Key words 
Plasmodium falciparum, malaria, artemether, lumefantrine, dispersible, 
neonates, infants, PK, pharmacokinetics. 


Novartis 
Confidential 
Page 16 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
1 
Introduction 
1.1 
Background 
Malaria caused by Plasmodium falciparum is one of the leading causes of death in the world.  
In 2017, an estimated 219 million cases of malaria and 435 000 deaths occurred worldwide: 
92% of malaria cases and 93% of malaria deaths were in the African Region; and about half of 
all malaria deaths (49%) came from six countries (Nigeria, Democratic Republic of the Congo, 
Burkina Faso, Tanzania, Sierra Leone and Niger) (WHO 2018). Children aged under 5 years 
are the most vulnerable group affected by malaria, which accounted for 61% (266 000) of all 
malaria deaths worldwide in 2017 (WHO 2018). 
Artemisinin (ACT) combination products are recommended by worldwide experts for the 
treatment of malaria (WHO 2018). Coartem dispersible tablet (artemether:lumefantrine 20 
mg:120 mg) contains a fixed dose combination of two anti-malarial agents, artemether (an 
artemisinin derivative) and lumefantrine. Artemether has a rapid onset of antiparasitic activity 
and is rapidly metabolized. Lumefantrine has a slower onset of activity and a half-life of around 
5 days. The pharmacokinetic properties of the two anti-malarial agents correlate with 
antiparasitic activity in which artemether is able to effect early parasite reduction while 
lumefantrine is effective in preventing recrudescence. 
Riamet®/Coartem® dispersible tablet is administered over 3 days using an initial dose, a second 
dose after 8 hours, and then twice daily (morning and evening) for the following 2 days for a 
total of 6 doses. The total number of tablets administered per dose depends on body 
weight. However, Riamet®/Coartem® is not approved for infants less than 5 kg body weight 
(BW), whereas neonates and infants <12 months of age constitute one of most vulnerable 
groups affected by malaria (WHO 2018). Although relatively infrequent, confirmed malaria in 
neonates and infants <5 kg does exist in certain endemic countries and calls for evaluation of 
appropriate treatment (Alao et al 2013). Recent reports from sub-Saharan Africa suggest that 
malaria is more common in neonates and young infants than previously thought, with an 
incidence ranging from 3.7-22% (Ceesay 2015, Ameade 2018). However, no consistent 
treatment guidelines are available for uncomplicated P. falciparum malaria in patients <5 kg 
BW and national treatment guidelines vary significantly across countries (Alao et al 2013), 
WHO itself recommends "an ACT at the same BW target dose as for children weighing 5 kg" 
(WHO 2015), but as there are no approved treatments, this vulnerable group of patients is 
treated with undocumented doses of anti-malarials including quinine, potentially posing a 
safety risk (Mbonye et al 2015). 
In 2010, as part of an EU pediatric development plan associated with the 
Riamet®/Coartem®dispersible 
tablet 
formulation, 
a 
clinical 
study, 
Study 
B2306 
(COA566B2306), with a design similar to the present study B2307 (COA566B2307), was 
conducted. That study found that, in around 20 patients <5 kg body weight and >28 days of age, 
artemether exposure following administration of dispersible tablets (artemether:lumefantrine 
20 mg:120 mg) was around 2-3 fold higher than anticipated safe exposures, whereas exposure 
to lumefantrine was as expected. 
Pre-clinical studies have shown neurotoxic effects of high artemether exposures in dogs. 
Monkeys were less susceptible to artemether-induced neurotoxicity while human clinical data 


Novartis 
Confidential 
Page 17 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
so far do not suggest that artemether Cmax values exceeding those associated with neurotoxicity 
in dogs have resulted in neurological findings in patients. 
Nevertheless, given the potential neurotoxicity of artemether at high exposures, and because 
the fixed artemether relative to lumefantrine ratio (1:6) in the Coartem dispersible tablet does 
not allow to reduce the amount of artemether alone, it was decided not to proceed with the 
second cohort of study B2306 (infants ≤28 days of age). This decision was endorsed by the 
study's Data Monitoring Committee (DMC).  
Detailed Physiology-Based Pharmacokinetic modeling (PBPK modeling) was subsequently 
performed to estimate the exposure of artemether and lumefantrine in different age groups of 
patients (from full term birth to 6 months of age) receiving different doses. As a result, a new 
dose ratio, with a lower amount of artemether relative to lumefantrine (1:12) has been selected 
for investigation in this population (<5 kg). 
This adaptive PK/safety/tolerability/efficacy clinical trial is therefore designed in order 
to identify the appropriate dose of the newly formulated artemether-lumefantrine dispersible 
tablet in neonates and infants < 5 kg with acute uncomplicated P. falciparum malaria. 
1.2 
Purpose 
This Phase II/III study aims to evaluate PK, safety, tolerability and efficacy of a new 
formulation of artemether-lumefantrine dispersible tablet in infants and neonates <5 kg body 
weight with acute uncomplicated Plasmodium falciparum malaria. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the key PK parameter of artemether in 
infants and neonates < 5 kg body weight dosed with 
the new formulation of artemether-lumefantrine 
dispersible tablet 
• 
Artemether Cmax (represents the 
higher concentration between the 
concentrations at 1 hour and 2 hours 
after first dose) 
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
• 
To assess other key PK parameters of artemether, 
DHA and lumefantrine in infants and neonates <5 
kg body weight dosed with the new formulation of 
artemether-lumefantrine dispersible tablet 
• 
Lumefantrine Day 8 concentration 
(C168h) Artemether AUC, DHA and 
Lumefantrine Cmax and AUC as 
appropriate 
• 
To evaluate the safety and tolerability of the new 
formulation of artemether-lumefantrine dispersible 
tablet in infants and neonates <5 kg body weight 
with acute uncomplicated P. falciparum malaria 
• 
Serious adverse events (SAEs), 
adverse events (AEs), and routine 
safety laboratory assessments 
• 
To determine the efficacy of the new formulation of 
artemether-lumefantrine dispersible tablet for 
treatment of acute uncomplicated P. falciparum 
malaria in infants and neonates <5 kg body weight 
• 
PCR-corrected Adequate Clinical 
and parasitological Response 
(ACPR) at Days 15, 29, and 43 
Uncorrected ACPR at Days 8, 15, 
29, and 43 


Novartis 
Confidential 
Page 18 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Objective(s) 
Endpoint(s) 
Incidence rate of recrudescence and 
new infections at Days 15, 29 and 43 
Parasite and Fever clearance Times 
(PCT and FCT)  
3 
Study design 
This will be a multicenter, open-label, single-arm, adaptive design with dose adaptation (de-
escalation or escalation) study in infants and neonates <5 kg body weight with P. falciparum 
malaria. 
A total of approximately 44 male and female infant/neonate patients (<5 kg) are planned to be 
recruited in the study. There will be two sequential and age-descending cohorts of 
approximately 22 patients each (see Figure 3-2), all <5 kg: Cohort 1 of infants >28 days of age, 
and Cohort 2 of neonates ≤ 28 days of age. Cohort 2 will include 3 age subgroups (15-28, 8-14 
and 1-7 days), starting with the highest age subgroup in Cohort 2.1. The two lower age 
subgroups (i.e., 8-14 and 1-7 days) will be recruited in parallel. These two subgroups will be 
optional, depending on recruitment feasibility. 
In the event of inadequate exposure (Section 4.2), determined at predefined PK checkpoints 
(i.e., after the first 9 patients in Cohort 1, and after the first 3 patients and then the first 9 patients 
of Cohort 2 (1-28 days of age)), additional patients may be recruited up to a total of 98 patients 
across the 2 cohorts (Figure 3-2). An additional PK check may be performed after the first 9 
patients of the 15-28 days age group in Cohort 2 have been recruited. For Cohort 2, if an 
adequate dose cannot be determined or if recruitment is not feasible in any age subgroup, the 
cohort may be closed and 22 additional patients may be recruited in Cohort 1 up to a total of 
approximately 44 patients treated with the same dose (instead of the planned 22 patients). 
Cohort 2.3 will start recruitment after the dose used in Cohort 2.2 has been assessed to be 
appropriate. 
Patients will be admitted to the hospital on or before Day 1 (see Figure 3-1). After meeting all 
the inclusion and exclusion criteria in the study, they will receive study drug. The starting dose 
regimen in Cohort 1 will be two dispersible tablets twice daily for three consecutive days. The 


Novartis 
Confidential 
Page 19 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
dose must be preceded and/or followed as much as possible by food/drinks rich in fat, e.g. breast 
milk, or formula milk. 
Patients will remain in the hospital under close supervision until they are discharged by the 
investigator or designee on Day 4. At the discretion of the investigator, patients may stay for a 
few additional days if needed. The patients will be then followed up at regular intervals until 
Day 43 (core follow-up), in order to assess study drug exposure, safety, tolerability and efficacy 
(See Visit schedule in Table 8-1). If symptoms re-emerge outside the scheduled study visits, 
parents/legal guardians of the patients will be instructed to contact the investigator. In case of 
treatment failure (as per WHO definition), rescue treatment according to local clinical practice 
will be provided. 
Patients will then attend a long term safety follow-up visit
 
 
Figure 3-1 
Patient participation overview 
 
In this study, a stepwise and sequential approach will be adopted in order to minimize the risk 
for patients (Figure 3-2). 
 
 
 
 
 
 
 
 
Hospitalisation 


Novartis 
Confidential 
Page 20 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Figure 3-2 
Study flow chart 
 
PK exposure checks (together with safety and efficacy data review as available) will be 
performed on a periodic basis to assess the dose included at the following timepoints: 
1) once the first 9 patients in Cohort 1 have been dosed and followed up to Day 15, 
2) once the first 3 patients in Cohort 2 (15-28 days age subgroup) have been dosed and followed 
up to Day 15, 
3) once the first 9 patients in Cohort 2 (1-28 days age subgroup) have been dosed and followed 
up to Day 15. In case exposure data in the 9 patients from the 1-28 day subgroup are not 
sufficient to make a decision on dose selection (e.g., due to a significantly different exposure 
across age subgroups), as many additional patients as needed to reach a total of 9 (across Cohort 
2.1 and 2.2) in the 15-28 day subgroup specifically will be recruited in Cohort 2.2 and treated 
with the same dose. An additional PK check will then be performed after these additional 
patients will have been followed up to Day 15. 
A total of 9 patients in a defined age group should allow to confirm with reasonable confidence 
if ART Cmax is within approximately 2-fold (safety interval) of the Cmax which has been found 
to be safe and efficacious in previous studies; a total of 3 patients will however allow to check at 
an early stage if the ART Cmax range is within the expected safety interval (Cohort 2 only). 
An Independent Data Monitoring Committee (DMC) will review the PK, efficacy and safety 
data at these checks, and also at two planned interim data assessments, one between the two 
cohorts, and another one after all patients in Cohort 2 have completed Day 43 (Figure 3-2). 


Novartis 
Confidential 
Page 21 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
The interim data assessment based on Cohort 1 data will serve to determine the starting dose 
level for Cohort 2 (for further details see Section 10.2.1). 
Based on these checks, the dose being considered will be assessed as suitable or not for the 
subgroup of patients treated. 
In Cohort 1: 
• if the dose is deemed adequate in the first 9 patients (based on PK, safety and efficacy data 
review as available), additional patients will be recruited up to approximately 22 treated 
with the same dose level (expansion phase). 
• if the dose is not adequate, the first set of 9 patients will be repeated, up to twice, using a 
different dose level, until a dose level is determined as suitable. 
In Cohort 2: 
• if the dose is deemed adequate in the 3 patients from the highest age subgroup (15-28 
days), recruitment of  6 additional patients in the 1-28 day subgroup will be attempted.  
• if the dose is not adequate, the first set of 3 patients from the highest age subgroup (15-28 
days) will be repeated, up to twice, using a different dose level, until a dose level is 
determined as suitable. Then, recruitment of 6 additional patients in the 1-28 day subgroup  
will be attempted. 
• Another PK check (together with safety and efficacy data as available) will then be 
performed when a total of 9 patients have been treated with the same suitable dose in the 
1-28 day subgroup.  In case exposure data from these 9 patients (1-28 day subgroup) is not 
sufficient to make a decision on dose selection, as many additional patients as needed to 
reach a total of 9 (across Cohort 2.1 and 2.2) in the 15-28 day subgroup specifically will 
be recruited in Cohort 2.2 and treated with the same dose. An additional PK check will 
then be performed after these additional patients will have been followed up to Day 15. If 
the former PK check shows that the dose is suitable for all subgroups, expansion of Cohort 
2 will include all age subgroups. If it is unsuitable for any of the two lower age subgroups, 
no further patients will be recruited in this/these lower age subgroup(s), 
and further expansion of Cohort 2 will only include patients from the 15-28 day subgroup. 
In the case the dose is not confirmed as suitable for the highest age subgroup, a repeat run 
with 9 patients (3+6 patients) will be performed using a different dose. 
In Cohort 2, if through the steps above, no suitable dose has been determined in the higher age 
subgroup (15-28 days), recruitment will be stopped in that cohort and an additional 22 patients 
will instead be recruited in Cohort 1 and treated with the dose that was deemed adequate in that 
cohort. 
Once either cohort's expansion has been completed with approximately 22 patients treated with 
the same, suitable dose, or any or the alternative scenarios described above, patients will be 
followed up to Day 43, when the complete set of key efficacy and safety parameters and PK 
exposures will be assessed. 
Note: Patients treated with dose levels deemed not suitable will also be closely followed up to 
Day 43 and at one year of age. 
In the unlikely case when all the iterations described above would have to be implemented, a 
maximum of 98 patients would be recruited. 


Novartis 
Confidential 
Page 22 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
4 
Rationale 
4.1 
Rationale for study design 
This will be a multicenter, open-label, single-arm, adaptive dosing study in infants and neonates 
<5 kg body weight with acute uncomplicated P. falciparum malaria. 
The objective of this Phase II/III study design is to test the new artemether-lumefantrine 
dispersible tablet formulation to determine exposure to artemether, DHA and lumefantrine as 
well as its safety, tolerability and efficacy in patients <5 kg with uncomplicated P. falciparum 
malaria. 
The open-label, adaptive, sequential-group design used in the study aims to minimize the risk 
by studying first a cohort of infants (>28 days of age, <5 kg) that is similar to the population 
already evaluated in previous clinical trials (i.e., infants ≥5 kg body weight, irrespective of age). 
The risk of bias arising from an open-label design is minimized as objective endpoints have 
been chosen for the study. 
Patients will be enrolled at sites experienced in managing the population targeted in the present 
study (neonates and infants <5 kg BW) and they will be hospitalized during the treatment period 
in order to ensure close monitoring. 
The planned periodic pharmacokinetic exposure check after dosing a limited number of patients 
(as specified in Section 3 of this protocol), along with the review of the available efficacy and 
safety data by the DMC, aims to minimize the risk for patients, and it will also allow to adjust 
the dose in case of inadequate outcome. 
The design of the core follow-up (up to Day 43) within each cohort is well established for 
malaria trials and follows WHO guidelines. 
 
 Since central nervous system 
(CNS) toxicity with artemisinin derivatives has been reported in animal studies, the 
neurological safety of artemether-lumefantrine has been a subject of much attention (Adjei et 
al 2009). However, CNS toxicity has not been reported in well designed clinical trials 
(Chattopadhyay et al 2007), including ototoxicity (Carrasquilla et al 2012), nor in the previous 
clinical study (COA566B2306 in infants >28 days and <5 kg) with a similar design to the 
current study's (Tiono et al 2015). 
4.2 
Rationale for dose/regimen and duration of treatment 
Dose selection in this study is based on extensive safety and efficacy experience with 
artemether:lumefantrine 20 mg:120 mg and also specifically based on data from the controlled 
clinical trial in infants and children ≥5 kg BW, study B2303 (COA566B2303) as well as on the 
results of a previous study, study B2306 (COA566B2306) in this very young population (infants 
< 5 kg BW and > 28 days) (See Table 4-1). 
In Study B2306, exposure to artemether and DHA was around 2-3 fold higher in 20 infants <5 
kg BW and >28 days compared to infants ≥5 kg BW, irrespective of age (Study B2303), 
whereas the exposure to lumefantrine was comparable between these two studies (Tiono et al 
2015). The dose regimen administered to infants <5 kg body weight (study B2306) and to those 


Novartis 
Confidential 
Page 23 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
5-<15 kg BW (study B2303) was the same (a 6-dose regimen of artemether:lumefantrine 20 
mg:120 mg of over 3 days). The higher artemether exposure at a lower age and weight could 
result from immature metabolic enzymes mainly CYP3A4 and CYP2B6 (Lin et al 2016). The 
safety profile associated with a higher systemic artemether exposure, could not be fully 
supported by preclinical data: 
• in dogs, pathological evidence of neurotoxicity was noted with intramuscular doses of 
artemether administered daily for 8 days. 
• monkeys were less susceptible to artemether-induced neurotoxicity (Li and Hickman 
2011). 
Although difficult to interpret, available clinical data do not suggest that artemether Cmax values 
exceeding those associated with neurotoxicity in dogs have resulted in neurological effects in 
infants. Given the highly vulnerable patient population in this study, it is nevertheless 
imperative to bring the exposure of artemether within the limits which have been clinically 
proven to be safe (See Table 4-1 below).  
On the other hand, lumefantrine exposure was generally comparable between Study B2306 and 
Study B2303 except for the Day 8 exposure which was more than 2-fold higher in Study B2306. 
A potential reason for this observation was a reduced intestinal absorption combined with 
reduced clearance in patients <5 kg BW leading to a comparable exposure during the dosing 
period between the two groups of infants /children. 
Table 4-1 
Historical exposure values from previous studies 
Study 
Body 
weight 
(age) 
ART Dose 
(mg) 
n 
First dose 
Artemether 
Cmax 
(ng/mL) 
LUM Cmax 
(µg/mL) 
LUM C168 h 
(ng/mL) 
B2306 
<5kg 
>28days 
20 
18 
509 ± 309 
6.38 
815 
B2303 
≥5 - <15 
20 
55 
196 ± 204 
5.16 
386 
B2303 
≥15 - <25 
40 
29 
150± 106 
8.03 
B2303 
≥25 - <35 
60 
8 
134 ± 56.7 
12.3 
ART: artemether; LUM: lumefantrine 
Based on the above data and on ontogeny data (course of development of the human organism), 
a full PBPK model was developed and validated. This model was used to simulate exposures 
to artemether and lumefantrine corresponding to different doses and at different neonate and 
infant ages (Report DMPK R1809279) (See Table 4-2 below). 
While selecting the doses for the present study, the following considerations were taken into 
account: 
• due to artemether's potential neurotoxicity (based on animal data), it is hypothesized that 
its exposure should be contained within the range that has been found to be well 
tolerated and efficacious in children ≥5 kg. 
• Exposure to lumefantrine should also be adequate, especially the Day 8 plasma 
concentration (which is a surrogate efficacy marker), i.e., it should be ≥ 200 ng/mL on 


Novartis 
Confidential 
Page 24 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Day 8 based on an extensive meta-analysis, (WWARN 2015) to achieve long-term 
parasite clearance. 
• within the exposures which were found to be well tolerated in children ≥5 kg BW, while 
kept on the higher side, due to lower immunity and potential lower exposure in pediatric 
patients (Kloprogge et al 2018, WWARN 2015). 
Table 4-2 
PBPK modeled exposures based on a 5:60 mg (A:L) dose regimen 
  
Neonates (≤28 days, <5 kg) 
Infants ( >28 days (1-7 
months), <5kg) 
Artemether (5 mg) 
First dose Cmax (ng/mL) 
234 
78.5 
Lumefantrine (60 mg) 
Full regimen Cmax (µg/mL) 
5.1 
5.4 
C168h (ng/mL)* 
530 
270 
Based on PBPK simulations, with an individual artemether dose of 10 mg, Cmax in infants <5 
kg BW is expected to be in the range of the Cmax observed in infants ≥5 kg BW, but at the high 
end. Because of the neurotoxicity risk, an individual artemether dose of 5 mg was selected in 
order to remain conservative. This dose is expected to provide a Cmax that is still efficacious but 
at least two fold lower than the highest exposures observed in infants/children ≥5 kg BW. Cmax, 
not AUC, was targeted because only two data points around Cmax can be captured in this 
population, due to limitation in blood draws. Due to the same limitation, a reliable estimate of 
AUC could not be established in study B2306 (COA566B2306). For lumefantrine, a 60 mg 
individual dose was selected which would provide a total exposure within the observed safe 
exposures. This dose is expected to provide a Cmax >10 fold of an effective concentration of 200 
ng/mL if patients are well fed. 
This leads to doses of 5 mg and 60 mg (ratio 1:12) respectively for artemether and lumefantrine 
that will be assessed in the present study. The ratio is therefore different from the 1:6 ratio 
(artemether:lumefantrine 20 mg:120 mg dispersible tablet) used in the rest of the population 
(≥5 kg BW), but it is not expected to adversely impact treatment outcome. The confidence in 
the prediction is moderate as the physiology affecting the exposure to these two compounds is 
not fully known and variability does exist, especially in the youngest patients (Cohort 2, ≤28 
days). As a consequence, in order to minimize the risk, an early exposure check will be 
performed in a staggered fashion: 
• in the first 9 patients in Cohort 1 (>28 days) where the risk is lower 
• in Cohort 2, in the first 3 patients in the highest age subgroup (15-28 days, Cohort 2.1), 
and only then in the lower two age subgroups (1-7 and 8-14 days, Cohort 2.2), to further 
decrease the risk 
• in the first 9 patients in Cohort 2 (1-28 days subgroup. Cohort 2.1 and 2.2), once the step 
directly above has been completed 
• in case exposure data in the 1-28 day subgroup in the step right above is not sufficient to 
inform about the optimal dose for this population, an additional PK check may be 
performed after 9 patients of the 15-28 day subgroup have been recruited at the same dose 
across Cohort 2.1 and 2.2 (additional patients will then be recruited in Cohort 2.2 to this 
effect)  


Novartis 
Confidential 
Page 25 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
 
The dose used in Cohort 1 and in the highest age subgroup in Cohort 2 may be modified as 
required, either upwards or downwards before including further patients. In the event the dose 
deemed suitable in the highest age subgroup in Cohort 2 is not suitable for either or both lower 
age subgroups in Cohort 2, recruitment will be stopped and no further doses will be evaluated 
in the concerned subgroup(s). If no dose at all can be determined as suitable in Cohort 2, the 
cohort will be stopped. 
The PBPK model will be updated and qualified periodically with the available PK data from 
Cohort 1 and/or Cohort 2 and PBPK simulations may be used to support the recommendation 
of an appropriate dose for this population.  
 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable. 
4.4 
Purpose and timing of interim analyses/design adaptations 
There will be two planned interim assessments performed:  
1. after all patients in Cohort 1 have completed Day 43 (core study period), when key 
efficacy and safety parameters and PK exposure data will be assessed in order to 
determine whether to proceed to Cohort 2 and if so, to select the starting dose for that 
Cohort. 
2. after all patients in Cohort 2 have completed Day 43 (core study period), when efficacy 
and safety parameters and PK exposure data from both cohorts will be assessed  
PK exposure checks (including safety and efficacy data review as available) will also be 
performed as described in  Section 3, Section 4.2 and Section 12.7. 
The PBPK model will be updated and qualified periodically with the available PK data from 
Cohort 1 and/or Cohort 2 and additional interim assessments including PBPK simulations may 
be used to support a recommendation of an appropriate dose for this population.  
4.5 
Rationale for public health emergency mitigation procedures 
During a public health emergency as declared by local or regional authorities e.g., pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participant safety and trial 
integrity may be implemented. Notification of the public health emergency as declared by local 
or regional authorities should be discussed among investigators and Novartis. All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. 
 


Novartis 
Confidential 
Page 26 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
4.6 
Risks and benefits 
The safety and efficacy of Coartem®/Riamet® has been characterized in adults and pediatric 
patients ≥5 kg BW. 
The safety profile of the current Coartem®/Riamet® 6-dose regimen has been well-characterized 
in approximately 6000 patients in Novartis-sponsored clinical trials (almost 500 of them having 
received the dispersible tablet). There have been two pooled safety analyses of randomized 
clinical trials data performed, one including 712 adolescent/adult patients (i.e., patients >12 
years of age and ≥35 kg BW) and another including 1262 infants and children (i.e., patients <12 
years of age and ≥5 kg to <35 kg BW) treated with the standard tablet or dispersible tablet 
formulation according to the 6-dose regimen. Overall, Coartem®/Riamet® is well tolerated in 
both pediatric and adult patients. The profile and frequency of adverse events seems comparable 
between these patient populations. A majority of the adverse events reported in these studies 
could also have been attributed to malaria: they were rated mild to moderate in intensity and 
not necessarily related to artemether-lumefantrine. Furthermore, extensive post-marketing 
experience confirmed that Coartem®/Riamet® (artemether:lumefantrine 20 mg:120 mg) has a 
well characterized risk-benefit profile. Currently, clinical data available in patients <5 kg were 
collected in study B2306 in 20 patients >28 days of age. In that study, artemether exposure 
following administration of the 6-dose regimen of Coartem® (one artemether:lumefantrine 20 
mg:120 mg dispersible tablet/dose) was around 2-3 fold higher than anticipated safe exposures, 
whereas exposure to lumefantrine was as expected. Given the potential neurotoxicity of 
artemether at high exposures, and based on preclinical data, it was decided not to proceed with 
the second cohort of the same study (infants ≤28 days of age).  
The safety profile associated with a higher systemic artemether exposure could not be fully 
supported by preclinical data: 
- in dogs, pathological evidence of neurotoxicity was noted with intramuscular doses of 
artemether administered daily for 8 days. 
- monkeys were less susceptible to artemether-induced neurotoxicity (Li and Hickman 2011). 
Although difficult to interpret, available clinical data do not suggest that artemether Cmax values 
exceeding those associated with neurotoxicity in dogs have resulted in neurological effects in 
infants. Given the highly vulnerable patient population in this study, it is nevertheless 
imperative to bring the exposure of artemether within the limits which have been clinically 
proven to be safe (See Table 4-1).  
However, there were no new or changing safety signal observed in study B2306 compared to 
the ≥5 kg population. Most AEs reported during the core period reflected the underlying disease 
of the patients, with the most commonly reported AE being malaria (55%), with anemia 
reported for 35% of patients, bronchitis reported for 30% of patients, pyrexia for 25% of patients 
and vomiting for 20% of patients. Most reported AEs were moderate in severity (55% of 
patients), with mild events reported for 15% of patients and severe events also for 15% of 
patients – severe AEs (anemia, diarrhea, cerebral malaria, meningitis, and death of unknown 
etiology) were all SAEs reported during the long-term follow-up period and none of them was 
attributed to the study medication. AEs suspected to be related to the study drug by the 
investigator were reported for 5 (25% of patients), including anemia and vomiting (each 
reported for 3 patients, 15%). One patient discontinued study medication during the core study 


Novartis 
Confidential 
Page 27 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
period for an AE (vomiting of moderate severity). Laboratory parameters did not show 
clinically meaningful changes from baseline during the study. A large proportion of patients 
had notable vital signs at baseline (55% with high systolic blood pressure (SBP), 40% with high 
Diastolic blood pressure (DBP) and pulse rate). There was no meaningful change in this over 
the course of the study. There were no deaths or SAEs reported during the core follow-up period 
of the study. Two patients died during the long-term follow-up period up to 12 months of age 
(one patient from dehydration due to acute diarrhea, the second of unknown etiology but 
 
later reported that the subject had experienced a one day history of anorexia on the day 
of death). Finally, there were no findings following the neurodevelopment assessment at 1 year 
of age. 
In the present B2307 study, a lower ratio of artemether relative to lumefantrine (1:12) has been 
selected for investigation, in order to minimize the risk of neurotoxicity. 
The risk to subjects in the present trial will be minimized by excluding neonates/infants with 
critical conditions, through ensuring close clinical monitoring, and in-patient status (during the 
treatment period). Regular safety laboratory measurements will be used including hematology 
and blood chemistry tests, in order to ensure a close monitoring beyond the hospitalization 
period. 
Furthermore, pain and fever control methods will be implemented at the investigator’s 
discretion including appropriate use of antipyretics (e.g., during and after a painful procedure 
such as venipuncture). In terms of PK assessments, a sparse blood sampling strategy (Djimdé 
et al 2011) will be used. The total blood volume drawn over 6 weeks in this population will not 
exceed the limit of 2.4 to 2.7 mL per kg BW, following WHO recommendations (Howie 
2011). In case of severe anemia developing during the study, the total blood volume drawn 
should be adjusted downwards as necessary at the investigator’s discretion. 
Finally, a DMC will be established to safeguard patient safety (see Section 10.2.1). The DMC 
will meet at regularly scheduled time points to review the PK, efficacy and safety data collected. 
The responsibilities and specific aspects of the DMC are described in the DMC charter.  
Hence, based on the risk-benefit profile and unmet medical need, Novartis has considered 
justified to explore the use of artemether:lumefantrine (1:12) in acute, uncomplicated P. 
falciparum malaria-infected infants and neonates <5 kg BW through the present study (B2307). 
5 
Population 
The study population will consist of a representative group of neonates and infants of both sexes 
with a BW <5 kg and a confirmed diagnosis of acute uncomplicated P. falciparum malaria or 
mixed infections by microscopy with asexual P. falciparum parasitemia of ≥500 and <100,000 
parasites/µL in Cohort 1 and of ≥100 and <100,000 parasites/µL in Cohort 2. 
The study population will be enrolled in two sequential cohorts, infants >28 days of age (Cohort 
1) and term neonates ≤28 days of age (Cohort 2). Cohort 2 is further divided into 3 age 
subgroups (15-28; 8-14; 1-7 days). In order to obtain for the primary endpoint approximately 
16 evaluable neonates/infants exposed to an adequate dose in each cohort, it is planned to have 
approximately 22 neonates/infants entering the study and exposed to an adequate dose in each 
cohort. In the event no suitable dose can be determined in the highest age subgroup (15-28 days) 


Novartis 
Confidential 
Page 28 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
of Cohort 2 or recruitment is not feasible, the cohort will be closed and an additional 22 patients 
will instead be recruited in Cohort 1 and treated with the dose that was deemed adequate. 
Additionally, PBPK modeling may be explored with existing data from Cohort 1 to support the 
dose recommendation in the study population. 
Patients will be recruited at approximately 10 sites across 8 countries in Sub-Saharan Africa. 
Reflecting the local legal and cultural context, effective community engagement will be sought 
and ensured by the clinical site team. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Male or female neonates / infants 
2. Body weight <5 kg but ≥ 2kg 
3. In Cohort 1, infants aged >28 days; in Cohort 2, neonates aged 1 to ≤28 days (3 
subgroups: 15-28 days; 8-14 days; 1-7 days) 
4. Microscopically confirmed diagnosis of P. falciparum malaria (or mixed infections)  
• in Cohort 1: of ≥500 and <100,000 parasites/µL asexual P. falciparum parasitemia 
• in Cohort 2: of ≥100 and <100,000 parasites/µL asexual P. falciparum parasitemia 
• either congenital or neonatal 
• either symptomatic or asymptomatic 
5. Parental/legal guardian informed consent obtained and signed prior to any study related 
procedure. If the parent/legal guardian is unable to read or write, then a witnessed consent 
according to local ethical standards is permitted (formally documented and witnessed, via 
an independent trusted witness) 
6. The parent/legal guardian 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 
Subjects meeting any of the following criteria are not eligible for inclusion in this study: 
1. Head circumference < - 2 SD z-score in cm following WHO age and sex-specific 
reference curves (suspicion of microcephaly) (See Section 16.1 Appendix 1) 
2. Severe malnutrition (body mass index (BMI) less than 70% of median normalized WHO 
reference weight) 
3. Presence of severe malaria (according to WHO 2015 definition - See Section 16.4 
Appendix 4) 
4. Hemoglobin < 7 g/dL 
5. HIV status:  
• in Cohort 1 : patient’s or patient's mother's current treatment with ARV 
• in Cohort 2 : Mother’s known HIV positive status at patient's birth or mother's current 
treatment with ARV 
6. Presence of the following signs of a critical condition: apnea-bradycardia, sustained 
bradycardia, tachycardia, desaturation, hypotension, hypothermia; or other severely 


Novartis 
Confidential 
Page 29 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
deteriorated general condition (based on IMCI criteria in sick infants, WHO 2005 - 
See Section 16.5 Appendix 5) 
7. Presence of any clinically significant neurological condition:  
• any episode of convulsion during the present illness (in keeping with the IMCI list of 
general danger signs) 
• known neurological disorders (e.g. chronic seizure disorders, cerebral palsy)  
8. Presence of clinically significant abnormality of the hepatic and renal systems 
9. History of malabsorption or previous gastrointestinal surgery, or history of radiation 
therapy that could affect drug absorption or metabolism, or any other disorder or history of 
a condition that could interfere with drug absorption, distribution, metabolism, or 
excretion 
10. Patients unable to swallow or whose drinking is impaired 
11. Known hypersensitivity of the patient or either patient's parent to artemether, 
lumefantrine, any of the excipients of Coartem®/Riamet® Dispersible tablet, or to drugs of 
similar chemical classes 
12. Known family history of congenital prolongation of the QTc interval or sudden death or 
with any other clinical condition known to be associated with prolongation of the QTc 
interval such as history of symptomatic cardiac arrhythmias, with clinically relevant 
bradycardia or with severe cardiac disease 
13. Disturbances of electrolyte balance (e.g. hypokalemia or hypomagnesemia) - See Section 
16.1 Appendix 1 as an example for reference 
14. Presence of any age-adjusted clinically or hematologically relevant laboratory and blood 
chemistry abnormalities 
15. Patients who received any antimalarial drug, including antibiotics with antimalarial 
activity, within 14 days of trial start, or any other prohibited drug (see Table 6-2) 
16. Patients who received an investigational drug within 5 half-lives of enrollment or 
participated in an investigational study or within 30 days, whichever is longer. 
NOTE: Where information is either not available or insufficient (e.g. from medical history, 
charts) to assess whether a patient meets a specific exclusion criterion, the study site team shall 
use its best medical judgement to make an inclusion/exclusion decision for the patient. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Novartis will supply artemether:lumefantrine 2.5 mg:30 mg (COA566 2.5 mg:30 mg) as an 
investigational product in the form of open label patient specific supplies (see Table 6-1). 
Table 6-1 
Investigational and control drug 
Treatment Title 
COARTEM/RIAMET, COA566 
Treatment 
Description 
dispersible tablet, 2.5 mg artemether / 30 mg lumefantrine, 1 to 4 tablets per dose, BID 
for 3 days, open label  


Novartis 
Confidential 
Page 30 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Type  
drug 
Dose Formulation 
dispersible tablet 
Unit Dose 
Strength(s) 
2.5 mg artemether / 30 mg lumefantrine 
 
Dosage Level(s) 
1 to 4 tablets per dose, BID for 3 days 
Route of 
Administration 
oral 
Use 
experimental 
IMP 
yes 
Sourcing 
provided centrally by the sponsor  
Packaging and 
Labeling 
Study treatment will be provided in blisters. Each blister will be labeled as required per 
country requirement.  
 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug is included in this trial. 
6.1.3 
Treatment arms/group 
Patients will receive artemether:lumefantrine 2.5 mg:30 mg dispersible tablet. Although it is 
anticipated to have one dose level assessed in the study, four possible dose levels (1 to 4 tablets 
per dose) may be used (See Section 6.5.1.2).  
In Cohort 1, a regimen of two dispersible tablets (i.e., 5 mg:60 mg artemether:lumefantrine) 
twice daily for 3 consecutive days will be administered as a starting dose to the first 9 patients. 
Following a PK check (including safety and efficacy data review as available), the dose level 
may be adjusted and administered to another 9 patients (up to two re-runs, see Figure 3-2 and 
Table 6-3). Once a suitable dose has been determined in 9 patients, about 13 additional patients 
will be recruited and administered the same dose.  
Cohort 2 will be further divided into 3 age subgroups. A PK check will be performed after 3 
patients have been treated in the highest age subgroup (15-28 days). In the event the exposure 
is not considered adequate (see Section 4.2), the dose may be adjusted and administered to 
another 3 patients of that age subgroup (up to two re-runs, see Figure 3-1 and Table 6-3).  
For more details, see Section 3. 
In case the suitable dose would not be the same across the 2 cohorts, or within Cohorts, 
treatment groups will be defined based on dose level. 
6.1.4 
Treatment duration 
After inclusion in the study, each patient will be dosed b.i.d. with study drug for 3 days (at the 
following time points: 0, 8, 24, 36, 48 and 60 hours) under hospital supervision.  
Patients may be discontinued from treatment at the discretion of the investigator 
or of the parents/legal guardian or due to: 
• Disease progression (see Section 6.2.3)  
• Use of prohibited treatment (see Table 6-2)   


Novartis 
Confidential 
Page 31 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
• Any situation in which study participation might result in a safety risk to the patient and/or 
any adverse events that in the judgement of the investigator, taking into account the 
patient's overall status, prevent the patient from continuing participation in the study 
• Deviation from the planned dose regimen for the study drug, for instance, if the patient 
vomits a dose within 1 hour of intake, as well as its replacement dose within 1 hour of 
intake. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
Concomitant medication is defined as any medication, other than the study drug, which is given 
at least once between the day of first dose of study medication and the last visit of core follow-
up period (including those which were started pre-baseline and continued into the treatment 
period), including prescription and over-the-counter medicines, and any traditional or herbal 
remedies. 
The investigator should instruct the patient’s legal guardian to notify the study site about any 
new medications the patient takes after the start of the study drug. All medications and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient starts treatment with study drug must be recorded on the appropriate CRF.  
Similarly, all medications and significant non-drug therapies administered during the core 
follow-up period to a mother breastfeeding a patient after the patient starts treatment with study 
drug must be listed on the appropriate CRF.  
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 
entering a subject in the study or allowing a new medication to be started during the study. If 
the subject is already recruited, the investigator should also contact Novartis to determine if the 
subject should continue participation in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
The following should be used with caution, i.e. with staggered dosing (unless already listed in 
Section 6.2.2) during the core follow-up period (6 weeks) 
• CYP3A4 inhibitors: The concurrent oral administration of ketoconazole with artemether-
lumefantrine 20 mg:120 mg led to a modest increase (≤2-fold) in artemether, DHA, and 
lumefantrine exposure in healthy adult subjects. This was not associated with increased 
side effects. However, there is a potential for increased concentrations of lumefantrine 
which could lead to QT prolongation, 
• Weak to moderate inducers of CYP3A4: When artemether:lumefantrine 20 mg:120 mg 
is co-administered with weak to moderate inducers of CYP3A4, it may result in decreased 
concentrations of artemether and/or lumefantrine and lower the antimalarial efficacy. 
Patients can experience this interaction even while they or the mother/breastfeeding 
person stops treatment around 2 weeks before the patient starts taking artemether-
lumefantrine. 
These restrictions result from potential interactions with study drug. 


Novartis 
Confidential 
Page 32 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
6.2.2 
Prohibited medication 
For the period(s) specified, use of the treatments displayed in Table 6-2 is not allowed in: 
• patients 
• the person providing breastmilk to the patients (as the prohibited drug is known to be 
secreted significantly in breastmilk), except for antimalarials or antimicrobials with 
antimalarial activity. 
These restrictions result from potential confounding of efficacy or from drug interaction. 
Table 6-2 
Prohibited medication 
Medication* 
Prohibition period** 
Action taken*** 
Drugs that are known to 
prolong the QTc interval such 
as: 
• 
antiarrhythmics of classes 
IA and III 
• 
neuroleptics, 
antidepressant agents 
• 
certain antibiotics including 
some agents of the 
following classes: 
macrolides, 
fluoroquinolones, 
imidazole, and triazole 
antifungal agents 
• 
certain non-sedating 
antihistaminics 
(terfenadine, astemizole) 
• 
cisapride 
At least 5 times their half-life 
before study entry and at least 
for 28 days after last AL dose  
Discontinue prohibited 
medication, monitor patient 
closely for any cardiac event, 
discontinue the study treatment 
in case of cardiac event 
Drugs which are metabolized 
by the cytochrome enzyme 
CYP2D6 especially those with 
a narrow therapeutic index e.g. 
flecainide, metoprolol, 
imipramine, amitriptyline, 
clomipramine 
At least for 28 days after last 
AL dose 
Discontinue prohibited 
medication, monitor for 
potential effects of 
overexposure of impacted 
drug. However patients taking 
one of these drugs should stay 
in the study and follow-up visits 
for efficacy should be 
performed according to the visit 
schedule, i.e. remaining visits 
for the entire core study period 
(until Day 43), and the follow-
up visit at 12 months of age 


Novartis 
Confidential 
Page 33 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Medication* 
Prohibition period** 
Action taken*** 
inducers of CYP3A4 Strong 
inducers of CYP3A4 like 
rifampicin and St. John’s wort 
can reduce the exposure of 
artemether and lumefantrine to 
a clinically significant level  
At least 5 times their half-life 
plus two weeks before study 
entry and during entire core 
study period (until Day 43)  
Discontinue prohibited 
medication. However patients 
taking one of these drugs 
should stay in the study and 
follow-up visits for efficacy 
should be performed according 
to the visit schedule, i.e. 
remaining visits for the entire 
core study period (until Day 
43), and the follow-up visit at 
12 months of age 
Herbal medication 
Entire core study period (until 
Day 43) except as rescue 
medication 
Discontinue study treatment. 
However, patients taking one of 
these drugs should stay in the 
study and follow-up visits for 
efficacy should be performed 
according to the visit schedule, 
i.e. remaining visits for the 
entire core study period (until 
Day 43), and the follow-up visit 
at 12 months of age 
Antimalarials other than the 
study drug 
At least  5 times their half-life 
before study entry and during 
entire core study period (until 
Day 43) except as rescue 
medication 
Discontinue study treatment. 
However, patients taking one of 
these drugs should stay in the 
study and follow-up visits for 
efficacy should be performed 
according to the visit schedule, 
i.e. remaining visits for the 
entire core study period (until 
Day 43), and the follow-up visit 
at 12 months of age 
other ACTs: 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 
  
  
  
  
  


Novartis 
Confidential 
Page 34 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Medication* 
Prohibition period** 
Action taken*** 
Other antimicrobials with 
antimalarial activity 
entire core study period (until 
Day 43) except as rescue 
medication 
Discontinue study treatment. 
However patients taking one of 
these drugs should stay in the 
study and follow-up visits for 
efficacy should be performed 
according to the visit schedule, 
i.e. remaining visits for the 
entire core study period (until 
Day 43), and the follow-up visit 
at 12 months of age 
antibiotics: tetracycline****, 
doxycycline, erythromycin, 
azythromycin, clindamycin, 
rifampicin, trimethoprim 
  
  
pentamidine 
  
  
  
  
  
* applicable to the patient AND the person breastfeeding the patient 
** based on the patient's time point of inclusion in the study  
*** applicable to the patient (except for prohibited drug discontinuation) 
****Topical tetracycline can be used. 
6.2.3 
Rescue medication 
The following circumstances warrant discontinuation of study treatment (during the treatment 
period) and the implementation of rescue medication by the investigator (Commencement of 
rescue medication may occur after the start of study drug and up to Day 43): 
Early Treatment Failure (ETF) 
• Development of danger signs or severe malaria on Day 2, Day 3, Day 4 in the presence of 
parasitemia. 
• Parasitemia on Day 3 higher than Day 1 count irrespective of axillary temperature. 
• Parasitemia on Day 4 with axillary temperature ≥37.5°. 
• Parasitemia on Day 4 equals to or more than 25% of count on Day 1. 
Late Clinical Failure (LCF) 
• Development of danger signs or severe malaria on any day from Day 5 to Day 43 in the 
presence of parasitemia without previously meeting any of the criteria of Early Treatment 
Failure. 
• Presence of parasitemia and axillary temperature ≥37.5° on any day from Day 5 to Day 43 
without previously meeting any of the criteria of Early Treatment Failure.   
Late Parasitological Failure (LPF) 
• Presence of parasitemia on any day from Day 8 to Day 43 and axillary temperature <37.5° 
without previously meeting any of the criteria of Early Treatment Failure or Late Clinical 
Failure. 


Novartis 
Confidential 
Page 35 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Rescue treatment involves therapy with an effective antimalarial available locally as per local 
medical practice or National Treatment Guidelines. Administration may be oral or parenteral 
depending on the subject’s clinical condition. Rescue treatment will not be considered study 
medication. The exact rescue regimen and route of administration must be recorded on the 
appropriate CRF. 
Patients will be monitored, either in clinic, or via home visits for the duration of treatment to 
ensure adherence to the rescue medication therapy. These patients will not discontinue the study 
(i.e., all the examinations as per the assessment schedule and all CRF for this patient will need 
to be completed), and they will not be replaced (unless the PK data cannot be properly analyzed 
due to treatment schedule discontinuation). 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is uniquely identified in the study by a Subject Number (Subject No.), that is 
assigned when the subject enters screening and it is retained as the primary identifier for the 
subject throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Once assigned to a subject, the Subject Number will not be reused. 
Upon their parent/legal guardian signing the informed consent form, the subject is assigned to 
the next sequential Subject No. available. The investigator or his/her staff will then contact the 
Interactive Response Technology (IRT) and provide the requested identifying information for 
the subject to register them into the IRT. The site must select the CRF book with a matching 
Subject Number from the electronic data capture (EDC) system to enter data. 
6.3.2 
Treatment assignment, randomization 
No randomization will be performed in this study. All eligible subjects will be assigned to one 
of the treatment packs via Interactive Response Technology (IRT). The investigator or their 
delegate will contact the IRT after confirming that the subject fulfills all the inclusion/exclusion 
criteria. The IRT will assign a unique medication number for the package of study treatment 
and the dose level to be dispensed to the patient. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the appropriate 
disposition CRF. 
6.4 
Treatment blinding 
This study is open label and treatment as well as the dose level will be open to the subjects' 
parents/legal guardian, investigator staff, persons performing the assessments, and the CTT. 


Novartis 
Confidential 
Page 36 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
6.5 
Dose escalation and dose modification 
6.5.1 
Dose escalation guidelines 
6.5.1.1 
Starting dose 
The starting dose in Cohort 1 in this trial is artemether:lumefantrine 5 mg:60 mg, i.e., 2 tablets 
bid for 3 days. 
6.5.1.2 
Provisional dose levels 
Table 6-3 describes the starting dose and the dose levels that may be evaluated during this trial. 
Table 6-3 
Provisional dose levels 
Dose level 
Proposed dose* 
Number of tablets per dose** 
1 
2.5 mg:30 mg 
1 
2 
5 mg:60 mg (starting dose in Cohort 1) 
2 
3 
7.5 mg:90 mg 
3 
4 
10 mg :120 mg 
4 
*administered bid over 3 days. 
**Dose level number 1 represent treatment regimen if a dose reduction is required from the starting 
dose level number 2 (used in Cohort 1) while Dose level numbers 3 and 4 represent treatment 
regimens if a dose increase is required. No dose reduction below dose level number 1 nor dose 
increase above dose level number 4 is permitted for this study. 
Dose modification in a particular subject is not permitted. However, each cohort will be divided 
into sequential groups (see Figure 3-2 and Table 6-3). A pharmacokinetic exposure check 
(together with a review of efficacy and safety data as available) will be performed as described 
in Section 3 and Section 4.2. Based on the outcome of these checks, the dose may be adjusted 
between dose levels 1-4 in further patients recruited, following a pattern specific to each cohort. 
For more details, see Section 6.1.3. 
6.5.2 
Dose modifications 
Dose level modification may not occur in an individual patient’s 6-dose regimen, but the dose 
level may be adjusted between patients after each PK exposure check (See Section 6.5.1.2). 
In addition, a replacement dose may be given to a patient in case of vomiting of a dose within 
1 hour of administration (see Section 6.7.2). In case this repeat dose is vomited within 1 hour 
of intake, rescue treatment should be immediately provided. 
6.5.3 
Follow-up for toxicities 
See Appendix 2 - Section 16.2 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
A limited number of qualified individuals, will be designated as appropriate by the investigator 
in order that two of these people ensure compliance by direct observation of both preparation 


Novartis 
Confidential 
Page 37 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
and administration of all doses of study medication for each patient. The exact dosages 
administered will be recorded on the Dosage Administration Record CRF, along with any 
comments about whether the patient swallowed all or only part of the medication, whether and 
when vomiting occurred, and whether replacement medication had to be initiated. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects, 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 CRF 
(see Section 6.2.1). 
6.6.3 
Emergency breaking of assigned treatment code 
Not applicable. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described in Table 6-1. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s) as well as the appropriate dose level. 
The study medication has a 2-part label (base plus tear-off label). Immediately before preparing 
and dispensing the medication kit to the subject, site personnel will detach the outer part of the 
label from the packaging and affix it to the source document. 
If a patient vomits study drug within 1 hour of intake, a replacement dose will be given to the 
patient and the investigator or designee will notify IRT. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, study treatment 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/ CO Quality Assurance. 
Medication labels will be in the appropriate 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 subject except for the medication number. 


Novartis 
Confidential 
Page 38 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.7.1.2 
Handling of additional treatment 
Rescue medication will be handled as per Section 6.2.3. 
6.7.2 
Instruction for prescribing and taking study treatment 
Two qualified individuals (from a limited number of people designated by the investigator for 
this task) will directly observe preparation and administration of all doses of study medication. 
They should promote compliance by ensuring that the patient take the study drug exactly as 
prescribed and by stating to the patient’s legal guardian that compliance is necessary for the 
patient’s safety and the validity of the study. 
The study drug (dispersible tablets) should be administered as follows: the appropriate number 
of dispersible tablets composing 1 dose should be completely dispersed in a small amount of 
clean water (approximately 3 mL per dose) using a syringe for oral use and its content should 
be shaken gently and administered immediately to the subject (i.e., within 10 min). The syringe 
should then be rinsed with an additional small amount of clean water (approximately 3 mL) and 
given immediately to the subject (further details can be found in the Pharmacist intruction 
manual). The dose should be preceded and/or followed as much as possible by food/drinks rich 
in fat such as breast milk, or formula milk, in order to enhance absorption as well as to avoid 
dehydration. 
In the event of vomiting of a dose within 1 hour of administration a repeat dose should be 
administered. In case this repeat dose is vomited within 1 hour of intake, rescue treatment 
should be immediately initiated and the infant discontinued from the study medication. The 
exact rescue regimen and route of administration (see Section 6.2.3) is to be recorded on the 
appropriate CRF. 
For Dose 2 (at Hour 8), the administration time window should not be greater than ± 1 hour to 
achieve effective plasma level as soon as possible after start of treatment. For the following 
doses at Hours 24, 36, 48 and 60 (twice daily), the time window should not be greater than ± 2 
hours. During the 3-day treatment period, study medication will be given under hospital 
supervision. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after IRB/IEC-approved informed consent 
(witnessed, where required by law or regulation) has been provided by their legally acceptable 
representative (LAR), i.e. parent or legal guardian. 


Novartis 
Confidential 
Page 39 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the informed 
consent and should be discussed with the subject's LAR during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
8 
Visit schedule and assessments 
The assessment schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the subject’s source documentation. 


Novartis 
Confidential 
Page 40 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Table 8-1 
Schedule of assessments 
 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) or as close to the designated day/time as possible. Missed or rescheduled visits should not 
lead to study discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit of the core follow-up period (Day 43) will be performed. At this final visit, all 
dispensed investigational product should be reconciled, and the adverse events and concomitant 
medications recorded on the CRF. 
8.1 
Screening 
The investigator or their delegate will contact the IRT when a patient enters screening. It is 
permissible to re-screen a subject if they fail the initial screening; however, each case must be 
discussed and agreed with the Sponsor on a case-by-case basis. 


Novartis 
Confidential 
Page 41 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
They will contact again IRT after confirming that the patient 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 patient. 
8.1.1 
Information to be collected on screening failures 
Subjects whose legal guardian sign an informed consent form and who are subsequently found 
to be ineligible will be considered a screen failure. The reason for screen failure should be 
entered on the applicable CRF. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure subjects. No other data 
will be entered into the clinical database for subjects who are screen failures, unless the subject 
experienced a serious adverse event during the screening phase (see SAE section for reporting 
details). 
Subjects whose legal guardian sign an informed consent and who are considered eligible but 
fail to be started on study treatment for any reason will be considered an early terminator. The 
reason for early termination should be captured on the appropriate disposition CRF. 
8.2 
Subject demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with the CRF. 
Patient demographic and baseline characteristic data to be collected on all patients include: age 
(in days), sex, race, ethnicity, birth weight, current body weight, height, temperature, and 
malaria blood smears/parasite counts. Relevant medical history/current medical condition data 
and concomitant medication significant non-drug therapies prior to start of study drug consist 
in data up to the start of study drug. Where possible, diagnoses and not symptoms will be 
recorded. 
In addition, all medications and significant non-drug therapies administered to a mother (or the 
person) providing breastmilk to a patient before the patient enters the study and starts treatment 
with study drug must be listed on the specific Concomitant medications/Significant non-drug 
therapies prior to start of study drug (e)CRF. 
8.3 
Efficacy 
Efficacy assessments will consist of parasitemia determinations in peripheral blood and body 
temperature measurement, as well as signs and symptoms of early treatment failure. 
Methods of parasitemia assessment 
• Giemsa stained thick (and thin) films will be examined. Thin films are only required in the 
case of confirmation of species other than P. falciparum. 
• Examination will be done using a light binocular microscope fitted with an oil immersion 
lens. 
• Thick film screening examination (prior to patient inclusion into the trial): 
• At least 200 thick film fields are examined. If there is no P. falciparum, the slide is 
declared negative, and the patient is not suitable for inclusion. 


Novartis 
Confidential 
Page 42 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
• If asexual forms of Plasmodia are found, a total of 200 thick film fields are to be screened 
for Plasmodium species other than P. falciparum. 
• When it has been ascertained that P. falciparum is present, a count is made of the asexual 
forms against leukocytes, using a tally counter. Counting needs to be done based on at 
least 200 leukocytes according to the WHO standards. If less than 100 parasites, counting 
will be extended to 500 leukocytes. 
• The parasite density will be calculated according to the following formula: 
Number of Plasmodium parasites x actual leukocytes (WBC*) 
Parasite density per µl = —————————————————————————— 
Number of leukocytes (WBC) counted (200) 
* WBC at screening or the latest available one 
• Blood examination during the 43-day core trial period: 
• A total of 200 thick films fields are examined (tally counter) before a slide can be 
pronounced negative. 
• If asexual forms of P. falciparum are present, a parasite count is required 
• If Plasmodium species other than P. falciparum are found, note species 
• If P. falciparum gametocytes are seen, perform a gametocyte count against 1000 
leukocytes 
The count should be made for each species and for the P. falciparum gametocytes. Thick (and 
thin blood) films will be taken at each visit and evaluated by standard techniques (Giemsa stain). 
This will be the definitive test for a positive P. falciparum infection. The parasite counts can 
also be quantified in ‰ (per 1000) of red cells in the thin film. 
For quality control purposes, all slides will be double read by two independent microscopists 
(as per each site’s laboratory standard procedure and quality control measures). 
In addition, central reading of all slides will be performed at a central reference laboratory. The 
results of the local reading will be entered in the (e)CRF and results of the central readings will 
be sent electronically by the central laboratory to Novartis (or a designated CRO). Results from 
the central reading will be used for the derivation of primary and secondary efficacy endpoints. 
Blood samples for molecular diagnostic purposes 
Blood will be sampled for parasite genotyping (PCR) as indicated in the assessment schedule 
(Table 8-1). At screening, a blood sample will be collected in all patients fulfilling eligibility 
criteria for inclusion in the study. A second blood sample will be analyzed only in patients 
showing treatment failure. This will allow to distinguish between recrudescence and a new 
infection. Sample analysis will be performed at a pre-selected reference laboratory. 
Microscopic species identification (parasitemia) will be confirmed and determined with PCR-
based methods on blood retained from samples collected at the time of treatment failure. 
All parasite samples at baseline will also be screened for specific genes/single-nucleotide 
polymorphisms (SNPs) that are known as markers for P. falciparum resistance. 
During the analysis process no human DNA will be amplified or analyzed by any means. 


Novartis 
Confidential 
Page 43 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
8.3.1 
Appropriateness of efficacy assessments 
The microscopy examination methods to quantify the malaria parasite and gametocyte in blood 
are validated methods (Sinden et al 2012; White et al 2014). 
8.4 
Safety 
Safety assessments are specified in Table 8-2 with the assessment schedule (Table 8-1) detailing 
when each assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
Table 8-2 
Assessments & Specifications 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the 
examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If 
indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed. 
At further visits an abbreviated one will include 
general appearance. At all visits, patients will be 
examined for signs of dehydration. 
At selected visits, head circumference will be 
measured in cm 
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 as medical history. Significant 
findings made after signing informed consent 
which meet the definition of an adverse event 
must be recorded as an adverse event. 
Vital signs 
Vital signs will include systolic and diastolic 
blood pressure, temperature and pulse rate. 
After the patient has been still for five minutes 
(as much as possible), systolic and diastolic 
blood pressure will be measured three times 
using an automated validated device, e.g. 
Dynamap/Denshi, 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. In case the cuff 
sizes available are not large enough for the 
patient's arm circumference, a 
sphygmomanometer with an appropriately sized 
cuff may be used. 
Temperature will be taken using a standard 
clinical thermometer, for 5 minutes before 
reading. Clinically notable vital signs are defined 
in Section 16.1 - Appendix 1 . 


Novartis 
Confidential 
Page 44 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Assessment 
Specification 
Height and weight 
Height in centimeters (cm) and body weight (in 
[g] to the nearest 10 g). Whenever available, 
birth weight (g) will also be collected at baseline 
visit. Infants should preferably be weighed and 
measured nude, alternatively wearing clean 
disposable diapers (weighing infants with too 
much clothing is one of the most frequent 
sources of error in infant weight measurements). 
8.4.1 
Laboratory evaluations 
At each site, a local laboratory (validated/accredited) will be used for analysis of all specimens 
collected, i.e., for hematology and blood chemistry (for either PCR [parasite identification and 
resistance markers], or PK measurements, a central reference laboratory will be used). 
All specimens will be processed and analyzed in the local laboratory. If any results are of 
clinical concern, a repeat sample will be collected at the next scheduled visit, while remaining 
within the overall blood volume limit for the patient (Howie 2011). 
 
Test Category 
Test Name 
Hematology 
Hemoglobin, hematocrit, red cell count (RBC and reticulocytes), white blood 
cell (WBC) count with differential (absolute value preferred, %s are acceptable) 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, 
Other), and platelet count 
Chemistry 
sodium, potassium, magnesium, glucose, creatinine, AST (SGOT), ALT 
(SGPT), and total bilirubin will be measured 
Urinalysis 
Not applicable 
8.4.2 
Other safety evaluations 
A specific follow up of liver events will be performed as per Section 16.2 - Appendix 2. 
 
 
 
 
 
 
 
 
 
 
 
8.4.3 
Appropriateness of safety measurements 
Safety measurements used in the 43-day follow-up are standard for this indication/subject 
population and follow WHO guidelines (WHO 2009; 2018) 


Novartis 
Confidential 
Page 45 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
All safety measurements, 
 were implemented 
in the previous study B2306 (Tiono et al 2015; EMA 2011). 
8.5 
Additional assessments 
No additional tests will be performed on subjects entered into this study.  
8.5.1 
Clinical Outcome Assessments (COAs) 
Not applicable. 
8.5.2 
Pharmacokinetics 
Rationale for Artemether Cmax (ART Cmax) as primary endpoint 
The previous study B2306 targeting the same population was stopped prematurely because the 
exposure to artemether and DHA was 2-3 fold higher in the first cohort (>28 days of age and 
<5 kg body weight) than what had been observed in earlier studies in children ≥5 kg body 
weight. There were no specific safety or efficacy related observations, however, absence of 
toxicity associated with the higher exposure, especially of neurotoxicity, could not be 
supported, by historical clinical or non-clinical data nor by the small sample size of study B2306 
itself. Therefore, in the present B2307 study, it is hypothesized that if the exposure to artemether 
and lumefantrine is contained within the range of exposures which have been established to be 
safe and efficacious in children ≥5 kg, a dosing recommendation can be made with reasonable 
confidence in this vulnerable population. Due to limitations in recruiting the target population, 
the sample size remains limited and similar to that of Study B2306. Based on available 
information (Beckman et al 2013) it is anticipated that a higher artemether exposure remains a 
major concern of potential neurotoxicity so that monitoring artemether exposure remains 
critical in this population. Due to the limited number of sampling time points (and limitation of 
the overall blood volume drawn) in this population, the exposure reference in infants is available 
only in terms of ART Cmax, achieving the target maximum concentration (Cmax) for initial rapid 
parasitemia reduction (efficacy), ART Cmax is also an appropriate measure of artemether 
exposure as artemether PK is described by a one compartment model ; ART Cmax was 
therefore  selected as the primary endpoint in this study. Nevertheless, other exposure 
parameters for artemether, DHA and lumefantrine will also be measured, wherever possible, 
along with safety and efficacy assessments in order to reach a conclusion in this study.   
Pharmacokinetic Assessments 
Blood samples will be collected for PK at the scheduled time points indicated in one of the 2 
possible sample schemes (See Section 16.3-Appendix 3). When the investigator or their 
delegate contacts the IRT to confirm that the subject is eligible, the IRT will assign one of 
the 2 possible sample schemes to the patient (following a 1:1 ratio in each cohort). Due to the 
limitation in volume and in the number of samples which can be drawn from patients in this 
study, a total of 5 samples (500 μL each) will be obtained from each subject. Each subject will 
be assigned to either of the 2 sampling schemes by the IRT. In every sample, artemether, DHA 
and lumefantrine will be assessed. The sample points are selected in such a way that will allow 


Novartis 
Confidential 
Page 46 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
comparison with historical data (concentration at specific time points and ART Cmax) and also 
collect useful information about AUC as appropriate. 
For artemether, ART Cmax is determined by collecting samples at 1h and 2h after first dose (as 
determined in study B2303 and study B2306) and ART Cmax  represents the higher concentration 
between the concentrations at 1 hour and 2 hours after first dose. 
Further details on collection, labeling and shipment of the PK samples can be found in Section 
16.3-Appendix 3 and the laboratory manual.  
The number of samples/blood draws and total blood volume collected will remain under the 
limits recommended in this population (Howie 2011). 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject’s parent/legal 
guardian or the investigator. 
The investigator must discontinue study treatment for a given subject if they believe that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Subject's parent/legal guardian decision 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the subject 
• Adverse events, abnormal laboratory values, or abnormal test result that indicate a safety 
risk to the subject (see Section 16.1-Appendix 1). For liver, see Section 16.2-Appendix 2.  
• Unsatisfactory therapeutic effect  
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study 
Subjects who discontinue study treatment or whose parent/legal guardian decide they do not 
wish their child 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., 
home visit) should be made to contact the subject’s 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 parent/legal guardian cannot or is unwilling to have the subject attend any visit(s), the site 
staff should maintain regular contact with them, or with a person pre-designated by them. This 
contact should preferably be done according to the study visit schedule. 


Novartis 
Confidential 
Page 47 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
9.1.1.1 
Replacement policy 
Escalation/de-escalation part 
Subjects will not be replaced in the study. However, if the dose is considered as unsuitable in 
the first few patients of the current cohort, enrollment of another set of new subjects to the 
current cohort to be treated with a different dose will be considered (for further details, see 
Section 3 and Figure 3-2). 
Expansion part 
During the dose expansion part of each cohort, no replacements will be needed. 
9.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject's legal guardian: 
• Does not want the infant to participate in the study anymore, and 
• Does not allow further collection of personal data from the infant 
In this situation, the investigator should make a reasonable effort (e.g., telephone or any other 
suitable means) to understand the primary reason for the subject’s legal guardian's decision to 
withdraw his/her consent and record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject's legal guardian 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 subject’s study withdrawal should be made as detailed in Table 8-
1. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal), as provided for in the 
ICF and according to applicable law. 
All biological samples not yet analyzed at the time of withdrawal will no longer be used, as 
provided for in the ICF, and they will be destroyed according to applicable legal requirements. 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without their 
legally acceptable representative stating an intention to discontinue or withdraw their child, the 
investigator must show "due diligence" by documenting in the source documents steps taken to 
contact the subject’s LAR, e.g. dates of home visits, etc. A subject should not be considered as 
lost to follow-up until due diligence has been completed or until the end of the study. 


Novartis 
Confidential 
Page 48 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
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 
slow enrollment), a DMC recommendation or for regulatory or medical reasons. In taking the 
decision to terminate, Novartis will always consider the subject's welfare and safety. Should 
early termination be necessary, subjects must be seen as soon as possible and treated as a 
prematurely withdrawn subject. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. Specifically, the investigator will inform the subject's legal guardian about 
the reasons for study termination. 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 
All treated subjects will have a safety follow-up visit at Day 43, and at 12 months of age. All 
SAEs reported during this time period must be reported as described in Section 10.1.3. 
Documentation of attempts to contact the subject’s parent/legal guardian should be recorded in 
the source documentation. 
Study completion is defined as when the last subject finishes their Study Completion visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision (Each subject will be required to complete the study in its entirety, including 
the safety follow up at the age of 12 months ). 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems and the relevant contact details will be provided to each site. 
The occurrence of adverse events must be sought by non-directive questioning of the subject’s 
parent/legal guardian at each visit during the study. Adverse events also may be detected when 
they are volunteered by the subject’s parent/legal guardian during or between visits or through 
physical examination findings, laboratory test findings, or other assessments. 


Novartis 
Confidential 
Page 49 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
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): 
2. The severity grade: 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
3. Its relationship to the study treatment. 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 subject 
4. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported whether it constitutes a SAE (see Section 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 
• Dose Reduced/increased 
• 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 subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued until the Day 43 Visit (end of the core follow-
up period). 
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 (IB). 
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 


Novartis 
Confidential 
Page 50 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
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 subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Sections 16.1-Appendix 1 and 16.2-Appendix 2. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the informed consent was signed 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
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 subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 


Novartis 
Confidential 
Page 51 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject’s 
parent/legal guardian has provided informed consent and until the last core follow-up study visit 
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. Information about all SAEs will be collected and 
recorded on the eCRF Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the last core follow-up study visit should only be reported to 
Novartis Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Not applicable. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, preparing, dispensing, 
administration or monitoring of a medicine while under the control of a healthcare professional, 
subject’s parent or legal guardian 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 


Novartis 
Confidential 
Page 52 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness (See Table10-1). 
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 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established (EMEA 
2005, FDA 2006 , EMA 2018), who will monitor at regular time points PK, safety and efficacy 
data collected, i.e. once the first 9 patients in Cohort 1 , 3 and 9 patients (1-28 days old) and/or 
optionally 9 patients 15-28 days old in Cohort 2 treated with one same dose in each cohort have 
completed Day 15 (See Figure 3-2): Cohort 1 (infants >28 days of age) and Cohort 2 (neonates 
≤28 days of age).  
In addition the DMC will meet for 2 planned interim assessments: 
Interim assessment 1 
At the completion of Cohort 1's core period (Day 43), i.e. in 22 patients minimum to discuss 
and evaluate analyses of the PK data, as well as safety and efficacy data collected in the full 
cohort. The DMC will make a recommendation on whether to proceed with Cohort 2, and if so, 
either with the same dose regimen that was deemed suitable in Cohort 1 or an alternative one.  
Interim assessment 2 
At the completion of Cohort 2's core period (Day 43) to discuss and evaluate analyses of the 
PK data, as well as safety and efficacy data collected in both cohorts, i.e. in approximately 44 
patients.  
Optional interim assessment 
Additional interim assessments along with DMC reviews may be conducted to support decision 
making for dose recommendations. 
 
Additional ad-hoc safety reviews may be requested by the DMC or Novartis if needed (e.g. in 
case of SAEs). 


Novartis 
Confidential 
Page 53 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock (including long term safety follow up data), the investigator will 
receive copies of the subject data for archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
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. 
Data about all study treatment (s) dispensed to the subject and all dose level administered 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 at 
specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 


Novartis 
Confidential 
Page 54 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eSource Data Direct 
Entry or eCRFs) with the investigators and their staff. During the study, Novartis employs 
several methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of subject records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data and the results of any other tests or assessments. All information 
on CRFs must be traceable to these source documents in the subject’s file.  The investigator 
must also keep the original informed consent form signed by the subject’s parent/legal guardian 
(a signed copy is given to them). 
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 effective informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Although there is only one study drug form (artemether 2.5 mg-lumefantrine 30 mg dispersible 
tablet), there are 4 possible dose levels (see Table 6-3). Therefore, treatment group in this study 
means study drug dose level and treatment group label will always include the study drug level 
even if there is only one study drug dose level in the whole study. In case that the dose level 
that passed the exposure check for the first 3 patients in the highest age subgroup in Cohort 2 is 
not appropriate for either or both the lower age subgroup(s) after the exposure check in 3 
patients, the recruitment in these subgroup(s) will be stopped, they will be separated out from 
Cohort 2 and analyzed separately as needed. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all subjects that received any study drug. Subjects will 
be analyzed according to the treatment(s) received. 


Novartis 
Confidential 
Page 55 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received. The Safety set will be used for safety 
analyses while FAS will be used for other analyses. 
The Per-Protocol Set (PPS) is a subset of subjects of the Full Analysis Set and is characterized 
by the following criteria: 
• did not have important protocol deviations affecting efficacy 
• took at least 80% of study medication 
• PCR corrected cure status at Day 29 can be defined. 
Important protocol deviations for exclusion from the PPS will be identified by the clinical team 
before database lock. 
The PK set is a subset of the Full Analysis Set who had evaluable PK parameter data. 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by cohort and treatment group for the 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, the 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized for 
FAS by system organ class and preferred term, by cohort and treatment group. 
12.3 
Treatments 
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in number of study drug doses taken will be summarized by means of 
descriptive statistics using the Safety Set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by cohort and treatment group. 
12.4 
Analysis of the primary endpoint(s) 
A pharmacokinetic parameter for artemether after the first dose, artemether Cmax (ART Cmax) 
will be assessed as the primary endpoint. The ART Cmax will be compared with historical data 
especially from children ≥5-<15 kg BW in Study B2303. 
12.4.1 
Definition of primary endpoint(s) 
ART Cmax (artemether Cmax) will be calculated using the peak plasma concentration of 
artemether following the first dose. For artemether, ART Cmax is determined by collecting 
samples at 1h and 2h after first dose (as determined in study B2303 and study B2306) and 


Novartis 
Confidential 
Page 56 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
ART Cmax represents the higher concentration between the concentrations at 1 hour and 2 hours 
post first dose. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Ninety percent (90%) confidence intervals for ART  Cmax will be calculated based on the log 
normal distribution by cohort and treatment group using the PK analysis set. The study 
objective will be considered to be met if 90% CIs for ART Cmax contain the desired values based 
on historical data especially those from children ≥5-<15kg BW in Study B2303. 
12.4.3 
Handling of missing values/censoring/discontinuations 
Patients without sufficient PK concentrations for the derivation of ART Cmax will not be 
included in the analysis. 
12.4.4 
Sensitivity and supportive analyses 
Sensitivity analyses 
Ninety percent (90%) confidence intervals for ART Cmax will be calculated based on the log 
normal distribution by cohort and treatment group using the PPS. Patients with missing 
ART Cmax will be excluded from the analysis.  
Supportive analyses 
If there are treatment groups that are used for multiple cohorts, ninety ercent (90%) confidence 
intervals for ART Cmax will be calculated for these treatment groups based on the log normal 
distribution using the PK set by pooling data from all cohorts.   
12.5 
Analysis of secondary endpoints 
Descriptive statistics for each secondary variable will be provided by cohort and treatment 
group. If there are treatment groups that are used for multiple cohorts, descriptive statistics will 
be calculated for these treatment groups by pooling data from all cohorts.  
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Secondary Efficacy variables are: 
• PCR-corrected ACPR at Day 15, Day 29 and Day 43.  
• Uncorrected ACPR at Day 8, Day 15, Day 29, and Day 43. 
• Incidence rate of recrudescence and new infections at Days 15, 29 and 43 
• Parasite and Fever clearance Times (PCT and FCT) 
At each visit, the ACPR rate with 95% confidence intervals will be provided using the Pearson-
Clopper method for each treatment group by cohort using PPS for PCR-corrected ACPR and 
FAS for uncorrected ACPR. Data will be handled as follows: 
• Treatment failures after 7 days (i.e., Study Day 8) due to new infections based on PCR 
genotyping are not considered as failure for PCR-corrected analyses. 


Novartis 
Confidential 
Page 57 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
• For uncorrected ACPR, patients will be treated as failure on and after the visit when a 
reinfection with P. falciparum or other species is detected (which might be either 
recrudescence or a new infection). 
• Patients who received rescue medication for the treatment of P. falciparum malaria 
(except for the treatment of a new infection) will be considered treatment failures. Patients 
who received other concomitant medication having an effect on malaria for reasons other 
than rescue therapy e.g., for the treatment of P. vivax (e.g., primaquine, certain antibiotics 
(sulfonamides, tetracycline, etc.) will be considered in the analysis as if they had not taken 
the drug. 
• Patients will be counted as failure at a visit (e.g. Study Day 15, etc.) if (a) they did not 
have a parasite count, i.e., missing parasite count at that visit unless these patients could be 
classified as cured based on absence of parasitemia (parasite count = 0) at a later time 
(e.g., Study Day 29), or (b) they did not have valid PCR evaluations at baseline and the 
visit if parasitaemia was present at that time (e.g., Study Day 15). 
• For intermediate missing data, (a) once a patient experienced a treatment failure at a 
timepoint (eg. Day 15), the patient is considered as treatment failure at all later timepoints 
(eg. Day 29), (b) is a patient is considered as cured at a timepoint (eg. Day 29), the patient 
is considered as cured at earlier timepoints (eg. Day 15).  
In addition, PCR-corrected ACPR rate will be calculated and plotted using the Kaplan-Meier 
method (Stepniewska and White 2006; WHO 2015) for each treatment group by cohort in the 
FAS. Treatment failure is the event for analysis. For patients who do not experience treatment 
failure and do not have Study Day 43 data, treatment failure is considered as censored. The 
PCR-corrected ACPR rate at Study Day 29 is estimated by the survival function at Study Day 
29. Patients who had a new infection with P. falciparum or other species without P. falciparum 
recrudescence on or after Study Day 8 will be censored at the time of the first PCR that indicate 
the infection; patients who took antimalarial medications for reinfection or reasons other than 
rescue medication given for P. falciparum related treatment failure will be censored at the first 
time of such antimalarial medications; other patients without treatment failure will be censored 
at the time of last parasitemia assessment. 
Recrudescence and new infection 
New infection is defined as appearance of asexual parasites after clearance of initial infection 
with a genotype different from those parasites present at baseline. New infection must be 
confirmed by PCR analysis. 
Recrudescence is defined as appearance of asexual parasites after clearance of initial infection 
with a genotype identical to that of parasites present at baseline. Recrudescence must be 
confirmed by PCR analysis. 
Incidence rates of recrudescence and new infection at Days 15, 29 and 43 will be estimated by 
Kaplan-Meier method based on the subset of FAS patients who have clearance of initial 
infection by Day 7. Time to event (recrudescence or new infection) will be calculated from the 
time of first study medication to the date of first event if a patient experience the event and be 
censored at the time of last parasite assessment if a patient does not experience the event. 


Novartis 
Confidential 
Page 58 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Parasite clearance time (PCT) and fever clearance time (FCT) 
Descriptive statistics (mean, standard error, median, quartiles) will be presented for each 
treatment by cohort using the Kaplan-Meier method based on the FAS. Kaplan-Meier curves 
will be provided. PCT will be calculated based on uncorrected parasite counts. Patients without 
parasite clearance for whatever reason will be censored at the time of last parasite assessment. 
Patients who had no fever at pre-dose will not be included in the analysis of FCT. Patients 
without fever clearance for whatever reason will be censored at the time of last temperature 
assessment. In case that a patient receives rescue medication before (parasite or fever) 
clearance, the time to event will be censored at the first use of rescue medication. 
12.5.2 
Safety endpoints 
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
cohort and treatment group. 
Safety summaries (tables, figures) include only data from the core period (up to Day 43) with 
the exception of baseline data which will also be summarized where appropriate (e.g. change 
from baseline summaries). In particular, summary tables for adverse events (AEs) will include 
only the core period events, with a start date during that period. 
Adverse events 
A treatment-emergent AE is defined as any AE that develops after initiation of the study 
treatments or any event already present that worsens following exposure to the study treatment. 
All information obtained on adverse events will be displayed by cohort, treatment group, and 
subject. 
The number (and percentage) of subjects with treatment emergent adverse events will be 
summarized in the following ways: 
• by cohort, treatment group, primary system organ class and preferred term. 
• by cohort, treatment group, primary system organ class, preferred term and maximum 
severity. 
• by cohort, treatment group, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment if there are enough events. 
The number (and proportion) of subjects with adverse events of special interest/related to 
identified and potential risks will be summarized by cohort and treatment group. 
A subject 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 data will be listed by cohort, treatment group, subject, and visit/time and if ranges 
are available, clinically notable abnormalities will be flagged. Summary statistics will be 
provided by cohort, treatment group, and visit/time. 


Novartis 
Confidential 
Page 59 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Weights and heights 
All weight and height data will be listed by cohort, treatment group, subject, and visit/time. 
Summary statistics will be provided by cohort, treatment group, and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by cohort, treatment group, subject, and visit/time and if 
normal ranges are available abnormalities will be flagged. Summary statistics will be provided 
by cohort, treatment group, and visit/time. Shift tables using the low/normal/high/ (low and 
high) classification will be used to compare baseline to the worst value. 
12.5.3 
Pharmacokinetics 
The PK set will be used for all PK analyses. Artemether, DHA and lumefantrine plasma 
concentration and AUC data (as applicable) will be listed by cohort, treatment group, subject, 
and visit/sampling time point. Descriptive summary statistics will be provided by cohort, 
treatment group, and visit/sampling time point, including the frequency (n, %) of concentrations 
below the lower limit of quantification (LLOQ) and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. PK concentrations below the LLOQ will be 
treated as zero in summary statistics and for the calculation of pharmacokinetic parameters by 
non-compartmental analysis. A geometric mean will be calculated using half LLOQ value for 
concentrations below LLOQ. 
For each PK parameter, the 90% confidence intervals will be calculated on the natural log scale 
and then anti-log transformed back to the original scale for the following comparisons: 
• Artemether vs. historical data (Reference) 
• DHA vs. historical data (Reference) 
• Lumefantrine vs. historical data (Reference) 
Artemether, DHA and lumefantrine PK is considered to be comparable with historical data if 
the 90% confidence interval contains the Historical values. 
For review of the first 9 patients in each cohort (treated with the same dose) and the first 3 
patients in each subgroup or optional PK checks in Cohort 2, the following data at all time 
points will be used to make a decision on a potential dose modification: 
• ART Cmax (higher concentration between the concentrations at 1 hour and 2 hours post 
first dose) (Primary) 
• Day 8 (168 h) lumefantrine concentration 
• Cmax of DHA following the first dose from patients providing 1 h and 2 h data 
• Cmax of artemether and DHA following the last dose from patients providing 1 h and 2 h 
data 
• Cmax of lumefantrine from patients providing data after the last dose (due to potential 
accumulation for lumefantrine). 


Novartis 
Confidential 
Page 60 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
For the first 3 patients in each age subgroup in Cohort 2, the PK check is intended to make sure 
that the exposure for these patients is within the expected safety interval based on the historical 
data. 
For the first 9 patients in each cohort or optional PK checks, the PK review is intended to check 
if the Cmax is within approximately 2-fold of the Cmax which has been found to be safe and 
efficacious in previous studies.  
Non-compartmental PK will be used to calculate the pharmacokinetic parameters. Due to the 
limited number of samples collected in this study, a naive pool approach for data analysis may 
also be followed for reporting PK parameters such as ART Cmax /other Cmax and AUC, if 
feasible. 
12.5.4 
PK/PD relationships 
A PK/PD analysis may be attempted based on available historical information. Due to the small 
sample size in this study, detailed PK/PD assessment based on this study alone may be of 
limited value. 
12.5.5 
Patient reported outcomes 
Not applicable 


Novartis 
Confidential 
Page 61 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
 
 
12.7 
Interim analyses 
There will be informal PK checks (together with a review of efficacy and safety data as 
available) at various time points, and two planned interim data assessments, one between 
cohorts 1 and 2, and one again (of both Cohorts' data) after all patients in Cohort 2 have 
completed Day 43. 
After the first 9 patients in Cohort 1 and the first 3 patients in the highest age subgroup of Cohort 
2 have completed Day 15, artemether, DHA, and lumefantrine concentrations will be reviewed 
(together with a review of efficacy and safety data as available) for potential dose modifications 
(See Section 6.5.1.2). Another such review will be done after the first 9 patients of Cohort 2 
have completed Day 15 (and optionally once 9 patients from the age group 15-28 days have 
completed Day 15). All available data including PK parameters, safety and efficacy will be 
reviewed by the DMC at these time points as described in Figure 3-2. 
After all patients in Cohort 1 have completed the core period (Day 43), artemether, DHA, and 
lumefantrine concentrations, PK parameters, key efficacy and safety endpoints will be analyzed 
by the study biostatistics team (interim assessment 1). These results will be reviewed by the 
DMC to reach a decision about progression to Cohort 2 and the starting dose level in that 
Cohort. A second interim assessment will be performed after all patients have completed the 
core period of the study (Day 43). For the second interim assessment, all data up to Day 43 will 
be cleaned and included.  
Additional interim assessments may be conducted to support decision making based on early 
read-out of study data.  
Additional ad-hoc safety reviews may be requested by the DMC or Novartis if needed (e.g. in 
case of SAEs).   
12.8 
Sample size calculation 
The sample size is calculated and justified based on the precision of estimating artemether Cmax 
(primary endpoint) and Day 8 (168 h) lumefantrine concentration (secondary endpoint) 
separately for Cohort 1 and Cohort 2. 
12.8.1 
Primary endpoint(s) 
Artemether Cmax (represents the higher concentration between the concentrations at 1 hour and 
2 hours) after the first dose is the primary endpoint. The distribution of Cmax is best described 
by log normal distribution. The half width of the 2-sided 90% confidence interval for log Cmax 
is the target for sample size calculation. The relevant historical data for sample size calculation 
are the standard deviations of log Cmax, which are usually invariant to the dosage (See Table 12-
1). 


Novartis 
Confidential 
Page 62 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Table 12-1 
Standard deviation for log Cmax in Coartem studies A2102 and B2306 
Study and formulation of artemether-
lumefantrine 
Artemether Cmax  
Day 8 Lumefantrine 
concentration  
A2102* (healthy volunteers) 80:480 mg tablet 
0.58 
- 
A2102 (healthy volunteers) 4 tablets of 20:120 
mg 
0.52 
- 
B2306 (infants >28 days of age) 20:120 mg 
dispersible tablet 
0.65 
0.654 
*Study CCOA566A2102; **Study CCOA566B2306 
The table shows that the standard deviation for log Cmax was about 12% to 25% higher for 
infants in Study B2306 than for healthy volunteers in Study A2102. The patient population in 
the current study (B2307) is similar to the patient population in Study B2306.  
For log Cmax, a standard deviation of 0.65 from Study B2306 will therefore be used. Based on 
the standard deviation of 0.65 in log scale, a sample size of 16 evaluable patients will provide 
80% probability that the observed half width of 2-sided 90% CI for log Cmax is ≤0.337 or 1.4 
times (covering the targeted Cmax) in terms of ratio (nQuery Advisor 8). This sample size is 
applied to each cohort. 
PK sampling will be designed in order to get all patients evaluable for artemether Cmax analysis. 
Taking into account about 10% of patients not evaluable for this PK analysis, about 18 patients 
should be enrolled in each cohort. 
For each cohort the sample size will be increased slightly to allow for higher dropouts for the 
secondary endpoint, Day 8 (168 h) lumefantrine concentration (see Section 12.8.2).  
12.8.2 
Secondary endpoint(s) 
Power consideration for Day 8 (168 h) lumefantrine concentration 
The Day 8 (168 h) lumefantrine concentration is the key secondary endpoint. The distribution 
of Day 8 lumefantrine concentration is best described by log normal distribution.  In Study 
B2306, the standard deviation for the log concentration from 16 infants was 0.65. Based on the 
standard deviation of 0.65 in log scale, a sample size of 16 evaluable patients will provide 80% 
probability that the observed half width of 2-sided 90% CI for the log concentration is ≤0.337 
or 1.4 times in terms of ratio (nQuery Advisor 8). This sample size is applied to each cohort. 
The percentage of patients who are not evaluable for Day 8 lumefantrine concentration may be 
higher than that for artemether Cmax which is based on the concentrations on Day 1. Taking into 
account about 25% of patients not evaluable for this PK analysis, about 22 patients will be 
enrolled in each cohort in order to achieve the number of patients evaluable for this analysis as 
specified above. 
Power consideration for PK checking in each cohort 
After about 9 patients have been enrolled in each cohort, PK checking will be performed to see 
if the dose level should be adjusted. Considering that about 10% of patients would be non-
evaluable for artemether Cmax , this will lead to about 8 patients evaluable for artemether Cmax. 


Novartis 
Confidential 
Page 63 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
The probability that the observed half width of 2-sided 90% CI in log scale is ≤0.693 or 2 in 
terms of ratio for artemether Cmax is 96% if the standard deviation in log scale is same as the 
assumed 0.65 or 80% if the standard deviation in log scale is as high as 0.85 (nQuery Advisor 
8). 
Note: 
The requirement for an evaluable number of patients is 16 for both the primary endpoint 
(artemether Cmax (max concentration between concentrations at 1 hour and 2 hours)) and the 
secondary endpoint (Day 8 (168 h) lumefantrine concentration). An additional number of 
patients is included due to potential dropouts for each endpoint. In case that the number of 
dropouts is less than expected, the enrollment for a cohort may be stopped after at least 16 
patients are deemed evaluable for PK analyses (Cmax or Day 8 concentration).  
In order to support an early readout of the study based on observed PK, efficacy and 
safety,enrollment may be stopped. Thereafter, the criterion of 0.337 for the observed half width 
of 2-sided 90% CI for the log concentration will be increased to a threshold that is appropriate 
for the sample size.  
Additional modeling and simulation may be performed to support the planned analyses. 
 
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 International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects’ parents/legal 
guardians. 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. 


Novartis 
Confidential 
Page 64 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
13.3 
Publication of study protocol and results 
The protocol 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 patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. 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 Novartisprocesses 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 


Novartis 
Confidential 
Page 65 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


Novartis 
Confidential 
Page 66 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
15 
References 
References are available upon request. 
Adjei GO, Goka BQ, Binka F, et al (2009) Artemether-lumefantrine: an oral antimalarial for 
uncomplicated malaria in children. Expert Rev Anti Infect Ther; 7: 669-81. 
Alao MJ, Gbadoé AD, Meremikwu M, et al (2013) Plasmodium falciparum malaria in infants 
under 5 kg: retrospective surveillance of hospital records in five sub-saharan African 
countries. J Trop Pediatr; 59: 154-9. 
Ambler MT, Dubowitz LM, Arunjerdja R, et al (2009) The neurological assessment in young 
children treated with artesunate monotherapy or artesunate-mefloquine combination therapy 
for uncomplicated Plasmodium falciparum malaria. Malar J; 8: 207. 
Ameade EPK, Amalba A, Mohammed BS (2018) Prevalence of dysmenorrhea among 
University students in Northern Ghana; its impact and management strategies. BMC Womens 
Health; 18: 39. 
Beckman DA, Youreneff M, Butt MT (2013) Neurotoxicity assessment of artemether in 
juvenile rats. Birth Defects Res (Part B); 98: 183-99. 
Carrasquilla G, Barón C, Monsell EM, et al (2012) Randomized, prospective, three-arm study 
to confirm the auditory safety and efficacy of artemether-lumefantrine in Colombian patients 
with uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg; 86:75-83. 
Ceesay SJ, Koivogui L, Nahum A, et al (2015) Malaria Prevalence among Young Infants in 
Different Transmission Settings, Africa. Emerging Infect Dis; 21: 1114-21. 
Chattopadhyay R, Mahajan B, Kumar S (2007) Assessment of safety of the major antimalarial 
drugs. Expert Opin Drug Saf; 6: 505-21. 
Djimdé AA, Tekete M, Abdulla S, et al (2011) Pharmacokinetic and pharmacodynamic 
characteristics of a new pediatric formulation of artemether-lumefantrine in African children 
with uncomplicated Plasmodium falciparum malaria. Antimicrob Agents Chemother; 55: 
3994-9. 
European Medicines Agency (EMA) (2005) Guideline on Data Monitoring Committees. p. 
EMEA/CHMP/EWP/5872/03 Corr, London, UK. 
European Medicines Agency (EMA) (2011) Opinion of the paediatric committee on the 
acceptance of a modification of an agreed investigation plan. p. EMEA-000777-PIP01-09-
M01, London, UK. 
European Medicines Agency (EMA) (2015) Opinion of the paediatric committee on the 
acceptance of a modification of an agreed investigation plan. p. EMEA-000777-PIP01-09-
M01, London, UK. 
European Medicines Agency (EMA) (2018) Guideline on good pharmacovigilance practices 
(GVP): Product- or Population- Specific Considerationss IV: Paediatric population. 
EMA/572054/2016. p. EMA/572054/2016. 


Novartis 
Confidential 
Page 67 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Haataja L, McGready R, Arunjerdja R, et al (2002) A new approach for neurological 
evaluation of infants in resource-poor settings. Ann Trop Paediatr; 22: 355-68. 
Hay WW Jr, Levin MJ, Deterding RR, et al (2018) Current Diagnosis and Treatment 
Pediatrics 24th edition. Mc Graw Hill Education, New York, USA 
Howie SR (2011) Blood sample volumes in child health research: review of safe limits. Bull. 
World Health Organ; 89: 46-53. 
ICH Harmonized Tripartite Guideline (2003) Post-Approval Safety Data Management 
Definitions and Standards for Expedited Reporting E2D. 
Kliegman RM, Behrman RE, Jenson HB et al (2007) Nelson Textbook of Pediatrics -18th 
edition. Saunders, Philadelphia, USA  
Kloprogge F, Workman L, Borrmann S, et al (2018) Artemether-lumefantrine dosing for 
malaria treatment in young children and pregnant women: A pharmacokinetic-
pharmacodynamic meta-analysis. PLoS Med; e1002579. 
Li Q, Hickman M (2011) Toxicokinetic and toxicodynamic (TK/TD) evaluation to determine 
and predict the neurotoxicity of artemisinins. Toxicology; 279:1-9. 
Lin W, Heimbach T, Jain JP, et al (2016) A Physiologically Based Pharmacokinetic Model to 
Describe Artemether Pharmacokinetics in Adult and Pediatric Patients. J Pharm Sci; 105: 
3205-3213. 
Manyando C, Mkandawire R, Puma L, et al (2010) Safety of artemether-lumefantrine in 
pregnant women with malaria: results of a prospective cohort study in Zambia. Malar J; 9: 
249. 
Mbonye MK, Burnett SM, Naikoba S, et al (2015) Malaria care in infants aged under six 
months in Uganda: an area of unmet needs! PLoS ONE; e0123283. 
Sinden RE, Blagborough AM, Churcher T, et al (2012) The design and interpretation of 
laboratory assays measuring mosquito transmission of Plasmodium. Trends Parasitol; 28: 
457-65. 
Stepniewska K, White NJ (2006) Some considerations in the design and interpretation of 
antimalarial drug trials in uncomplicated falciparum malaria. Malar J; 5: 127. 
Tiono AB, Tinto H, Alao MJ, et al (2015) Increased systemic exposures of artemether and 
dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria 
treated with artemether-lumefantrine (Coartem®). Malar J; 14: 157. 
US Food and Drug Administration (2006) Guidance for Clinical Trial Sponsors. 
Establishment and Operation of Clinical Trial Data Monitoring Committees. 
White NJ, Ashley EA, Recht J, et al (2014) Assessment of therapeutic responses to 
gametocytocidal drugs in Plasmodium falciparum malaria. Malar J; 13: 483. 
World Health Organization (2005) IMCI integrated management of childhood illness. 
World Health Organization (2009) Methods for surveillance of antimalarial drug efficacy. 


Novartis 
Confidential 
Page 68 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
World Health Organization (2015) Guidelines for the treatment of malaria. Third Edition. 
World Health Organization (2018) Malaria Surveillance, Monitoring & Evaluation: a 
Reference Manual. 
World Health Organization (2018) This year's World malaria report at a glance. 
WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group. 
(2015) Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: 
a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic 
response using individual patient data. BMC Med; 13: 227. 


Novartis 
Confidential 
Page 69 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and reference 
ranges (vital signs, 
) 
Table 16-1 
Normal Vital Signs according to Age 
Age 
Heart Rate * 
(beats/min) 
Blood Pressure (mm Hg) 
Respiratory Rate 
(breaths/min) 
  
  
Systolic 
Diastolic 
  
0-3 months 
100-150* 
65-85 
45-55 
35-55 
3-6 months 
90-120 
70-90 
50-65 
30-45 
6-12 months 
80-120 
80-100 
55-65 
25-40 
Reference: Kliegman et al 2007. 
* In sleep, infant heart rates may drop significantly lower, but if perfusion is maintained, no intervention 
is required 
For information only, Premature : Heart rate (beats/min): 120-170*; Blood pressure (mm Hg): 55-
75/35-45; Respiratory rate (breaths/min): 40-70 
Reference ranges for magnesium are presented in Table 16-2 and for potassium in Table 16-3 
(adapted from Hay et al 2018). 
Table 16-2 
Reference ranges for magnesium (mg/dL) by age range (male-female) 
Age 
Male 
Female 
0-7 days 
1.2-1.6 
1.2-1.6 
>7-30 days 
1.6-2.4 
1.6-2.4 
>1 mo-2 y 
1.6-2.6 
1.6-2.6 
>2-6 y 
1.5-2.4 
1.5-2.4 
>6-10 y 
1.6-2.3 
1.6-2.3 
>10-14 y 
1.6-2.2 
1.6-2.2 
>14 y 
1.5-2.3 
1.5-2.3 
Table 16-3 
Reference ranges for potassium (mmol/L) by age range (male-female) 
Age 
Male 
Female 
0-7 days 
3.7-5.9 
3.7-5.9 
>7 d-3 mo 
4.1-5.3 
4.1-5.3 
>3 mo-18 y 
3.4-4.7 
3.4-4.7 
>18 y 
3.5-5.0 
3.5-5.0 
Reference curves from WHO for head circumference are presented in Figure 16-1 and Figure 
16-2 
for 
males, 
and 
in 
Figure 
16-3 
and 
Figure 
16-4. 
for 
females 
(https://www.who.int/childgrowth/standards/hc_for_age/en/). 


Novartis 
Confidential 
Page 70 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Figure 16-1 
Reference ranges for head circumference in males (0-13 weeks) 
 


Novartis 
Confidential 
Page 71 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Figure 16-2 
Reference ranges for head circumference in males (0-2 years) 
 


Novartis 
Confidential 
Page 72 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Figure 16-3 
Reference ranges for head circumference in females (0-13 weeks) 
 


Novartis 
Confidential 
Page 73 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
Figure 16-4 
Reference ranges for head circumference in females (0-2 years) 
 


Novartis 
Confidential 
Page 74 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
16.2 
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements 
Table 16-4 
Follow up requirements for liver events and laboratory triggers 
ALT 
TBL  
Liver 
symptoms 
Action  
ALT increase without bilirubin increase 
If normal at baseline:  
ALT > 3 x ULN  
Normal 
None 
No change to study treatment  • 
Measure ALT, AST, ALP*, GGT*, 
TBIL, INR*, albumin*, CK*, and 
GLDH* in 48-72 hours. • Follow-
up for symptoms.  
If elevated at 
baseline:  ALT > 2 x 
baseline or > 200 U/L 
(whichever occurs 
first) 
For patients with 
Gilbert’s syndrome: No 
change in baseline 
TBL  
None 
 No change to study treatment  
• Measure ALT, AST, ALP*, 
GGT*, TBIL, INR*, albumin*, CK*, 
and GLDH* in 48-72 hours. • 
Follow-up for symptoms. 
If normal at baseline:  
ALT > 5 x ULN for 
more than two weeks 
Normal 
None 
Interrupt study drug  • Measure 
ALT, AST, ALP*, GGT*, TBIL, 
INR*, albumin*, CK*, and GLDH* 
in 48-72 hours. • Follow-up for 
symptoms. • Initiate close 
monitoring and workup for 
competing etiologies. • Study drug 
can be restarted only if another 
etiology is identified and liver 
enzymes return to baseline.  
If elevated at 
baseline:  ALT > 3 x 
baseline or > 300 U/L 
(whichever occurs 
first) for more than two 
weeks  
For patients with 
Gilbert's syndrome: No 
change in baseline 
TBL. 
None 
Interrupt study drug  
• Measure ALT, AST, ALP*, 
GGT*, TBIL, INR*, albumin*, CK*, 
and GLDH* in 48-72 hours. • 
Follow-up for symptoms. • Initiate 
close monitoring and workup for 
competing etiologies. • Study drug 
can be restarted only if another 
etiology is identified and liver 
enzymes return to baseline.  
If normal at baseline:  
ALT > 8 x ULN 
Normal 
• 
  
None 
Interrupt study drug  • Measure 
ALT, AST, ALP*, GGT*, TBIL, 
INR*, albumin*, CK*, and GLDH* 
in 48-72 hours. • Follow-up for 
symptoms. • Initiate close 
monitoring and workup for 
competing etiologies. • Study drug 
can be restarted only if another 
etiology is identified and liver 
enzymes return to baseline.  
ALT increase with 
bilirubin increase:  
  
  
  


Novartis 
Confidential 
Page 75 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
ALT 
TBL  
Liver 
symptoms 
Action  
If normal at baseline:  
ALT > 3 x ULN  
TBL > 2 x ULN (or INR 
> 1.5) 
None 
IInterrupt study drug  • Measure 
ALT, AST, ALP*, GGT*, TBIL, 
INR*, albumin*, CK*, and GLDH* 
in 48-72 hours. • Follow-up for 
symptoms. • Initiate close 
monitoring and workup for 
competing etiologies. • Study drug 
can be restarted only if another 
etiology is identified and liver 
enzymes return to baseline. 
If elevated at 
baseline: ALT > 2 x 
baseline or > 200 U/L 
(whichever occurs 
first)  
For patients with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin  
None 
Interrupt study drug  • Measure 
ALT, AST, ALP*, GGT*, TBIL, 
INR*, albumin*, CK*, and GLDH* 
in 48-72 hours. • Follow-up for 
symptoms. • Initiate close 
monitoring and workup for 
competing etiologies. • Study drug 
can be restarted only if another 
etiology is identified and liver 
enzymes return to baseline.  
If normal at baseline:  
ALT > 3 x ULN  
Normal elevated 
Severe 
fatigue, 
nausea,  vo
miting, right 
upper 
quadrant 
pain 
Interrupt study drug  • Measure 
ALT, AST, ALP*, GGT*, TBIL, 
INR*, albumin*, CK*, and GLDH* 
in 48-72 hours. • Follow-up for 
symptoms. • Initiate close 
monitoring and workup for 
competing etiologies. • Study drug 
can be restarted only if another 
etiology is identified and liver 
enzymes return to baseline.  
If elevated at 
baseline:  ALT > 2 x 
baseline or > 200 U/L 
(whichever occurs 
first) 
Normal elevated 
evere 
fatigue, 
nausea,  vo
miting, right 
upper 
quadrant 
pain 
Interrupt study drug  • Measure 
ALT, AST, ALP*, GGT*, TBIL, 
INR*, albumin*, CK*, and GLDH* 
in 48-72 hours. • Follow-up for 
symptoms. • Initiate close 
monitoring and workup for 
competing etiologies. • Study drug 
can be restarted only if another 
etiology is identified and liver 
enzymes return to baseline.  
* If clinically indicated and within blood draw limitations 


Novartis 
Confidential 
Page 76 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
16.3 
Appendix 3: Pharmacokinetic sampling 
Table 16-5 
PK Sampling scheme 
Time (post first 
dose)* 
1 h 
2 h 
62 h 
66 h 
68 h 
84 h 
168 h 
Sample number 
101 
102 
103 
104 
105 
106 
107 
Scheme n°1 
X 
X 
X 
X 
  
  
X 
Scheme n°2 
X 
X 
  
  
X 
X 
X 
*Dosing times are 0, 8, 24, 36, 48 and 60 h 
Perform the PK blood collection as outlined in the assessment schedule assigned to the patient 
(Table 16-4). 
Methodology for whole blood sampling: 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. 
Handling of blood samples for plasma collection: 
Artemether is rapidly degraded in whole blood and by products of haemolysis in plasma. It is 
essential that the samples are handled as follows: 
• Collect 500 µL blood in K2EDTA. 
• Immediately after each tube is drawn (within 5 minutes after collection), the sample 
should be inverted gently several times to ensure mixing and centrifuged at 4°C at 4000 
rpm (2200 g) for 10min. 
• Remove plasma (about 200 µL should be obtained) quickly and transfer into 
polypropylene, screw cap tubes (NUNC barcoded 1D plus 2D tubes from Thermofischer). 
• Freeze aliquots immediately at ≤-70°C until analysis. No interim freezing at lower 
temperature should be done. If necessary, storage on dry ice for no more than one hour is 
acceptable. 
The actual sample collection date and time will be entered on the PK blood collection page of 
the (e)CRF. Sampling problems will be commented on in the (e)CRFs. 
16.4 
Appendix 4: Signs and symptoms indicative of severe P. 
falciparum malaria (WHO 2015) 
In a patient with P. falciparum asexual parasitaemia and no other obvious cause of symptoms, 
the presence of one or more of the following clinical or laboratory features classifies the patient 
as suffering from severe malaria. These severe manifestations can occur singly or, more 
commonly, in combination in the same patient. The full clinical picture should be considered 
rather than just one isolated parameter. 
Clinical Features: 
• Impaired consciousness A Glasgow coma score < 11 in adults or a Blantyre coma score < 
3 in children. 


Novartis 
Confidential 
Page 77 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
• Prostration, i.e. generalized weakness so that the patient is unable walk or sit up without 
assistance. 
• Multiple convulsions – more than two episodes in 24 h 
• Deep breathing, respiratory distress (acidotic breathing) 
• Shock: compensated shock is defined as capillary refill ≥ 3s 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). 
• Clinical jaundice plus evidence of other vital organ dysfunction: plasma or serum bilirubin 
> 50 µmol/L (3 mg/dL) with a parasite count > 100 000/µL. 
• Abnormal spontaneous bleeding: including recurrent or prolonged bleeding from the nose, 
gums or venepuncture sites; haematemesis or melaena. 
• Pulmonary oedema: radiologically confirmed or oxygen saturation < 92% on room air 
with a respiratory rate > 30/min, often with chest indrawing and crepitations on 
auscultation. 
Laboratory findings 
• Hypoglycemia (blood or plasma glucose < 2.2 mmol/L or < 40 mg/dL) 
• Severe malaria anaemia: haemoglobin concentration ≤ 5g/dL or a haematocrit of ≤ 15% in 
children < 12 years of age (< 7g/dL and < 20%, respectively, in adults) with a parasite 
count > 10 000/µL. 
• Acidosis: a base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level of < 
15 mmol/L or venous plasma lactate ≥ 5 mmol/L. 
• Hyperparasitaemia:  P.Falciparum parasitaemia > 10% 
• Renal impairment: plasma or serum creatinine > 265 µmol/L (3 mg/dL) or blood urea > 20 
mmol/L. 
16.5 
Appendix 5: IMCI guidelines 
Infants aged >2 months– check for danger signs 
1. Not able to drink or breast feed 
• Too weak to drink and is not able to suck or swallow when offered a drink or breast-fed 
• If not sure ask mother to offer child a drink of clean water or breast milk 
• A child may have difficulty sucking when his nose is blocked. If the nose is blocked, clean 
2. Vomiting everything 
• A child is not able to hold anything down at all 
• If in doubt offer the child water 
3. Convulsions (during this illness) 
• Arms and legs stiffen because muscles are contracting 
• The child may lose consciousness or not be able to respond to spoken directions or 
handling, even if eyes are open 


Novartis 
Confidential 
Page 78 
Amended Protocol Version v01 Clean 
 
Protocol No. CCOA566B2307 
 
• “Fits” or “spasms” or “jerky movements” 
Note: shiver is not a convulsion. There is no loss of consciousness. 
4. Abnormally sleepy or difficult to awaken 
• Drowsy and does not show interest in what is happening around him 
• Stare blankly and appear not to notice what is going on around him 
• Does not respond when touched, shaken or spoken to 
Note: If the child is asleep and has cough or difficult breathing, count the number of breaths 
before you try to wake the child. 
Infants aged 0- 2 months- check for signs of bacterial infection (except for 
fever: 37.5°C* or above) 
Possible serious bacterial infection 
• Convulsions 
• Fast breathing (60 breaths per minute or more) 
• Severe chest indrawing 
• Nasal flaring 
• Grunting 
• Bulging fontanelle 
• Pus draining from ear 
• Umbilical redness extending to the skin 
• Low body temperature (less than 35.5 °C* or feels cold) 
• Many or severe skin pustules 
• Lethargic or unconscious 
• Less than normal movement 
*These thresholds are based on axillary temperature. The thresholds for rectal temperature 
readings are approximately 0.5 °C higher 
Possible local bacterial infection 
• Red umbilicus 
• Draining pus 
• Skin pustules 

SAP_001.pdf: 
Clinical Development 
COA566 
CCOA566B2307 / NCT04300309
A multicenter, open-label, single-arm study to evaluate the 
PK, safety, tolerability and efficacy of a new artemether-
lumefantrine (2.5 mg:30 mg) dispersible tablet in the 
treatment of infants and neonates <5 kg body weight with 
acute uncomplicated Plasmodium falciparum malaria 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final amendment 2 
Release date: 
28-Sep-2023
Number of pages: 
30 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis. 


Novartis 
For business use only 
Page 2 
SAP 
 
CCOA566B2307 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for update 
Outcome for update 
Section and 
title impacted 
(Current) 
14-
Sep-
2020 
 Final 
version 
Creation of final version 
N/A - First version 
NA 
08-
Oct-
2021 
Amendment 
1 
Update of notable ranges 
to be in line with protocol. 
 
 
28-
Aug-
2023 
Amendment 
2 
Updated table values 
 
 
Updated planned analyses 
 
 
 
Specified the sensitivity 
analysis 
 
Adopted updated text and 
Figure from Protocol V01 
 
Table 
5-5 
(Normal body 
temperature) 
 
Section 2.5.4 
(sensitivity 
analyses) 
 
Section 
2.7.2.1.2 
 
Section 1.1, 
Figure 1-2 
 
 
 
 
 
 


Novartis 
For business use only 
Page 3 
SAP 
 
CCOA566B2307 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design ............................................................................................................ 6 
1.2 
Study objectives and endpoints ............................................................................. 10 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 13 
2.3.1 
Patient disposition ................................................................................. 14 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 14 
2.4.1 
Study treatment / compliance ................................................................ 14 
2.4.2 
Prior, concomitant and post therapies ................................................... 15 
2.5 
Analysis of the primary objective .......................................................................... 15 
2.5.1 
Primary endpoint ................................................................................... 15 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 15 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 15 
2.5.4 
Supportive analyses ............................................................................... 15 
2.6 
Analysis of the key secondary objective ............................................................... 16 
2.6.1 
Key secondary endpoint ........................................................................ 16 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 16 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 16 
2.7.1 
Secondary endpoints ............................................................................. 16 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.8 
Safety analyses....................................................................................................... 18 
2.8.1 
Adverse events (AEs) ............................................................................ 19 
2.8.2 
Laboratory data ..................................................................................... 20 
2.8.3 
Other safety data ................................................................................... 21 
2.9 
Pharmacokinetic endpoints .................................................................................... 21 
2.10 
PD and PK/PD analyses ........................................................................................ 22 
 
 22 
2.12 
Interim analysis ...................................................................................................... 22 


Novartis 
For business use only 
Page 4 
SAP 
 
CCOA566B2307 
 
3 
Sample size calculation ..................................................................................................... 23 
3.1.1 
Primary endpoint(s) ............................................................................... 23 
3.1.2 
Secondary endpoint(s) ........................................................................... 24 
4 
Change to protocol specified analyses .............................................................................. 24 
5 
Appendix ........................................................................................................................... 25 
5.1 
Imputation rules ..................................................................................................... 25 
5.1.1 
Study drug ............................................................................................. 25 
5.1.2 
AE date imputation ............................................................................... 25 
5.1.3 
Concomitant medication date imputation ............................................. 25 
5.2 
Visit windows ........................................................................................................ 25 
5.3 
AEs coding/grading ............................................................................................... 26 
5.4 
Laboratory parameters derivations ........................................................................ 26 
5.5 
Vital signs and Laboratory – definition of clinically notable values ..................... 27 
5.6 
Historical exposure values from previous studies ................................................. 28 
5.7 
Statistical models ................................................................................................... 28 
5.7.1 
Primary analysis .................................................................................... 28 
5.7.2 
Key secondary analysis ......................................................................... 29 
5.8 
Rule of exclusion criteria of analysis sets.............................................................. 29 
6 
References ......................................................................................................................... 30 


Novartis 
For business use only 
Page 5 
SAP 
 
CCOA566B2307 
 
List of abbreviations 
ACPR 
Adequate Clinical and Parasitological Response 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ART Cmax 
Artemether Cmax 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
CDC 
Centers for Diease Control and Prevention 
CM 
Concomitant medications 
Cmax 
Maximum concentration 
CSR 
Clinical Study report 
CV 
Coefficient of variation 
DAIDS 
Division of AIDS 
DBL 
Database lock 
DHA 
Dihydroartemisinin 
DMC 
Data Monitoring Committee  
eCRF 
Electronic Case Report Form 
ETF 
Early treatment failure 
FAS 
Full Analysis Set 
FCT 
Fever Clearance Time 
FDA 
Food and Drug Administration 
GM 
Geometric mean 
IRT 
Interactive Response Technology 
LCF 
Late clinical failure 
LPF 
Late parasitological failure 
LUM 
Lumefantrine 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PCT 
Parasite Clearance Time 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


Novartis 
For business use only 
Page 6 
SAP 
 
CCOA566B2307 
 
1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis which is planned in the protocol. This study is composed of two cohorts, 
Cohort 1 consisting of infants aged more than 28 days (<5kg) and Cohort 2 consisting of 
neonates aged 28 days or less (<5kg). After the core period of each Cohort an interim 
assessment will be performed by Novartis and results presented to an independent Data 
Monitoring Committee (DMC). Potential outputs for the DMC will be included in the CSR TFL 
shell document. No separate SAP or TFL shell document will be prepared for the interim 
assessments. This SAP will be used as a basis for the clinical study report, which will be 
prepared after the final database lock (DBL). 
1.1 
Study design 
This is a multicenter, open-label, single-arm, adaptive design with dose adaptation (de-
escalation or escalation) study in infants and neonates <5 kg body weight with P. falciparum 
malaria. 
A total of approximately 44 male and female infants/neonates patients (<5 kg) are planned to 
be recruited in the study. There will be two sequential and age-descending cohorts of 
approximately 22 patients each (see Figure 1-1), all <5 kg: Cohort 1 of infants >28 days of age, 
and Cohort 2 of neonates ≤ 28 days of age. Cohort 2 will include 3 age subgroups (15-28, 8-14 
and 1-7 days), starting with the highest age subgroup in Cohort 2.1. The two lower age 
subgroups (i.e., 8-14 and 1-7 days) will be recruited in parallel. These two subgroups will be 
optional, depending on recruitment feasibility. 
In the event of inadequate exposure (study protocol section 4.2), determined at predefined PK 
checkpoints (i.e., after the first 9 patients in Cohort 1, and after the first 3 patients and then the 
first 9 patients of Cohort 2 (1-28 days of age)), additional patients may be recruited up to a total 
of 98 patients across the 2 cohorts (Figure 1-2). An additional PK check may be performed after 
the first 9 patients of the 15-28 days age group in Cohort 2 have been recruited. For Cohort 2, 
if an adequate dose cannot be determined at all or if recruitment is not feasible in any of the 3 
age subgroups, the cohort may be closed and 22 additional patients may be recruited in Cohort 
1 up to a total of approximately 44 patients treated with the same dose (instead of the planned 
22 patients). Cohort 2.3 will start recruitment after the dose used in Cohort 2.2 has been assessed 
to be appropriate. 
Patients will be admitted to the hospital on or before Day 1 (see Figure 1-1). After meeting all 
the inclusion and exclusion criteria in the study, they will receive study drug. The starting dose 
regimen in Cohort 1 will be two dispersible tablets twice daily for three consecutive days. The 
dose must be preceded and/or followed as much as possible by food/drinks rich in fat, e.g. breast 
milk, or formula milk. 
Patients will remain in the hospital under close supervision until they are discharged by the 
investigator or designee on Day 4. At the discretion of the investigator, patients may stay for a 
few additional days if needed. The patients will be then followed up at regular intervals until 
Day 43 (core follow-up), in order to assess study drug exposure, safety, tolerability and efficacy. 
If symptoms re-emerge outside the scheduled study visits, parents/legal guardians of the 


Novartis 
For business use only 
Page 7 
SAP 
 
CCOA566B2307 
 
patients will be instructed to contact the investigator. In case of treatment failure (as per WHO 
definition), rescue treatment according to local clinical practice will be provided. 
Patients will then attend a long term safety follow-up visit
 
Figure 1-1 
Patient participation overview 
 
In this study, a stepwise and sequential approach will be adopted in order to minimize the risk 
for patients (Figure 1-2). 
Hospitalisation 


Novartis 
For business use only 
Page 8 
SAP 
 
CCOA566B2307 
 
Figure 1-2 
Study flow chart 
 
PK exposure checks (together with safety and efficacy data review as available) will be 
performed on a periodic basis to assess the dose included at the following timepoints: 
1) once the first 9 patients in Cohort 1 have been dosed and followed up to Day 15, 
2) once the first 3 patients in Cohort 2 (15-28 days age subgroup) have been dosed and followed 
up to Day 15, 
3) once the first 9 patients in Cohort 2 (15-28 days age subgroup) have been dosed and followed 
up to Day 15. In case exposure data in the 9 patients from the 1-28 day subgroup are not 
sufficient to make a decision on dose selection (e.g., due to a significantly different exposure 
across age subgroups), as many additional patients as needed to reach a total of 9 (across Cohort 
2.1 and 2.2) in the 15-28 day subgroup specifically will be recruited in Cohort 2.2 and treated 
with the same dose. An additional PK check will then be performed after these additional 
patients will have been followed up to Day 15. 
A total of 9 patients in a defined age group should allow to confirm with reasonable confidence 
if ART Cmax is within approximately 2-fold (safety interval) of the Cmax which has been found 
to be safe and efficacious in previous studies; a total of 3 patients will however allow to check at 
an early stage if the ART Cmax range is within the expected safety interval (Cohort 2 only). 
An Independent Data Monitoring Committee (DMC) will review the PK, efficacy and safety 
data at these checks, and also at two planned interim data assessments, one between the two 
cohorts, and another one after all patients in Cohort 2 have completed Day 43 (Figure 1-2). 


Novartis 
For business use only 
Page 9 
SAP 
 
CCOA566B2307 
 
The interim data assessment based on Cohort 1 data will serve to determine the starting dose 
level for Cohort 2 (for further details see study protocol section 10.2.1). 
Based on these checks, the dose being considered will be assessed as suitable or not for the 
subgroup of patients treated. 
In Cohort 1: 
• if the dose is deemed adequate in the first 9 patients (based on PK, safety and efficacy data 
review as available), additional patients will be recruited up to approximately 22 treated 
with the same dose level (expansion phase). 
• if the dose is not adequate, the first set of 9 patients will be repeated, up to twice, using a 
different dose level, until a dose level is determined as suitable. 
In Cohort 2: 
• if the dose is deemed adequate in the 3 patients from the highest age subgroup (15-28 
days), recruitment of  6 additional patients in the 1-28 day subgroup will be attempted.  
• if the dose is not adequate, the first set of 3 patients from the highest age subgroup (15-28 
days) will be repeated, up to twice, using a different dose level, until a dose level is 
determined as suitable. Then, recruitment of 6 additional patients in the 1-28 day subgroup 
will be attempted. 
• Another PK check (together with safety and efficacy data as available) will then be 
performed when a total of 9 patients have been treated with the same suitable dose in the 
1-28 day subgroup. In case exposure data from these 9 patients (1-28 day subgroup) is not 
sufficient to make a decision on dose selection, as many additional patients as needed to 
reach a total of 9 (across Cohort 2.1 and 2.2) in the 15-28 day subgroup specifically will 
be recruited in Cohort 2.2 and treated with the same dose. An additional PK check will 
then be performed after these additional patients will have been followed up to Day 15. If 
the former PK check shows that  the dose is suitable for all subgroups, expansion of 
Cohort 2 will include all age subgroups. If it is unsuitable for any of the two lower age 
subgroups, no further patients will be recruited in this/these lower age subgroup(s), 
and further expansion of Cohort 2 will only include patients from the 15-28 day subgroup. 
In the case the dose is not confirmed as suitable for the highest age subgroup, a repeat run 
with 9 patients (3+6 patients) will be performed using a different dose. 
In Cohort 2, if through the steps above, no suitable dose has been determined in the higher age 
subgroup (15-28 days), recruitment will be stopped in that cohort and an additional 22 patients 
will instead be recruited in Cohort 1 and treated with the dose that was deemed adequate in that 
cohort. 
Once either cohort's expansion has been completed with approximately 22 patients treated with 
the same, suitable dose, or any or the alternative scenarios described above, patients will be 
followed up to Day 43, when the complete set of key efficacy and safety parameters and PK 
exposures will be assessed. 
Note: Patients treated with dose levels deemed not suitable will also be closely followed up to 
Day 43 and at one year of age. 


Novartis 
For business use only 
Page 10 
SAP 
 
CCOA566B2307 
 
In the unlikely case when all the iterations described above would have to be implemented, a 
maximum of 98 patients would be recruited. 
 
Randomization 
Due to single arm, treatment randomization will not be performed in this study. But patient will 
be randomly allocated to PK scheme 1 or 2. 
Interim analyses 
There will be two planned interim assessments performed at :  
1. after all patients in Cohort 1 have completed Day 43 (core study period), when key 
efficacy and safety parameters and PK exposure data will be assessed in order to 
determine whether to proceed to Cohort 2 and if so, to select the starting dose for that 
Cohort. 
2. after all patients in Cohort 2 have completed Day 43 (core study period). Efficacy and 
safety parameters and PK exposure data from both cohorts will be assessed.  
 
Optional interim assessment 
Additional interim assessments along with DMC reviews may be conducted to support 
decision making for dose recommendations. 
 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the key PK parameter of artemether in 
infants and neonates < 5 kg body weight dosed with 
the new formulation of artemether-lumefantrine 
dispersible tablet 
• 
Artemether Cmax (represents the 
higher concentration between the 
concentrations at 1 hour and 2 hours 
after first dose) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess other key PK parameters of artemether, 
DHA and lumefantrine in infants and neonates <5 
kg body weight dosed with the new formulation of 
artemether-lumefantrine dispersible tablet 
• 
Lumefantrine Day 8 concentration 
(C168h) Artemether AUC, DHA and 
Lumefantrine Cmax and AUC as 
appropriate 
• 
To evaluate the safety and tolerability of the new 
formulation of artemether-lumefantrine dispersible 
tablet in infants and neonates <5 kg body weight 
with acute uncomplicated P. falciparum malaria 
• 
Serious adverse events (SAEs), 
adverse events (AEs), and routine 
safety laboratory assessments 
• 
To determine the efficacy of the new formulation of 
artemether-lumefantrine dispersible tablet for 
treatment of acute uncomplicated P. falciparum 
malaria in infants and neonates <5 kg body weight 
• 
PCR-corrected Adequate Clinical 
and Parasitological Response 
(ACPR) at Days 15, 29, and 43 
Uncorrected ACPR at Days 8, 15, 
29, and 43 


Novartis 
For business use only 
Page 11 
SAP 
 
CCOA566B2307 
 
Objective(s) 
Endpoint(s) 
Incidence rate of recrudescence and 
new infections at Days 15, 29 and 43 
Parasite and Fever clearance Times 
(PCT and FCT)  
 
2 
Statistical methods 
2.1 
Data analysis general information 
Data will be analyzed by 
 on behalf of Novartis after the final DBL using 
SAS version 9.4 according to the data analysis presented in Section 12 of the study protocol 
which will also be available in Appendix 16.1.1 of the CSR.  Important information is given in 
the following sections and details will be provided, as applicable, in Appendix 16.1.9 of the 
CSR.  
There will be two planned interim assessments, one after Cohort 1, the second one after Cohort 
2. More details can be found in Section 2.12. 
Data analyses required for the interim assessments will also be analyzed by 
 and 
corresponding outputs will be provided to the DMC. Outputs for the DMC will be part of the 
CSR shell document. No separate SAP or TFL shell document will be prepared. 
After the first 9 patients in Cohort 1 and the first 3 and 9 patients in the higher age subgroup 
of Cohort 2 (1-28 days) and after the first 3 patients in the 2 younger subgroups of Cohort 2 
(if they are recruited) have been treated with the same dose and followed up for at least 2 
weeks (and optionally once 9 patients from the age group 15-28 days have completed Day 
15), the database will be cleaned reasonably, data management reports using the raw data will 
be used for the regular review meetings and PK summaries will be generated by Novartis PK 
scientist. 
Statistical analyses will be performed by cohort and treatment group. If there are treatment 
groups that are used for multiple cohorts, descriptive statistics will be calculated for these 
treatment groups by pooling data from all cohorts for the primary and key secondary endpoints. 


Novartis 
For business use only 
Page 12 
SAP 
 
CCOA566B2307 
 
Unless otherwise stated, summary tables/figures/listings will be on all patients included in the 
population under consideration.  
Categorical data will be summarized as frequencies and percentages. For continuous data mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
the 25th and 75th percentile will also be presented. 
There is no stratification done in this study. 
2.1.1 
General definitions  
Study treatment: COA566 (artemether: lumefantrine 2.5 mg:30 mg dispersible tablet) is the 
investigation treatment. As this is a single-arm study there is no control treatment. COA566 is 
referred to as study treatment in the document. 
Treatment group: Treatment group in this study means study drug dose level. Note that 
although there is only one study treatment, there are 4 possible dose levels (1 to 4 tablets per 
dose). The treatment group label will always include the study drug level even if there is only 
one study drug dose level in the whole study. In case that the dose level that passed the 
exposure check for the first 3 patients in the highest age subgroup in Cohort 2 is not 
appropriate for either or both the lower age subgroup(s) after the exposure check in 3 patients, 
the recruitment in these subgroup(s) will be stopped, they will be separated out from Cohort 2 
and analyzed separately as needed. 
Date of first administration of study treatment: The date of first intake of study treatment 
within the study. 
Date of last administration of study treatment: The date of last intake of study treatment 
within the study. 
Baseline: The last available measurement prior to first administration of study treatment.  
Study day: The day of first administration of study treatment is defined as Day 1 (opposed to 
WHO terminology where this would be Day 0). Day -1 will be the day before Day 1. Day 0 
does not exist.  
Core period: Core period of the study starting with (and including) Day 1 until (and 
including) Day 43. 
Parasitaemia: P. falciparum asexual parasite count greater than zero. 
2.1.1.1 
Clearance and treatment failure definitions 
Fever Clearance time (FCT), defined as time from the first dose until the first time the 
axillary body temperature decreased below and remained below 37.5°C axillary or 38.0°C 
oral/tympanic/rectal for at least a further 24 hours. Note: 38.0°C is the temperature threshold 
for fever using oral/tympanic/rectal, which will be also used in the treatment failure 
definition. 
Parasite clearance time (PCT), defined as time from the first dose until the first total and 
continued disappearance of asexual parasite forms which remained at least a further 48 hours. 
Early Treatment Failure (ETF) 
• Development of danger signs or severe malaria on Day 2, Day 3, Day 4 in the presence of 
parasitaemia. 


Novartis 
For business use only 
Page 13 
SAP 
 
CCOA566B2307 
 
• Parasitaemia on Day 3 higher than Day 1 count irrespective of axillary temperature. 
• Parasitaemia on Day 4 with axillary temperature ≥37.5°. 
• Parasitaemia on Day 4 equals to or more than 25% of count on Day 1. 
Late Clinical Failure (LCF) 
• Development of danger signs or severe malaria on any day from Day 5 to Day 43 in the 
presence of parasitaemia without previously meeting any of the criteria of Early Treatment 
Failure. 
• Presence of parasitaemia and axillary temperature ≥37.5° on any day from Day 5 to Day 
43 without previously meeting any of the criteria of Early Treatment Failure.   
Late Parasitological Failure (LPF) 
• Presence of parasitaemia on any day from Day 8 to Day 43 and axillary temperature 
<37.5° without previously meeting any of the criteria of Early Treatment Failure or Late 
Clinical Failure. 
2.2 
Analysis sets 
The Full Analysis Set (FAS) comprises all subjects that received any study drug and had 
Plasmodium falciparum present at Screening visit. Subjects will be analyzed according to the 
treatment(s) received as per protocol. 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received as per protocol. The Safety Set will 
be used for safety analyses while FAS will be used for other analyses.  
The Per-Protocol Set (PPS) is a subset of subjects of the Full Analysis Set and is characterized 
by the following criteria: 
• 
did not have important protocol deviations affecting efficacy 
• 
took at least 80% of study medication 
• 
PCR corrected cure status at Day 29 can be defined. 
Important protocol deviations for exclusion from the PPS will be identified by the clinical team 
before database lock. 
The PK set is a subset of the Full Analysis Set who had evaluable PK parameter data. 
2.2.1 
Subgroup of interest 
Not applicable. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by cohort and treatment group for the FAS. 


Novartis 
For business use only 
Page 14 
SAP 
 
CCOA566B2307 
 
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, 
the 25th and 75th percentiles will also be presented. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. Relevant medical histories and 
current medical conditions at baseline will be summarized for FAS by cohort, treatment group 
system organ class and preferred term. 
In addition, all medications and significant non-drug therapies administered to a mother (or the 
person) providing breastmilk to a patient before the patient enters the study and starts treatment 
with study drug will be summarized under Concomitant medications/Significant non-drug 
therapies prior to start of study drug. 
 
2.3.1 
Patient disposition 
The number and percentage of patients screened will be presented. 
The number and percentage of patients who completed and who discontinued prematurely will 
be presented for each epoch (treatment and follow-up) by cohort for each treatment group. 
For each protocol deviation, the number and percentage of patients for whom the deviation 
applies will be tabulated.  
Data will be presented using FAS. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Number and percentage of tablets taken will be presented by cohort and treatment group. The 
percentage will be calculated based on the planned number of tablets per treatment group. Both 
number and percentage mean, standard deviation, median, 25th and 75th percentiles, minimum, 
and maximum will be presented. 
Planned number of tablets in a treatment group = planned number of days of dosing x number 
of tablets to be administered per day in that treatment group.  
For example, planned number of tablets for starting dose level 2 is 3 (planned number of days 
of dosing) x 2 (number of tablets) x 2 (twice a day) = 12 tablets. 
Percentage of tablets taken will be calculated as  Number of tablets consumed/Number of tablets 
planned x 100. 
Compliance will be categorized by < 80 % and >=80 % of tablets taken and summarized by 
cohort and treatment group. 
Number and percentage of patients with study drug vomiting and dose replacement will be 
presented by cohort and treatment group. 
Safety set will be used. 


Novartis 
For business use only 
Page 15 
SAP 
 
CCOA566B2307 
 
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the latest version of WHO Drug 
Reference List dictionary which employs the Anatomical Therapeutic Chemical (ATC) 
classification system. The summaries will be presented by cohort, treatment group, ATC class 
and preferred term (PT). Data will be summarized as frequencies and percentages. Safety set 
will be used. 
2.5 
Analysis of the primary objective 
A pharmacokinetic parameter for artemether after the first dose, artemether Cmax (ART Cmax) 
will be assessed as the primary endpoint. 
2.5.1 
Primary endpoint 
ART Cmax (artemether Cmax) will be calculated using the peak plasma concentration of 
artemether following the first dose. For artemether, ART Cmax is determined by collecting 
samples at 1h and 2h after first dose and ART Cmax represents the higher concentration between 
the concentrations at 1 hour and 2 hours post first dose. 
The PK analysis set will be used. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Ninety percent (90%) 2-sided confidence intervals for ART  Cmax for the geometric mean will 
be presented by cohort and treatment group. Calculation will be based on the log normal 
distribution. The study objective will be considered to be met if 90% CIs for ART Cmax contain 
the desired values based on historical data especially those from children ≥5-<15kg BW in 
Study B2303. The desired values are displayed in the Appendix in Table 5-7. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Patients without sufficient PK concentrations for the derivation of ART Cmax will not be 
included in the analysis. 
2.5.4 
Supportive analyses 
Sensitivity analyses 
Ninety percent (90%) 2-sided confidence intervals for the geometric mean of ART Cmax will be 
calculated based on the log normal distribution by cohort and treatment group using the PPS. 
Patients with missing ART Cmax will be excluded from the analysis. 
Supportive analyses 
If there are treatment groups that are used for multiple cohorts, ninety percent (90%) two –sided 
confidence intervals for the geometric mean of ART Cmax will be calculated for these treatment 
groups based on the log normal distribution using the PK set by pooling data from all cohorts.   


Novartis 
For business use only 
Page 16 
SAP 
 
CCOA566B2307 
 
2.6 
Analysis of the key secondary objective 
2.6.1 
Key secondary endpoint 
The Day 8 (168 h) lumefantrine concentration (LUM C168h) is a key secondary endpoint. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Ninety percent (90%) 2-sided confidence intervals for the geometric mean will be calculated 
for Day 8 (168 h) lumefantrine concentration based on the log normal distribution by cohort 
and treatment group using the PK analysis set. 
LUM C168h is considered to be comparable with historical data if the upper limit of 90% 
confidence interval is not less than the Historical values. The desired historical values are 
displayed in the Appendix in Table 5-7. 
2.6.3 
Handling of missing values/censoring/discontinuations 
Patients without evaluable Day 8 lumefantrine concentrations will be excluded from the 
analysis. 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
Secondary Efficacy endpoints are: 
• PCR-corrected ACPR at Day 15, Day 29 and Day 43.  
• Uncorrected ACPR at Day 8, Day 15, Day 29, and Day 43. 
• Incidence rate of recrudescence and new infections at Days 15, 29 and 43 
• Parasite and Fever clearance Times (PCT and FCT) 
2.7.2 
Statistical hypothesis, model, and method of analysis 
There are no pre-specified hypotheses for secondary endpoints. Model and method of analysis 
are presented in the following sub-sections by topic. 
If there are treatment groups that are used for multiple cohorts, descriptive statistics will be 
calculated for these treatment groups by pooling data from all cohorts.  
2.7.2.1 
PCR-corrected ACPR and uncorrected ACPR 
At each visit, the ACPR rate with 95% 2-sided confidence intervals will be provided using the 
Clopper-Pearson method for each treatment group by cohort using PPS for PCR-corrected 
ACPR and FAS for uncorrected ACPR. 
Data will be handled as follows: 
• Treatment failures after 7 days (i.e., Study Day 8) due to new infections based on PCR 
genotyping are not considered as failure for PCR-corrected analyses. 


Novartis 
For business use only 
Page 17 
SAP 
 
CCOA566B2307 
 
• For uncorrected ACPR, patients will be treated as failure on and after the visit when a 
reinfection with P. falciparum or other species is detected (which might be either 
recrudescence or a new infection). 
• Patients who received rescue medication for the treatment of P. falciparum malaria 
(except for the treatment of a new infection) will be considered treatment failures. Patients 
who received other concomitant medication having an effect on malaria for reasons other 
than rescue therapy e.g., for the treatment of P. vivax (e.g., primaquine, certain antibiotics 
(sulfonamides, tetracycline, etc.) will be considered in the analysis as if they had not taken 
the drug. 
• Patients will be counted as failure at a visit (e.g. Study Day 15, etc.) if (a) they did not 
have a parasite count, i.e., missing parasite count at that visit unless these patients could be 
classified as cured based on absence of parasitaemia (parasite count = 0) at a later time 
(e.g., Study Day 29), or (b) they did not have valid PCR evaluations at baseline and the 
visit if parasitaemia was present at that time (e.g., Study Day 15). 
• For intermediate missing data, (a) once a patient experienced a treatment failure at a 
timepoint (eg. Day 15), the patient is considered as treatment failure at all later timepoints 
(eg. Day 29), (b) is a patient is considered as cured at a timepoint (eg. Day 29), the patient 
is considered as cured at earlier timepoints (eg. Day 15).  
2.7.2.1.1 Analysis of PCR-corrected ACPR using Kaplan-Meier method 
In addition, PCR-corrected ACPR rate will be calculated and plotted using the Kaplan-Meier 
method (Stepniewska and White 2006; WHO 2015) for each treatment group by cohort in the 
FAS for Study Day 29 and 43. The PCR-corrected ACPR rate at Study Day 29 (43) is estimated 
by the survival function at Study Day 29 (43).  
Event is defined as treatment failure. The censoring rules are as follows: 
• For patients who do not experience treatment failure and do not have Study Day 43 
data, time to treatment failure is considered as censored at the time of last parasitaemia 
assessment.  
• Patients who had a new infection with P. falciparum or other species without P. 
falciparum recrudescence on or after Study Day 8 will be censored at the time of the 
first PCR that indicate the infection.  
• Patients who took antimalarial medications for reinfection or reasons other than rescue 
medication given for P. falciparum related treatment failure will be censored at the first 
time of such antimalarial medications.  
•  Time to treatment failure (event or censored) will be truncated at Day 43 to avoid 
sudden 
drop 
in 
number 
of 
patients 
at 
risk 
after 
Day 
43.  
 
2.7.2.1.2 Sensitivity Analysis 
For the CSR, not for IA01, there will be a sensitivity analysis of ACPR wherein patients are 
excluded from the PPS if they have a new infection prior to Day 29. 


Novartis 
For business use only 
Page 18 
SAP 
 
CCOA566B2307 
 
 
2.7.2.2 
Recrudescence and new infection 
New infection is defined as appearance of asexual parasites after clearance of initial infection 
with a genotype different from those parasites present at baseline. New infection must be 
confirmed by PCR analysis. 
Recrudescence is defined as appearance of asexual parasites after clearance of initial infection 
with a genotype identical to that of parasites present at baseline. Recrudescence must be 
confirmed by PCR analysis. 
Incidence rates of recrudescence and new infection at Days 15, 29 and 43 will be estimated by 
Kaplan-Meier method based on the subset of FAS patients who have clearance of initial 
infection by Day 7. Time to event (recrudescence or new infection) will be calculated from the 
time of first study medication to the date of first event if a patient experiences the event and be 
censored at the time of last parasite assessment if a patient does not experience the event. 
Patients with new infection will be censored at the time of first new infection when analyzing 
time to recrudescence. Patients with recrudescence will be censored at the time of first 
recrudescence when analyzing time to new infection. Undetermined treatment failures due to 
missing PCR data will be considered as censored at the time of treatment failure. 
Time (event or censored) will be truncated at Day 43 to avoid sudden drop in number of patients 
at risk after Day 43. 
2.7.2.3 
Parasite clearance time (PCT) and fever clearance time (FCT) 
Descriptive statistics (mean, standard error, median, quartiles) will be presented for each 
treatment by cohort using the Kaplan-Meier method based on the FAS. Kaplan-Meier curves 
will be provided.  
Parasite clearance time 
PCT will be calculated based on uncorrected parasite counts. Patients without parasite clearance 
for whatever reason will be censored at the time of last parasite assessment.  
Fever clearance time 
Patients who had no fever at pre-dose will not be included in the analysis of FCT. Patients 
without fever clearance for whatever reason will be censored at the time of last temperature 
assessment.  
Handling of missing values/censoring/discontinuations 
In case that a patient receives rescue medication before (parasite or fever) clearance, the time 
to event will be censored at the first use of rescue medication. 
2.8 
Safety analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
cohort and treatment group. 


Novartis 
For business use only 
Page 19 
SAP 
 
CCOA566B2307 
 
Safety summaries (tables, figures) include only data from the core period (up to Day 43) with 
the exception of baseline data which will also be summarized where appropriate (e.g. change 
from baseline summaries). In particular, summary tables for adverse events (AEs) will include 
only the core period events, with a start date during that period. 
2.8.1 
Adverse events (AEs) 
A treatment-emergent AE is defined as any AE that develops after initiation of the study 
treatments or any event already present that worsens following exposure to the study treatment. 
Adverse events will be summarized by presenting, for each cohort and treatment group, the 
number and percentage of patients having at least one AE, having an AE in each primary system 
organ class and having each individual AE (preferred term).  
For summaries by maximum severity the following applies: if a patient reported more than one 
adverse event with the same preferred term, the adverse event with the greatest severity will be 
presented. If a patient reported more than one adverse event within the same primary system 
organ class, the patient will be counted only once with the greatest severity at the system organ 
class level. 
The MedDRA version used for reporting the adverse events will be described in a footnote. 
All information obtained on adverse events will be listed by cohort, treatment group, and subject. 
The number and percentage of subjects with treatment emergent adverse events will be 
summarized in the following ways: 
• by cohort, treatment group, primary system organ class and preferred term. 
• by cohort, treatment group, primary system organ class, preferred term and maximum 
severity. 
• by cohort, treatment group, Standardized MedDRA Query (SMQ) and preferred term. 
Additionally the number and percentage of patients will be presented for the following 
summaries: 
• AEs related to study medication. 
• Deaths. 
• Serious adverse events. 
• AEs leading to discontinuation of study treatment. 
• AEs leading to dose adjustment. 
These summaries will be presented by cohort, treatment group, primary system organ class 
and preferred term. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 5% 
and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by primary system organ class and preferred term on the safety set. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 


Novartis 
For business use only 
Page 20 
SAP 
 
CCOA566B2307 
 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE’s in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE. 
 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
The number (and proportion) of subjects with adverse events of special interest/related to 
identified and potential risks will be summarized by risk name, PT, cohort and treatment group. 
Risk names will be sorted alphabetically, and, within each risk name, the PTs will be sorted in 
descending order of frequency. If a patient reported more than one adverse event with the same 
PT, the AE will be counted only once. If a patient reported more than one AE within the same 
risk, the patient will be counted only once at that risk. 
The adverse events of special interest are defined in the Case retrieval Sheet (CRS) which is 
updated for each MedDRA dictionary. 
 
2.8.2 
Laboratory data 
All laboratory data will be listed by cohort, treatment group, subject, and visit/time and if 
normal ranges are available abnormalities will be flagged. Notable values will be flagged as 
well. 
Descriptive statistics will be generated for all clinical laboratory tests performed (actual values 
and changes from baseline) for two groups of laboratory tests (hematology and blood chemistry) 
by laboratory test, cohort, treatment group and visit/time. Change from baseline will only be 
summarized for patients with both baseline and post baseline values and will be calculated as: 
change from baseline = post baseline value – baseline value. 
The following laboratory parameters will be analyzed for hematology test group: hemoglobin, 
platelets, white blood cell count, Reticulocytes, hematocrit, red blood cell (RBC) count, 
lymphocytes, lymphocytes (%),  monocytes, monocytes (%), eosinophils, eosinophils (%),  
neutrophils, neutrophils (%) , basophils,  basophils (%), bands, bands (%), differential other and 
differential other (%). 
The following laboratory parameters will be analyzed for blood chemistry test group: sodium, 
potassium, magnesium, glucose, creatinine, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin. 
Shift tables using the low/normal/high/ (low and high) classification will be used to compare 
baseline to the worst value within the core period. The direction of interest for worst value 
within core period for each laboratory parameter is given in Table 5-3. 


Novartis 
For business use only 
Page 21 
SAP 
 
CCOA566B2307 
 
2.8.3 
Other safety data 
2.8.3.1 
Vital signs 
All vital signs data will be listed by cohort, treatment group, subject, and visit/time and if ranges 
are available, clinically notable abnormalities will be flagged.  
The following quantitative variables will be summarized: Temperature (oC), Pulse (beats/min),  
Systolic blood pressure (mmHg) and Diastolic blood pressure (mmHg). 
Analysis in vital sign measurements using descriptive summary statistics for the actual value 
and change from baseline will be performed by vital sign, cohort, treatment group and visit/time. 
Change from baseline will only be summarized for patients with both baseline and post-baseline 
values and will be calculated as: 
Change from baseline = post-baseline value – baseline value. 
2.8.3.2 
Weights and heights 
Weight (g) and Height (cm) will be summarized using descriptive summary statistics for the 
actual value and the change from baseline by cohort, treatment group and visit/time. For 
presentation of change from baseline the same rules as stated for vital signs do apply. 
All weight and height data will be listed by cohort, treatment group, subject, and visit/time.  
2.9 
Pharmacokinetic endpoints   
The PK set will be used for all PK analyses.  
Artemether, DHA and lumefantrine plasma concentration, Cmax and AUC data (as applicable) 
will be listed by cohort, treatment group, subject, and visit/sampling time point.  
Descriptive summary statistics will be provided by cohort, treatment group, and visit/sampling 
time point, including the frequency (n, %) of concentrations below the lower limit of 
quantification (LLOQ). Summary statistics will include mean (arithmetic and geometric), SD, 
CV (arithmetic and geometric), median, minimum, and maximum. PK concentrations below 
the LLOQ will be treated as zero in summary statistics and for the calculation of 
pharmacokinetic parameters by non-compartmental analysis. A geometric mean will be 
calculated using half LLOQ value for concentrations below LLOQ. CV for arithmetic mean 
will be computed as mean/SD x 100. CV for geometric mean will be computed as   
√𝑒𝑒𝑣𝑣𝑣𝑣𝑣𝑣(log 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) −1 𝑥𝑥 100. 
For DHA Cmax and Lumefantrine Cmax (LUM Cmax) the 90% 2-sided confidence intervals for 
the geometric mean will be calculated on the natural log scale and then anti-log tranformed back 
to the original scale for the following comparisons: 
• DHA Cmax vs. historical data (Table 5-7) 
• Lumefantrine Cmax vs. historical data (Table 5-7) 
DHA Cmax and lumefantrine Cmax are considered to be comparable with historical data if the 90% 
confidence 
interval 
contains 
the 
Historical 
values.  
The analysis of ART Cmax is described in Section 2.5, the analysis of LUM C168h in Section 2.6. 


Novartis 
For business use only 
Page 22 
SAP 
 
CCOA566B2307 
 
Non-compartmental PK will be used to calculate the pharmacokinetic parameters wherever 
possible. Due to the limited number of samples collected in this study, a naive pool approach 
for data analysis may also be followed for reporting PK parameters such as ART Cmax /other 
Cmax and AUC, if feasible. 
2.10 
PD and PK/PD analyses 
A PK/PD analysis may be attempted  based on available historical information. Due to the small 
sample size in this study, detailed PK/PD assessment based on this study alone may be of 
limited value. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
This analysis will be reported outside of the CSR.  
2.12 
Interim analysis 
Interim assessment 1 
Interim assessment 1 will be done after all patients in Cohort 1 have completed the core period 
(Day 43). Artemether, DHA, and lumefantrine concentrations, PK parameters, key efficacy and 
safety endpoints will be analyzed by the study biostatistics team. These results will be reviewed 
by Novartis Clinical team and the DMC to reach a decision about progression to Cohort 2 and 
the starting dose level in that Cohort.  
Interim assessment 2 


Novartis 
For business use only 
Page 23 
SAP 
 
CCOA566B2307 
 
Interim assessment 2 will be done after all patients in Cohort 2 have completed the core period 
(Day 43). For this interim assessment all data up to Day 43 will be cleaned and included. 
Efficacy and safety parameters and PK exposure data from both cohorts will be assessed. 
 
Additional interim assessments may be conducted to support decision making based on early 
read-out of study data. 
Additional ad-hoc safety reviews may be requested by the DMC or Novartis if needed (e.g. in 
case of SAEs).   
3 
Sample size calculation 
The sample size is calculated and justified based on the precision of estimating artemether Cmax 
(primary endpoint) and Day 8 (168 h) lumefantrine concentration (secondary endpoint) 
separately for Cohort 1 and Cohort 2. 
3.1.1 
Primary endpoint(s) 
Artemether Cmax (represents the higher concentration between the concentrations at 1 hour and 
2 hours) after the first dose is the primary endpoint. The distribution of Cmax is best described 
by log normal distribution. The half width of the 2-sided 90% confidence interval for log Cmax 
is the target for sample size calculation. The relevant historical data for sample size calculation 
are the standard deviations of log Cmax, which are usually invariant to the dosage (See Table 3-
1). 
Table 3-1 
Standard deviation for log Cmax in Coartem studies A2102 and B2306 
Study and formulation of artemether-
lumefantrine 
Artemether Cmax  
Day 8 Lumefantrine 
concentration  
A2102* (healthy volunteers) 80:480 mg tablet 
0.58 
- 
A2102 (healthy volunteers) 4 tablets of 20:120 
mg 
0.52 
- 
B2306 (infants >28 days of age) 20:120 mg 
dispersible tablet 
0.65 
0.654 
*Study CCOA566A2102; **Study CCOA566B2306 
The table shows that the standard deviation for log Cmax was about 12% to 25% higher for 
infants in Study B2306 than for healthy volunteers in Study A2102. The patient population in 
the current study (B2307) is similar to the patient population in Study B2306.  
For log Cmax, a standard deviation of 0.65 from Study B2306 will therefore be used. Based on 
the standard deviation of 0.65 in log scale, a sample size of 16 evaluable patients will provide 
80% probability that the observed half width of 2-sided 90% CI for log Cmax is ≤0.337 or 1.4 
times (covering the targeted Cmax) in terms of ratio (nQuery Advisor 8). This sample size is 
applied to each cohort. 
PK sampling will be designed in order to get all patients evaluable for artemether Cmax analysis. 
Taking into account about 10% of patients not evaluable for this PK analysis, about 18 patients 
should be enrolled in each cohort. 


Novartis 
For business use only 
Page 24 
SAP 
 
CCOA566B2307 
 
For each cohort the sample size will be increased slightly to allow for higher dropouts for the 
secondary endpoint, Day 8 (168 h) lumefantrine concentration (see Section 3.1.2).  
3.1.2 
Secondary endpoint(s) 
Power consideration for Day 8 (168 h) lumefantrine concentration 
The Day 8 (168 h) lumefantrine concentration is the key secondary endpoint. The distribution 
of Day 8 lumefantrine concentration is best described by log normal distribution.  In Study 
B2306, the standard deviation for the log concentration from 16 infants was 0.65. Based on the 
standard deviation of 0.65 in log scale, a sample size of 16 evaluable patients will provide 80% 
probability that the observed half width of 2-sided 90% CI for the log concentration is ≤0.337 
or 1.4 times in terms of ratio (nQuery Advisor 8). This sample size is applied to each cohort. 
The percentage of patients who are not evaluable for Day 8 lumefantrine concentration may be 
higher than that for artemether Cmax which is based on the concentrations on Day 1. Taking into 
account about 25% of patients not evaluable for this PK analysis, about 22 patients will be 
enrolled in each cohort in order to achieve the number of patients evaluable for this analysis as 
specified above. 
Power consideration for PK checking in each cohort 
After about 9 patients have been enrolled in each cohort, PK checking will be performed to see 
if the dose level should be adjusted. Considering that about 10% of patients would be non-
evaluable for artemether Cmax , this will lead to about 8 patients evaluable for artemether Cmax. 
The probability that the observed half width of 2-sided 90% CI in log scale is ≤0.693 or 2 in 
terms of ratio for artemether Cmax is 96% if the standard deviation in log scale is same as the 
assumed 0.65 or 80% if the standard deviation in log scale is as high as 0.85 (nQuery Advisor 
8). Additional optional PK checks can also be implemented. 
Note: 
The requirement for an evaluable number of patients is 16 for both the primary endpoint 
(artemether Cmax (max concentration between concentrations at 1 hour and 2 hours)) and the 
secondary endpoint (Day 8 (168 h) lumefantrine concentration). An additional number of 
patients is included due to potential dropouts for each endpoint. In case that the number of 
dropouts is less than expected, the enrollment for a cohort may be stopped after at least 16 
patients are deemed evaluable for PK analyses (Cmax or Day 8 concentration).  
In order to support an early readout of the study based on observed PK, efficacy and safety, 
enrollment may be stopped. Thereafter, the criterion of 0.337 for the observed half width of 2- 
sided 90% CI for the log concentration will be increased to a threshold that is appropriate for 
the sample size.  
Additional modeling and simulation may be performed to support the planned analyses. 
4 
Change to protocol specified analyses 
No change from protocol specified analysis was made. 


Novartis 
For business use only 
Page 25 
SAP 
 
CCOA566B2307 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Not applicable.  
5.1.2 
AE date imputation 
Imputation of partial AE start dates will follow the general Novartis rules for imputation of AE 
start dates. Missing or partial AE end dates will not be imputed. 
5.1.3 
Concomitant medication date imputation 
 Concomitant medication date imputation will follow the general Novartis rules for imputation 
of CM start and end dates. 
5.2 
Visit windows 
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Day 4 visit of a patient is delayed and occurs on Day 7, say, it 
will be re-aligned to visit window Day 8. In the case of major deviations from the visit schedule, 
or due to unscheduled visits, several assessments of a patient may fall in a particular visit 
window (either scheduled or unscheduled). Statistical approaches to handle multiple 
assessments in a given visit window are specified below.  
• The following rules are used to determine the window for other visits post baseline: 
−  “Lower limit” = “upper limit of prior applicable visit” + 1 
− “Upper limit” = “target day of current visit” + integer part of (“target day of next 
applicable visit” – “target day of current visit”)/2 with the exception of Day 43 
− Upper limit for analysis visit Day 43 is day 50 
Based on the different assessments Table 5-1 describes the analysis visit window mapping. 
Repeat and/or unscheduled visits (which will be numbered in the database according to new 
NCDS standards) will be mapped for analysis purposes in the same way. If there are multiple 
measurements within an analysis window, the conventions  defined in Table 5-2 will be used 
to determine the appropriate measurement to be selected for analysis. 
The mapped visits will be used in the by visit analyses. However, the listings will show the 
collected data regardless of used in the by visit analyses. 
Table 5-1 
Analysis visit windows based on study day and time 
Analysis 
Visit 
Analysis 
timepoint 
 
Vital signs 
Weight/Height 
Blood chemistry/ 
Hematolgy 
 
 
Malaria blood film 
Baseline 
<0 h 
up to 0 h 
up to 0 h 
up to 0 h 
up to 0 h 
Day 1 
8 h 
>0 to 16 h 
- 
- 
>0 to 16 h 


Novartis 
For business use only 
Page 26 
SAP 
 
CCOA566B2307 
 
Day 2 
24 h 
>16 to 30 h 
> 0 to 36 h 
> 0 hrs to 42 h 
>16 to 30 h 
36 h 
>30 to 42 h 
- 
- 
>30 to 42 h 
Day 3 
48 h 
>42 to 54 h 
> 36 to 60 h 
- 
>42 to 54 h 
60 h 
>54 to 66 h 
- 
> 42 to 114 h 
>54 to 66 h 
Day 4 
72 h 
>66  to 84 h 
>60  to 84 h 
- 
>66  to 84 h 
Day 5 
96 h 
> 84 to 132 
h 
> 84 to 132 h 
 
- 
> 84 to 132 h 
Day 8 
168 h 
> 132 h to 
Day 11 
> 132 h to Day 11 
> 114 h to Day 
11 
> 132 h to Day 11 
Day 15 
NA 
Day 12 – 
22 
Day 12 – 22 
Day 12 – 29 
Day 12 – 22 
Day 29 
NA 
Day 23 – 
36 
Day 23 – 36 
- 
Day 23 – 36 
Day 43 
NA 
Day 37 - 50 
Day 37 – 50 
Day 30 – 50 
Day 37 - 50 
Age 365 
days 
NA 
- 
Aged between 
335 – 395 days 
 
- 
 
- 
Table 5-2 
Rules for flagging variables 
Timing of 
measurement 
Type of data 
Rule 
Baseline 
All data 
The last measurement made prior to and including 
administration of the first dose of study treatment – note this 
may include measurements taken on the day of randomization. 
If a patient did not receive any dose of study treatment then the 
IRT date for the first study drug will be used. 
Post-baseline efficacy 
All data 
The measurement closest to the target day/time will be used. In 
the event that two measurements are taken equally apart (e.g. 1 
day before target date and 1 day after) the first one will be used. 
Post-baseline safety 
Summary visit 
information (e.g. lab, 
vital signs, etc.) 
The measurement closest to the target day/time will be used. In 
the event that two measurements are taken equally apart, the 
first one will be used.  
Post-baseline safety  
Notable abnormalities 
(e.g. lab) 
The most extreme measurement in the window will be used.  
Note this means a patient can have a notably high and notably 
low measurement within a window 
 
5.3 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.  
5.4 
Laboratory parameters derivations 
The following table shows the direction of interest when analyzing worst case values within 
core period for laboratory shift tables. If the direction of interest is given as "High" the 
maximum value will be calculated and used as worst value, if the direction is given as "Low" 
the minimum value will be taken, and if it is given as "Low and high", both the minimum value 
and the maximum value will be calculated and presented in shift tables. 


Novartis 
For business use only 
Page 27 
SAP 
 
CCOA566B2307 
 
Table 5-3 
Directions of interest for worst case value for laboratory parameters 
Laboratory test 
group 
Parameter 
Directions of interest for worst case value 
Hematology 
Hemoglobin 
low 
Hematology 
Hematocrit 
low 
Hematology 
Reticulocytes 
high 
Hematology 
RBC 
low 
Hematology 
WBC 
low and high 
Hematology 
Basophils 
high 
Hematology 
Eosinophils 
high 
Hematology 
Lymphocytes 
low and high 
Hematology 
Monocytes 
high 
Hematology 
Neutrophils 
low and high 
Hematology 
Platelets 
low 
Hematology 
Bands 
Not applicable 
Hematology 
Differential other 
Not applicable 
Blood chemistry 
Sodium 
low and high 
Blood chemistry 
Potassium 
low and high 
Blood chemistry 
Magnesium 
low and high 
Blood chemistry 
Glucose 
low and high 
Blood chemistry 
Creatinine 
high 
Blood chemistry 
AST 
high 
Blood chemistry 
ALT 
high 
Blood chemistry 
Total bilirubin 
high 
5.5 
Vital signs and Laboratory – definition of clinically notable 
values 
The following two tables show the clinical notable criteria for vital signs. Clinically notable 
ranges for laboratory parameters will be defined as values graded or worse 3 (see Table 5-6)  
using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events (Corrected version 2.1, July 2017). 
Table 5-4 
Normal Vital Signs according to Age 
Values below the lower limit or above the upper limit of normal will be listed as Abnormal. 
Age 
Heart Rate 
(beats/min) 
Blood Pressure (mm Hg) 
Respiratory Rate 
(breaths/min) 
  
  
Systolic 
Diastolic 
 
0-<3 months 
100-150* 
65-85 
45-55 
35-55 
3-<6 months 
90-120 
70-90 
50-65 
30-45 
6-12 months 
80-120 
80-100 
55-65 
25-40 
Reference: Kliegman et al 2007. 
* In sleep, infant heart rates may drop significantly lower, but if perfusion is maintained, no intervention 
is required 


Novartis 
For business use only 
Page 28 
SAP 
 
CCOA566B2307 
 
For information only, Premature : Heart rate (beats/min): 120-170*; Blood pressure (mm Hg): 55-
75/35-45; Respiratory rate (breaths/min): 40-70 
 
 
Table 5-5 
Normal body temperature 
Vital sign parameter 
Normal range 
Oral/Tympanic/rect
al body temperature 
(°C) 
>= 37.0 and <= 37.9 
Axillary body 
temperature (°C) 
>= 36.5 and <= 37.4 
 
5.6 
Historical exposure values from previous studies 
Table 5-6 
Reference values for PK analyses 
Study 
Body weight in 
kg (and age in 
days for B2306) 
ART 
Dose 
(mg) 
First dose 
Artemether 
Cmax (ng/mL) 
n, geo-mean 
DHA Cmax 
(ng/mL) 
n, geo-mean 
LUM Cmax 
(µg/mL) 
n, geo-mean 
LUM 
C168h  (ng/m
L) 
n, geo-
mean 
B2306 
<5 kg  
>28 days 
20 
- 
18, 70.2 
19, 5.2 
16, 666 
B2303 
≥5 kg - <15 kg 
20 
52, 101 
52, 31.7  
102, 3.9 
27, 212  
B2303 
≥15 kg - <25 kg 
40 
30, 105 
30, 45.0 
48, 6.6 
4, 388 
B2303 
≥25 kg - <35 kg 
60 
9, 112 
9, 57.5 
9, 8.3 
- 
ART: artemether; LUM: lumefantrine 
5.7 
Statistical models 
 
5.7.1 
Primary analysis 
The primary analysis is detailed in Section 2.5. 
The primary endpoint ART Cmax will be displayed by cohort and treatment group using the 
geometric mean. The geometric mean will be calculated by deriving the mean of the log-
transformed values followed by an exponential transformation, i.e. 𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 (𝐺𝐺𝐺𝐺) =
 𝑒𝑒𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚(log (𝑥𝑥)) with x = ART Cmax of a participant. 
Corresponding 2-sided 90% confidence intervals for the GM will be calculated assuming a log 
normal distribution of the primary endpoint. The lower and upper limits will be calculated as 
follows: 
exp (𝑥𝑥 ഥ± 𝑡𝑡ቀ1−𝛼𝛼
2;𝑛𝑛−1ቁ × 𝑠𝑠
√𝑛𝑛) 


Novartis 
For business use only 
Page 29 
SAP 
 
CCOA566B2307 
 
with 𝑥𝑥 ഥ= the arithmetic mean of the log-transformed endpoint, 𝑡𝑡ቀ1−𝛼𝛼
2;𝑛𝑛−1ቁ = the (1 −
𝛼𝛼
2) critical 
value of the Student's 𝑡𝑡 statistic with 𝑛𝑛−1 degrees of freedom, 𝑠𝑠 = the standard deviation of 
the log-transformed endpoint, and 𝑛𝑛 = the number of patients with available endpoint in the 
corresponding cohort and treatment group.  
The logarithm to the natural base is used.  
The calculation will be implemented in SAS using PROC MEANS on log data followed by an 
exponential transformation. 
5.7.2 
Key secondary analysis 
The key secondary analysis is detailed in Section 2.6. 
The calculation of the geometric mean and the corresponding 2-sided 90% confidence intervals 
will be done similarly as for the primary endpoint, see Section 5.4.1. 
 
 
5.8 
Rule of exclusion criteria of analysis sets  
 
Table 5-7 
Protocol deviations and non-PD criteria leading to exclusion from 
analysis sets ce values for PK analyses 
Analysis Set 
PD (description and ID) that 
causes 
subjects 
to 
be 
excluded 
Non-PD criteria that cause subjects to be 
excluded 
FAS 
Informed Consent for study 
participation 
not 
obtained 
(INCL05) 
Plasmodium falciparum not 
present as parasite species at 
Screening visit (INCL04) 
No study drug taken 
SAF 
Informed Consent for study 
participation 
not 
obtained 
(INCL05) 
No study drug taken 
PPS 
Baseline 
Plasmodium 
falciparum parasite count is 
not  >=500 and <100,000/µL 
at screening visit for patients 
in Cohort 1 (INCL04A) 
Baseline 
Plasmodium 
falciparum parasite count is 
not >=100 and <100,000/µL at 
Not in FAS 
Did take less than 80% of planned study 
medication (see Section 2.4.1) 
PCR corrected cure status at Day 29 can not 
be defined 
Not classified as non-responder before Day 
8, no positive blood smear parasite on Day 8 


Novartis 
For business use only 
Page 30 
SAP 
 
CCOA566B2307 
 
Analysis Set 
PD (description and ID) that 
causes 
subjects 
to 
be 
excluded 
Non-PD criteria that cause subjects to be 
excluded 
screening visit  for patients in 
Cohort 2 (INCL04B) 
Prohibited concomitant  anti-
malarial 
medication 
administered 
without 
experiencing ETF, LCF, LPF 
(PROH02) 
Prohibited concomitant  non-
malaria 
medications 
with 
potential 
impact 
on 
efficacy/antimalarial activity 
(PROH01A)   
Presence of another critical 
condition (EXCL06) 
 
onwards, and blood smear parasite result is 
missing at Day 29. 
Not classified as non-responder before Day 
8, have at least one positive blood smear 
parasite result between Day 8 and Day 29 
which cannot be determined as recrudescent 
or new infection based on PCR genotyping. 
PK 
 
Not in FAS 
No evaluable PK parameter data available 
6 
References 
Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in 
children from birth to 18 years of age: a systematic review of observational studies. Lancet. 
2011;377(9770):1011-1018. doi:10.1016/S0140-6736(10)62226-X. 
Stepniewska K, White NJ (2006) Some considerations in the design and interpretation of 
antimalarial drug trials in uncomplicated falciparum malaria. Malar J; 5: 127. 
World Health Organization (2015) Guidelines for the treatment of malaria. Third Edition.